Comprehensive Physiology Wiley Online Library
For Librarians For Authors Editors About

Pathogenesis of Type 2 Diabetes

Kenneth Cusi, Ralph A. Defronzo

10.1002/cphy.cp070237

Source: Supplement 21: Handbook of Physiology, The Endocrine System, The Endocrine Pancreas and Regulation of Metabolism

Originally published: 2001

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Insulin Secretion in T2DM
1.1 Fasting Insulin Concentration
1.2 Glucose‐Stimulated Insulin Secretion
1.3 Other Abnormalities in Insulin Secretion in T2DM
2 Mechanisms of Impaired Insulin Secretion
2.1 Glucose Toxicity
2.2 Lipotoxicity
2.3 Other Mechanisms of Impaired Insulin Secretion in T2DM
3 Impaired Insulin Secretion: Primary Genetic Defect Responsible for Type 2 Diabetes
3.1 Prospective Studies
3.2 Studies in First‐Degree Relatives
3.3 Studies in Twins
3.4 Subjects with History of Gestational Diabetes Mellitus
4 Hypersecretion of Insulin as the Cause of Type 2 Diabetes: A New Hypothesis
5 Summary: Insulin Secretion in T2DM
6 Insulin Sensitivity in Type 2 Diabetes
6.1 Site of Insulin Resistance in Type 2 Diabetes
6.2 Fasting Hyperglycemia: Role of Pancreas, Muscle and Liver
6.3 Postprandial Hyperglycemia: Lessons from the Oral Glucose Tolerance Test
7 Dynamic Interaction Between Insulin Sensitivity and Insulin Secretion in Type 2 Diabetes Mellitus
8 Cellular Mechanisms of Insulin Resistance in Type 2 Diabetes
8.1 Overview of Insulin Action
8.2 Insulin Receptor/Insulin Receptor Signal Transduction Defects
8.3 Glucose Transport
8.4 Glucose Phosphorylation
8.5 Glycogen Synthesis
8.6 Glycolysis/Glucose Oxidation
9 Metabolic, Hemodynamic, Endocrine, and Cytokine Abnormalities in Type 2 Diabetes Mellitus
9.1 Glucose Toxicity
9.2 Lipid Oxidation and Insulin Resistance
9.3 Skeletal Muscle Capillary Density, Fiber Type and Endothelial Transport
9.4 Blood Flow
9.5 Amylin and Calcitonin Gene‐Related Peptide
9.6 Tumor Necrosis Factor‐Alpha
9.7 Acquired Determinants of Insulin Resistance
10 Summary of Insulin Resistance in Type 2 Diabetes Mellitus
11 Genetic Defects
12 Pathogenesis of Type 2 Diabetes Mellitus: Summary and Synthesis
12.1 Primary Defect in Insulin Sensitivity
12.2 Primary Defect in Insulin Secretion?
12.3 Combined Defects in Insulin Sensitivity and Insulin Secretion
13 Conclusion
Figure 1. Figure 1.

Schematic representation of glucose production and glucose utilization in the normal human in the postabsorptive state

[Drawn from data presented in DeFronzo et al. 2, 3, 4 and 239.]
Figure 2. Figure 2.

Relationship between fasting plasma glucose concentration and fasting plasma insulin concentration in normal‐weight controls, in individuals with impaired glucose tolerance, and in T2DM subjects with varying degrees of fasting hyperglycemia. As fasting plasma glucose concentration rises from baseline to 140 mg/dl, there is a progressive increase in fasting insulin concentration. Thereafter, further rises in fasting glucose level are associated with a progressive decline in fasting insulin concentration. In diabetic subjects with fasting glucose concentrations in excess of 200–220 mg/dl, fasting insulin level declines to values observed in control subjects.

[Reproduced from DeFronzo et al. 40, with permission.]
Figure 3. Figure 3.

Starling's curve of the pancreas for insulin secretion. In normal‐weight patients with impaired glucose tolerance and mild diabetes mellitus, the plasma insulin response to ingested glucose (OGTT) increases progressively until the fasting glucose reaches 120 mg/dl. Thereafter, further increases in fasting glucose concentration are associated with a progressive decline in insulin secretion

[Reproduced from DeFronzo 1, with permission.]
Figure 4. Figure 4.

Summary of plasma glucose (bottom panel) and plasma insulin (top panel, open circles) responses during a 100 g OGTT, and tissue sensitivity to insulin (top panel, closed circles) in control (CON), obese nondiabetic (OB), obese glucose‐intolerant (OB‐GLU INTOL), obese hyperinsulinemic diabetic (OB‐DIAB Hi INS) and obese hypoinsulinemic diabetic subjects (OB‐DIAB Lo INS). See text for a detailed discussion

[Reproduced from DeFronzo 1, with permission.]
Figure 5. Figure 5.

Relationship between lipid metabolism and insulin secretion. An increase in fatty acid acyl CoA can augment insulin secretion by 1 increasing intracellular calcium which stimulates exocytosis of insulin containing granules and/or 2 enhancing exocytosis directly or through protein kinase C (PKC). The latter mechanism involves generation of phosphatidic acid (PA) and diacylglycerol (DAG). It should be noted that malonyl CoA generated from the metabolism of glucose is a potent inhibitor of carnitine palmitoyl transferase (CPT) I. Inhibition of CPT I increases fatty acyl CoA which contributes to the stimulation of insulin secretion. Thus, a mechanism exists via which increased lipid metabolism within the beta cell potentiates glucose‐stimulated insulin secretion.

[Adapted from Matchinsky 119, with permission.]
Figure 6. Figure 6.

Whole‐body insulin‐mediated glucose disposal during a 20 mU/m2 per minute (+40 μU/ml) and 40 mU/m2 per minute (+80 μU/ml) euglycemic insulin clamp performed with indirect calorimetry in control subjects (shaded bars) and normal glucose‐tolerant offspring (probands) of two diabetic parents (solid bars). FFM = fat‐free mass.

[Drawn from data presented in Gulli et al. 55.]
Figure 7. Figure 7.

Lower panel: Effect of chronic (72 h) sustained physiologic hyperinsulinemia (from 7 to 24 uU; shml) on whole‐body insulin‐mediated glucose disposal during the basal state and during a three‐step euglycemic insulin clamp. *P < 0.01, **P < 0.02, †P < 0.05 for the insulin clamp performed after versus before the chronic insulin infusion. Upper panel: All impairment in insulin‐mediated whole‐body glucose disposal was the result of a decrease in nonoxidative glucose disposal (glycogen synthesis). Whole‐body insulin‐mediated glucose oxidation (not shown) increased slightly following chronic insulin infusion.

[Reproduced from Del Prato et al. 199, with permission.]
Figure 8. Figure 8.

Insulin‐mediated whole‐body glucose uptake in 38 normal‐weight T2DM patients (right panel) and in 33 control subjects matched for age and weight (left panel). Tissue sensitivity to insulin was reduced by approximately 40% in the type II diabetic group; each individual diabetic subject is represented by a solid circle.

[Drawn from data presented in DeFronzo et al. 1, 4, 30, Golay et al. 172, 225, Simonson et al. 224, and Felber et al. 291.]
Figure 9. Figure 9.

Dose‐response curve relating plasma insulin concentration to rate of insulin‐mediated whole‐body glucose uptake in control (solid circles) and T2DM (open circles) subjects. *P <0.01 versus controls.

[From Groop et al. 14, with permission.]
Figure 10. Figure 10.

Summary of hepatic glucose production in 77 normal‐weight T2DM subjects (open circles) with fasting plasma glucose concentrations ranging from 105 mg/dl to greater than 300 mg/dl; 72 controls matched for age and weight are shown (solid circles). In 33 diabetic subjects with fasting plasma glucose levels below 140 mg/dl (shaded area), mean rate of HGP was identical to that of controls. In diabetic subjects with fasting plasma glucose concentrations over 140 mg/dl, there was a progressive rise in hepatic glucose production that correlated closely (r= 0.847, P < 0.001) with fasting plasma glucose concentration.

[Reproduced from DeFronzo 1, with permission.]
Figure 11. Figure 11.

Dose‐response curve relating plasma insulin concentration to suppression of hepatic glucose production in control (solid circles) and T2DM (open circles) subjects with moderately severe fasting hyperglycemia. *P < 0.05, **P <0.01 versus controls.

[Reproduced from Reaven 15, with permission.]
Figure 12. Figure 12.

Time‐course of change in net splanchnic glucose balance in T2DM (open circles) and control (solid circles) subjects. The difference between diabetic and control subjects is statistically insignificant and cannot account for the marked impairment in total‐body glucose metabolism observed during the euglycemic insulin clamp study. Also note that total amount of glucose disposed of by the splanchnic area represents less than 10% of infused glucose load in both groups.

[Reproduced from DeFronzo et al. 4, with permission.]
Figure 13. Figure 13.

Time‐course of change in leg glucose uptake in T2DM (open circles) and control (solid circles) subjects. In the postabsorptive state, glucose uptake in the diabetic group was significantly greater than that in controls. However, the ability of insulin (euglycemic insulin clamp) to stimulate leg glucose uptake was reduced by 50% in the diabetic subjects.

[Reproduced from DeFronzo et al. 4, with permission.]
Figure 14. Figure 14.

Summary of glucose metabolism during euglycemic insulin (+ 100 μU/ml) clamp studies performed in normal‐weight T2DM and control subjects; see text for more detailed discussion.

[Reproduced from DeFronzo 1, with permission.]
Figure 15. Figure 15.

Summary of the metabolic clearance rate of glucose in 77 normal‐weight T2DM subjects (open circles) with fasting plasma glucose concentrations ranging from 105 mg/dl to greater than 300 mg/dl; 72 controls matched for age and weight are shown (closed circles). In the 33 diabetic subjects with fasting plasma glucose concentrations of less than 140 mg/dl (shaded area), glucose clearance rate fell precipitously and was inversely correlated (r = ‐0.697, P < 0.001) with the increase in plasma glucose concentration. At fasting plasma glucose levels above 140 mg/dl, rate of decline in glucose clearance began to slow and reached a plateau at glucose levels above 180 mg/dl.

[Reproduced from DeFronzo 1, with permission.]
Figure 16. Figure 16.

The effect of overnight insulin infusion to normalize basal rate of hepatic glucose production in 19 normal‐weight T2DM subjects (shaded bars) and in 72 controls matched for age and weight (crosshatched bars). Despite similar rates of HGP and a more than doubled plasma insulin concentration (P < 0.01), fasting plasma glucose remained significantly elevated in T2DM versus controls. Decreased glucose clearance in T2DM subjects indicates diminished efficiency of tissue glucose uptake.

[Reproduced from DeFronzo et al. 40, with permission.]
Figure 17. Figure 17.

Insulin‐mediated rates (+100 μU/ml euglycemic insulin clamp) of whole‐body glucose uptake (total height of bar), glucose oxidation (lower portion of each bar), and nonoxidative glucose disposal (upper part of each bar) in control, lean diabetic, obese non‐diabetic and obese diabetic subjects. Obese diabetic patients were further subdivided into hyperinsulinemic and hypoinsulinemic groups based upon plasma insulin response during a 100 g OGTT. *P < 0.001 versus controls.

[Reproduced from DeFronzo 1. with permission.]
Figure 18. Figure 18.

Plasma glucose and insulin concentrations during a 100 g OGTT in control (solid circles), normal‐weight diabetic (open circles), and obese nondiabetic (squares) subjects whose tissue sensitivity to insulin is shown in Figure 17

[Drawn from data presented in DeFronzo 1, Golay et al. 172, 225 and Felber et al. 226, 291.]
Figure 19. Figure 19.

Plasma glucose and insulin concentrations in control (solid circles), obese hyperinsulinemic diabetic (solid triangles) and obese hypoinsulinemic diabetic (open squares) subjects whose tissue sensitivity to insulin is shown in Figure 17.

[Drawn from data presented in DeFronzo 1, Golay et al. 172, 225 and Felber et al. 226, 291.]
Figure 20. Figure 20.

Schematic representation of insulin receptor and the cascade of intracellular signaling molecules that has been implicated in insulin action; see text for more detailed discussion.
Figure 21. Figure 21.

Effect of euglycemic hyperinsulinemia (63 uU/ml) for 4 h on hexokinase (HK), glycogen synthase (GS), and GLUT‐4 mRNA levels (upper panel), protein content (middle panel) and activity (lower panel) in healthy young subjects **P < 0.05, *P < 0.01, †P = 0.10.

[Reproduced from Mandarino et al. 330, with permission.]
Figure 22. Figure 22.

Rates of transmembrane glucose influx into forearm muscle at baseline and during the insulin clamp (∼65 uU/ml). Study 1 was performed in T2DM patients at euglycemia (∼5.0 mM/l) as in controls, whereas study 2 was performed at hyperglycemia (∼13 mMl/l). *P <0.01 insulin clamp vs. baseline in controls, **P < 0.05 T2DM vs. controls.

[Reproduced from Bonadonna et al. 337, with permission.]
Figure 23. Figure 23.

Rates of intracellular glucose phosphorylation in forearm muscle at baseline and during insulin clamp (∼65 mU/ml) study. Study 1 performed in T2DM patients at euglycemia (∼mM/l) as in controls; study 2 performed at hyperglycemia (∼13 mM/l). *P < 0.05 insulin clamp vs. baseline in controls, **P < 0.05 TZDM vs. controls during insulin clamp, ***P < 0.01 T2DM vs. controls during insulin clamp.

[Reproduced from Bonadonna et al. 337, with permission.]
Figure 24. Figure 24.

Glucose concentration in the available intracellular glucose space in forearm muscle at baseline and during insulin clamp (∼65 mU/ml) study. Study 1 performed in T2DM patients at euglycemia (∼mM/L) as in controls; study 2 performed at hyperglycemia (∼13mM/l). *P <0.05 insulin clamp vs. baseline in controls, **P < 0.01 TZDM vs. controls during insulin clamp, ***P < 0.05 study 2 vs. study 1 in TZDM patients.

[Reproduced from Bonadonna et al. 337, with permission.]
Figure 25. Figure 25.

Insulin‐mediated glucose uptake during a + 100 μU/ml euglycemic insulin clamp performed in control (solid bar) and 90% pancreatectomized (PANX) (stippled bar) rats. Phlorizin treatment (crosshatched bars) restored tissue sensitivity to insulin to normal. Withdrawal of phlorizin (open bar) was associated with the return of severe insulin resistance.

[Drawn from data presented in Rossetti et al. 381.]
Figure 26. Figure 26.

Hexosamine pathway. See text for detailed discussion.
Figure 27. Figure 27.

Schematic representation of effect of increased plasma FFA oxidation on muscle glucose metabolism and hepatic glucose production. See text for more detailed discussion.

[Reproduced from DeFronzo 1, with permission.]
Figure 28. Figure 28.

Pathogenetic sequence of events leading to development of insulin resistance in T2DM. Note that whether the primary defect initiating the glucose intolerance resides in the beta cell or in peripheral tissues, development of insulin resistance eventually will ensue or become aggravated, respectively. By the time that overt fasting hyperglycemia (>140 mg/dl) develops, both impaired insulin secretion and severe insulin resistance are present. Positive feedback loops (broken arrows), result in self‐perpetuation of primary defects.

[Reproduced from DeFronzo 1, with permission.]
Figure 29. Figure 29.

Schematic representation of potential defects that can lead to development of insulin resistance in T2DM. Regardless of etiology of insulin resistance, the beta cell will enhance secretion of insulin in an attempt to offset defect in insulin action. The resultant compensatory hyperinsulinemia will down‐regulate a variety of intracellular events involved in insulin action and, thus, serve as a self‐perpetuating cause of the insulin resistance.


Figure 1.

Schematic representation of glucose production and glucose utilization in the normal human in the postabsorptive state

[Drawn from data presented in DeFronzo et al. 2, 3, 4 and 239.]


Figure 2.

Relationship between fasting plasma glucose concentration and fasting plasma insulin concentration in normal‐weight controls, in individuals with impaired glucose tolerance, and in T2DM subjects with varying degrees of fasting hyperglycemia. As fasting plasma glucose concentration rises from baseline to 140 mg/dl, there is a progressive increase in fasting insulin concentration. Thereafter, further rises in fasting glucose level are associated with a progressive decline in fasting insulin concentration. In diabetic subjects with fasting glucose concentrations in excess of 200–220 mg/dl, fasting insulin level declines to values observed in control subjects.

[Reproduced from DeFronzo et al. 40, with permission.]


Figure 3.

Starling's curve of the pancreas for insulin secretion. In normal‐weight patients with impaired glucose tolerance and mild diabetes mellitus, the plasma insulin response to ingested glucose (OGTT) increases progressively until the fasting glucose reaches 120 mg/dl. Thereafter, further increases in fasting glucose concentration are associated with a progressive decline in insulin secretion

[Reproduced from DeFronzo 1, with permission.]


Figure 4.

Summary of plasma glucose (bottom panel) and plasma insulin (top panel, open circles) responses during a 100 g OGTT, and tissue sensitivity to insulin (top panel, closed circles) in control (CON), obese nondiabetic (OB), obese glucose‐intolerant (OB‐GLU INTOL), obese hyperinsulinemic diabetic (OB‐DIAB Hi INS) and obese hypoinsulinemic diabetic subjects (OB‐DIAB Lo INS). See text for a detailed discussion

[Reproduced from DeFronzo 1, with permission.]


Figure 5.

Relationship between lipid metabolism and insulin secretion. An increase in fatty acid acyl CoA can augment insulin secretion by 1 increasing intracellular calcium which stimulates exocytosis of insulin containing granules and/or 2 enhancing exocytosis directly or through protein kinase C (PKC). The latter mechanism involves generation of phosphatidic acid (PA) and diacylglycerol (DAG). It should be noted that malonyl CoA generated from the metabolism of glucose is a potent inhibitor of carnitine palmitoyl transferase (CPT) I. Inhibition of CPT I increases fatty acyl CoA which contributes to the stimulation of insulin secretion. Thus, a mechanism exists via which increased lipid metabolism within the beta cell potentiates glucose‐stimulated insulin secretion.

[Adapted from Matchinsky 119, with permission.]


Figure 6.

Whole‐body insulin‐mediated glucose disposal during a 20 mU/m2 per minute (+40 μU/ml) and 40 mU/m2 per minute (+80 μU/ml) euglycemic insulin clamp performed with indirect calorimetry in control subjects (shaded bars) and normal glucose‐tolerant offspring (probands) of two diabetic parents (solid bars). FFM = fat‐free mass.

[Drawn from data presented in Gulli et al. 55.]


Figure 7.

Lower panel: Effect of chronic (72 h) sustained physiologic hyperinsulinemia (from 7 to 24 uU; shml) on whole‐body insulin‐mediated glucose disposal during the basal state and during a three‐step euglycemic insulin clamp. *P < 0.01, **P < 0.02, †P < 0.05 for the insulin clamp performed after versus before the chronic insulin infusion. Upper panel: All impairment in insulin‐mediated whole‐body glucose disposal was the result of a decrease in nonoxidative glucose disposal (glycogen synthesis). Whole‐body insulin‐mediated glucose oxidation (not shown) increased slightly following chronic insulin infusion.

[Reproduced from Del Prato et al. 199, with permission.]


Figure 8.

Insulin‐mediated whole‐body glucose uptake in 38 normal‐weight T2DM patients (right panel) and in 33 control subjects matched for age and weight (left panel). Tissue sensitivity to insulin was reduced by approximately 40% in the type II diabetic group; each individual diabetic subject is represented by a solid circle.

[Drawn from data presented in DeFronzo et al. 1, 4, 30, Golay et al. 172, 225, Simonson et al. 224, and Felber et al. 291.]


Figure 9.

Dose‐response curve relating plasma insulin concentration to rate of insulin‐mediated whole‐body glucose uptake in control (solid circles) and T2DM (open circles) subjects. *P <0.01 versus controls.

[From Groop et al. 14, with permission.]


Figure 10.

Summary of hepatic glucose production in 77 normal‐weight T2DM subjects (open circles) with fasting plasma glucose concentrations ranging from 105 mg/dl to greater than 300 mg/dl; 72 controls matched for age and weight are shown (solid circles). In 33 diabetic subjects with fasting plasma glucose levels below 140 mg/dl (shaded area), mean rate of HGP was identical to that of controls. In diabetic subjects with fasting plasma glucose concentrations over 140 mg/dl, there was a progressive rise in hepatic glucose production that correlated closely (r= 0.847, P < 0.001) with fasting plasma glucose concentration.

[Reproduced from DeFronzo 1, with permission.]


Figure 11.

Dose‐response curve relating plasma insulin concentration to suppression of hepatic glucose production in control (solid circles) and T2DM (open circles) subjects with moderately severe fasting hyperglycemia. *P < 0.05, **P <0.01 versus controls.

[Reproduced from Reaven 15, with permission.]


Figure 12.

Time‐course of change in net splanchnic glucose balance in T2DM (open circles) and control (solid circles) subjects. The difference between diabetic and control subjects is statistically insignificant and cannot account for the marked impairment in total‐body glucose metabolism observed during the euglycemic insulin clamp study. Also note that total amount of glucose disposed of by the splanchnic area represents less than 10% of infused glucose load in both groups.

[Reproduced from DeFronzo et al. 4, with permission.]


Figure 13.

Time‐course of change in leg glucose uptake in T2DM (open circles) and control (solid circles) subjects. In the postabsorptive state, glucose uptake in the diabetic group was significantly greater than that in controls. However, the ability of insulin (euglycemic insulin clamp) to stimulate leg glucose uptake was reduced by 50% in the diabetic subjects.

[Reproduced from DeFronzo et al. 4, with permission.]


Figure 14.

Summary of glucose metabolism during euglycemic insulin (+ 100 μU/ml) clamp studies performed in normal‐weight T2DM and control subjects; see text for more detailed discussion.

[Reproduced from DeFronzo 1, with permission.]


Figure 15.

Summary of the metabolic clearance rate of glucose in 77 normal‐weight T2DM subjects (open circles) with fasting plasma glucose concentrations ranging from 105 mg/dl to greater than 300 mg/dl; 72 controls matched for age and weight are shown (closed circles). In the 33 diabetic subjects with fasting plasma glucose concentrations of less than 140 mg/dl (shaded area), glucose clearance rate fell precipitously and was inversely correlated (r = ‐0.697, P < 0.001) with the increase in plasma glucose concentration. At fasting plasma glucose levels above 140 mg/dl, rate of decline in glucose clearance began to slow and reached a plateau at glucose levels above 180 mg/dl.

[Reproduced from DeFronzo 1, with permission.]


Figure 16.

The effect of overnight insulin infusion to normalize basal rate of hepatic glucose production in 19 normal‐weight T2DM subjects (shaded bars) and in 72 controls matched for age and weight (crosshatched bars). Despite similar rates of HGP and a more than doubled plasma insulin concentration (P < 0.01), fasting plasma glucose remained significantly elevated in T2DM versus controls. Decreased glucose clearance in T2DM subjects indicates diminished efficiency of tissue glucose uptake.

[Reproduced from DeFronzo et al. 40, with permission.]


Figure 17.

Insulin‐mediated rates (+100 μU/ml euglycemic insulin clamp) of whole‐body glucose uptake (total height of bar), glucose oxidation (lower portion of each bar), and nonoxidative glucose disposal (upper part of each bar) in control, lean diabetic, obese non‐diabetic and obese diabetic subjects. Obese diabetic patients were further subdivided into hyperinsulinemic and hypoinsulinemic groups based upon plasma insulin response during a 100 g OGTT. *P < 0.001 versus controls.

[Reproduced from DeFronzo 1. with permission.]


Figure 18.

Plasma glucose and insulin concentrations during a 100 g OGTT in control (solid circles), normal‐weight diabetic (open circles), and obese nondiabetic (squares) subjects whose tissue sensitivity to insulin is shown in Figure 17

[Drawn from data presented in DeFronzo 1, Golay et al. 172, 225 and Felber et al. 226, 291.]


Figure 19.

Plasma glucose and insulin concentrations in control (solid circles), obese hyperinsulinemic diabetic (solid triangles) and obese hypoinsulinemic diabetic (open squares) subjects whose tissue sensitivity to insulin is shown in Figure 17.

[Drawn from data presented in DeFronzo 1, Golay et al. 172, 225 and Felber et al. 226, 291.]


Figure 20.

Schematic representation of insulin receptor and the cascade of intracellular signaling molecules that has been implicated in insulin action; see text for more detailed discussion.



Figure 21.

Effect of euglycemic hyperinsulinemia (63 uU/ml) for 4 h on hexokinase (HK), glycogen synthase (GS), and GLUT‐4 mRNA levels (upper panel), protein content (middle panel) and activity (lower panel) in healthy young subjects **P < 0.05, *P < 0.01, †P = 0.10.

[Reproduced from Mandarino et al. 330, with permission.]


Figure 22.

Rates of transmembrane glucose influx into forearm muscle at baseline and during the insulin clamp (∼65 uU/ml). Study 1 was performed in T2DM patients at euglycemia (∼5.0 mM/l) as in controls, whereas study 2 was performed at hyperglycemia (∼13 mMl/l). *P <0.01 insulin clamp vs. baseline in controls, **P < 0.05 T2DM vs. controls.

[Reproduced from Bonadonna et al. 337, with permission.]


Figure 23.

Rates of intracellular glucose phosphorylation in forearm muscle at baseline and during insulin clamp (∼65 mU/ml) study. Study 1 performed in T2DM patients at euglycemia (∼mM/l) as in controls; study 2 performed at hyperglycemia (∼13 mM/l). *P < 0.05 insulin clamp vs. baseline in controls, **P < 0.05 TZDM vs. controls during insulin clamp, ***P < 0.01 T2DM vs. controls during insulin clamp.

[Reproduced from Bonadonna et al. 337, with permission.]


Figure 24.

Glucose concentration in the available intracellular glucose space in forearm muscle at baseline and during insulin clamp (∼65 mU/ml) study. Study 1 performed in T2DM patients at euglycemia (∼mM/L) as in controls; study 2 performed at hyperglycemia (∼13mM/l). *P <0.05 insulin clamp vs. baseline in controls, **P < 0.01 TZDM vs. controls during insulin clamp, ***P < 0.05 study 2 vs. study 1 in TZDM patients.

[Reproduced from Bonadonna et al. 337, with permission.]


Figure 25.

Insulin‐mediated glucose uptake during a + 100 μU/ml euglycemic insulin clamp performed in control (solid bar) and 90% pancreatectomized (PANX) (stippled bar) rats. Phlorizin treatment (crosshatched bars) restored tissue sensitivity to insulin to normal. Withdrawal of phlorizin (open bar) was associated with the return of severe insulin resistance.

[Drawn from data presented in Rossetti et al. 381.]


Figure 26.

Hexosamine pathway. See text for detailed discussion.



Figure 27.

Schematic representation of effect of increased plasma FFA oxidation on muscle glucose metabolism and hepatic glucose production. See text for more detailed discussion.

[Reproduced from DeFronzo 1, with permission.]


Figure 28.

Pathogenetic sequence of events leading to development of insulin resistance in T2DM. Note that whether the primary defect initiating the glucose intolerance resides in the beta cell or in peripheral tissues, development of insulin resistance eventually will ensue or become aggravated, respectively. By the time that overt fasting hyperglycemia (>140 mg/dl) develops, both impaired insulin secretion and severe insulin resistance are present. Positive feedback loops (broken arrows), result in self‐perpetuation of primary defects.

[Reproduced from DeFronzo 1, with permission.]


Figure 29.

Schematic representation of potential defects that can lead to development of insulin resistance in T2DM. Regardless of etiology of insulin resistance, the beta cell will enhance secretion of insulin in an attempt to offset defect in insulin action. The resultant compensatory hyperinsulinemia will down‐regulate a variety of intracellular events involved in insulin action and, thus, serve as a self‐perpetuating cause of the insulin resistance.

References
 1. De Fronzo R A. Lilly Lecture. The triumvirate: beta cell, muscle, liver. A collusion responsible for NIDDM. Diabetes 37: 667–87, 1988.
 2. De Fronzo R A, Ferrannini E. Regulation of hepatic glucose metabolism in humans. Diabetes Metab Rev 415–59, 1987.
 3. De Fronzo R A, Jacot E, Jequier E, Maeder E., Wahren J, Felber J P. The effect of insulin on the disposal of intravenous glucose: results from indirect calorimetry. Diabetes 30: 1000–1007, 1981.
 4. De Fronzo R A, Gunnarsson R, Bjorkman O, Olsson M, Wahren J. Effects of insulin on peripheral and splanchnic glucose metabolism in non‐insulin dependent diabetes mellitus. J Clin Invest 76: 149–155, 1985.
 5. De Fronzo R A. Pathogenesis of type 2 (non‐insulin dependent) diabetes mellitus: a balanced overview. Diabetologia 35: 389–397, 1992.
 6. Mari A, Wahren J, De Fronzo R A, Ferrannini E. Glucose absorption and production following oral glucose: comparison of compartmental and arteriovenous‐difference methods. Metabolism 43: 1419–1425, 1994.
 7. Katz L D, Glickman M G, Rapoport S, Ferrannini E, De Fronzo R A. Splanchnic and peripheral disposal of oral glucose in man. Diabetes 32: 675–679, 1983.
 8. Ferrannini E, Bjorkman O, Reichard G A Jr, Pilo A, Olsson M, Wahren J, De Fronzo R A. The disposal of an oral glucose load in healthy subjects. Diabetes 34: 580–588, 1985.
 9. Taylor R, Magnusson I, Rothman D L, Cline G W, Caumo A, Co‐belli C, Shulman G I. Direct assessment of liver glycogen storage by 13C nuclear magnetic resonance spectroscopy and regulation of glucose homeostasis afer a mixed meal in normal subjects. J Clin Invest 97: 126–132, 1996.
 10. Bjorntorp P, Sjostrom L. Carbohydrate storage in man: speculations and some quantitative considerations. Metabolism 27 (suppl 2): 853–865, 1978.
 11. Bjorntorp P, Berchtold P, Holm J. The glucose uptake of human adipose tissue in obesity. Eur J Clin Invest 1: 480–485, 1971.
 12. Jansson P‐A, Larsson A, Smith U, Lonroth P. Lactate release from the subcutaneous tissue in lean and obese men. J Clin Invest 93: 240–246, 1994.
 13. Kalant N, Leibovici D, Fukushima J, Kuyumjian J, Ozaki S. Insulin responsiveness of superficial forearm tissues in type 2 (non‐insulin‐dependent) diabetes. Diabetologia 22: 239–244, 1982.
 14. Groop L C, Bonadonna R C, Del Prato S, Ratheiser K, Zych K, Ferrannini E, De Fronzo R A. Glucose and free fatty acid metabolism in non‐insulin dependent diabetes mellitus. Evidence for multiple sites of insulin resistance. J Clin Invest 84: 205–215, 1989.
 15. Reaven G M. The fourth musketeer—from Alexandre Dumas to Claude Bernard. Diabetologia 38: 3–13, 1995.
 16. Randle P J. Glucokinase and candidate genes for type 2 (non‐insulin‐dependent) diabetes mellitus. Diabetologia 36: 269–275, 1993.
 17. Foley J E. Rationale and application of fatty acid oxidation inhibitors in treatment of diabetes mellitus. Diabetes Care 15: 773–784, 1992.
 18. Prentki M, Corkey B E. Are the beta cell signaling molecules malonyl‐CoA and cytosolic long‐chain acyl‐CoA implicated in multiple tissue defects of obesity and NIDDM? Diabetes 45: 273–283, 1996.
 19. Unger R H. Lipotoxicity in the pathogenesis of obesity‐dependent NIDDM. Genetic and clinical implications. Diabetes 44: 863–870, 1995.
 20. Arner P, Pollare T, Lithell H. Different aetiologies of type 2 (non‐insulin‐dependent) diabetes mellitus in obese and non‐obese subjects. Diabetologia 34: 483–487, 1991.
 21. Banerji M A, Lebovitz H E. Insulin action in black Americans with NIDDM. Diabetes Care 15: 1295–1302, 1992.
 22. Banerji M A, Chaiken R L, Gordon D, Kral J G, Lebovitz H E. Does intra‐abdominal adipose tissue in black men determine whether NIDDM is insulin‐resistant or insulin‐sensitive? Diabetes 44: 141–146, 1995.
 23. Zimmet P Z. The pathogenesis and prevention of diabetes in adults. Diabetes Care 18: 1050–1064, 1995.
 24. Bynre M M, Sturis J, Fajans S S, Ortiz F J, Stoltz A, Stoffel M, Smith M J, Bell G I, Halter J B, Polonsky K S. Altered insulin secretory responses to glucose in subjects with a mutation in the MODY1 gene on chromosome 20. Diabetes 44: 699–704, 1995.
 25. Sturis, J., Kurland I J, Byrne M M, Mosekilde E, Froguel P, Pilkis S J, Bell G I, Polonsky K S. Compensation in pancreatic ã‐cell function in subjects with glucokinase mutations. Diabetes 43: 718–723, 1994.
 26. Clement K, Pueyo M E, Vaxillaire M, Rakotoambinina B, Thuillier F, Passa P H, Froguel P H, Robert J J, Velho G. Assessment of insulin sensitivity in glucokinase‐deficient subjects. Diabetologia 39: 82–90, 1996.
 27. Halter J B, Graf R J, Porte D. Potentiation of insulin secretory responses by plasma glucose levels in man: evidence that hyperglycemia in diabetes compensates for impaired glucose potentiation. J Clin Endocrinol Metab 48: 946–954, 1979.
 28. Ward W K, Bolgiano D C, McKnight B. Halter J, Porte D.. Diminished beta cell secretory capacity in patients with non‐insulin‐dependent diabetes mellitus. J Clin Invest 74: 1318–1328, 1984.
 29. Hales C N. The pathogenesis of NIDDM. Diabetologia 37: S162–S168, 1994.
 30. De Fronzo R A, Ferrannini E, Koivisto V. New concepts in the pathogenesis and treatment of non‐insulin‐dependent diabetes mellitus. Am J Med 740 (IA): 52–81, 1983.
 31. Polonsky K S, Sturis J, Bell G I. Non‐insulin‐dependent diabetes mellitus—a genetically programmed failure of the beta cell to compensate for insulin resistance. N Engl J Med 334: 777–783, 1996.
 32. Polonsky K S. Lilly Lecture 1994. The beta cell in diabetes: from molecular genetics to clinical research. Diabetes 44: 705–717, 1995.
 33. Davies M J, Metcalfe J, Gray I P, Day J L, Hales C N. Insulin deficiency rather than hyperinsulinaemia in newly diagnosed type 2 diabetes mellitus. Diabetic Med 10: 305–312, 1993.
 34. Nesher R, Della Casa, L, Litvin Y, Sinai J, Del Rio G, Pevsner B, Wax Y, Cerasi E. Insulin deficiency and insulin resistance in type 2 (non‐insulin‐dependent) diabetes: quantitative contributions of pancreatic and peripheral responses to glucose homeostasis. Eur J Clin Invest 17: 266–274, 1987.
 35. Cerasi E. Insulin deficiency and insulin resistance in the pathogenesis of NIDDM: is a divorce possible? Diabetologia 38: 992–997, 1995.
 36. O'Rahilly S P, Turner R C, Matthews D R. Impaired pulsatile secretion of insulin in relatives of patients with non‐insulin‐dependent diabetes. N Engl J Med 318: 1225–1230, 1988.
 37. O'Rahilly S P, Nugent Z, Rudenski A S, Hosker J P, Burnett M A, Darling P, Turner R C. B‐cell dysfunction, rather than insulin insensitivity, is the primary defect in familial type 2 diabetes. Lancet 2: 360–364, 1986.
 38. Temple R C, Carrington C A, Luzio S D, Owens D R, Schneider A E, Sobey W J, Hales C N. Insulin deficiency in non‐insulin‐dependent diabetes. Lancet 1: 293–295, 1989.
 39. Bonadonna R C, Groop L, Kraemer N., Ferrannini E, Del Prato S, De Fronzo R A. Obesity and insulin resistance in man. A dose response study. Metabolism 39: 452–459, 1990.
 40. De Fronzo R A, Ferrannini E, Simonson D C. Fasting hyperglycemia in non‐insulin‐dependent diabetes mellitus: contributions of excessive hepatic glucose production and impaired tissue glucose uptake. Metabolism 38: 387–395, 1989.
 41. Matsuda M, De Fronzo R A. Isolation of hepatic and peripheral insulin sensitivity: application to the investigation of inherited or acquired defects in NIDDM. Diabetes 45 (suppl. 1): 17A, 1996.
 42. Bogardus C, Lillioja S, Howard B V, Reaven G, Mott D. Relationships between insulin secretion, insulin action, and fasting plasma glucose concentration in non‐diabetic and noninsulin‐dependent subjects. J Clin Invest 74: 1238–1246, 1984.
 43. Zimmet P, Whitehouse S, Alford F, Chisholm D. The relationship of insulin response to a glucose stimulus over a wide range of glucose tolerance. Diabetologia 15: 23–27, 1978.
 44. Reaven G M, Miller R G. An attempt to define the nature of chemical diabetes using a multidimensional analysis. Diabetologia 16: 17–24, 1979.
 45. Zimmet P, Whitehouse S. Biomodality of fasting and two‐hour glucose tolerance distributions in a Micronesian population. Diabetes 27: 793–800, 1978.
 46. Sicree R A, Zimmet P, King H O, Coventry J O. Plasma insulin response among Nauruans. Prediction of deterioration in glucose tolerance over 6 years. Diabetes 36: 179–186, 1987.
 47. Saad M F, Knowler W C, Pettitt D J, Nelson R G, Mott D M, Bennett P H. Sequential changes in serum insulin concentration during development of non‐insulin‐dependent diabetes. Lancet 1: 1356–1359, 1989.
 48. Reaven G M, Hollenbeck C, Jeng C‐Y, Wu, M S, Chen Y‐D I. Measurement of plasma glucose, free fatty acid, lactate, and insulin for 24 hours in patients with NIDDM. Diabetes 37: 1020–1024, 1988.
 49. Garvey W T, Olefsky J M, Rubenstein A H, Koltherman O G. Daylong integrated urinary C‐peptide excretion. Diabetes 37: 590–599, 1988.
 50. Lillioja S, Mott D M, Howard B V, Bennett P H, Yki‐Jarvinen H, Freymond D, Nyomba B L, Zurlo F, Swinburn B, Bogardus C. Impaired glucose tolerance as a disorder of insulin action. Longitudinal and cross‐sectional studies in Pima Indians. N Engl J Med 318: 1217–1225, 1988.
 51. Warram J H, Martin B C, Krolewski A S, Soeldner J S, Kahn C R. Slow glucose removal rate and hyperinsulinemia precede the development of type II diabetes in the offspring of diabetic parents. Ann Intern Med 113: 909–915, 1990.
 52. Yudkin J S, Alberti K G M M, McClarity D G, Swai A B M. Impaired glucose tolerance—Is it a risk factor for diabetes or a diagnostic ragbag? Br Med J 301: 397–401, 1990.
 53. Saad M F, Knowler W C, Pettitt D J, Nelson R G, Mott D M, Bennett P H. The natural history of impaired glucose tolerance in the Pima Indians. N Engl J Med 319: 1500–1505, 1988.
 54. Jallut D, Golay A, Munger R, Frascarolo P, Schutz Y, Jequier E, Felber J P. Impaired glucose tolerance and diabetes in obesity: a 6 year follow‐up study of glucose metabolism. Metabolism 39: 1068–1075, 1990.
 55. Gulli G, Ferrannini E, Stern M, Haffner S, De Fronzo R A. The metabolic profile of NIDDM is fully established in glucose‐tolerant offspring of two Mexican‐American NIDDM parents. Diabetes 41: 1575–1586, 1992.
 56. Haffner S M, Miettinen H, Gaskill S P, Stern M P. Decreased insulin secretion and increased insulin resistance are independently related to the 7‐year risk of NIDDM in Mexican‐Americans. Diabetes 44: 1386–1391, 1995.
 57. Haffner S M, Miettinen H, Stern M P. Insulin secretion and resistance in nondiabetic. Mexican Americans and non‐hispanic whites with a parental history of diabetes. J Clin Endrocrinol Metab 81: 1846–1851, 1996.
 58. Lillioja S, Mott D M, Spraul M, Ferraro R, Foley J E, Ravussin E, Knowler W C, Bennett P H, Bogardus C. Insulin resistance and insulin secretory dysfunction as precursors of non‐insulin‐dependent diabetes mellitus. N Engl J Med 329: 1988–1992, 1993.
 59. Dowse G K, Zimmet P Z, Collins V R. Insulin levels and the natural history of glucose intolerance in Nauruans. Diabetes 45: 1367–1372, 1996.
 60. Hansen B C, Bodkin N H. Heterogeneity of insulin responses: phases leading to type 2 (noninsulin‐dependent) diabetes mellitus in the rhesus monkey. Diabetologia 29: 713–719, 1986.
 61. Bodkin N L, Metzger B L, Hansen B C. Hepatic glucose production and insulin sensitivity preceding diabetes in monkeys. Am J Physiol 256: E676–E681, 1989.
 62. Haffner S M, Stern M P, Hazuda H P, Pugh J A, Patterson J K. Hyperinsulinemia in a population at high risk for non‐insulin‐dependent diabetes mellitus. N Engl J Med 315: 220–224, 1986.
 63. Haffner S M, Stern M P, Mitchell B D, Hazula H P, Patterson J K. Incidence of type II diabetes in Mexican Americans predicted by fasting insulin and glucose levels, obesity, and body‐fat distribution. Diabetes 39: 283–288, 1990.
 64. Haffner S M, Stern M P, Hazuda H P, Mitchell B D, Patterson J K. Increased insulin concentrations in non‐diabetic offspring of diabetic parents. N Engl J Med 319: 1297–301, 1988.
 65. Eriksson J, Franssila‐Kallunki A, Ekstrand A, Saloranta C, Widen E, Schalin C, Groop L. Early metabolic defects in persons at increased risk for non‐insulin‐dependent diabetes mellitus. N Engl J Med 321: 337–343, 1989.
 66. Efendic S, Luft R, Wajngot A. Aspects of the pathogenesis of type 2 diabetes. Endocr Rev 5: 395–419, 1984.
 67. Ho L T, Chang Z Y, Wang J T, Li S H, Liu Y F, Chen Y‐D I, Reaven G M. Insulin insensitivity in offspring of parents with type 2 diabetes mellitus. Diabetic Med 7: 31–34, 1990.
 68. Martin B C, Warram J H, Krolewski A S, Bergman R N, Soeldner J S, Kahn R C. Role of glucose and insulin resistance in development of type 2 diabetes mellitus: results of a 25‐year follow‐up study. Lancet 340: 925–929, 1992.
 69. Fajans S S. Maturity‐onset diabetes of the young (MODY). Diabetes Metab Rev 5: 579–606, 1989.
 70. Beck‐Nielsen H, Nielsen O H, Pedersen O, Bak J, Faber O, Schmitz O. Insulin action and insulin secretion in identical twins with MODY: evidence for defects in both insulin action and insulin secretion. Diabetes 37: 730–735, 1988.
 71. Mohan V, Sharp P S, Aber V R, Mather H M, Kohner E M. Insulin resistance in maturity‐onset diabetes of the young. Diabetes Metab 13: 193–197, 1988.
 72. Velho G, Petersen K, Perseghin G, Hwang J‐H, Pueyo M E, Rothman D L, Pueyo M E, Cline G W, Froguel P, Shulman G I. Impaired hepatic glycogen synthesis in glucokinase‐deficient (MODY‐2) subjects. J Clin Invest 98: 1755–1761, 1996.
 73. Clement K, Pueyo M E, Vaxillaire M, Rakotoambinina B, Thuillier F, Passa P, Froguel P, Robert J‐J, Velho G. Assessment of insulin sensitivity in glucokinase‐deficient subjects. Diabetologia 39: 82–90, 1996.
 74. Bell G I, Zian K, Newman M, Wu S, Wright L, Fajans S, Spielman R S, Cox N J. Gene for non‐insulin‐dependent diabetes mellitus (maturity‐onset diabetes of the young subtype) is linked to DNA polymorphism on human chromosome 20q. Proc Natl Acad Sci USA 88: 1484–1488, 1991.
 75. Froguel P, Vaxillaire M, Sun F, Velho G, Zouali H, Butel M O, Lesage S, Vionnet N, Clement K, Fougerousse F, Tanizawa Y, Weissenbach J, Beckmann J S, Lathrop G M, Passa P, Permutt M A, Cohen D. Close linkage of glucokinase locus on chromosome 7p to early‐onset non‐insulin‐dependent diabetes mellitus. Nature 356: 162–614, 1992.
 76. Froguel P H, Zouali H, Vionnet N, Velho G, Vaxillaire M, Sun F, Lesage S, Stoffel M, Takeda J, Passap P. Familial hyperglycaemia due to mutations in glucokinase: definition of a subtype of diabetes mellitus. N Engl J Med 328: 697–702, 1993.
 77. Menzel S, Yamagata K, Trabb J B, Nerup J, Permutt M A, Fajans S S, Menzel R, Iwasaki N, Omori Y, Cox N, Bell G I. Localization of MODY3 to a 5‐cM region of human chromosome 12. Diabetes 44: 1408–1413, 1995.
 78. Lesage S, Hani E, Phippi A, Vaxillaire M, Hager J, Passa P, Demenais F, Froguel P, Vionnet N. Linkage analyses of the MODY3 locus on chromosome 12q with late‐onset NIDDM. Diabetes 44: 1243–1247, 1995.
 79. Zouali H, Vaxillaire M, Lesage S, Sun F, Velho G, Vionnet N, Chiu K, Passa P, Permutt A, Demenais F, Cohen D, Beckmann S, Froguel P. Linkage analysis and molecular scanning of glucokinase gene in NIDDM families. Diabetes 42: 1238–1245, 1993.
 80. Chiu K C, Tanizawa Y, Permutt M A. Glucokinase gene vaiants in the common form of NIDDM. Diabetes 42: 579–582, 1993.
 81. Efendic S, Grill V, Luft R, Wajngot A. Low insulin response: a marker of pre‐diabetes. Adv Exp Med Biol 246: 167–174, 1988.
 82. Chen K‐W, Boyko E J, Bergstrom R W, Leonetti D L, Newell‐Morris L, Wahl P W, Fujimoto W Y. Earlier appearance of impaired insulin secretion than of visceral adiposity in the pathogenesis of NIDDM. 5‐year follow‐up of initially nondiabetic Japanese‐American men. Diabetes Care 18: 747–753, 1995.
 83. Temple R, Clark P M S, Hales C N. Measurement of insulin secretion in type 2 diabetes: problems and pitfalls. Diabetic Med 9: 503–512, 1992.
 84. Calles‐Escandon J, Robbins D C. Loss of early phase of insulin release in humans impairs glucose tolerance and blunts thermic effect of glucose. Diabetes 36: 1167–72, 1987.
 85. Bruce D G, Chisholm D J, Storlien L H, Kraegen E W. Physiological importance of deficiency in early prandial insulin secretion in non‐insulin dependent diabetes. Diabetes 37: 736–44, 1988.
 86. Luzi L, De Fronzo R A. Effect of loss of first phase insulin secretion on hepatic glucose production and tissue glucose disposal in humans. Am J Physiol 257: E241–E246, 1989.
 87. Brunzell J D, Robertson R P, Lerner R L, Hazzard W R, Ensinck J W, Bierman E L, Porte D. Relationships between fasting plasma glucose levels and insulin secretion during intravenous glucose tolerance tests. J Clin Endocrinol 46: 222–229, 1976.
 88. Vague P, Moulin J‐P. The defective glucose sensitivity of the B cell in insulin dependent diabetes. Improvement after twenty hours of normoglycaemia. Metabolism 31: 139–142, 1982.
 89. Savage P J, Bennion L J, Flock E V. Diet‐induced improvement of abnormalities in insulin and glucagon secretion and in insulin receptor binding in diabetes mellitus. J Clin Endocrinol Metab 48: 999–1007, 1979.
 90. Kosaka K, Kuzuya T, Akanuma Y, Hagura R. Increase in insulin response after treatment of overt maturity onset diabetes mellitus is independent of the mode of treatment. Diabetologia 18: 23–8, 1980.
 91. Cusi K, Cunningham G, Comstock J P. Safety and efficacy of normalizing fasting glucose with bedtime NPH insulin alone in NIDDM. Diabetes Care, 18: 843–851, 1995.
 92. Rossetti L, Giaccari A, De Fronzo R A. Glucose toxicity. Diabetes Care 13: 610–630, 1990.
 93. Polonsky K S, Given B D, Van Cauter E. Twenty‐four‐hour profiles and pulsatile patterns of insulin secretion in normal and obese subjects. J Clin Invest 81: 442–448, 1988.
 94. Goodner C J, Walike B C, Koerker D J, Brown A C, Chideckel E W, Palmer J, Kalnasy L. Insulin, glucagon, and glucose exhibit synchronous, sustained oscillations in fasting monkeys. Science 195: 177–179, 1977.
 95. Sturis J, Scheen A J, Leproult R, Polonsky K S, Van Cauter E. 24‐hour glucose profiles during continuous or oscillatory insulin infusion: demonstration of the functional significance of ultradian insulin oscillations. J Clin Invest 95: 1464–1471, 1995.
 96. Gumbiner B, Van Cauter E, Beltz W F, Ditzler T M, Griver K, Polonsky K S, Henry R R. Abnormalities of insulin pulsatility and glucose oscillations during meals in obese noninsulin‐dependent diabetic patients: effects of weight reduction. J Clin Endocrinol Metab 81: 2061–2068, 1996.
 97. O'Meara N M, Sturis J, Van Cauer E, Polonsky K S. Lack of control by glucose of ultradian insulin secretory oscillations in impaired glucose tolerance and in non‐insulin‐dependent diabetes mellitus. J Clin Invest 92: 262–271, 1993.
 98. O'Rahilly S, Turner R C, Matthews D R. Impaired pulsatile secretion of insulin in relatives of patients with non‐insulin‐dependent diabetes. N Engl J Med 318: 1225–1230, 1988.
 99. Rhodes C J, Alarcon C. What beta cell defect could lead to hyperproinsulinemia in NIDDM? Diabetes 43: 511–517, 1994.
 100. Glauber H S, Revers R R, Henry R, Schmeiser L, Wallace P, Kolterman O G, Cohen R M, Rubenstein A H, Galloway J A, Frank B H. In vivo glucose deactivation of pro‐insulin action on glucose disposal and hepatic glucose production in normal man. Diabetes 35: 311–317, 1986.
 101. Ward W K, LaCava E C, Paquette T L, Beard J C, Wallum B J, Porte D. Disproportionate elevation of immunoreactive pro‐insulin in type 2 (non‐insulin‐dependent) diabetes mellitus and in experimental insulin resistance. Diabetologia 30: 698–702, 1987.
 102. Yoshioka N, Kuzuya T, Matsuda A, Taniguchi M, Iwamoto Y. Serum proinsulin levels at fasting and after oral glucose load in patients with type 2 (non‐insulin‐dependent) diabetes mellitus. Diabetologia 31: 355–360, 1988.
 103. Reaven G M, Chen Y D, Hollenbeck C B, Sheu W H, Ostrega D, Polonsky K S. Plasma insulin, C‐peptide and proinsulin concentrations in obese and nonobese individuals with varying degrees of glucose tolerance. J Clin Endocrinol Metab 76: 44–48, 1993.
 104. Unger R H, Grund S. Hyperglycaemia as an inducer as well as a consequence of impaired islet cell function and insulin resistance: implications for the management of diabetes. Diabetologia 28: 119–21, 1985.
 105. Leahy J L. Natural history of beta cell dysfunction in non‐insulin‐dependent diabetes mellitus. Diabetes Care 13: 992–1010, 1990.
 106. Garvey W T, Olefsky J M, Griffin J, Hamman R F, Kolterman O G. The effect of insulin treatment on insulin secretion and insulin action in type II diabetes mellitus. Diabetes 34: 222–234, 1985.
 107. Hidaka H, Nagulesparan M, Klimes I, Clark R, Sasaki H, Aronoff S L, Vasquez B, Rubenstein A H, Unger R H. Improvement of insulin secretion but not insulin resistance after short term control of plasma glucose in obese type II diabetics. J Clin Endocrinol Metab 54: 217–222, 1982.
 108. Stanik S, Marcus R. Insulin secretion improves following dietary control of plasma glucose in severely hyperglycemic obese patients. Metabolism 29: 346–350, 1980.
 109. Andrews W J, Vasquez B, Nagulesparan M, Klimes 1, Foley J, Unger R, Reaven G M. Insulin therapy in obese, non‐insulin‐dependent diabetes induces improvements in insulin action and secretion that are maintained for two weeks after insulin withdrawal. Diabetes 33: 634–642, 1984.
 110. Dimitrakoudis D, Vranic M, Klip A. Effects of hyperglycemia on glucose transporters of the muscle: use of the renal glucose reabsorption inhibitor phlorizin to control glycemia. J Am Soc Nephrol 3: 1078–1091, 1992.
 111. Leahy J L, Bonner‐Weir S, Weir G C. Abnormal glucose regulation of insulin secretion in models of reduced beta‐cell mass. Diabetes 33: 667–673, 1984.
 112. Leahy J L, Bonner Weir S, Weir G C. Minimal chronic hyperglycemia is a critical determinant of impaired insulin secretion after an incomplete pancreatectomy. J Clin Invest 81: 1407–1414, 1988.
 113. Leahy J L, Cooper H E, Weir G C. Impaired insulin secretion associated with near normoglycemia. Diabetes 36: 459–464, 1987.
 114. Giroix M H, Portha B, Kergoat M, Bailbe D, Picon L. Glucose insensitivity and amino‐acid hypersensitivity of insulin release in rats with non‐insulin‐dependent diabetes. Diabetes 32: 445–451, 1983.
 115. Grill V, Westberg M, Ostenson C G. Beta cell insensitivity in a rat model of non‐insulin‐dependent diabetes. J Clin Invest 80: 664–669, 1987.
 116. Imamura T, Koffler M, Helderman J H, Prince D, Thirlby R, Inman L, Unger R H. Severe diabetes induced in subtotally depancreatectomized dogs by sustained hyperglycemia. Diabetes 37: 600–609, 1988.
 117. Robertson R P, Olson I K, Zhang H‐J. Differentiating glucose toxicity from glucose desensitization: a new message from the insulin gene. Diabetes 43: 1085–1089, 1994.
 118. Chen S, Ogawa A, Ohneda M, Unger R H, Foster D W, McGarry J D. More direct evidence for a maloyl‐CoA‐carnitine palmitoyltransferase I interaction as a key event in pancreatic beta cell signaling. Diabetes 43: 878–883, 1994.
 119. Matchinsky F M. Banting Lecture 1995. A lesson in metabolic regulation inspired by the glucokinase glucose sensor paradigm. Diabetes 45: 223–241, 1996.
 120. Newgard C B, McGarry J D. Metabolic coupling factors in pancreatic beta cell signal transduction. Annu Rev Biochem 64: 689–719, 1995.
 121. Nishizuka Y. Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science 258: 607–614, 1992.
 122. Corkey B E, Deeney J T. Acyl CoA regulation of metabolism and signal transduction. Prog Clin Biol Res 321: 217–232, 1990.
 123. Zhou Y P, Grill V E. Long‐term exposure of rat pancreatic islets to fatty acids inhibits glucose‐induced insulin secretion and biosynthesis through a glucose fatty acid cycle. J Clin Invest 93: 870–876, 1994.
 124. Zhou Y‐P, Ling Z‐C, Grill V E. Inhibitory effects of fatty acids on glucose‐regulated beta cell function: association with increased islet triglyceride stores and altered effect of fatty acid oxidation on glucose metabolism. Metabolism 45: 981–986, 1996.
 125. Saito K, Yaginuma N, Takahashi T. Differential volumetry of alpha, beta, and delta cells in the pancreatic islets of diabetic and nondiabetic subjects. Tohoku J Exp Med 129: 273–283, 1979.
 126. Kloppel G, Lohr M, Habich K, Oberholzer M, Heitz P U. Islet pathology and the pathogenesis of type 1 and type 2 diabetes mellitus revisited. Surv Synth Path Res 4: 110–125, 1985.
 127. Clark A, Wells C A, Buley I D, Cruickshank J K, Vanhegan R I, Matthews D R, Cooper G J, Holman R R, Turner R C. Islet amyloid, increased alpha‐cells, reduced beta‐cells and exocrine fibrosis: quantitative changes in the pancreas in type 2 diabetes. Diabetes Res 9: 151–159, 1988.
 128. Stefan Y, Orci L, Malaisse‐Lagae F, Perrelet A, Patel Y, Unger R. Quantitation of endocrine cell content in the pancreas of nondiabetic and diabetic humans. Diabetes 31: 694–700, 1982.
 129. Eisenbarth G S, Connelly J, Soeldner J S. The “natural” history of type I diabetes. Diabetes Metab Rev 3: 873–891, 1987.
 130. McCance D R, Pettitt D J, Hanson R L, Jacobson L T, Knowler W C, Bennett P H. Birth weight and non‐insulin dependent diabetes: thrifty genotype, thrifty phenotype, or surviving small baby genotype? Br Med J 308: 942–945, 1994.
 131. Hales C N, Barker D J P. Type 2 (non‐insulin‐dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia 35: 595–601, 1993.
 132. Purdy L P, Metzger B E. Influences of the intrauterine metabolic environment on adult disease: what may we infer from size at birth? Diabetologia 39: 1126–1130, 1996.
 133. Eriksson U J. Lifelong consequences of metabolic adaptations in utero? Diabetologia 39: 1123–1125, 1996.
 134. Phillips D I W. Insulin resistance as a programmed response to fetal undernutrition. Diabetologia 39: 1119–1122, 1996.
 135. Johnson K H, O'Brien T D, Betysholtz C, Westermark P. Islet amyloid, islet‐amyloid polypeptide, and diabetes mellitus. N Engl J Med 321: 513–518, 1989.
 136. Cooper G J S, Willis A C, Clark A, Turner R C, Sim R B, Reid K B M. Purification and characterization of a peptide from amyloid‐rich pancreases of type 2 diabetic patients. Proc Natl Acad Sci USA 84: 8628–8632, 1987.
 137. Ohsawa H, Kanatsuka A, Yamaguchi T, Makino H, Yoshida S. Islet amyloid polypeptide inhibits glucose‐stimulated insulin secretion from isolated rat pancreatic islets. Biochem Biophys Res Comm 160: 961–967, 1989.
 138. Howard C F. Longitudinal studies on the development of diabetes in individual macaca nigra. Diabetologia 29: 301–306, 1986.
 139. Bretherton‐Watt D, Ghatei M A, Bloom S R, Jamal H, Ferrier G J, Girgis S I, Legon S. Altered islet amyloid polypeptide (amylin) gene expression in rat models of diabetes. Diabetologia 32: 881–883, 1989.
 140. Hartter E, Svoboda T, Ludvik B, Schuller M, Lell B, Kuenburg E, Brunnbauer M, Woloszczuk W, Prager R. Basal and stimulated plasma levels of pancreatic amylin indicate its co‐secretion with insulin in humans. Diabetologia 34: 52–54, 1991.
 141. Eriksson J, Nakazato M, Miyazato M, Shiomi K, Matsukura S, Groop L. Islet amyloid polypeptide: plasma‐concentrations in individuals at increased risk of developing type 2 (non‐insulin‐dependent) diabetes mellitus. Diabetologia 35: 292–293, 1992.
 142. Ghatei M A, Datta H K, Zaidi M, Bretherton Watt D, Wimalawansa S J, MacIntyre 1, Bloom S R. Amylin and amylin‐amide lack an acute effect on blood glucose and insulin. J Endocrinol 124: R9–11, 1990.
 143. Bretherton‐Watt D, Gilbey S G, Ghatei M A, Beacham J, Bloom S R. Failure to establish islet amyloid polypeptide (amylin) as a circulating beta cell inhibiting hormone in man. Diabetologia 33: 115–117, 1990.
 144. Hoppener J W M, Verbeek J S, de Koning E J P, Oosterwijk C, van Hulst K L, Visser‐Vernooy H J, Hofhuis F M A, van Gaalen S, Berends M J H, Hackeng W H L, Jansz H S, Morris J F, Clark A, Capel P J A, Lipis C J M. Chronic overproduction of islet amyloid polypeptide‐amylin in transgenic mice: lysosomal localization of human islet amyloid polypeptide and lack of marked hyperglycaemia or hyperinsulinaemia. Diabetologia 36: 1258–1265, 1993.
 145. Westermark G T, Christmanson L, Terenghi G, Permerth J, Betsoltz C, Larsson J, Polak J M, Westermark P. Islet amyloid polypeptide: demonstration of mRNA in human pancreatic islets by in situ hybridization in islets with and without amyloid deposits. Diabetologia 36: 323–328, 1993.
 146. Thorens B, Waeber G. Glucagon‐like peptide‐1 and the control of insulin secretion in the normal state and in NIDDM. Diabetes 42: 1219–1225, 1993.
 147. Nauck M, Stockmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type II (non‐insulin‐dependent) diabetes. Diabetologia 29: 46–52, 1986.
 148. Gutniak M, Orskov C, Holst J J, Ahren B, Efendic S. Antidiabetogenic effect of glucagon‐like peptide I (7–36) amide in normal subjects and patients with diabetes mellitus. N Engl J Med 326: 1316–1322, 1992.
 149. Nanauck M A, Kleine N, Orskov C, Holst J J, Willms B, Creutzfeldt W. Normalization of fasting hyperglycaemia by exogenous glucagon‐like peptide 1 (7–36 amide) in type 2 (non‐insulin‐dependent) diabetic patients. Diabetologia 36: 741–744, 1993.
 150. Wang Z, Wang R M, Owji A A, Smith D M, Ghatei M A, Blod S R. Glucagon‐like peptide 1 is a physiologic incretin in rat. J Clin Invest 95: 417–421, 1995.
 151. Kolligs F, Fehmann H‐C, Goke R, Goke B. Reduction of the incretin effects in rats by the glucagon‐like peptide 1 receptor antagonist exendin (9–39) amide. Diabetes 44: 16–19, 1995.
 152. D'Alessio D A, Vogel R, Prigeon R, Laschansky E, Koerker D, Eng J, Ensinck J W. Elimination of the action of glucagon‐like peptide 1 causes an impairment of glucose tolerance after nutrient ingestion by healthy baboons. J Clin Invest 97: 133–138, 1996.
 153. Gerbitz K‐D, van den Ouweland J M W, Maassen J A, Jaksch M. Mitochondrial diabetes mellitus: a review. Biochim Biophys Acta 1271: 253–260, 1995.
 154. Maassen J A, Kadowaki T. Maternally inherited diabetes and deafness: a new diabetes subtype. Diabetologia 39: 375–382, 1996.
 155. Gerbitz K‐D, Gempel K, Brdiczka D. Mitochondria and diabetes. Genetic, biochemical, and clinical implications of the cellular energy circuit. Diabetes 45: 113–126, 1996.
 156. Wallace D C. Mitochondrial DNA sequence variation in human evolution and disease. Proc Natl Acad Sci USA 91: 8739–8746, 1994.
 157. Suzuki S, Hinokio Y, Hirai S, Onoda M, Matsumoto M, Ohtomo M, Kawaski H, Satoh Y, Akai H, Abe K, Miyabayashi S, Kawasaki E, Negataki S, Toyote T. Pancreatic beta‐cell secretory defect associated with mitochondrial point mutation of the tRNALeu gene: a study in seven families with mitocondrial encephalomyopathy, lactic acidosis and stroke‐like episodes (MELAS). Diabetologia 37: 818–825, 1994.
 158. Okay Y, Katagiri H, Tshihara H, Asan T, Kikuchi M, Kobayashi T. Mitochondrial diabetes mellitus glucose‐induced signaling defects and beta‐cell loss. Muscle Nerve (Suppl 3): S131–S136, 1995.
 159. Vionnet N, Passa P, Froguel P. Prevalence of mitochondrial gene mutations in families with diabetes mellitus. Lancet 342: 1429–1430, 1993.
 160. Pimenta W, Korytkowski M, Mitrakou A, Jenssen T, Yki‐Jarvinen H, Evron W, Dailey G, Gerich J. Pancreatic beta‐cell dysfunction as the primary genetic lesion in NIDDM. Evidence from studies in normal glucose‐tolerant individuals with a first degree NIDDM relative. JAMA 273: 1855–1861, 1995.
 161. Yki‐Jarvinen H. Role of insulin resistance in the pathogenesis of NIDDM. Diabetologia 38: 1378–1388, 1995.
 162. Groop L C, Widen E, Ferrannini E. Insulin resistance and insulin deficiency in the pathogenesis of type 2 (non‐insulin‐dependent) diabetes mellitus: errors of metabolism or of methods. Diabetologia 36: 1326–1331, 1993.
 163. Kahn C R. Insulin action, diabetogenes, and the cause of type II diabetes. Diabetes 43: 1066–1084, 1994.
 164. Eriksson K‐F, Lindgarde F. Poor physical fitness, and impaired early insulin response but late hyperinsulinaemia, as predictors of NIDDM in middle‐aged Swedish men. Diabetologia 39: 573–579, 1996.
 165. Danowski T, Lambardo Y, Mendelsohn L, Corredor D, Morgan C, Sabeh G. Insulin patterns prior to and after onset of diabetes. Metabolism 18: 731–740, 1969.
 166. Charles M A, Fontbonne A, Thibult N, Warnet J‐M, Rosselin G E, Eschwege E. Risk factors for NIDDM in white population. Paris Prospective Study. Diabetes 40: 769–799, 1991.
 167. Savage P, Bennett P, Gorden P, Miller M. Insulin responses to oral carbohydrate in true prediabetic and controls. Lancet 1: 300–302, 1975.
 168. Strauss W, Hales C. Plasma insulin in minor abnormalities of glucose tolerance: a 5 year follow‐up. Diabetologia 10: 237–243, 1974.
 169. Cerasi E, Luft R. Follow‐up of non‐diabetic subjects with normal and decreased insulin response to glucose infusion‐first report. Horm Metab Res 6: 113–120, 1974.
 170. Lundren H, Bengtsson C, Blohme G, Lapidus L, Waldenstrom J. Fasting serum insulin concentration and early insulin response as risk of determinants for developing diabetes. Diabetic Med 7: 407–413, 1990.
 171. Skarfors E, Selinus K, Lithell H. Risk factors for developing non‐insulin dependent diabetes: a 10 year follow‐up of men in Uppsala. Br Med J 303: 755–760, 1991.
 172. Golay A, Felber J P, Jequier E, De Fronzo R A, Ferrannini E. Metabolic basis of obesity and noninsulin‐dependent diabetes mellitus. Diabetes Metab Rev 4: 727–747, 1988.
 173. Lillioja S, Bogardus C. Obesity and insulin resistance: lessons learned from the Pima Indians. Diabetes Metab Rev 4: 515–540, 1988.
 174. Lillioja S, Mott D M, Zawadzki J K, Young A A, Abbott W G, Knowler W C, Bennett P H, Moll P, Bogardus C. In vivo insulin action is familial characteristic in nondiabetic Pima Indians. Diabetes 36: 1329–1335, 1987.
 175. Mitchell B D, Kammerer C M, Hixson J E, Atwood L D, Hackelman S, Blangero J, Haffner S M, Stern M P, MacCluer J W. Evidence for a major gene affecting postchallenge insulin levels in Mexican‐Americans. Diabetes 44: 284–289, 1995.
 176. Elbein S C, Hoffman M D, Bragg K L, Mayorga R A. The genetics of NIDDM. An update. Diabetes Care 17: 1523–1533, 1994.
 177. Ghosh S, Schork N J. Perspectives in diabetes. Genetic analysis of NIDDM. The study of quantitative traits. Diabetes 45: 1–14, 1996.
 178. Gelding S, Nithyananthan R, Chan S, Robinson S, Gray I, Mather H, Johnston D. Insulin sensitivity in non‐diabetic relatives of patients with non‐insulin‐dependent diabetes from two ethnic groups. Clin Endocrinol 40: 55–62, 1994.
 179. Birkeland K, Torjesen P, Eriksson J, Valler S, Groop L. Hyperproinsulinemia of type 2 diabetes is not present before the development of hyperglycemia. Diabetes Care 17: 1307–1310, 1994.
 180. Viswanathan M, Mohan M, Snehalatha C, Ramachandran A. High prevalence of type 2 (non‐insulin‐dependent) diabetes using the offspring of conjugal type 2 diabetic parents. Diabetologia 28: 901–910, 1985.
 181. Knowler W C, Pettitt D J, Saad M F, Bennett P H. Diabetes mellitus in the Pima Indians: incidence, risk factors and pathogenesis. Diabetes Metab Rev 6: 1–27, 1990.
 182. Vaag A, Henriksen J E, Madsbad S, Holm N, Beck‐Nielsen H. Insulin secretion, insulin action, and hepatic glucose production in identical twins discordant for non‐insulin‐dependent diabetes mellitus. J Clin Invest 95: 690–698, 1995.
 183. Gottlieb M S, Soeldner J S, Kyner J L, Gleason R E. Oral glucose‐stimulated insulin release in nondiabetic twin siblings of diabetic twins. Diabetes 23: 684–692, 1974.
 184. Barnett A H, Spilipoulos A J, Pyke D A, Stubbs W A, Burrin J, Alberti K G M M. Metabolic studies in unaffected co‐twins of non‐insulin‐dependent diabetics. Brit Med J 282: 1656–1658, 1981.
 185. Pyke D A, Taylor K W. Glucose tolerance and serum insulin in unaffected identical twins of diabetics. Brit Med J 4: 21–22, 1967.
 186. Cerasi E, Luft R. Insulin response to glucose infusion in diabetic and non‐diabetic monozygotic twin pairs. Genetic control of insulin response? Acta Endocrinol 55: 330–345, 1967.
 187. Pendergrass M, Fazioni E, De Fronzo R A. Non‐insulin dependent diabetes mellitus and gestational diabetes mellitus: same disease, another name? Diabetes Rev 3: 566–583, 1995.
 188. Buchanan T A, Catalano P M. The pathogenesis of GDM: implications for diabetes after pregnancy. Diabetes Rev 3: 584–601, 1995.
 189. O'Sullivan J B. Diabetes mellitus after GDM. Diabetes 40 (Suppl 2): 131–135, 1991.
 190. Kjos S L, Peters R K, Xiang A, Henry Q A, Montoro M, Buchanan T A. Predicting future diabetes in latino women with gestational diabetes, utility of early postpartum glucose tolerance testing. Diabetes 44: 586–591, 1995.
 191. Catalano P M, Tyzbir E D, Wolfe R R, Calles J, Roman N M, Amini S B, Sims E A H. Carbohydrate metabolism during pregnancy in control subjects and women with gestational diabetes. Am J Physiol 264: E60–E67 1993.
 192. Catalano P M, Bernstein I M, Wolfe R R, Srikanta S, Tyzbir E, Sims E A H. Subclinical abnormalities of glucose metabolism in subjects with previous gestational diabetes. Am J Obstet Gynecol 155: 1255–1262, 1986.
 193. Ward V K, Johnston C L W, Beard J C, Benedetti T J Jr, Halter J B, Porte D. Insulin resistance and impaired insulin secretion in subjects with a history of gestational diabetes mellitus. Diabetes 34: 861–869, 1985.
 194. Ryan E A, Imes S, Liu D, McManus R, Finegood D T, Polonsky K S, Sturis J. Defects in insulin secretion and action in women with a history of gestational diabetes. Diabetes 44: 506–512, 1995.
 195. Efendic S, Hanson U, Persson B, Wajngot A, Luft R. Glucose tolerance, insulin release, and insulin sensitivity in normal‐weight women with previous gestational diabetes mellitus. Diabetes 36: 413–419, 1987.
 196. Damm P, Kuhl C, Hornnes P, Molsted‐Pedersen L. A longitudinal study of plasma insulin and glucagon in women with previous gestational diabetes. Diabetes Care 18: 654–665, 1995.
 197. Stoffel M, Bell K L, Blackburn C L, Powell K L, Seo T S, Takeda J, Vionnet N, Xiang K‐S, Gidh‐Jain M, Pilkis S J, Ober C, Bell G I. Identification of glucokinase mutations in subjects with gestational diabetes mellitus. Diabetes 42: 937–940, 1993.
 198. Jeanranaud B. Central nervous system and peripheral abnormalities: clues to the understanding of obesity and NIDDM. Diabetologia 37 (suppl 2): S169–S178, 1994.
 199. Del Prato S, Leonetti E, Simonson D C, Sheehan P, Matsuda M, De Fronzo R A. Effect of sustained physiologic hyperinsulinaemia and hyperglycaemia on insulin secretion and insulin sensitivity in man. Diabetologia 37: 1025–1035, 1994.
 200. Diamond M P, Thornton K, Connolly‐Diamond M, Sherwin R S, De Fronzo R A. Reciprocal variations in insulin‐stimulated glucose uptake and pancreatic insulin secretion in women with normal glucose tolerance. J Soc Gynecol Invest 2: 708–715, 1995.
 201. De Fronzo R A. Glucose intolerance and aging. Evidence for tissue insensitivity to insulin. Diabetes 28: 1095–1109, 1979.
 202. De Fronzo R A. Glucose intolerance and aging. Diabetes Care 4: 483–501, 1981.
 203. Reaven G M, Brand R J, Ida Chen Y‐D, Mathur A K, Goldfine I. Insulin resistance and insulin secretion are determinants of oral glucose tolerance in normal individuals. Diabetes 42: 1324–1332, 1993.
 204. Reaven G M, Olefsky J M. Relationship between heterogeneity of insulin responses and insulin resistance in normal subjects and patients with chemical diabetes. Diabetologia 13: 201–206, 1977.
 205. Hollenbeck C B, Reaven G M. Variations in insulin‐stimulated glucose uptake in healthy individuals with normal glucose tolerance. J Clin Endocrinol Metab 64: 1169–1173, 1987.
 206. Lillioja S, Nyomba B L, Saad M F, Ferraro R, Castillo C, Bennett P H, Bogardus C. Exaggerated early insulin release and insulin resistance in a diabetes‐prone population: a metabolic comparison of Pima Indians and Caucasians. J Clin Endocrinol Metab 73: 866–876, 1991.
 207. Le Stunff C, Bougneres P. Early changes in postprandial insulin secretion, not in insulin sensitivity, characterize juvenile obesity. Diabetes 43: 696–702, 1994.
 208. Williams G, McKibbin P E, McCarthy H D. Hypothalamic regulatory peptides and the regulation of food intake and energy balance: signals or noise? Proc Nutr Soc 50: 527–544, 1991.
 209. Reaven G M, Hollenbeck C B, Chen Y D I. Relationship between glucose tolerance, insulin secretion, and insulin action in non‐obese individuals with varying degrees of glucose tolerance. Diabetologia 32: 52–55, 1989.
 210. Bergman R N. Lilly Lecture. Toward physiological understanding of glucose tolerance—minimal‐model approach. Diabetes 38: 1512–26, 1989.
 211. Himsworth H P, Kerr R B. Insulin‐sensitive and insulin‐insensitive types of diabetes mellitus. Clin Sci 4: 120–152, 1939.
 212. Shen S W, Reaven G M, Farquhar J W. Comparison of impedance to insulin‐mediated glucose uptake in normal subjects with latent diabetes. J Clin Invest 49: 2151–2160, 1970.
 213. Ginsberg H, Kimmerling G, Olefsky J M, Reaven G M. Demonstration of insulin resistance in untreated adult‐onset diabetic subjects with fasting hyperglycemia. J Clin Invest 55: 454–461, 1975.
 214. Reaven G M. Banting Lecture. Role of insulin resistance in human disease. Diabetes 37: 1595–607, 1988.
 215. Butterfield W J H, Whichelow M J. Peripheral glucose metabolism in control subjects and diabetic patients during glucose, glucose‐insulin, and insulin sensitivity tests. Diabetologia 1: 43–53, 1965.
 216. Beck‐Nielsen H, Hother‐Nielsen O, Vaag A, Alford F. Pathogenesis of type 2 diabetes mellitus (NIDDM): the role of skeletal muscle glucose uptake and hepatic glucose production in the development of hyperglycaemia. A critical comment. Diabetologia 37: 217–221, 1994.
 217. Bowen H F, Moorhouse J A. Glucose turnover and disposal in maturity‐onset diabetes. J Clin Invest 52: 3033–3045, 1973.
 218. Katz H, Homan M, Jensen M, Caumo A, Cobelli C, Rizza R. Assessment of insulin action in NIDDM in the presence of dynamic changes in insulin and glucose concentration. Diabetes 43: 289–296, 1994.
 219. Welch S, Gebhart S S P, Bergman R N, Phillips L S. Minimal models analysis of intravenous glucose tolerance test‐derived insulin sensitivity in diabetic subjects. J Clin Endocrinol Metab 71: 1508–1518, 1990.
 220. Coates P A, Ollerton R L, Luzio S D. Reduced sampling protocols in estimation of insulin sensitivity and glucose effectiveness using the minimal model in NIDDM. Diabetes 42: 1635–1641, 1993.
 221. De Fronzo R A, Tobin J D, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 6: E214–E223, 1979.
 222. De Fronzo R A, Deibert D, Hendler R, Felig P. Insulin sensitivity and insulin binding to monocytes in maturity‐onset diabetes. J Clin Invest 63: 939–946, 1982.
 223. De Fronzo R A, Simonson D, Ferrannini E. Hepatic and peripheral insulin resistance: a common feature in non‐insulin‐dependent and insulin‐dependent diabetes. Diabetologia 23: 313–319, 1982.
 224. Simonson D, Ferrannini E, Bevilacqua S, Smith D, Barrett E, Carlson R, De Fronzo R A. Mechanism of improvement in glucose metabolism following chronic glyburide therapy. Diabetes 33: 838–845, 1984.
 225. Golay A, De Fronzo R A, Ferrannini E, Simonson D C, Thorin D, Acheson K, Thiebaud D, Curchod B, Jequier E, Felber J P. Oxidative and non‐oxidative glucose metabolism in non‐obese type 2 (non‐insulin dependent) diabetic patients. Diabetologia 31: 585–591, 1988.
 226. Felber J P, Golay A, Jequier E, Curchod B, Temler E, De Fronzo R A, Ferrannini E. The metabolic consequences of long‐term human obesity. Int J Obesity 12: 377–389, 1988.
 227. Hollenbeck C B, Chen Y‐D I, Reaven G M. A comparison of the relative effects of obesity and non‐insulin dependent diabetes mellitus on in vivo insulin stimulated glucose utilization. Diabetes 33: 622–624, 1984.
 228. Firth R, Bell P, Rizza R. Insulin action in non‐insulin‐dependent diabetes mellitus: the relationship between hepatic and extrahepatic insulin resistance and obesity. Metabolism 36: 1091–1095, 1987.
 229. Campbell P J, Mandarino L J, Gerich J E. Quantification of the relative impairment in actions of insulin on hepatic glucose production and peripheral glucose uptake in non‐insulin dependent diabetes mellitus. Metabolism 37: 15–21, 1988.
 230. Shulman G I, Rothman D L, Jue T, Stein P, De Fronzo R A, Shulman R G. Quantitation of muscle glycogen synthesis in normal subjects and subjects with non‐insulin‐dependent diabetes by 13C nuclear magnetic resonance spectroscopy. N Engl J Med 322: 223–228, 1990.
 231. Grill V. A comparison of brain glucose metabolism in diabetes as measured by positron emission tomography or by arteriovenous techniques. Ann Med 22: 171–175, 1990.
 232. Firth R G, Bell P M, Marsh H M, Hansen I, Rizza R A. Postprandial hyperglycemia in patients with non‐insulin‐dependent diabetes mellitus. J Clin Invest 77: 1525–1532, 1986.
 233. Chen I Y‐D, Jeng C‐Y, Hollenbeck C B, Wu M‐S, Reaven G M. Relationship between plasma glucose and insulin concentration, glucose production, and glucose disposal in normal subjects and patients with non‐insulin‐dependent diabetes. J Clin Invest 82: 21–25, 1988.
 234. Clore J N, Blackard W G. Suppression of gluconeogenesis after a 3‐day fast does not deplete liver glycogen in patients with NIDDM. Diabetes 43: 256–262, 1994.
 235. Jeng C‐Y, Sheu WHH, Fuh M M‐T, Chen I, Reaven G M. Relationship between hepatic glucose production and fasting plasma glucose concentration in patients with NIDDM. Diabetes 43: 1440–1444, 1994.
 236. Fery F. Role of hepatic glucose production and glucose uptake in the pathogenesis of fasting hyperglycemia in type 2 diabetes: normalization of glucose kinetics by short‐term fasting. J Clin Endocrinol Metab 78: 536–542, 1994.
 237. Tayek J A, Katz J. Glucose production, recycling, and gluconeogenesis in normals and diabetics: a mass isotopomer [U‐13C] glcuose study. Am J Physiol 270: E709–E717, 1996.
 238. Kolterman O G, Gray R S, Griffin J, Burstein P., Insel J, Scarlett J A, Olefsky J M. Receptor and postreceptor defects contribute to the insulin resistance in non‐insulin‐dependent diabetes mellitus. J Clin Invest 68: 957–69, 1981.
 239. De Fronzo R A, Ferrannini E, Hendler R, Felig P. Wahren J, Regulation of splanchnic and peripheral glucose uptake by insulin and hyperglycemia. Diabetes 32: 35–45, 1983.
 240. De Fronzo R A, Ferrannini E. Influence of plasma glucose and insulin concentration on plasma glucose clearance in man. Diabetes 31: 683–638, 1982.
 241. Consoli A, La Penna, Cusi K. Hyperglycemia suppresses glycogenolysis more than gluconeogenesis in man. Diabetes 43 (suppl 1, abstr no 818), 1994.
 242. Cherrington A D, Stevenson R W, Steiner K E, Davis M A, Myers S R, Adkins B A, Abumrad N N, Williams P E. Insulin, glucagon, and glucose as regulators of hepatic glucose uptake and production in vivo. Diabetes Metab Rev 3: 307–332, 1987.
 243. Waldhausl W, Bratusch‐Marrain P, Gasic S, Korn A, Nowotny P. Insulin production rate, hepatic insulin retention, and splanchnic carbohydrate metabolism after oral glucose ingestion in hyperinsulinemic type II (non‐insulin dependent) diabetes mellitus. Diabetologia 23: 6–15, 1982.
 244. Consoli A, Nurjhan N, Capani F, Gerich J. Predominent role of gluconeogenesis in increased hepatic glucose production in NIDDM. Diabetes 38: 550–556, 1989.
 245. Nurjhan N, Consoli A, Gerich J. Increased lipolysis and its consequences on gluconeogenesis in noninsulin‐dependent diabetes mellitus. J Clin Invest 89: 169–175, 1992.
 246. Consoli A, Nurjhan N, Reilly J, Bier D, Gerich J. Mechanism of increased gluconeogenesis in noninsulin dependent diabetes mellitus: role of alterations in systemic, hepatic and muscle lactate and alanine metabolism. J Clin Invest 86: 2038–2045, 1990.
 247. Puhakainen I, Koivisto V, Yki‐Jarvinen H. Lipolysis and gluconeogenesis from glycerol are increased in patients with noninsulin‐dependent diabetes mellitus. J Clin Endocrinol Metab 75: 789–794, 1992.
 248. Landau B. Estimating gluconeogenic rates in NIDDM. Advances Exp Med Biol 334: 209–220, 1993.
 249. Cusi K, Consoli A, De Fronzo R A. Metabolic effects of metformin on glucose and lactate metabolism in NIDDM. J Clin Endocrinol Metab 81: 4059–4067, 1996.
 250. Stumvoll M, Perriello G, Nurjhan N, Bucci A, Welle S, Jansson P‐A, Dailey G, Bier D, Jenssen T, Gerich J. Glutamine and alanine metabolism in NIDDM. Diabetes 45: 863–868, 1996.
 251. Magnusson I, Rothman D, Katz L, Shulman R, Shulman G. Increased rate of gluconeogenesis in type II diabetes: a 13C nuclear magnetic resonance study. J Clin Invest 90: 1323–1327, 1992.
 252. Baron A D, Schaeffer L, Shragg P, Kolterman O G. Role of hyperglucagonemia in maintenance of increased rates of hepatic glucose output in type II diabetics. Diabetes 36: 274–283, 1987.
 253. Matsuda M, Consoli A, Bressler P, De Fronzo R A, Del Prato S. Sustained response of hepatic glucose production (HGP) to glucagon in type 2 diabetic subjects. Diabetologia 35 (suppl 1): A37, 1992.
 254. Felig P, Wahren J, Hendler R. Influence of maturity‐onset diabetes on splanchnic balance after oral glucose ingestion. Diabetes 27: 121–126, 1978.
 255. Adkins, Myers S R, Hendrik G K, Stevenson R W, Williams P E, Cherrington A D. Importance of the route of glucose delivery to hepatic glucose uptake in the conscious dog. J Clin Invest 79: 557–565, 1987.
 256. Ferrannini E, Simonson D C, Katz L D, Reichard G Jr, Bevilacqua S, Barrett E J, Olsson M, De Fronzo R A. The disposal of an oral glucose load in patients with non‐insulin dependent diabetes. Metabolism 37: 79–85, 1988.
 257. Gerich J E, Mitrakou A, Kelley D, Mandarino L, Nurjhan N, Reilly J, Jenssen T, Veneman T, Consoli A. Contribution of impaired muscle glucose clearance to reduced postabsorptive systematic glucose clearance in NIDDM. Diabetes 39: 211–216, 1990.
 258. Best J D, Kahn S E, Ader M, Watanabe R M, Ni T‐C, Bergman R N. Role of glucose effectiveness in the determination of glucose tolerance. Diabetes Care 19: 1018–1030, 1996.
 259. Mitrakou A, Kelley D, Veneman T, Jensen T, Pangburn T, Reilly J, Gerich J. Contribution of abnormal muscle and liver glucose metabolism to postprandial hyperglycemia in NIDDM. Diabetes 39: 1381–1390, 1990.
 260. Capaldo B, Napoli R, Dimarino L, Picardi A, Riccardi G, Sacca L. Quantitation of forearm glucose and free fatty acid (FFA) disposal in normal subjects and type 2 diabetic patients: evidence against an essential role for FFA in the pathogenesis of insulin resistance. J Clin Endocrinol Metab 67: 893–898, 1988.
 261. Utriainen T, Nuutila P, Takala T, Rönnemaa T, Raitakari M, Tolvanen T, Ruotsalainen U, Kirvelä O, Yki‐Järvinen H: Direct quantitation of regional muscle glucose uptake and blood flow using 18FDG and H215O in NIDDM. Diabetologia 39: A45, 1996.
 262. Kida Y, Esposito‐DelPuente A, Bogardus C, Mott D. Insulin resistance is associated with reduced fasting and insulin‐stimulated glycogen synthase phosphatase activity in human skeletal muscle. J Clin Invest 85: 476–481, 1990.
 263. Del Prato S, Bonadonna R C, Bonora E, Gulli G, Solini A, Shank M, De Fronzo R A. Characterization of cellular defects of insulin action in type 2 (non‐insulin‐dependent) diabetes mellitus. J Clin Invest 91: 484–494, 1993.
 264. Avogaro A, Toffolo G, Miola M, Valerio A, Tiengo A, Cobelli C, Del Prato S. Intracellular lactate‐ and pyruvate‐interconversion rates are increased in muscle tissue of non‐insulin‐dependent diabetic individuals. J Clin Invest 98: 108–115, 1996.
 265. Henry R R, Wallace P, Olefsky J M. Effects of weight loss on mechanisms of hyperglycemia in obese non‐insulin dependent diabetes mellitus. Diabetes 35: 990–998, 1986.
 266. National Diabetes Group. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 28: 1039–1057, 1979.
 267.Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 21 (suppl 1): S5–S19, 1997.
 268. Gerich J E. Is muscle the major site of insulin resistance in type 2 (non‐insulin‐dependent) diabetes mellitus? Diabetologia 34: 607–610, 1991.
 269. Gottesman L, Mandarino L, Gerich J. Use of glucose uptake and glucose clearance for the evaluation of insulin action in vivo. Diabetes 33: 184–191, 1984.
 270. Best J, Taborsky G, Halter J, Porte D. Glucose disposal is not proportional to plasma glucose level in man. Diabetes 30: 847–850, 1981.
 271. Doberne L, Greenfield M S, Rosenthal M, Didstrom A, Reaven G. Effects of variation in basal plasma glucose concentration on glucose utilization and metabolic clearance rate during insulin clamp studies in patients with non‐insulin‐dependent diabetes mellitus. Diabetes 31: 396–400, 1982.
 272. De Fronzo R A, Their S O. Inherited disorders of renal tubular function. In: The Kidney, ed. Brenner B M, Rector F C. Philadelphia: W B Saunders, 1986, pp 1297–1340.
 273. Theibaud D, Jacot E, De Fronzo R A, Maeder E, Jequier E, Felber J P. The effect of graded doses of insulin on total glucose uptake, glucose oxidation, and glucose storage in man. Diabetes 31: 957–963, 1982.
 274. Marshall S, Olefsky J. Effect of insulin incubation on insulin binding, glucose transport, and insulin degradation by isolated adipocytes. Evidence of hormone‐induced desensitization at the receptor and post‐receptor level. J Clin Invest 66: 763–772, 1980.
 275. Rizza R A, Mandarino L A, Genest J, Baker B A, Gerich J E. Production of insulin resistance by hyperinsulinemia in man. Diabetologia 28: 70–75, 1985.
 276. Marangou A G, Weber K M, Boston R C, Aitken P M, Heggie J C, Kirsner R L, Best J D, Alford F P. Metabolic consequences of prolonged hyperinsulinemia in humans. Evidence for induction of insulin insensitivity. Diabetes 35: 1383–1389, 1986.
 277. Gjedde A, Crone C. Blood‐brain glucose transfer: repression in chronic hyperglycemia. Science 214: 456–457, 1981.
 278. McCall A L, Millington W R, Wurtman R J. Metabolic fuel and amino acid transport into the brain in experimental diabetes mellitus. Proc Natl Acad Sci USA 79: 5406–5410, 1982.
 279. Matthaei S, Horuk R, Olefsky J M. Blood‐brain glucose transfer in diabetes mellitus. Diabetes 35: 1181–1184, 1986.
 280. McCall A L, Fixman L B, Fleming N, Tornheim K, Chick W, Ruderman N B. Chronic hypoglycemia increases brain glucose transport. Am J Physiol 251: E442–E447, 1986.
 281. Kelley D, Mitrakou A, Marsh H, Schwenk F, Benn J, Sonnenberg G, Arcangeli M, Aoki T, Sorensen J, Berger M, Sonksen P, Gerich J. Skeletal muscle glycolysis oxidation, and storage of an oral glucose load. J Clin Invest 81: 1563–1571, 1988.
 282. Jackson R A, Roshania R D, Hawa M I, Sim B M, DiSilvio L. Impact of glucose ingestion on hepatic and peripheral glucose metabolism in man: an analysis based on simultaneous use of the forearm and double isotope techniques. J Clin Endocrinol Metab 63: 541–549, 1986.
 283. Mitrakou A, Kelley D, Mokan M, Veneman T, Pangburn T, Reilly J, Gerich J. Role of reduced suppression of glucose production and diminished early insulin release in impaired glucose tolerance. N Engl J Med 326: 22–29, 1992.
 284. Jackson R A, Perry G, Rogers J, Advoni U, Pilkington TRE. Relationship between the basal glucose concentration, glucose tolerance, and forearm glucose uptake in maturity onset diabetes. Diabetes 22: 751–761, 1973.
 285. McMahon V, Marsh H M, Rizza R A. Effects of basal insulin supplementation on disposition of mixed meal in obese patients with NIDDM. Diabetes 38: 291–303, 1989.
 286. Firth R G, Bell P M, Rizza R A. Effects of tolazamide and exogeneous insulin on insulin action in patients with non‐insulin‐dependent diabetes mellitus. N Engl J Med 314: 1280–1286, 1986.
 287. Chen Y‐D I, Jeng C Y, Hollenbeck C B, Wu M S, Reaven G M. Relationship between plasma glucose and insulin concentration, glucose production, and glucose disposal in normal subjects and patients with non‐insulin‐dependent diabetes. J Clin Invest 82: 21–25, 1988.
 288. Dall'Aglio E, Chang H, Hollenbeck C B, Mondon C E, Sims C, Reaven GM. In vivo and in vitro resistance to maximal insulin‐stimulated glucose disposal in insulin deficiency. Am J Physiol 249: E312–E316, 1985.
 289. Reaven G M, Chen Y‐D I, Donner C C, Fraze E, Hollenbeck C B. How insulin resistant are patients with non‐insulin‐dependent diabetes mellitus? J Clin Endocrinol Metab 61: 32–36, 1985.
 290. Bogardus C, Lillioja S, Mott D, Reaven G R, Kashiwagi A, Foley J. Glucose uptake in vivo and in vitro in Pima Indians. J Clin Invest 73: 800–805, 1984.
 291. Lillioja A, Mott D M, Zawadzki J K, Young A A, Abbott W G, Bogardus C. Glucose storage is a major determinant of in vivo “insulin resistance” in subjects with normal glucose tolerance. J Clin Endocrinol Metab 62: 922–927, 1986.
 292. Felber J P, Ferrannini E, Golay A, Meyer H V, Theibaud D, Curchod B, Maeder E, Jequier E. DeFronzo R Role of lipid oxidation in the pathogenesis of the insulin resistance of obesity and type II diabetes. Diabetes 36: 1341–1350, 1987.
 293. Cheatham B, Kahn C R. Insulin action and the insulin signaling network. Endocrine Rev 16: 177–138, 1995.
 294. Saltiel A R. Diverse signaling pathways in the cellular actions of insulin. Am J Physiol 280: E375–E385, 1996.
 295. White M F. The IRS‐signaling system: a network of docking proteins that mediate insulin action. Molecular & Cellular Biochemistry 182: 3–11, 1998.
 296. Zhou L, Chen H, Xu P, Cong L N, Sciacchitano S, Li Y, Graham D, Jacobs A R, Taylor S I, Quon M J. Action of insulin receptor substrate‐3 (IRS‐3) and IRS‐4 to stimulate translocation of GLUT4 in rat adipose cells. Molecular Endocrinology 13: 505–514, 1999.
 297. Ruderman N, Kapeller R, White M F, Cantley L C. Activation of phosphatidylinositol‐3‐Kinase by insulin. Proc Natl Acad Sci USA 87: 1411–1415, 1990.
 298. Virkamaki A, Ueki K, Kahn C R. Protein‐protein interaction in insulin signaling and the molecular mechanisms of insulin resistance. J Clin Invest 103: 931–943, 1999.
 299. Rizza R A, Mandarino L J. Gerich JE.. Mechanism and significance of insulin resistance in noninsulin‐dependent diabetes mellitus. Diabetes 30: 990–995, 1981.
 300. Freidenberg G R, Henry R R, Klein H H, Reichart D R, Olefsky J M. Decreased kinase activity of insulin receptors from adipocytes of noninsulin‐dependent diabetic studies. J Clin Invest 79: 240–250, 1987.
 301. Trichitta V, Brunetti A, Chiavetta A, Benzi L, Papa V, Vigneri R. Defects in insulin‐receptor internalization and processing in monocytes of obese subjects and obese NIDDM patients. Diabetes 38: 1579–1584, 1989.
 302. Caro J F, Ittoop O, Pories W J, Meelheim D, Flickinger EG, Thomas F, Jenquin M, Silverman J F, Khazanie P G, Sinha M K. Studies on the mechanism of insulin resistance in the liver from humans with non‐insulin‐dependent diabetes. Insulin action and binding in isolated hepatocytes, insulin receptor structure, and kinase activity. J Clin Invest 78: 249–258, 1986.
 303. Caro J F, Sinha M K, Raju S M, Ittoop O, Pories W J, Flickinger E G, Meelheim D, Dohm G L. Insulin receptor kinase in human skeletal muscle from obese subjects with and without non‐insulin dependent diabetes. J Clin Invest 79: 1330–1337, 1987.
 304. Klein H H, Vestergaard H, Kotzke G, Pedersen O. Elevation of serum insulin concentration during euglycemic hyperinsulinemic clamp studies leads to similar activation of insulin receptor kinase in skeletal muscle of subjects with and without NIDDM. Diabetes 344: 1310–1317, 1995.
 305. Grasso G, Frittitta L, Anello M, Russo P, Sesti G, Trischitta V. Insulin receptor tyrosine‐kinase activity is altered in both muscle and adipose tissue from non‐obese normoglycaemic insulin‐resistant subjects. Diabetologia 38: 55–61, 1995.
 306. Olefsky J M, Reaven G M. Insulin binding in diabetes. Relationships with plasma insulin levels and insulin sensitivity. Diabetes 26: 680–688, 1977.
 307. Seino S, Seino M, Bell G I. Human insulin‐receptor gene. Diabetes 39: 129–133, 1990.
 308. Taylor S I, Kadowsaki T, Kadowsaki H, Accili D, Cama A, McKern C. Mutations in insulin receptor gene in insulin resistant patients. Diabetes Care 13: 257–275, 1990.
 309. McClain D A, Henry R R, Ullrich A, Olefsky J M. Restriction‐fragment‐length polymorphism in insulin‐receptor gene and insulin resistance in NIDDM. Diabetes 37: 1071–1075, 1988.
 310. O'Rahilly S, Trembath R C, Patel P, Galton D J, Turner R C, Wainscoat J S. Linkage analysis of the human insulin receptor gene in type II (noninsulin‐dependent) diabetic families and a family with maturity onset diabetes of the young. Diabetologia 31: 797–805, 1988.
 311. Cox N J, Epstein P A, Speilman R S. Linkage studies on NIDDM and the insulin and insulin receptor genes. Diabetes 38: 653–658, 1989.
 312. Moller D E, Yakota A, Flier J S. Normal insulin receptor cDNA sequence in Pima Indians with non‐insulin‐dependent diabetes mellitus. Diabetes 38: 1496–1500, 1989.
 313. O'Rahilly S, Choi W H, Patel P, Turner R C, Flier J S, Moller D E. Detection of mutations in insulin‐receptor gene in NIDDM patients by analysis of single‐stranded conformation polymorphisms. Diabetes 40: 777–782, 1991.
 314. Kusari J, Verma U S, Buse J B, Henry R R, Olefsky J M. Analysis of the gene sequences of the insulin receptor and the insulin‐sensitive glucose transporter (GLUT4) in patients with common‐type non‐insulin‐dependent diabetes mellitus. J Clin Invest 88: 1323–1330, 1991.
 315. Cocozza S, Procellini A, Riccardi G, Monticelli A, Condorelli G, Ferrara A, Pianese L, Miele C, Capaldo B, Beguinot F, Varrone S. NIDDM associated with mutation in tyrosine kinase domain of insulin receptor gene. Diabetes 41: 521–526, 1992.
 316. Freidenberg G R, Reichart D, Olefsky J M, Henry R R. Reversibility of defective adipocyte insulin receptor kinase activity in noninsulin dependent diabetes mellitus. Effect of weight loss. J Clin Invest 82: 1398–1406, 1988.
 317. Maegwa H, Shigeta Y, Egawa K, Kobayshai M. Impaired auto‐phosphorylation of insulin receptors from abdominal skeletal muscles in non‐obese subjects with NIDDM. Diabetes 40: 815–819, 1993.
 318. Nolan J J, Friedenberg G, Henry R, Reichart D, Olefsky J M. Role of human skeletal muscle insulin receptor kinase in the in vivo insulin resistance of noninsulin‐dependent diabetes and obesity. J. Clin Endocrinol Metab 78: 471–477, 1994.
 319. Bak J F, Moller N, Schmitz O, Saaek A, Pedersen O. In vivo insulin action and muscle glycogen synthase activity in type 2 (non insulin dependent) diabetes mellitus: effects of diet treatment. Diabetologia 35: 777–794, 1992.
 320. Bolangu L N, Ossowski V M, Bogardus C, Mott D. Insulin‐sensitive tyrosine kinase: relationship with in vivo insulin action in humans. Am J Physiol 258: E964–E974, 1990.
 321. Almind K, Bjorbaek C, Vestergaard H, Hansen T, Echwald S, Pederson O. Amino acid polymorphisms of insulin receptor substrate‐1 in non‐insulin dependent diabetes mellitus. Lancet 342: 828–832, 1993.
 322. Hitman G A, Hawrami K, McCarthy M I, Viswanathan M, Snehalatha C, Ramachandran A, Tuomilehto J, Tuomilehto‐Wolf E, Nissinen A., Pedersen O.. Insulin receptor substrate‐1 gene mutations in NIDDM; implications for the study of polygenic disease. Diabetologia 38: 481–486, 1995.
 323. Folli, F., Saad J A, Backer J M, Kahn C R. Regulation of phosphatidylinositol 3‐kinase activity in liver and muscle of animal models of insulin‐resistant and insulin‐deficient diabetes mellitus. J Clin Invest 92: 1787–1794, 1993.
 324. Cusi K, Maezono K, Osman A, Pendergrass M, Patti M E, Pranawatapatr T, De Fronzo R A, Kahn C R, Mandarino L. Insulin resistance differentially affects the PI 3‐kinase and MAP kinase pathways of insulin receptor signaling in human muscle. J Clin Invest 105: 311–320, 2000.
 325. Reynet C, Kahn C R. Rad: a member of the ras family over‐expressed in muscle of type II diabetic humans. Science 262: 1441–1444, 1993.
 326. Dorrestijn J, Ouwens D M, Van den Berghe N, Box J L, Maassen J A. Expression of dominant‐negative Ras mutant does not affect stimulation of glucose uptake and glycogen synthesis by insulin. Diabetologia 39: 558–563, 1996.
 327. Bell G L, Kayano T, Buse J B, Burant C F, Takeda J, Lin D, Fikomoto H, Seino S. Molecular biology of mammalian glucose transporters. Diabetes Care 13: 198–200, 1990.
 328. Kahn B B. Facilitative glucose transporters: regulatory mechanisms and dysregulation in diabetes. J Clin Invest 89: 1367–1374, 1992.
 329. Garvey W T, Huecksteadt T P, Mattaei S, Olefsky J M. Role of glucose transporters in the cellular insulin resistance of type II non‐insulin dependent diabetes mellitus. J Clin Invest 81: 1528–1536, 1988.
 330. Ciaraldi T P, Abrams L, Nikoulina S, Mudaliar S, Henry R R. Glucose transport in cultured human skeletal muscle cells. J Clin Invest 96: 2820–2827, 1995.
 331. Carey J O, Azevedo J L Jr, Morris P G, Pories W J, Dohn G L. Okadaic acid, vanadate and phenylarsine oxide stimulate 2‐deoxyglucose transport in insulin‐resistant human skeletal muscle. Diabetes 44: 682–688, 1995.
 332. Pedersen O, Bak J, Andersen P, Lund S, Moller D E, Flier J S, Kahn B B. Evidence against altered expression of GLUT1 or GLUT4 in skeletal muscle of patients with obesity or NIDDM. Diabetes 39: 865–870, 1990.
 333. Schalin‐Jantti C, Yki‐Jarvinen H, Koranyi L, Bourey R, Lindstrom J, Nikula‐Ijas P, Franssila‐Kallunki A, Groop L C. Effect of insulin on GLUT‐4 mRNA and protein concentrations in skeletal muscle of patients with NIDDM and their first‐degree relatives. Diabetologia 37: 401–407, 1994.
 334. Mandarino L J, Printz R L, Cusi K, Kinchington P, O'Doherty R M, Osawa H, Sewell C, Consoli A, Granner D K, De Fronzo R A. Regulation of hexokinase II and glycogen synthase mRNA, protein, and activity in human muscle. Am J Physiol 269: E701–E708, 1995.
 335. Kusari J, Verma U S, Buse J B, Henry R R, Olefsky J M. Analysis of the gene sequences of the insulin receptor and the insulin‐sensitive glucose transporter (GLUT 4) in patients with common type non insulin dependent diabetes mellitus. J Clin Invest 88: 1323–1330, 1991.
 336. Choi W H, O'Rahilly S, Rees A, Morgan R, Flier J S, Moller D E. Molecular scanning of the insulin‐responsive glucose transporter (GLUT 4) gene in patients with non‐insulin dependent diabetes mellitus. Diabetes 40: 1712–1718, 1991.
 337. Cobelli C, Saccomani M P, Ferrannini E, De Fronzo R A, Gelfand R, Bonadonna R. A compartmental model to quantitate in vivo glucose transport in the human forearm. Am J Physiol 257: E943–E958, 1989.
 338. Saccomani M P, Bonadonna R C, Bier D M, De Fronzo R A, Cobelli C. A model to measure insulin effects on glucose transport and phosphorylation in muscle: a three‐tracer study. Am J Physiol Endocrinol Metab 33: E170–E185, 1996.
 339. Bonadonna R C, Saccomani M P, Seely L, Zych K S, Ferrannini E, Cobelli C, De Fronzo R A. Glucose transport in human skeletal muscle. The in vivo response to insulin. Diabetes 42: 191–198, 1993.
 340. Bonadonna R C, Del Prato S, Saccomani M P, Bonora E, Gulli G, Ferrannini E, Bier D, Cobelli C, De Fronzo R A. Transmembrane glucose transport in skeletal muscle of patients with non‐insulin‐dependent diabetes. J Clin Invest 92: 486–494, 1993.
 341. Bonadonna R C, Del Prato S, Bonora E, Saccomani M P, Gulli G, Natali A, Frascerra S, Pecro N, Ferrannini E, Bier D, Cobelli C, De Fronzo R A. Roles of glucose transport and glucose phosphorylation in muscle insulin resistance of NIDDM. Diabetes 45: 915–925, 1996.
 342. Guma A, Zierath J R, Wallberg‐Henriksson H, Klip A. Insulin induces translocation of GLUT‐4 glucose transporters in human skeletal muscle. Am J Physiol 268: E613–E622, 1995.
 343. Kelley D E, Mintun M A, Watkins S C, Simoneau J‐A, Jadali F, Fredrickson A. The effect of non‐insulin‐dependent diabetes mellitus and obesity on glucose transport and phosphorylation in skeletal muscle. J Clin Invest 97: 2705–2713, 1996.
 344. Napoli R, Hirschman M F, Horton F S. Mechanisms of increased skeletal muscle glucose transport activity after an oral glucose load in rats. Diabetes 44: 1362–1368, 1995.
 345. Goodyear L J, Hirschman M F, Napoli R, Calles J, Markuns J F, Ljungqvist O, Horton E S. Glucose ingestion causes GLUT4 translocation in human skeletal muscle. Diabetes 45: 1051–1056, 1996.
 346. Cushman S W, Goodyear L J, Pilch P F, Ralston E, Galbo H, Ploug T, Kristiansen S, Klip A. Molecular mechanisms involved in GLUT4 translocation in muscle during insulin and contraction stimulation. Advances in Experimental Medicine & Biology 441: 63–71, 1998.
 347. Printz R L, Ardehali H, Koch S, Granner D K. Human hexokinase II mRNA and gene structure. Diabetes 44: 290–294, 1995.
 348. Postic C A, Leturque A, Rencurel F, Printz R, Forest C, Granner D, Girard J. The effect of hyperinsulinemia and hyperglycemia on GLUT4 and hexokinase II mRNA and protein in rat skeletal muscle and adipose tissue. Diabetes 42: 922–929, 1993.
 349. Rothman D L, Shulman R G, Shulman G I. 31P nuclear magnetic resonance measurements of muscle glucose‐6‐phosphate. Evidence for reduced insulin‐dependent muscle glucose transport or phosphorylation activity in non‐insulin‐dependent diabetes mellitus. J Clin Invest 89: 1069–1075, 1992.
 350. Pendergrass M, Fazioni E, Saccomani M P, Collins D, Bonadonna R, Gulli G. In vivo glucose transport and phosphorylation in skeletal muscle is impaired in insulin resistant, normal glucose tolerant offspring of two NIDDM parents. Diabetes 44 (suppl 1): 197A, 1995.
 351. Rothman D L, Magnusson I, Cline G, Gerard D, Kahn C R, Shulman R G, Shulman G I. Decreased muscle glucose transport/phosphorylation is an early defect in the pathogenesis of non‐insulin‐dependent diabetes mellitus. Proc Natl Acad Sci USA 92: 983–987, 1995.
 352. Manchester J, Kong X, Nerbonne J, Lowry O H, Lawrence J C Jr.. Glucose transport and phosphorylation in single cardiac myocytes: rate‐limiting steps in glucose metabolism. Am J Physiol 266: E326–333, 1994
 353. Pendergrass M, Koval J, Vogt C, Yki‐Jarvinen H, Iozzo P, Pipek R, Ardehali H, Printz R, Granner D, De Fronzo R A, Mandarino L J. Insulin‐induced hexokinase II expression is reduced in obesity and NIDDM. Diabetes 47: 387–394, 1998.
 354. Vestergaard H, Bjorbaek C, Hansen T, Larsen F S, Granner D K, Pedersen O. Impaired activity and gene expression of hexokinase Il in muscle from non‐insulin‐dependent diabetes mellitus patients. J Clin Invest 96: 2639–2645, 1995.
 355. Lehto M, Huang X, Davis E M, Le Beau M M, Laurila E, Eriksson K F, Bell G I, Groop L. Human hexokinase II gene: exon‐intron organization, mutation screening in NIDDM, and its relationship to muscle hexokinase activity. Diabetologia 38: 1466–1474, 1995.
 356. Laakso M, Malkki M, Kekalainen P, Kuusito J, Deeb S S. Polymorphisms of the human hexokinase II gene: lack of association with NIDDM and insulin resistance. Diabetologia 38: 617–622, 1995.
 357. Laakso M, Malkki M, Deeb S S. Amino acid substitutions in hexokinase II among patients with NIDDM. Diabetes 44: 330–334, 1995.
 358. Echwald S M, Bjorbaek C, Hansen T, Clausen J O, Vestergaard H, Zierath J R, Printz R L, Granner D K, Pedersen O. Identification of four amino acid substitutions in hexokinase II and studies of relationships to NIDDM, glucose effectiveness, and insulin sensitivity. Diabetes 44: 347–353, 1995.
 359. Vidal‐Puig A, Printz R L, Stratton I M, Granner D K, Moller D E. Analysis of the hexokinase II gene in subjects with insulin resistance and NIDDM and detection of a Gln142 His substitution. Diabetes 44: 340–346, 1995.
 360. Taylor R W, Printz R L, Armstrong M, Granner D K, Alberti K G M M, Turnbull D M, Walker M. Variant sequences of the hexokinase II gene in familial NIDDM. Diabetologia 39: 322–328, 1996.
 361. Vaxillaire M, Vionnet N, Vigouroux C, Sun F, Espinosa R, Lebeau M M, Stoffel M, Lehto M, Beckman J S, Detheux M, Passa P, Cohen D, Schaftinger E V, Volho G, Bell G I, Froguel P. Search for a third susceptibility gene for maturity‐onset diabetes of the young. Diabetes 43: 389–395, 1994.
 362. Simonson D C, De Fronzo R A. Measurement of substrate oxidation and energy expenditure in man by indirect calorimetry: practical and theoretical consideration. Am J Physiol 258: E399–E412, 1990.
 363. Schalin‐Jantti C, Harkonen M, Groop L C. Impaired activation of glycogen synthase in people at increased risk for developing NIDDM. Diabetes 41: 598–604, 1992.
 364. Vaag A, Henriksen J E, Beck Nielsen H. Decreased insulin activation of glycogen synthase in skeletal muscles in young non‐obese caucasian first‐degree relatives of patients with non‐insulin‐dependent diabetes mellitus. J Clin Invest 89: 782–788, 1992.
 365. Vestergaard H, Lund S, Bjorbaek C, Pedersen O. Unchanged gene expression of glycogen synthase in muscle from patients with NIDDM following sulfonylurea‐induced improvement of glycaemic control. Diabetologia 38: 1230–1238, 1995.
 366. Vestergaard H, Lund S, Larsen F S, Bjerrum O J, Pedersen O. Glycogen synthase and phosphofructokinase protein and mRNA levels in skeletal muscle from insulin‐resistant patients with non‐insulin‐dependent diabetes mellitus. J Clin Invest 91: 2342–2350, 1993.
 367. Kelley D E, Mandarino L J. Hyperglycemia normalizes insulinstimulated skeletal muscle glucose oxidation and storage in noninsulin‐dependent diabetes mellitus. J Clin Invest 86: 1999–2007, 1990.
 368. Mandarino L J, Wright K S, Verity L S, Nichols J, Bell J M, Kolterman O G, Beck‐Nielsen H. Effects of insulin infusion on human skeletal muscle pyruvate dehydrogenase, phosphofructokinase, and glycogen synthase. Evidence for their role in oxidative glucose metabolism. J Clin Invest 80: 655–663, 1987.
 369. Beck‐Nielsen H, Baag A, Damsbo O P, Handberg A, Nielsen O H, Henriksen J E, Thye‐Ronn P. Insulin resistance in skeletal muscle of patients with NIDDM. Diabetes Care 15: 418–429, 1992.
 370. Bak J F, Moller N, Schmitz O, Saaek A, Pedersen O. In vivo insulin action and muscle glycogen synthase activity in type 2 (non‐insulin‐dependent) diabetes mellitus: effects of diet treatment. Diabetologia 35: 777–784, 1992.
 371. Majer M, Mott D M, Mochizuki H, Rowles J C, Pederson O, Knowler W C, Bogardus C, Prochazka M. Association of the glycogen synthase locus on 19q13 with NIDDM in Pima Indians. Diabetologia 39: 314–321, 1996.
 372. Browner M F, Nakano K, Bang A G, Fleffenzk R J. Human muscle glycogen synthase with DNA sequence: a negatively charged protein with ansymmetric charge distribution. Proc Natl Acad Sci USA 86: 1443–1447, 1989.
 373. Kuroyama H, Sanke T, Ohagi S, Furuta M, Nanjo K. Simple tandem repeat DNA polymorphism in the human glycogen synthase gene is associated with NIDDM in Japanese subjects. Diabetologia 37: 536–539, 1994.
 374. Zouali H, Velho G, Froguel P. Polymorphism of the glycogen synthase gene and non‐insulin‐dependent diabetes mellitus (letter). N Engl J Med 328: 1568, 1993.
 375. Groop L C, Kankuri M, Schalin‐Jantti, Ekstrand A, Nikul‐Ijas P, Widen E, Kusimanen E, Eriksson J, Franssila‐Kallunki A, Saloranta C, Koskimies S. Association between polymorphism of the glycogen synthase gene and non‐insulin‐dependent diabetes mellitus. N Engl J Med 328: 10–14, 1993.
 376. Hamada Y, Ikegami H, Fuijoka Y, Yamato E, Takekawa K, Fijisawa T, Nakagawa Y, Ueda H, Fu J, Shen G‐Q, Mild T, Ogihara T. The glycogen synthase gene in NIDDM and hypertension. Diabetologia 38: 1249–1250, 1995.
 377. Elbein S C, Hoffman M, Ridinger D, Otterud B, Leppert M. Description of a second microsatellite marker and linkage analysis of the muscle glycogen synthase locus in familial NIDDM. Diabetes 43: 1061–1065, 1994.
 378. Orho M, Nikua‐Ijas P, Schalin‐Jantti C, Permutt M A, Groop L C. Isolatation and characterization of the human muscle glycogen synthase gene. Diabetes 44: 1099–1105, 1995.
 379. Bjorbaek C, Echward S M, Hubricht P, Vestergaard H, Hansen T, Zierath J, Pedersen O. Genetic variants in promoters and coding regions of the muscle glycogen synthase and the insulin‐responsive GLUT4 genes in NIDDM. Diabetes 43: 976–983, 1994.
 380. Bjorbaek C, Fik T A, Echward S M, Yang P‐Y, Vestergaard H, Wang J P, Webb G C, Richmond K, Hansen T, Erikson R L, Miklos G L G, Cohen P T W, Pedersen O. Cloning of human insulin‐stimulated protein kinase (ISPK‐1) gene and analysis of coding regiions and mRNA levels of the ISPK‐1 and the protein phosphatase‐1 genes in muscle from NIDDM patients. Diabetes 44: 90–97, 1995.
 381. Procharzka M, Michizuki H, Baier L J, Cohen P T W, Bogardus C. Molecular and linkage analysis of type‐1 protein phosphatase catalytic beta‐subunit gene: lack of evidence for its mjaor role in insulin resistance in Pima Indians. Diabetologia 38: 461–466, 1995.
 382. Falholt K, Jensen I, Lindkaer Jensen S, Mortensen H B, Volund A, Heding L G, Norskov Petersen P, Falholt W. Carbohydrate and lipid metabolism of skeletal muscle in type 2 diabetic patients. Diabetic Medi 5: 27–31, 1988.
 383. Wells A M, Sutcliffe I C, Johnson A B, Taylor R. Abnormal activation of glycogen synthesis in fibroblasts from NIDDM subjects. Evidence for an abnormality specific to glucose metabolism. Diabetes 42: 583–589, 1993.
 384. Mandarino L J, Consoli A, Jain A, Kelley D E. Interaction of carbohyrate and fat fuels in human skeletal muscle: impact of obesity and NIDDM. Am J Physiol 270: E463–E470, 1996.
 385. Mandarino L J, Madar Z, Kolterman O G, Bell J M, Olefsky J M. Adipocyte glycogen synthase and pyruvate dehydrogenase in obese and type II diabetic patients. Am J Physiol 251: E489–E496, 1986.
 386. Rossetti L, Smith D, Shulman G I, Papachristou D, De Fronzo R A. Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin. J Clin Invest 79: 1510–1515, 1987.
 387. Kahn B B, Shulman G I, De Fronzo R A, Cushman S W, Rossetti L. Normalization of blood glucose in diabetic rats with phlorizin treatment reverses insulin‐resistant glucose transport in adipose cells without restoring glucose transporter gene expression. J Clin Invest 87: 561–570, 1991.
 388. Dimitrakoudis D, Ramlal T, Rastogi S, Vranic M, Klip A. Glycemia regulates the glucose transporter number in the plasma membrane of rat skeletal muscle. Biochem J 284: 341–348, 1992.
 389. Marshall S, Bacote V, Traxinger R R. Discovery of a metabolic pathway mediating glucose‐induced desensitization of the glucose transport system. J Biol Chem 266: 4706–4712, 1991.
 390. McClain D A, Crook E D. Perspectives in diabetes. Hexosamines and insulin resistance. Diabetes 45: 1003–1009, 1996.
 391. Crook E D, McClain D A. Regulation of glycogen synthase and protein phosphatase‐1 by hexosamines. Diabetes 45: 322–327, 1996.
 392. Rossetti L, Hawkins M, Chen W, Gindi J, Barzilai N. In vivo glucosamine infusion induces insulin resistance in normoglycemic but not in hyperglycemic conscious rats. J Clin Invest 96: 132–140, 1995.
 393. Hebert L F Jr, Daniels M C, Zhou J, Crook E D, Turner R L, Simmons S T, Neidigh J L, Zhu J‐S, Baron A D, McClain D A. Overexpression of glutamine:fructose‐6‐phosphate amidotransferase in transgenic mice leads to insulin resistance. J Clin Invest 98: 930–936, 1996.
 394. Yki‐Jarvinen H, Daniels M C, Virkamaki A, Makimatila S, De Fronzo R A, McClain D. Increased gluctamine: fructokinase‐6‐phosphate amidotransferase activity in skeletal muscle of patients with NIDDM. Diabetes 45: 302–207, 1996.
 395. Yki‐Jarvinen H, Helve E, Koivisto V A. Hyperglycemia decreases glucose uptake in type I diabetes. Diabetes 36: 892–896, 1987.
 396. Yki‐Jarvinen H, Sahlin K, Ren J M, Koivisto V A. Localization of the rate‐limiting defect for glucose disposal in skeletal muscle of insulin resistant type 1 diabetic patients. Diabetes 39: 157–167, 1990.
 397. Yki‐Jarvinen H. Glucose toxicity. Endocr Rev 13: 415–431, 1992.
 398. Ni T, C.M. Ader, Bergman R N. Reassessment of glucose effectiveness and insulin sensitivity from minimal model analysis: a theoretical evaluation of the single‐compartment glucose distribution assumption. Diabetes 46: 1813–21, 1997.
 399. Laakso M, Uusitupa M, Takala J, Majander H., Reijonen T, Penttila I. Effects of hypocaloric diet and insulin therapy on metabolic control and mechanisms of hyperglycemia in obese noninsulin‐dependent diabetic subjects. Metabolism 37: 1092–1100, 1988.
 400. Kolterman O G, Gray R S, Shapiro G, Scarlett J A, Griffin J, Olefsky J M. The acute and chronic effects of sulfonylurea therapy in type II diabetes. Diabetes 33: 346–354, 1984.
 401. Simonson D C, Ferrannini E, Bevilacqua S, Smith D, Barrett E, Carlson R, De Fronzo R A. Mechanism of improvement in glucose metabolism after chronic glyburide therapy. Diabetes 33: 838–845, 1984.
 402. Groop L, Schalin C, Franssila‐Kallunki A, Widen E, Ekstrand A, Eriksson J. Characteristics of non‐insulin‐dependent diabetic patients with secondary failure to oral antidiabetic therapy. Am J Med 87: 183–190, 1989.
 403. Beck‐Nielsen H, Richelsen B, Hasling C, Neilsen O H, Heding L, Sorensen N S. Improved in vivo insulin effect during continuous subcutaneous insulin infusion in patients with IDDM. Diabetes 33: 832–837, 1984.
 404. Simonson D C, Tamborlane W C, Sherwin R S, De Fronzo R A. Improved insulin sensitivity in patients with type I diabetes mellitus after CSII. Diabetes 34 (suppl 3): 80–86, 1985.
 405. Yki‐Jarvinen H, Koivisto V A. Insulin sensitivity in newly diagnosed type I diabetics after ketoacidosis and after three months of insulin therapy. J Clin Endocrinol Metab 59: 371–378, 1984.
 406. Gray R S, Cowan P, Duncan L J P, Clarke B F. Reversal of insulin resistance in type I diabetes following initiation of insulin treatment. Diabetic Med 3: 18–23. 1986.
 407. Wititsuwannakul D, Kim K. Mechanism of palmityl coenzyme A inhibition or liver glycogen synthase. J Biol Chem 252: 7812–17, 1977.
 408. Kelley D E, Mokan M, Simoneau J A, Mandarino L J. Interaction between glucose and free fatty acid metabolism in human skeletal muscle. J Clin Invest 92: 91–98, 1993.
 409. Roden M, Price T B, Perseghin G, Petersen K F, Rothman D L, Cline G W, Shulman G I. Mechanism of free fatty acid‐induced insulin resistance in humans. J Clin Invest 97: 2859–2865, 1996.
 410. Thiebaud D, De Fronzo R A, Jacot E, Golay A, Acheson K, Maeder E, Jequier E, Felber J P. Effect of long‐chain triglyceride infusion on glucose metabolism in man. Metabolism 31: 1128–1136, 1982.
 411. Ferrannini E, Barrett E J, Bevilacqua S, De Fronzo R A. Effect of fatty acids on glucose production and utilization in man. J Clin Invest 72: 1737–1747, 1983.
 412. Piatti P M, Monti L D, Davis S N, Conti M, Brown M D, Pozza G, Alberti KGMM. Effects of an acute decrease in non‐esterified fatty acid levels on muscle glucose utilization and forearm indirect calorimetry in lean NIDDM patients. Diabetologia 39: 103–112, 1996.
 413. Felber J P, Magnenat G, Casthelaz M, Geser C A, Muller‐Hess R, de Kalbermatten N, Ebiner J R, Curchod B, Pittet P, Jequier E. Carbohydrate and lipid oxidation in normal and diabetic subjects. Diabetes 26: 693–699, 1977.
 414. Felber J P, Meyer H U, Curchod B, Iselin H U, Rousselle J, Maeder E, Pahud P, Jequier E. Glucose storage and oxidation in different degrees of human obesity measured by continuous indirect calorimetry. Diabetologia 20: 39–44, 1981.
 415. Phillips DIW, Caddy S, Illic V, Fielding B A, Frayn K N, Borthwick A C, Taylor R. Intramuscular triglyceride and mucle insulin sensitivity: evidence for a relationship in nondiabetic subjects. Metabolism 45: 947–950, 1996.
 416. Bonadonna R C, Zych K, Boni C, Ferrannini E, De Fronzo R A. Time dependence of the interaction between lipid and glucose metabolism in humans. Am J Physiol 20: E49–E56, 1989.
 417. Bonadonna R C, Groop L C, Zych K, Shank M, De Fronzo R A. Dose dependent effect of insulin on plasma free fatty acid turnover and oxidation in humans. Am J Physiol 22: 736–750, 1990.
 418. Bjorkman M, Storlien L H, Pan D A, Jenkins A B, Chisholm D J, Campbell L B. The relationship between insulin sensitivity and the fatty acid composition of skeletal‐muscle phospholipids. N Engl J Med 328: 238–244, 1993.
 419. Vessby B, Tengblad S, Lithell H. Insulin sensitivity is related to the fatty acid composition of serum lipids and skeletal muscle phospholipids in 70‐year‐old men. Diabetologia 37: 1044–1050, 1994.
 420. Vessby B, Aro A, Skarfors E, Berglund L, Salminen I, Lithell H. The risk to develop NIDDM is related to the fatty acid composition of the serum cholesterol esters. Diabetes 43: 1353–1357, 1994.
 421. Groop L, Saloranta C, Shank M, Bonadonna R C, Ferrannini E, and De Fronzo R A. The role of free fatty acid metabolism in the pathogensis of insulin resistance in obesity and non‐insulin dependent diabetes mellitus. J Clin Endocrinol Metab 72: 96–107, 1991.
 422. Blumenthal S A. Stimulation of gluconeogenesis by palmitic acid in rat hepatocytes: evidence that this effect can be dissociated from provision of reducing equivalents. Metabolism 32: 971–976, 1983.
 423. Bevilacqua S, Bonadonna R, Buzzigoli G, Boni C, Ciociaro D, Maccari F, Giorico M A, Ferrannini E. Acute elevation of free fatty acid levels leads to hepatic insulin resistance in obese subjects. Metabolism 36: 502–506, 1987.
 424. Golay A, Swislocki A L M, Chen Y‐D I, Reaven G M. Relationships between plasma free fatty acid concentration, endogenous glucose production, and fasting hyperglycemia in normal and non‐insulin‐dependent diabetic individuals. Metabolism 36: 692–696, 1987.
 425. Felig P, Wahren J, Hendler R. Splanchnic glucose and amino acid metabolism in obesity. J Clin Invest 53: 582–590, 1974.
 426. Reaven G M, Chen Y‐D I, Golay A, Swislocki A L, Jaspan J B. Documentation of hyperglucagonemia throughout the day in non‐obese and obese patients with non‐insulin dependent diabetes mellitus. J Clin Endocrinol Metab 64: 106–110, 1987.
 427. Saloranta C, Franssila‐Kallunki A, Ekstrand A, Taskinen M‐R, Groop L C. Modulation of hepatic glucose production by non‐esterified fatty acids in type 2 (non‐insulin‐dependent) diabetes mellitus. Diabetologia 34: 409–415, 1991.
 428. Puhakainen I, Yki‐Jarvinen H. Inhibition of lipolysis decreases lipid oxidation and gluconeogenesis from lactate but not fasting hyperglycemia or total hepatic glucose production in NIDDM. Diabetes 42: 1694–1699, 1993.
 429. Jeng C‐H, Sheu W H‐H, Fug M M‐T, Shieh S‐M, Chen Y‐D I, Reaven G M. Gemfibrozil treatment of endogenous hypertriglyceridemia: effect on insulin‐mediated glucose disposal and plasma insulin concentrations. J Clin Endocrinol Metab 81: 2550–2558, 1996.
 430. Krotkiewski M, Seidell J C, Bjorntop P. Glucose tolerance and hyperinsulinemia in obese women: role of adipose tissue distribution, muscle fiber characteristics and androgens. J Intern Med 228: 385–392, 1990.
 431. Lillioja S, Young A A, Culter C L, Ivy J L, Abbott W G, Zawadzki J K, Yki‐Jarvinen H, Christin L, Secomb T W, Bogardus C. Skeletal muscle capillary density and fiber type are possible determinants of in vivo insulin resistance in man. J Clin Invest 80: 415–24, 1987.
 432. Garvey W T, Maianu L, Hancock J, A. Golichowski, Baron A M A. Gene expression of glut4 in skeletal muscle from insulin‐resistant patients with obesity, IGT, GDM, and NIDDM. Diabetes 41: 465–475, 1992.
 433. Yeon J Y, Hope I D, Ader M, Bergman R N. Insulin transport across capillaries is rate limiting for insulin action in dogs. J Clin Invest 84: 1620–1628, 1989.
 434. Ader M, Poulin R A, Yang Y J, Bergman R N. Dose‐response relationship between lymph insulin and glucose uptake reveals enhanced insulin sensitivity of peripheral tissues. Diabetes 41: 241–253, 1992.
 435. Poulin R A, Steil G M, Moore D M, Ader M, Bergman R N. Dynamics of glucose production and uptake are more closely related to insulin in hindlimb lymph than in thoracic duct lymph. Diabetes 43: 180–190, 1994.
 436. Miles P D G, Levisetti M, Reichart D, Reichart D, Khoursheed M, Moossa A R, Olefsky J M. Kinetics of isulin in vivo. Identification of rate‐limiting steps. Diabetes 44: 947–953, 1995.
 437. Jansson P E, Fowelin J P, Henning F, Von Schenck P, Smith U P, Lonnroth P N. Measurement by microdialysis of the insulin concentration in subcutaneous interstitial fluid. Diabetes 42: 1469–1473, 1993.
 438. Prakash S, Mokshagundam L, Peiris A N, Stagner J I, Gingerich R L, Samols E. Interstitial insulin during euglycemic‐hyperinsulinemic clamp in obese and lean individuals. Metabolism 45: 951–956, 1996.
 439. Castillo C, Bogardus C, Bergman R, Thuillez P, Lillioja S. Interstitial insulin concentrations determine glucose uptake rates but not insulin resistance in lean and obese men. J Clin Invest 93: 10–16, 1994.
 440. Baron A D. Hemodynamic actions of insulin. Am J Physiol 267: E187–E202, 1994.
 441. Baron A D, Laakso M, Brechtel G, Edelman S V. Reduced capacity and affinity of skeletal muscle for insulin‐mediated glucose uptake in noninsulin‐dependent diabetic subjects. Effects of insulin therapy. J Clin Invest 87: 1186–1194, 1991.
 442. Laakso M, Edelman S V, Brechtel G, Baron A D. Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man. A novel mechanism for insulin resistance. J Clin Invest 85: 1844–1852, 1990.
 443. Steinberg H O, Chaker H, Leaming R, Johnson A, Brechtel A, Baron A D. Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance. J Clin Invest 97: 2601–2610, 1996.
 444. Anderson E A, Hoffman R P, Balon T W, Sinkey C A, Mark A L. Hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans. J Clin Invest 87: 2246–2252, 1991.
 445. Jamerson K A, Julius S, Gudbrandsson T, Andersson O, Brant D O. Reflex smpathetic activation induces acute insulin resistance in the human forearm. Hypertension 21: 618–623, 1993.
 446. Neahring J M, Stepniakowski K, Green A S, Egan B M. Insulin does not reduce forearm alpha‐vasoreactivity in obese hypertensive or lean normotensive men. Hypertension 22: 584–590, 1993.
 447. De Fronzo R A, Cooke C R, Andres R, Faloona G R, and Davis P J. The effect of insulin on renal handling of sodium, potassium, calcium and phosphate in man. J Clin Invest 55: 845–855, 1975.
 448. Capaldo B, Napoli R, DiBonito R P, Albano G, Sacca L. Glucose and gluconeogenic substrate exchange by the forearm skeletal muscle in hyperglycemia and insulin treated type II diabetic patients. J Clin Endocrinol Metab 71: 1220–1223, 1990.
 449. Neahring J M, Stepniakowski K, Egan B M. Forearm vascular alphareceptor sensitivity is normal and not altered by insulin in obese men with mild hypertension. Hypertension 22: 147–151, 1993.
 450. Nuutila P, Raitakari M, Laine H, Kirvela O, Takala T, Utriainen T, Makimattila S, Pitkanen O‐P, Ruotsalainen U, Iida H, Knuuti J, Yki‐Jarvinen. Role of blood flow in regulating insulin‐stimulated glucose uptake in humans. J Clin Invest 97: 1741–1747, 1996.
 451. Utriainen T, Malmstrom R, Makimattila S, Yki‐Jarvinen H. Methodological aspects, dose‐response characteristics and causes of interindividual variation in insulin stimulation of limb blood flow in normal subjects. Diabetologia 38: 555–564, 1995.
 452. Natali A, Bonadonna R, Santoro D, Galvan A Q, Baldi S, Frascerra S, Palombo C, Ghione S, Ferrannini E. Insulin resistance and vasodilation in essential hypertension. Studies with adenosine. J Clin Invest 94: 1570–1576, 1994.
 453. Cooper G J S, Leighton B. Pancreatic amylin and calcitonin generelated peptide cause resistance to insulin in skeletal muscle in vitro. Nature 335: 632–635, 1988.
 454. Molina J M, Cooper G J S, Leighton B, Olefsky J M. Induction of insulin resistance in vivo by amylin and calcitonin gene‐related peptide. Diabetes 39: 260–264, 1990.
 455. Butler P C, Chou J, Carter W B, Wang Y N, Bu B H, Chang D, Chang J K, Rizza R A. Effects of meal ingestion on plasma amylin concentration in NIDDM and nondiabetic humans. Diabetes 39: 752–755, 1990.
 456. Wilding J P H, Khandan‐Nia N, Bennet W M, Gilbey S G, Beachan J, Ghatei M A, Blood S R. Lack of acute effect of amylin (islet associated polypeptide) on insulin sensitivity during hyperinsulinaemic euglycaemic clamp in humans. Diabetologia 37: 166–169, 1994.
 457. Mitchell J H, Schmidt R F. Cardiovascular reflex control by afferent fibers from skeletal muscle receptors. In: Handbook of Physiology. The Cardiovascular System, Peripheral and Organ Blood Flow ed., Shepherd J T, Abboud F M Bethesda, M D: Am Physiol Soc, 1983, sect. 2, vol. 3, pp 623–658.
 458. Hotamisligil G S, Spiegelman B M. Tumor necrosis factor alpha: a key component of the obesity‐diabetes link. Diabetes 43: 1271–1278, 1994.
 459. Hotamisligil G S, Budavari A, Murray D L, Spiegelman B M. Reduced tyrosine kinase activity of the insulin receptor in obesity‐diabetes: central role of tumor necrosis factor‐a. J Clin Invest 95: 2409–2415, 1995.
 460. Saghizadeh M, Ong J M, Garvey W T, Henry R R, Kern P A. The expression of TNF alpha by human muscle. Relationship to insulin resistance. J Clin Invest 97: 1111–1116, 1996.
 461. Ohno Y, Aoki N, Nishimura A. In vitro production of interleukin‐1, interleukin‐6, and tumor necrosis factor‐a in insulin‐dependent diabetes mellitus. J Clin Endocrinol Metab 77: 1072–1077, 1993.
 462. Ofei F, Hurel S, Newkirk J, Sopwith M, Taylor R. Effects of an engineered human anti‐TNF‐a antibody (CDP571) on insulin sensitivity and glycemic control in patients with NIDDM. Diabetes 45: 881–885, 1996.
 463. De Fronzo R A, Ferrannini E. Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and ASCVD. Diabetes Care Rev 14: 173–194, 1991.
 464. Schneider S, Morgado A. Effects of fitness and physical training on carbohydrate metabolism and associated cardiovascular risk factors in patients with diabetes. Diabetes Metab Rev 3: 379–403, 1995.
 465. Faccini F S, Hollenbeck C B, Jeppesen J, Chen Y D, Reaven G M. Insulin resistance and cigarette smoking. Lancet 339: 1128–1130, 1992.
 466. Attorall S, Fowelin J, Lager I, Smith U. Smoking induces insulin resistance—a potential link with the insulin resistance syndrome. J Int Med 233: 327–333, 1993.
 467. Groop L, Ekstrand A, Forsblom C, Widen E, Groop P H, Tappo A M, Eriksson J. Insulin resistance, hypertension, and microalbuminuria in patients with type 2 (non‐insulin‐dependent) diabetes mellitus. Diabetologia 36: 642–647, 1993.
 468. Nuutila P, Maki M, Laine H, Knuuti J M, Ruotsalainen U, Luotolahti M, Haaparanta M, Solin O, Jula A, Koivisto V A, Voipio‐Pulkki L‐M, Yki‐Jarvinen H. Insulin action on heart and skeletal muscle glucose uptake in essential hypertension. J Clin Invest 96: 1003–1009, 1995.
 469. Dengel D R, Pratley R E, Hagberg J M, Goldberg A P. Impaired insulin sensitivity and maximal responsiveness in older hypertensive men. Hypertension 23: 320–324, 1994.
 470. Ravussin E, Gautier J F. Metabolic predictors of weight gain. International Journal of Obesity & Related Metabolic Disorders 23 (suppl 1): 37–41, 1999.
 471. Los S S, Tun R Y, Hawa M, Leslie R D. Studies of diabetic twins. Diabetes Metab Rev 7: 223–238, 1991.
 472. Medici F, Hawa M, Ianari A, Pyke D A, Leslie R D. Concordance rate for type II diabetes mellitus in monozygotic twins: actuarial analysis. Diabetologia 42: 146–50, 1999.
 473. Rich S S. Mapping genes in diabetes: genetic epidemiological perspective. Diabetes 39: 1315–1319, 1990.
 474. O'Rahilly S O, Wainscoat J S, Turner R C. Type 2 (non‐insulin‐dependent) diabetes mellitus. New genetics for old nightmares. Diabetologia 31: 407–414, 1988.
 475. Martin B C, Warram J H, Rosner B, Rich S S, Soeldner J S, Krolewski A S. Familial clustering of insulin sensitivity. Diabetes 41: 850–854, 1992.
 476. Jansen R C, Bogardus C, Takeda J, Knowler W C, Thompson C B. Linkage analysis of acute insulin secretion with GLUT2 and glucokinase in Pima Indians and the identification of a missense mutation in GLUT2. Diabetes 43: 558–563, 1994.
 477. McCarthy M I, Froguel P, Hitman G A. The genetics of noninsulin‐dependent diabetes mellitus: tools and aims. Diabetologia 37: 959–968, 1994.
 478. Turner R C, Hattersley A T, Shaw J T E, Levy J C. Type II diabetes: clinical aspects of molecular biological studies. Diabetes 44: 1–10, 1995.
 479. Hanis C L, Boerwinkle E, Chakroborty R, Ellsworth D L, Conannon P, Stirling B, Morrison V A, Wapelhorst B, Spielman R S, Gogolin‐Ewens K J, Shephard J M, Williams S R, Risch N, Hinds D, Iwasaki N, Ogata M, Omori Y, Petzold C, Rietzsch H, Schroder H‐E, Schulze J, Cox N J, Menzel S, Boriraj V V, Chen X, Lim L R, Lindner T, Mereu L E, Wang Y‐Q, Xiang K, Yamagata K, Yang Y, Bell G I. A genome‐wide search for human non‐insulin‐dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2. Nature Genetics 13: 161–166, 1996.
 480. Elbein S C, Bragg K L, Hoffman M D, Mayorga R A, Leppert M F. Linkage studies of NIDDM with 23 chromosome 11 markers in a sample of whites of northern European descent. Diabetes 45: 370–375, 1996.
 481. Zhang Y, Warren‐Perry M, Sakura H, Adelman J, Stoffel M, Bell G I, Ashcroft F M, Turner R C. No evidence for mutations in a putative beta cell ATP‐sensitive K+ channel subunit in MODY, NIDDM, or GDM. Diabetes 44: 597–600, 1995.
 482. Tanizawa Y, Riggs A C, Chiu K C, Janssen R C, Bell D S H, Go R P C, Roseman J M, Acton R T, Permutt M A. Variability of the pancreatic islet beta cell/liver (GLUT2) glucose transporter gene in NIDDM patients. Diabetologia 37: 420–427, 1994.
 483. Lander E, Kruglyak L. Genetic dissection of complex traits: Guidelines for interpreting and reporting linkage results. Nature Genetics 11: 241–247, 1995.
 484. Stern M P, Duggirala R, Mitchell B D, Reinhart L J, Shivakumar S, Shipman P A, Uesandi O C, Benavides E, Blangero J, O'Connell P. Evidence for linkage of regions on chromosomes 6 and 11 to plasma glucose concentrations in Mexican Americans. Genome Res 724–734, 1996.
 485. Thompson D B, Janssen R C, Ossowski V M, Prochazka M, Knowler W C, Bogardus C. Evidence for linkage betweeen a region on chromosome 1p and the acute insulin response in Pima Indians. Diabetes 44: 478–481, 1995.
 486. Prochazka M, Lillioja S, Tait J F, Knowler W C, Mott D M, Spraul M, Bennett P H, Bogardus C. Linkage of chromosomal markers on 4q with a putative gene determining maximal insulin action in Pima Indians. Diabetes 42: 514–519, 1993.
 487. Tsui L C, Donis‐Keller H, Grzeschik K‐H. Report of the second international workshop on human chromosome 7 mapping. Cytogenetics and Cell Genetics 71: 2–31, 1995.
 488. Elbein S C, Hoffman M, Mayorga R, Wegner K, Miles C, Leppert M. Evidence for an NIDDM susceptibility locus in caucasians at a reported Piman Indian diabetes locus. Diabetes 45 (suppl 2): 231A, 1996.
 489. Mahtani M M, Widen E, Lehto M, Thomas J, McCarthy M, Brayer J, Bryant B, Chan G, Daly M, Forsblom C, Kanninen T, Kirby A, Kruglyak L, Munnelly K, Parkkonen M, Reeve‐Daly M P, Weaver A, Brettin T, Duyk G, Lander S, Groop L C. Mapping of a gene for type 2 diabetes associated with an insulin secretion defect by a genome scan in Finnish families. Nature Genetics 13: 90–94, 1996.
 490. Collins F S. Positional cloning moves from perditional to traditional. Nature Genetics 9: 347–350, 1995.
 491. Gormley M J J, Hadden D R, Woods R, Sheridan B, Andrews W J. One month's insulin treatment of type II diabetes: the early and medium‐term effects following insulin withdrawal. Metabolism 35: 1029–1036, 1986.
 492. Scarlett J A, Kolterman O G, Ciaraldi T P, Kao M, Olefsky J M. Insulin treatment reverses the postreceptor defect in adipocyte 3–0‐methyl‐glucose transport in type II diabetes mellitus. J Clin Endocrinol Metab 56: 1195–1201. 1983.
 493. Samanta A, Burden A C, Jones G R, Clarkson L. The effect of short term intensive insulin therapy in non‐insulin‐dependent diabetics who had failed on sulphonylurea therapy. Diabetes Res 3: 269–271, 1986.
 494. Hollenbeck C B, Reaven G M. Treatment of patients with noninsulin‐dependent diabetes mellitus: diabetic control and insulin secretion and action after different treatment modalities. Diabetic Med 4: 311–316, 1987.
 495. Garvey W T, Olefsky J M, Griffin J, Hamman R F, Kolterman O G. The effect of insulin treatment on insulin secretion and insulin action in type II diabetes mellitus. Diabetes 34: 222–234, 1985.
 496. Reaven G M, Chen Y I, Coulston A M, Greenfield M S, Hollenbeck C, Lardinois C, Liu G, Schwartz H. Insulin secretion and action in noninsulin‐dependent diabetes mellitus. Is insulin resistance secondary to hypoinsulinemia? Am J Med 75: 85–93, 1983.
 497. Castillo M, Scheen A J, Paolisso G, Lefebvre P J. The addition of glipizide to insulin therapy in type II diabetic patients with secondary failure to sulfonylureas is useful only in the presence of a significant residual insulin secretion. Acta Endocrinol 116: 364–372, 1987.
 498. Yki‐Jarvinen H, Nikkila E, Eero H, Taskinen M R. Clinical benefits and mechanisms of a sustained response to intermittent insulin therapy in type II diabetic patients with secondary drug failure. Am J Med 84: 185–192, 1988.
 499. Beck‐Nielsen H, Richelsen B, Hasling C, Neilsen O H, Heding L, Sorensen N S. Improved in vivo insulin effect during continuous subcutaneous insulin infusion in patients with IDDM. Diabetes 33: 832–837, 1984.
 500. Simonson D C, Tamborlane W C, Sherwin R S, De Fronzo R A. Improved insulin sensitivity in patients with type I diabetes mellitus after CSII. Diabetes 34 (suppl 3): 80–86, 1985.
 501. Yki‐Jarvinen H, Koivisto V A. Continuous subcutaneous insulin infusion therapy decreases insulin resistance in type I diabetes. J Clin Endocrinol Metab 58: 659–666, 1984.
 502. Yki‐Jarvinen H, Koivisto V A. Insulin sensitivity in newly diagnosed type I diabetics after ketoacidosis and after three months of insulin therapy. J Clin Endocrinol Metab 59: 371–378, 1984.
 503. Lager L, Lonnroth P, Von Schenck H, Smith U. Reversal of insulin resistance in type I diabetes after treatment with continuous subcutaneous insulin infusion. Br Med J 287: 101–104, 1983.
 504. Kruszynski Y T, Petrany G, Home P D, Taylor R, Alberti K G M M. Muscle enzyme activity and insulin sensitivity in type I (insulin‐dependent) diabetes mellitus. Diabetologia 29: 699–705, 1986.
 505. Gray R S, Cowan P, Duncan L J P, Clarke B F. Reversal of insulin resistance in type I diabetes following initiation of insulin treatment. Diabet Med 3: 18–23, 1986.

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Pathogenesis of Type 2 Diabetes
 

How to Cite

Kenneth Cusi, Ralph A. Defronzo. Pathogenesis of Type 2 Diabetes. Compr Physiol 2011, Supplement 21: Handbook of Physiology, The Endocrine System, The Endocrine Pancreas and Regulation of Metabolism: 1115-1168. First published in print 2001. doi: 10.1002/cphy.cp070237