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Insulin Resistance, Compensatory Hyperinsulinemia, and Coronary Heart Disease: Syndrome X Revisited

Gerald M. Reaven

10.1002/cphy.cp070238

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 Terminology
2 Insulin Resistance Versus Compensatory Hyperinsulinemia
3 Nature Versus Nurture in The Development of Syndrome X
3.1 Ethnicity
3.2 Obesity: Overall and Regional
3.3 Habitual Physical Activity
3.4 Smoking
3.5 Alcohol
4 Glucose Intolerance
5 Dyslipidemia
5.1 Relationship between Insulin Resistance, Compensatory Hyperinsulinemia, Increased Hepatic VLDL‐TG Secretion and Hypertriglyceridemia
5.2 Abnormalities Associated with Hypertriglyceridemia
6 Hemostatic System
7 Syndrome X and High Blood Pressure
8 Uric Acid
9 Microalbuminuria is not The “Cause” of Syndrome X!
10 Conclusion: Syndrome X and Coronary Heart Disease (CHD)
10.1 Glucose Intolerance
10.2 Hypertriglyceridemia
10.3 Hypertension
Figure 1. Figure 1.

Mean (± SEM) plasma glucose and insulin concentrations before and after 75 g oral glucose challenge in 20 patients with microvascular angina (MVA) and 20 healthy control subjects matched for age, gender distribution, body mass index, waist‐to‐hip ratio and other relevant variables.

[Reprinted from Fuh 50 with permission.]
Figure 2. Figure 2.

Steady‐state plasma insulin and glucose concentrations in patients with microvascular angina (MVA) and normal volunteers. Mean (± SEM) steady‐state plasma insulin (SSPI) and glucose (SSPG) concentrations during last 30 min of a 180 min infusion of somatostatin, insulin, and glucose in the 20 normal volunteers and the 20 patients with microvascular angina (MVA) shown in Figure 1.

[Adapted from data published in Fuh 50 with permission.]
Figure 3. Figure 3.

Comparison of plasma glucose, insulin, FFA and glycerol concentrations in response to meals in insulin resistant subjects with hypertriglyceridemia (solid circles) and normal volunteers (open circles).

[Reprinted from Jeng 75 with permission.]
Figure 4. Figure 4.

Steady‐state plasma glucose (SSPG, top) and steady‐state plasma insulin (SSPI, bottom) concentrations in men and women of either South Asian Indian or European ancestry.

[Reprinted from Laws 94 with permission.]
Figure 5. Figure 5.

Plasma glucose and insulin concentrations before and after 75 g oral glucose challenge in non‐Hispanic white (NHW) (open squares), and Mexican American (solid circles) women.

[Reprinted from Aguire 5 with permission.]
Figure 6. Figure 6.

Mean (± SE) plasma insulin concentration in nonobese (n = 32) and obese (n = 32) hyperinsulinemic (solid circles) and normoinsulinemic (open circles) individuals before and after a 75 g oral glucose challenge. There were 16 subjects in each of four subgroups. Left panel, all subjects; middle panel, nonobese subjects; right panel, obese subjects.

[Reprinted from Zavaroni 182 with permission.]
Figure 7. Figure 7.

Mean (± SE) fasting plasma triglyceride (TG, left panel), cholesterol (middle panel) and high‐density lipoprotein (HDL) cholesterol (right panel) concentrations in nonobese and obese hyperinsulinemic (solid bars) and normoinsulinemic (open bars) individuals. There were 16 subjects in each of four subgroups.

[Reprinted from Zavaroni 182 with permission.]
Figure 8. Figure 8.

Relationship between estimates of habitual activity (VO2max) and insulin‐mediated glucose disposal, or glucose metabolic clearance rate (MCR) during hyperinsulinemic clamp studies, in normal men (solid circles) and women (open circles) volunteers. The higher the glucose MCR, the more insulin sensitive.

[Reprinted from (Rosenthal 145 with permission.]
Figure 9. Figure 9.

Atherogenic changes in lipoprotein metabolism (accompanying hypertriglyceridemia.) Postulated relationship between fasting hypertriglyceridemia and changes in high‐density lipoprotein (HDL) cholesterol, low‐density lipoprotein (LDL) particle composition and postprandial lipemia.
Figure 10. Figure 10.

Relationship between insulin resistance, plasma insulin concentration, hepatic VLDL‐TG‐secretion rate and plasma TG concentration. Summary of correlation coefficients between resistance to insulin‐mediated glucose disposal, plasma insulin response to oral glucose, very low density lipoprotein (VLDL) triglyceride (TG) secretion, and plasma TG concentration over a range of fasting plasma TG concentrations, 69–546 mg/dl (A) or 37–174 mg/dl (B).

[Adapted from data in (A) Olefsky 111, and (B) Tobey 167 with permission.]
Figure 11. Figure 11.

Relationship between Sf > 20 triglyceride turnover rate (V) and concentration (S). Units: V (velocity) = Sf > 20 triglyceride turnover per kilogram body weight per hour; [S] = milligrams Sf > 20 triglyceride per 100 ml plasma; Vmax = maximal estimated velocity; Km = [S] at one‐half maximal velocity.

[Reprinted from (Reaven 137 with permission.]
Figure 12. Figure 12.

Plasma glucose (left) and insulin (right) responses to 75 g oral glucose challenge in subjects divided into pattern A (solid circles, broken line), an intermediate pattern (open squares, solid line) and pattern B (open circles, solid line) on the basis of their LDL particle diameter, matched for age, gender and BMI.

[Reprinted from Reaven 132 with permission.]
Figure 13. Figure 13.

Frequency distribution of the plasma insulin response 2 hours after 75 g oral glucose challenge in normotensive (open squares) and hypertensive (solid squares) factory workers.

[Reprinted from Zavaron 186 with permission.]
Figure 14. Figure 14.

Summary of relationship between insulin resistance [steady‐state plasma glucose concentration (SSPG)], insulin response and various measures of uric acid metabolism.

[Reprinted from Facchini 39 with permission.]
Figure 15. Figure 15.

Plasma insulin responses and corresponding UAE rates. Experimental population divided into quartiles (right panel) on the basis of their plasma insulin responses to oral glucose (left panel). The data in the right panel show the corresponding urinary albumin excretion (UAE) rates of the four quartiles separated on the basis of the insulin response.

[Reprinted from Zavaroni 184 with permission.]
Figure 16. Figure 16.

Plasma Triglyceride and HDL‐Cholesterol Concentrations and Corresponding UAE Rates Experimental population divided into four quartiles on the basis of either their fasting plasma triglyceride or HDL cholesterol concentration. The adjacent panels show the corresponding urinary albumin excretion (UAE) rates of the four quartiles separated on the basis of their fasting triglyceride and HDL cholesterol concentrations.

[Reprinted from Zavaroni 184 with permission.]
Figure 17. Figure 17.

Proposed role of insulin resistance and compensatory hyperinsulinemia in CHD. A diagramatic representation of the relationship between insulin resistance plus compensatory hyperinsulinemia, the cluster of abnormalities that comprise syndrome X and coronary heart disease. TG = triglyceride; PP = postprandial; HDL‐Chol, high density lipoprotein‐cholesterol; PHLA = plasma post‐heparin lipolytic activity; Na = sodium; SNS = sympathetic nervous system; PAI‐1 = plasminogen activator inhibitor‐1.


Figure 1.

Mean (± SEM) plasma glucose and insulin concentrations before and after 75 g oral glucose challenge in 20 patients with microvascular angina (MVA) and 20 healthy control subjects matched for age, gender distribution, body mass index, waist‐to‐hip ratio and other relevant variables.

[Reprinted from Fuh 50 with permission.]


Figure 2.

Steady‐state plasma insulin and glucose concentrations in patients with microvascular angina (MVA) and normal volunteers. Mean (± SEM) steady‐state plasma insulin (SSPI) and glucose (SSPG) concentrations during last 30 min of a 180 min infusion of somatostatin, insulin, and glucose in the 20 normal volunteers and the 20 patients with microvascular angina (MVA) shown in Figure 1.

[Adapted from data published in Fuh 50 with permission.]


Figure 3.

Comparison of plasma glucose, insulin, FFA and glycerol concentrations in response to meals in insulin resistant subjects with hypertriglyceridemia (solid circles) and normal volunteers (open circles).

[Reprinted from Jeng 75 with permission.]


Figure 4.

Steady‐state plasma glucose (SSPG, top) and steady‐state plasma insulin (SSPI, bottom) concentrations in men and women of either South Asian Indian or European ancestry.

[Reprinted from Laws 94 with permission.]


Figure 5.

Plasma glucose and insulin concentrations before and after 75 g oral glucose challenge in non‐Hispanic white (NHW) (open squares), and Mexican American (solid circles) women.

[Reprinted from Aguire 5 with permission.]


Figure 6.

Mean (± SE) plasma insulin concentration in nonobese (n = 32) and obese (n = 32) hyperinsulinemic (solid circles) and normoinsulinemic (open circles) individuals before and after a 75 g oral glucose challenge. There were 16 subjects in each of four subgroups. Left panel, all subjects; middle panel, nonobese subjects; right panel, obese subjects.

[Reprinted from Zavaroni 182 with permission.]


Figure 7.

Mean (± SE) fasting plasma triglyceride (TG, left panel), cholesterol (middle panel) and high‐density lipoprotein (HDL) cholesterol (right panel) concentrations in nonobese and obese hyperinsulinemic (solid bars) and normoinsulinemic (open bars) individuals. There were 16 subjects in each of four subgroups.

[Reprinted from Zavaroni 182 with permission.]


Figure 8.

Relationship between estimates of habitual activity (VO2max) and insulin‐mediated glucose disposal, or glucose metabolic clearance rate (MCR) during hyperinsulinemic clamp studies, in normal men (solid circles) and women (open circles) volunteers. The higher the glucose MCR, the more insulin sensitive.

[Reprinted from (Rosenthal 145 with permission.]


Figure 9.

Atherogenic changes in lipoprotein metabolism (accompanying hypertriglyceridemia.) Postulated relationship between fasting hypertriglyceridemia and changes in high‐density lipoprotein (HDL) cholesterol, low‐density lipoprotein (LDL) particle composition and postprandial lipemia.



Figure 10.

Relationship between insulin resistance, plasma insulin concentration, hepatic VLDL‐TG‐secretion rate and plasma TG concentration. Summary of correlation coefficients between resistance to insulin‐mediated glucose disposal, plasma insulin response to oral glucose, very low density lipoprotein (VLDL) triglyceride (TG) secretion, and plasma TG concentration over a range of fasting plasma TG concentrations, 69–546 mg/dl (A) or 37–174 mg/dl (B).

[Adapted from data in (A) Olefsky 111, and (B) Tobey 167 with permission.]


Figure 11.

Relationship between Sf > 20 triglyceride turnover rate (V) and concentration (S). Units: V (velocity) = Sf > 20 triglyceride turnover per kilogram body weight per hour; [S] = milligrams Sf > 20 triglyceride per 100 ml plasma; Vmax = maximal estimated velocity; Km = [S] at one‐half maximal velocity.

[Reprinted from (Reaven 137 with permission.]


Figure 12.

Plasma glucose (left) and insulin (right) responses to 75 g oral glucose challenge in subjects divided into pattern A (solid circles, broken line), an intermediate pattern (open squares, solid line) and pattern B (open circles, solid line) on the basis of their LDL particle diameter, matched for age, gender and BMI.

[Reprinted from Reaven 132 with permission.]


Figure 13.

Frequency distribution of the plasma insulin response 2 hours after 75 g oral glucose challenge in normotensive (open squares) and hypertensive (solid squares) factory workers.

[Reprinted from Zavaron 186 with permission.]


Figure 14.

Summary of relationship between insulin resistance [steady‐state plasma glucose concentration (SSPG)], insulin response and various measures of uric acid metabolism.

[Reprinted from Facchini 39 with permission.]


Figure 15.

Plasma insulin responses and corresponding UAE rates. Experimental population divided into quartiles (right panel) on the basis of their plasma insulin responses to oral glucose (left panel). The data in the right panel show the corresponding urinary albumin excretion (UAE) rates of the four quartiles separated on the basis of the insulin response.

[Reprinted from Zavaroni 184 with permission.]


Figure 16.

Plasma Triglyceride and HDL‐Cholesterol Concentrations and Corresponding UAE Rates Experimental population divided into four quartiles on the basis of either their fasting plasma triglyceride or HDL cholesterol concentration. The adjacent panels show the corresponding urinary albumin excretion (UAE) rates of the four quartiles separated on the basis of their fasting triglyceride and HDL cholesterol concentrations.

[Reprinted from Zavaroni 184 with permission.]


Figure 17.

Proposed role of insulin resistance and compensatory hyperinsulinemia in CHD. A diagramatic representation of the relationship between insulin resistance plus compensatory hyperinsulinemia, the cluster of abnormalities that comprise syndrome X and coronary heart disease. TG = triglyceride; PP = postprandial; HDL‐Chol, high density lipoprotein‐cholesterol; PHLA = plasma post‐heparin lipolytic activity; Na = sodium; SNS = sympathetic nervous system; PAI‐1 = plasminogen activator inhibitor‐1.

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Article Title: Insulin Resistance, Compensatory Hyperinsulinemia, and Coronary Heart Disease: Syndrome X Revisited
 

How to Cite

Gerald M. Reaven. Insulin Resistance, Compensatory Hyperinsulinemia, and Coronary Heart Disease: Syndrome X Revisited. Compr Physiol 2011, Supplement 21: Handbook of Physiology, The Endocrine System, The Endocrine Pancreas and Regulation of Metabolism: 1169-1197. First published in print 2001. doi: 10.1002/cphy.cp070238