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The Prevention and Correction of Hypoglycemia

Philip E. Cryer

10.1002/cphy.cp070235

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 Systemic Glucose Balance
1.1 Postabsorptive State
1.2 Postprandial State
1.3 Exercise
1.4 Other Conditions
2 Physiological Responses to Hypoglycemia
2.1 Hormonal, Neural and Substrate Responses
2.2 Symptoms, Cognitive Dysfunction and Signs
2.3 Glycemic Thresholds
2.4 Impact of Substrates other than Glucose
3 Physiological Actions of Glucoregulatory Factors
3.1 Regulatory Factor: Insulin
3.2 Counterregulatory Factors
4 Integrated Physiology of Glucose Counterregulation
4.1 Correction of Hypoglycemia
4.2 Prevention of Hypoglycemia
4.3 Insight from Pathophysiology
4.4 Hierarchy of the Redundant Glucose‐Counterregulatory Factors
5 Summary
Figure 1. Figure 1.

Maintenance of systemic glucose balance through regulation of endogenous glucose production and glucose utilization by insulin‐sensitive tissues prevents hypoglycemia and assures a continuous supply of glucose to the brain in the fed and fasted state.
Figure 2. Figure 2.

Neurogenic (autonomic) and neuroglycopenic symptoms of hypoglycemia in healthy humans. Among the neurogenic symptoms sweaty, hungry and tingling are cholinergic while shaky/tremulous, heart pounding and nervous/anxious are adrenergic. See text for discussion. Mean (± SE) subject scores for awareness of hypoglycemia (blood sugar low) during euglycemia (EU) and hypoglycemia (HYPO) alone (solid column), with combined α‐and β‐adrenergic blockade (ADB, cross‐hatched column) and with panautonomic blockade (PAB, stippled column) with both adrenergic and cholinergic antagonists are also shown. *p < 0.001 EU vs. HYPO alone. + p < 0.001 HYPO alone vs. PAB.

[Data from Towler et al. 245. Figure from Cryer 63, reproduced with permission of the American Diabetes Association.]
Figure 3. Figure 3.

Mean (± SE) arterialized venous glycemic thresholds for decrements in insulin secretion (determined by measurement of plasma C‐peptide concentrations), increments in plasma glucagon, epinephrine, growth hormone and cortisol concentrations, symptoms and hypoglycemic cognitive dysfunction during decrements in the plasma glucose concentration in normal humans.

[Drawn from data in Schwartz et al. 227 (solid columns), Mitrakou et al. 180 (open columns) and Fanelli et al. 95 (cross‐hatched columns).]
Figure 4. Figure 4.

Mechanisms of the hyperglycemic effect of epinephrine.

[From Cryer 61, reproduced with permission of the American Diabetes Association.]
Figure 5. Figure 5.

Mean (±SE) plasma insulin and glucose concentrations and rates of glucose utilization (disappearance, Rd) and glucose production (appearance, Ra) before and after rapid intravenous injection of regular insulin (0.1 U/kg) in healthy human subjects.

[Modified from Garber et al. 113, reproduced with permission of the American Society for Clinical Investigation.]
Figure 6. Figure 6.

Mean (± SE) plasma epinephrine (E), norepinephrine (NE), glucagon, cortisol and growth hormone concentrations before and after rapid intravenous injection of regular insulin (0.1 U/kg) in healthy human subjects.

[Modified from Garber et al. 113, reproduced with permission of the American Society for Clinical Investigation.]
Figure 7. Figure 7.

Summary of studies of the mechanisms of the correction of brief hypoglycemia. Plasma glucose curves during insulin‐induced hypoglycemia in healthy humans during control studies (solid curves, same in all panels) and as modified (dashed curves) by: (A) somatostatin infusion (glucagon + growth hormone [GH] deficiency); (B) somatostatin + growth hormone replacement (glucagon deficiency); (C) somatostatin + glucagon replacement (GH deficiency); (D) phentolamine and propranolol infusion (combined α and β‐adrenergic blockade) or studies performed in bilaterally adrenalectomized individuals (epinephrine deficiency); (E) somatostatin + phentolamine and propranolol (glucagon deficiency + α and β‐adrenergic blockade); (F) somatostatin infusion in bilaterally adrenalectomized individuals (glucagon + epinephrine deficiency). Insulin was injected intravenously at time 0 min. Interventions were started at time 0 min. and stopped at time 90 min (i.e., between the vertical lines in each panel).

[Curves derived from data in Clarke et al. 48, Gerich et al. 6 117 and Rizza et al. 204. Figure from Cryer 58, reproduced with permission of the American Diabetes Association.]
Figure 8. Figure 8.

Mean (± SE) plasma glucose, glucagon, growth hormone, cortisol, epinephrine and norepinephrine concentrations before and after rapid intravenous injection of regular insulin (0.05 U/kg) in healthy humans in a control study (solid symbols and continuous lines) and during infusion of somalostatin (SRIF) (open symbols and interrupted lines).

[Figure from Gerich et al. 117, reproduced with permission of the American Physiological Society.]
Figure 9. Figure 9.

Mean (± SE) plasma glucose, glucagon, norepinephrine and growth hormone concentrations before and after rapid intravenous injection of regular insulin (0.05 U/kg) during infusion of saline (closed symbols and continuous lines) or somatostatin (SRIF) (open symbols and interrupted lines) in bilaterally adreneralectomized and glucocorticoid‐and mineralocorticoid‐pretreated human subjects.

[Figure from Gerich et al. 117, reproduced with permission of the American Physiological Society.]
Figure 10. Figure 10.

Mean (± SE) plasma glucose concentrations and rates of glucose production, utilization and clearance during brief hypoglycemia produced by the intravenous injection of regular insulin (left) and during prolonged hypoglycemia produced by the subcutaneous infusion of regular insulin (right) in healthy humans. Note the different time scales.

Figure from De Feo et al. 74, reproduced with permission of the American Diabetes Association.
Figure 11. Figure 11.

Summary of studies of the roles of glucagon, catecholamines, cortisol and growth hormone in defense against prolonged hyperinsulinemia and slowly developing hypoglycemia in healthy humans.

[Drawn from data in De Feo et al. 75, 76, 77 and 78. Figure from Gerich 116, reproduced with permission of the American Diabetes Association.]
Figure 12. Figure 12.

Mean (± SE) plasma glucose concentrations and rates of glucose production and utilization during subcutaneous insulin infusions in healthy humans during increments in counterregulatory hormones (open symbols) and in the isolated absence of an increment in glucagon (solid symbols).

[Figure from De Feo et al. 75, reproduced with permission of the American Physiological Society.]
Figure 13. Figure 13.

Mean (± SE) plasma glucose concentrations and rates of glucose production and utilization during subcutaneous insulin infusions in healthy humans during increments in counterregulatory hormones (open symbols) and during combined α‐and β‐adrenergic blockade (solid symbols).

Figure from De Feo et al. 76, reproduced with permission of the American Physiological Society.
Figure 14. Figure 14.

Mean (± SE) plasma glucose concentrations and rates of glucose production and utilization during subcutaneous insulin infusions in healthy humans during increments in counterregulatory hormones (open symbols) and in the isolated absence of an increment in cortisol (solid symbols).

[Figure from De Feo et al. 77, reproduced with permission of the American Physiological Society.]
Figure 15. Figure 15.

Mean (± SE) plasma glucose concentrations and rates of glucose production and utilization during subcutaneous insulin infusions in healthy humans during increments in counterregulatory hormones (open symbols) and in the isolated absence of an increment in growth hormone (closed symbols).

[Figure from De Feo et al. 78, reproduced with permission of the American Physiological Society.]
Figure 16. Figure 16.

Mean (± SE) plasma glucose concentrations during intravenous insulin infusions in healthy subjects (controls, closed circles) and in patients with hypopituitarism (hypopit) without pretreatment (open circles) or with pretreatment with cortisol and growth hormone (open squares).

[Figure from Boyle and Cryer 24, reproduced with permission of the American Physiological Society.]
Figure 17. Figure 17.

Mean (± SE) plasma glucose concentrations, rates of glycogenolysis and gluconeogenesis and glycogenolysis and gluconeogenesis as percent of total glucose production during prolonged hypoglycemia in healthy humans.

[Figure from Lecavalier et al. 161, reproduced with permission of the American Physiological Society.]
Figure 18. Figure 18.

Composite of studies of the mechanisms of the prevention of hypoglycemia. Mean (± SE) plasma glucose concentrations are shown. Upper Left: Glucose levels during infusion of somatostatin (SRIF) with partial insulin replacement alone (closed symbols) and with combined α‐and β‐adrenergic blockade with propranolol (PRP) and phentolamine (PTL) (open symbols) after an overnight fast in normal humans. [Data from Rosen et al. 212]. Upper Right: Glucose levels after overnight (closed symbols) and 3‐day (open symbols) fasts during insulin replacement in a dose estimated to produce portal insulin levels after the 3‐day fast comparable to those after the overnight fast (Ins Alone), continued insulin replacement plus somatostatin infusion to produce glucagon deficiency (↓G), combined α‐and β‐adrenergic blockade alone (↓α/β), and adrenergic blockade plus glucagon deficiency produced by insulin replacement and somatostatin infusion (↓α/β+↓ G) in normal humans. [Data from Boyle et al. 27]. Lower Left: Glucose levels before and after oral glucose (75 g) ingestion in normal humans (between the continuous lines) and bilaterally adrenalectomized humans without intervention (open symbols, Epinephrine Deficient) and with somatostatin infusion with partial insulin replacement (both starting at 220 min.) to produce glucagon deficiency (closed symbols, Epinephrine + Glucagon Deficient). [Data from Tse et al. 246]. Lower Right: Glucose levels before (open columns) and after (closed columns) 60 min of moderate (60% of peak VO2) cycle exercise in normal humans with no intervention (control), somatostatin infusion with insulin and glucagon replacement at fixed, basal rates throughout (Clamp, No; gD Insulin or Glucagon), somatostatin infusion with insulin and glucagon replacement in altered doses during exercise to approximate the decrements in insulin and increments in glucagon that occurred during the control study (Clamp with ↓ Insulin and ↑ Glucagon), α‐and β‐adrenergic blockade alone (Adrenergic Blockade), and somatostatin infusion with insulin and glucagon replacement at fixed, basal rates plus adrenergic blockade (Clamp, No Δ Insulin or Glucagon + Adrenergic Blockade). Data from Hirsch et al. 140 and Marker et al. 170.

Figure from Cryer 63, reproduced with permission of the American Diabetes Association.
Figure 19. Figure 19.

Hormonal, neural and substrate factors that regulate systemic glucose balance. The arrows to the left of each factor indicate the directional effect of that factor on glucose production. The arrows to the right of each factor indicate the directional effect of that factor on glucose utilization.
Figure 20. Figure 20.

Mean (± SE) plasma glucose concentrations, rates of glucose production (Ra) and utilization (Rd), plasma C‐peptide and peripheral insulin concentrations, calculated rates of insulin secretion and estimated hepatic portal insulin concentrations in healthy humans during a control study (shaded area) and during infusions of insulin in a dose of 0.6 mU.kg−1.min−1 (3.6 pM.kg−1.min−1) from 0 to 80 min followed, from 80 to 180 min, by doses of 0.0 (closed circles), 0.1 (open circles), 0.2 (closed squares), 0.4 (open squares) or 0.6 (closed triangles) mU.kg.−1.min−1 (0.0, 0.6, 1.2, 2.4 and 3.6 pM.kg−1.min−1 respectively). The numbers in the glucose concentration panel refer to the latter insulin infusion doses.

[From Heller and Cryer 131, reproduced with permission of the American Physiological Society.]
Figure 21. Figure 21.

Mean (± SE) plasma glucagon, epinephrine, norepinephrine, cortisol and growth hormone concentrations in healthy humans during a control study (shaded areas) and during infusions of insulin in a dose of 0.6 mgN.kg−1.min−1 (3.6 pM.kg−1.min−1) form 0 to 80 min followed, from 80 to 180 min, by doses of 0.0 (closed circles), 0.1 (open circles), 0.2 (closed squares), 0.4 (open squares) or 0.6 (closed triangles) U.kg−1.min−1 (0.0, 0.6, 1.2, 2.4 and 3.6 gmM.kg−1.min−1 respectively).

[From Heller and Cryer 131, reproduced with permission of the American Physiological Society.]
Figure 22. Figure 22.

Schematic representation of the physiology of glucose counterregulation in healthy humans.


Figure 1.

Maintenance of systemic glucose balance through regulation of endogenous glucose production and glucose utilization by insulin‐sensitive tissues prevents hypoglycemia and assures a continuous supply of glucose to the brain in the fed and fasted state.



Figure 2.

Neurogenic (autonomic) and neuroglycopenic symptoms of hypoglycemia in healthy humans. Among the neurogenic symptoms sweaty, hungry and tingling are cholinergic while shaky/tremulous, heart pounding and nervous/anxious are adrenergic. See text for discussion. Mean (± SE) subject scores for awareness of hypoglycemia (blood sugar low) during euglycemia (EU) and hypoglycemia (HYPO) alone (solid column), with combined α‐and β‐adrenergic blockade (ADB, cross‐hatched column) and with panautonomic blockade (PAB, stippled column) with both adrenergic and cholinergic antagonists are also shown. *p < 0.001 EU vs. HYPO alone. + p < 0.001 HYPO alone vs. PAB.

[Data from Towler et al. 245. Figure from Cryer 63, reproduced with permission of the American Diabetes Association.]


Figure 3.

Mean (± SE) arterialized venous glycemic thresholds for decrements in insulin secretion (determined by measurement of plasma C‐peptide concentrations), increments in plasma glucagon, epinephrine, growth hormone and cortisol concentrations, symptoms and hypoglycemic cognitive dysfunction during decrements in the plasma glucose concentration in normal humans.

[Drawn from data in Schwartz et al. 227 (solid columns), Mitrakou et al. 180 (open columns) and Fanelli et al. 95 (cross‐hatched columns).]


Figure 4.

Mechanisms of the hyperglycemic effect of epinephrine.

[From Cryer 61, reproduced with permission of the American Diabetes Association.]


Figure 5.

Mean (±SE) plasma insulin and glucose concentrations and rates of glucose utilization (disappearance, Rd) and glucose production (appearance, Ra) before and after rapid intravenous injection of regular insulin (0.1 U/kg) in healthy human subjects.

[Modified from Garber et al. 113, reproduced with permission of the American Society for Clinical Investigation.]


Figure 6.

Mean (± SE) plasma epinephrine (E), norepinephrine (NE), glucagon, cortisol and growth hormone concentrations before and after rapid intravenous injection of regular insulin (0.1 U/kg) in healthy human subjects.

[Modified from Garber et al. 113, reproduced with permission of the American Society for Clinical Investigation.]


Figure 7.

Summary of studies of the mechanisms of the correction of brief hypoglycemia. Plasma glucose curves during insulin‐induced hypoglycemia in healthy humans during control studies (solid curves, same in all panels) and as modified (dashed curves) by: (A) somatostatin infusion (glucagon + growth hormone [GH] deficiency); (B) somatostatin + growth hormone replacement (glucagon deficiency); (C) somatostatin + glucagon replacement (GH deficiency); (D) phentolamine and propranolol infusion (combined α and β‐adrenergic blockade) or studies performed in bilaterally adrenalectomized individuals (epinephrine deficiency); (E) somatostatin + phentolamine and propranolol (glucagon deficiency + α and β‐adrenergic blockade); (F) somatostatin infusion in bilaterally adrenalectomized individuals (glucagon + epinephrine deficiency). Insulin was injected intravenously at time 0 min. Interventions were started at time 0 min. and stopped at time 90 min (i.e., between the vertical lines in each panel).

[Curves derived from data in Clarke et al. 48, Gerich et al. 6 117 and Rizza et al. 204. Figure from Cryer 58, reproduced with permission of the American Diabetes Association.]


Figure 8.

Mean (± SE) plasma glucose, glucagon, growth hormone, cortisol, epinephrine and norepinephrine concentrations before and after rapid intravenous injection of regular insulin (0.05 U/kg) in healthy humans in a control study (solid symbols and continuous lines) and during infusion of somalostatin (SRIF) (open symbols and interrupted lines).

[Figure from Gerich et al. 117, reproduced with permission of the American Physiological Society.]


Figure 9.

Mean (± SE) plasma glucose, glucagon, norepinephrine and growth hormone concentrations before and after rapid intravenous injection of regular insulin (0.05 U/kg) during infusion of saline (closed symbols and continuous lines) or somatostatin (SRIF) (open symbols and interrupted lines) in bilaterally adreneralectomized and glucocorticoid‐and mineralocorticoid‐pretreated human subjects.

[Figure from Gerich et al. 117, reproduced with permission of the American Physiological Society.]


Figure 10.

Mean (± SE) plasma glucose concentrations and rates of glucose production, utilization and clearance during brief hypoglycemia produced by the intravenous injection of regular insulin (left) and during prolonged hypoglycemia produced by the subcutaneous infusion of regular insulin (right) in healthy humans. Note the different time scales.

Figure from De Feo et al. 74, reproduced with permission of the American Diabetes Association.


Figure 11.

Summary of studies of the roles of glucagon, catecholamines, cortisol and growth hormone in defense against prolonged hyperinsulinemia and slowly developing hypoglycemia in healthy humans.

[Drawn from data in De Feo et al. 75, 76, 77 and 78. Figure from Gerich 116, reproduced with permission of the American Diabetes Association.]


Figure 12.

Mean (± SE) plasma glucose concentrations and rates of glucose production and utilization during subcutaneous insulin infusions in healthy humans during increments in counterregulatory hormones (open symbols) and in the isolated absence of an increment in glucagon (solid symbols).

[Figure from De Feo et al. 75, reproduced with permission of the American Physiological Society.]


Figure 13.

Mean (± SE) plasma glucose concentrations and rates of glucose production and utilization during subcutaneous insulin infusions in healthy humans during increments in counterregulatory hormones (open symbols) and during combined α‐and β‐adrenergic blockade (solid symbols).

Figure from De Feo et al. 76, reproduced with permission of the American Physiological Society.


Figure 14.

Mean (± SE) plasma glucose concentrations and rates of glucose production and utilization during subcutaneous insulin infusions in healthy humans during increments in counterregulatory hormones (open symbols) and in the isolated absence of an increment in cortisol (solid symbols).

[Figure from De Feo et al. 77, reproduced with permission of the American Physiological Society.]


Figure 15.

Mean (± SE) plasma glucose concentrations and rates of glucose production and utilization during subcutaneous insulin infusions in healthy humans during increments in counterregulatory hormones (open symbols) and in the isolated absence of an increment in growth hormone (closed symbols).

[Figure from De Feo et al. 78, reproduced with permission of the American Physiological Society.]


Figure 16.

Mean (± SE) plasma glucose concentrations during intravenous insulin infusions in healthy subjects (controls, closed circles) and in patients with hypopituitarism (hypopit) without pretreatment (open circles) or with pretreatment with cortisol and growth hormone (open squares).

[Figure from Boyle and Cryer 24, reproduced with permission of the American Physiological Society.]


Figure 17.

Mean (± SE) plasma glucose concentrations, rates of glycogenolysis and gluconeogenesis and glycogenolysis and gluconeogenesis as percent of total glucose production during prolonged hypoglycemia in healthy humans.

[Figure from Lecavalier et al. 161, reproduced with permission of the American Physiological Society.]


Figure 18.

Composite of studies of the mechanisms of the prevention of hypoglycemia. Mean (± SE) plasma glucose concentrations are shown. Upper Left: Glucose levels during infusion of somatostatin (SRIF) with partial insulin replacement alone (closed symbols) and with combined α‐and β‐adrenergic blockade with propranolol (PRP) and phentolamine (PTL) (open symbols) after an overnight fast in normal humans. [Data from Rosen et al. 212]. Upper Right: Glucose levels after overnight (closed symbols) and 3‐day (open symbols) fasts during insulin replacement in a dose estimated to produce portal insulin levels after the 3‐day fast comparable to those after the overnight fast (Ins Alone), continued insulin replacement plus somatostatin infusion to produce glucagon deficiency (↓G), combined α‐and β‐adrenergic blockade alone (↓α/β), and adrenergic blockade plus glucagon deficiency produced by insulin replacement and somatostatin infusion (↓α/β+↓ G) in normal humans. [Data from Boyle et al. 27]. Lower Left: Glucose levels before and after oral glucose (75 g) ingestion in normal humans (between the continuous lines) and bilaterally adrenalectomized humans without intervention (open symbols, Epinephrine Deficient) and with somatostatin infusion with partial insulin replacement (both starting at 220 min.) to produce glucagon deficiency (closed symbols, Epinephrine + Glucagon Deficient). [Data from Tse et al. 246]. Lower Right: Glucose levels before (open columns) and after (closed columns) 60 min of moderate (60% of peak VO2) cycle exercise in normal humans with no intervention (control), somatostatin infusion with insulin and glucagon replacement at fixed, basal rates throughout (Clamp, No; gD Insulin or Glucagon), somatostatin infusion with insulin and glucagon replacement in altered doses during exercise to approximate the decrements in insulin and increments in glucagon that occurred during the control study (Clamp with ↓ Insulin and ↑ Glucagon), α‐and β‐adrenergic blockade alone (Adrenergic Blockade), and somatostatin infusion with insulin and glucagon replacement at fixed, basal rates plus adrenergic blockade (Clamp, No Δ Insulin or Glucagon + Adrenergic Blockade). Data from Hirsch et al. 140 and Marker et al. 170.

Figure from Cryer 63, reproduced with permission of the American Diabetes Association.


Figure 19.

Hormonal, neural and substrate factors that regulate systemic glucose balance. The arrows to the left of each factor indicate the directional effect of that factor on glucose production. The arrows to the right of each factor indicate the directional effect of that factor on glucose utilization.



Figure 20.

Mean (± SE) plasma glucose concentrations, rates of glucose production (Ra) and utilization (Rd), plasma C‐peptide and peripheral insulin concentrations, calculated rates of insulin secretion and estimated hepatic portal insulin concentrations in healthy humans during a control study (shaded area) and during infusions of insulin in a dose of 0.6 mU.kg−1.min−1 (3.6 pM.kg−1.min−1) from 0 to 80 min followed, from 80 to 180 min, by doses of 0.0 (closed circles), 0.1 (open circles), 0.2 (closed squares), 0.4 (open squares) or 0.6 (closed triangles) mU.kg.−1.min−1 (0.0, 0.6, 1.2, 2.4 and 3.6 pM.kg−1.min−1 respectively). The numbers in the glucose concentration panel refer to the latter insulin infusion doses.

[From Heller and Cryer 131, reproduced with permission of the American Physiological Society.]


Figure 21.

Mean (± SE) plasma glucagon, epinephrine, norepinephrine, cortisol and growth hormone concentrations in healthy humans during a control study (shaded areas) and during infusions of insulin in a dose of 0.6 mgN.kg−1.min−1 (3.6 pM.kg−1.min−1) form 0 to 80 min followed, from 80 to 180 min, by doses of 0.0 (closed circles), 0.1 (open circles), 0.2 (closed squares), 0.4 (open squares) or 0.6 (closed triangles) U.kg−1.min−1 (0.0, 0.6, 1.2, 2.4 and 3.6 gmM.kg−1.min−1 respectively).

[From Heller and Cryer 131, reproduced with permission of the American Physiological Society.]


Figure 22.

Schematic representation of the physiology of glucose counterregulation in healthy humans.

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Article Title: The Prevention and Correction of Hypoglycemia
 

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Philip E. Cryer. The Prevention and Correction of Hypoglycemia. Compr Physiol 2011, Supplement 21: Handbook of Physiology, The Endocrine System, The Endocrine Pancreas and Regulation of Metabolism: 1057-1092. First published in print 2001. doi: 10.1002/cphy.cp070235