Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction.

To define glycemic thresholds for activation of counterregulatory hormone secretion, initiation of symptoms (autonomic and neuroglycopenic), and onset of deterioration of cognitive function, we measured indexes of these responses during glycemic plateaus of 90, 78, 66, 54, and 42 mg/dl in 10 normal volunteers, with the use of the hyperinsulinemic glucose clamp technique. Activation of glucagon, epinephrine, norepinephrine, and growth hormone secretion began at arterialized venous plasma glucose concentrations of 68 +/- 1, 68 +/- 1, 65 +/- 1, and 67 +/- 2 (SE) mg/dl, respectively. Autonomic symptoms (anxiety, palpitations, sweating, irritability, and tremor) began at 58 +/- 2 mg/dl, which was significantly (P = 0.0001) lower. Neuroglycopenic symptoms (hunger, dizziness, tingling, blurred vision, difficulty thinking, and faintness) and deterioration in cognitive function tests began at 51 +/- 3 and 49 +/- 2 mg/dl, respectively, values that were both significantly (P = 0.018 and 0.004, respectively) lower than that for initiation of autonomic symptoms. We therefore conclude that there is a distinct hierarchy of responses to decrements in plasma glucose, such that the threshold for activation of counterregulatory hormone secretion occurs at higher plasma glucose levels than that for initiation of autonomic warning symptoms, which in turn occurs at higher plasma glucose levels than that for onset of neuroglycopenic symptoms and deterioration in cerebral function. Such a hierarchy would maximize the opportunity to avoid incapacitating hypoglycemia.

[1]  J. Gerich,et al.  Glucose Counterregulation and Its Impact on Diabetes Mellitus , 1988, Diabetes.

[2]  H. Hoagland,et al.  CEREBRAL METABOLISM AND ELECTRICAL ACTIVITY DURING INSULIN HYPOGLYCEMIA IN MAN , 1939 .

[3]  P Fenwick,et al.  The effect of hypoglycaemia on visual function: a clinical and electrophysiological study. , 1985, Clinical science.

[4]  P. Brunetti,et al.  Modest decrements in plasma glucose concentration cause early impairment in cognitive function and later activation of glucose counterregulation in the absence of hypoglycemic symptoms in normal man. , 1988, The Journal of clinical investigation.

[5]  W. Tamborlane,et al.  Effect of Intensive Insulin Therapy on Glycemic Thresholds for Counterregulatory Hormone Release , 1988, Diabetes.

[6]  I. Mühlhauser,et al.  HYPOGLYCAEMIC UNAWARENESS AND HUMAN INSULIN , 1989, The Lancet.

[7]  J. Hayes,et al.  Psychomotor Performance and Counterregulatory Responses During Mild Hypoglycemia in Healthy Volunteers , 1989, Diabetes Care.

[8]  R. Sherwin,et al.  Influence of continuous physiologic hyperinsulinemia on glucose kinetics and counterregulatory hormones in normal and diabetic humans. , 1979, The Journal of clinical investigation.

[9]  R. D. Lawrence.  INSULIN HYPOGLYCÆMIA CHANGES IN NERVOUS MANIFESTATIONS , 1941 .

[10]  P. Brunetti,et al.  Role of hepatic autoregulation in defense against hypoglycemia in humans. , 1985, The Journal of clinical investigation.

[11]  R. DeFronzo,et al.  Intensive insulin therapy reduces counterregulatory hormone responses to hypoglycemia in patients with type I diabetes. , 1985, Annals of internal medicine.

[12]  E. Ipp,et al.  Sparing of cognitive function in mild hypoglycemia: dissociation from the neuroendocrine response. , 1987, The Journal of clinical endocrinology and metabolism.

[13]  EFFECT ON THE ELECTROENCEPHALOGRAM OF CHANGING THE BLOOD SUGAR LEVEL , 1943 .

[14]  P. Cryer,et al.  Epinephrine, norepinephrine, glucagon, and growth hormone release in association with physiological decrements in the plasma glucose concentration in normal and diabetic man. , 1980, The Journal of clinical endocrinology and metabolism.

[15]  M. Massi-Benedetti,et al.  Counterregulatory hormones during moderate, insulin-induced, blood glucose decrements in man. , 1981, The Journal of clinical endocrinology and metabolism.

[16]  R. Maddock,et al.  INSULIN REACTIONS: Manifestations and Need for Recognition of Long-Acting Insulin Reactions , 1953 .

[17]  W. Tamborlane,et al.  Defective glucose counterregulation after strict glycemic control of insulin-dependent diabetes mellitus. , 1987, The New England journal of medicine.

[18]  P. Cryer,et al.  Glucose counterregulation, hypoglycemia, and intensive insulin therapy in diabetes mellitus. , 1985, The New England journal of medicine.

[19]  B. Frier.  Hypoglycaemia and Diabetes , 1986 .

[20]  K. Polonsky,et al.  Variable Deterioration in Cortical Function During Insulin-induced Hypoglycemia , 1985, Diabetes.

[21]  P. Cryer,et al.  Abnormal glucose counterregulation after subcutaneous insulin in insulin-dependent diabetes mellitus. , 1984, The New England journal of medicine.

[22]  E. Gemsenjäger,et al.  ENDEMIC GOITRE , 1931, The Lancet.

[23]  R. DeFronzo,et al.  Rate of Glucose Fall Does Not Affect Counterregulatory Hormone Responses to Hypoglycemia in Normal and Diabetic Humans , 1987, Diabetes.

[24]  K. Polonsky,et al.  Hypoglycmic Thresholds for Cognitive Dysfunction in Humans , 1990, Diabetes.

[25]  P. Cryer,et al.  Plasma glucose concentrations at the onset of hypoglycemic symptoms in patients with poorly controlled diabetes and in nondiabetics. , 1988, The New England journal of medicine.

[26]  P. Cryer,et al.  Glycemic thresholds for activation of glucose counterregulatory systems are higher than the threshold for symptoms. , 1987, The Journal of clinical investigation.