Ventura, M. M.

To compare glucose counter regulatory mechanisms during short-term hypoglycemia and prolonged hypoglycemia, insulin was infused either intravenously (160 mil · M−2 · min) for 10 min or subcutaneously (15 mU · M−2 · min) for 12 h in normal volunteers. With each type of insulin infusion, hypoglycemia (∼50 mg/dl) was either allowed to develop or was prevented (control experiments) by the glucose-clamp technique. During prolonged hypoglycemia, both increased glucose production (1.55 ± 0.05 versus 0.33 ± 0.14 mg · kg−1 · min in control experiments at 12 h, P < 0.01) and suppressed glucose utilization (1.55 ± 0.06 versus 3.17 ± 0.15 mg · kg−1 · min in control studies at 12 h, P < 0.01) were involved in counterregulation. During short-term hypoglycemia, only increased glucose production (3.23 ± 0.33 versus 0.06 ± 0.03 mg · kg−1 · min in control experiments at 60 min) was involved, since glucose clearance actually increased (3.99 ± 0.20 versus 2.88 ± 0.02 ml · kg−1 · min in control experiments at 60 min, P < 0.01). Estimated portal venous insulin concentrations decreased 40% (basal 24 ± 3 versus 14 ± 1 mU/ml at 60 min, P < 0.01) in the short-term hypoglycemia experiments but remained at basal levels (basal 25 ± 1 versus ∼26 μU/min between 1 and 12 h) during prolonged hypoglycemia. Despite the fact that hypoglycemia was more gradually induced in the prolonged hypoglycemia model, peak counterregulatory hormone responses were at least as great as those during short-term hypoglycemia. Plasma free fatty acids and ketone bodies increased 150–200% above basal (both P < 0.01) with counterregulation during prolonged hypoglycemia but did not increase above basal levels with counterregulation during short-term hypoglycemia. Finally, plasma alanine remained unchanged during short-term hypoglycemia but decreased nearly 40% during prolonged hypoglycemia (basal 327 ± 20 versus 208 ± 21 μM at 12 h, P < 0.01). We conclude that glucose counterregulatory mechanisms differ during short-term and prolonged hypoglycemia. In the former, only an increase in glucose production mediated by suppression of insulin secretion and increased glucagon secretion is involved, whereas during prolonged hypoglycemia, both a suppression of glucose utilization, and an increase in glucose production are important. These latter changes in glucose production and utilization may be influenced by changes in circulating nonglucose substrates (e.g., alanine, free fatty acids, and ketone bodies) as well as by hormonal factors acting on both hepatic and extrahepatic tissues.

The safety, reproducibility, and reliability of an insulin infusion test for assessment of adequate glucose counterregulation were evaluated in 18 patients with type I (insulin-dependent) diabetes mellitus. When the test (a 60-min, 30-mU/m2/min insulin infusion) was administered on three separate occasions at 3–4-wk intervals, coefficients of variation for plasma glucose and counterregulatory hormone (glucagon, epinephrine, cortisol, and growth hormone) responses averaged less than 8%. No patient experienced symptoms requiring discontinuation of the test and plasma glucose concentrations increased spontaneously after stopping the insulin infusion. Using objective criteria based on plasma glucose nadirs or postnadir rates of plasma glucose recovery, no patient judged to have adequate glucose counterregulation by the test (post-nadir rates of plasma glucose recovery or plasma glucose nadir above 0.4 mg/dl/min and 45 mg/dl) developed severe hypoglycemia (plasma glucose < 40 mg/dl) during up to 7 mo of intensive insulin therapy, whereas nearly all patients with inadequate counter-regulation did. We conclude that this test, when performed in standardized conditions, is safe and reproducible and can reliably predict those patients with type I diabetes who are at risk of developing severe hypoglycemia during intensive insulin therapy.

To ascertain whether the dawn phenomenon occurs in nondiabetic individuals and, if so, whether it is due to an increase in glucose production or a decrease in glucose utilization, we determined plasma concentrations of glucose, insulin, C-peptide, and counter regulatory hormones, as well as rates of glucose production, glucose utilization, and insulin secretion at one-halfhourly intervals between 1:00 and 9:00 a.m. in eight normal volunteers. After 5:30 a.m., plasma glucose, insulin, and C-peptide concentrations all increased significantly; rates of glucose production, glucose utilization, and insulin secretion also increased (all P < 0.05). Plasma cortisol, epinephrine, and norepinephrine increased significantly from nocturnal nadirs between 4:00 and 6:30 a.m. Plasma growth hormone, which had increased episodically between 1:00 and 4:30 a.m., decreased thereafter nearly 50% (P < 0.05). Plasma glucagon did not change significantly throughout the period of observation. These results indicate that a dawn-like phenomenon, initiated by an increase in glucose production, occurs in nondiabetic individuals. Thus, early morning increases in plasma glucose concentrations and insulin requirements observed in IDDM and NIDDM may be an exaggeration of a physiologic circadian variation in hepatic insulin sensitivity induced by antecedent changes in catecholamine and/or growth hormone secretion.