Perriello, G.

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 assess the effects of glycemie control on glucose counterregulation, rates of plasma glucose recovery from hypoglycemia and counterregulatory hormonal responses were studied in 18 C-peptide-negative patients with insulin-dependent diabetes mellitus (IDDM) before and after either improvement, no change, or deterioration in glycemic control. Hypoglycemia was induced by an i.v. insulin infusion (30 mU/m2 · min for 1 h) after maintenance of euglycemia overnight with i.v. insulin. In 13 patients with long duration of IDDM (9 ± 0.5 yr, mean ± SEM) and initially poor glycemic control (mean diurnal blood glucose, MBG 199 ± 8 mg/dl, ketoamine-HbA1 12.4 ± 0.2%; nondiabetic subjects 104 ± 4 mg/dl and 6.8 ± 0.09%, respectively), rates of plasma glucose recovery from hypoglycemia (0.30 ± 0.01 versus 0.60 ± 0.01 mg/dl · min in nondiabetic subjects, P < 0.001) and plasma glucagon (AUC 0.56 ± 0.09 versus 6.3 ± 0.50 ng/ml ·150 min in non-diabetic subjects, P < 0.01) and epinephrine (AUC 16.9 ± 0.2 versus 25.7 ± 0.2 ng/ml 150 min in nondiabetic subjects, P < 0.001) responses to hypoglycemia were impaired. Intensive therapy (three daily injections of insulin) instituted in 7 out of 13 IDDM patients for up to 9 mo improved MBG (124 ± 6 mg/dl, P < 0.01) and ketoamine-HbA1 (7.9 ± 0.02%, P < 0.01) but not rates of plasma glucose recovery (0.31 ± 0.01 mg/dl · min) and plasma glucagon (AUC 0.69 ± 0.07 ng/ml · 150 min) and epinephrine (AUC 14.9 ± 0.17 ng/ml ·150 min) responses. Similarly, no changes in glucose counterregulation were observed in the six IDDM patients in whom glycemic control was poorly maintained for 6–8 mo (MBG 201 ± 7 mg/dl, ketoamine-HbA112.3 ± 0.2%). In five patients with short duration of IDDM (11 ± 0.5 mo) and optimized glycemic control (MBG 131 ± 8 mg/dl, ketoamine-HbA1 7.9 ± 0.2%), rates of plasma glucose recovery, as well as counterregulatory responses of plasma glucagon and epinephrine, were normal. Neither deterioration of glycemic control for 2 wk (MBG 229 ± 12 mg/dl, ketoamine-HbA1 9.1 ± 0.2%) nor its improvement over the 2 subsequent wk (MBG 120 ± 8 mg/dl, ketoamine-HbA1 8.5 ± 0.2%) resulted in any significant change in glucose counterregulation. It is concluded that near-normalization of glycemic control for up to 9 mo is insufficient to reverse the impairment in glucose counterregulation found in long-term IDDM. Short-term deterioration in glycemic control, when not accompanied by alterations in counterregulatory hormone secretion, does not impair glucose counterregulation.

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.

In order to assess the adrenergic contribution to hypoglycemie glucose counterregulation in type | diabetes mellitus and to determine whether the adrenergic contribution is mediated through beta1- or beta2-adrenergic receptors, hypoglycemia was induced by an i.v. insulin infusion (30 mU/m2 · min) for 60 min in 11 insulin-dependent diabetic patients (IDDM), 5 with normal plasma glucagon responses and 6 with blunted responses, and also in 7 age-weight-matched nondiabetic subjects. Rates of plasma glucose decrease and postnadir increase, as well as plasma concentrations of free insulin and of counterregulatory hormones, were measured when insulin was infused alone, and when insulin was infused along with propranolol (a beta1- and beta2-adrenergic receptor antagonist) or metoprolol (a selective beta1-antagonist). Postnadir plasma glucose recovery was decreased in IDDM with blunted plasma glucagon responses (21 ± 0.8 µmol. L−1 min−1, P < 0.001), but was normal in patients with normal plasma glucagon responses (30 ± 0.4 versus 33 ± 0.5 μmol · L−1 · min−1 in nondiabetic subjects, P = NS). Postnadir plasma glucose recovery was not affected by either propranolol or metoprolol in normal subjects and in IDDM with normal glucagon responses. However, in IDDM with blunted plasma glucagon responses, postnadir plasma glucose recovery was further decreased by propranolol (14 ± 0.6 µmol. L−1 min1, P < 0.01), but was unaffected by metoprolol (22 ± 0.9 μmol. L 1 min1, P = NS). These results demonstrate that, as in normal man, adrenergic mechanisms are not essential for normal plasma glucose recovery from hypoglycemia in IDDM with normal plasma glucagon responses. However, in IDDM with blunted plasma glucagon responses, adrenergic mechanisms become important for glucose counterregulation although they do not fully compensate for the blunted plasma glucagon responses. Since propranolol delayed plasma glucose recovery from hypoglycemia in IDDM with blunted glucagon responses but metoprolol had no effect, the adrenergic contribution to glucose counterregulation appears to be mediated through beta2-adrenergic receptors.