Citations

To assess the normality of islet A- and B-cell responses to a nonglucose secretogogue as well as the modulating effect of glucose in NIDDM, we examined plasma C-peptide and glucagonresponses to arginine in eight patients with NIDDM and in six age- and weight-matched nondiabeticvolunteers under conditions of identical hypoglycemia (∼70 mg/dl), euglycemia (94 mg/dl), and hyperglycemia (∼190 mg/dl). Plasma C-peptide responses to glucose and to arginine in the diabetic subjects were both significantly reduced at all glucose concentrations studied (P < 0.01–0.005). The modulating effect of glucose on both islet A- and B-cell responses (slope of relation between plasma Cpeptide or glucagon response versus plasma glucose concentration) was reduced 80% in the diabetic subjects (P < 0.01). We conclude that islet A- and B-cell responses to nonglucose secretogogues are abnormal in patients with NIDDM and that this may result from a functional defect in the modulating effect of glucose on insulin and glucagon secretion, which in some patients may be compensated for by hyperglycemia.

Sixty-five patients with mild to moderate nonproliferative diabetic retinopathy who enrolled in a prospective controlled clinical trial had stereofundus photographs assessed for change over an 8-mo period. The entire study group showed a worsening of retinopathy with time (P < 0.001). The worsening was greater in the pump-treated group (15/32) than in the conventionally treated group (9/33). The significance of this difference ranged from P = 0.67, if changes in mean retinopathy level for each patient were compared, to P = 0.177 if a grading system keyed to the worse eye was compared. The difference in rates of change between treatment groups was found to be related to the baseline mean retinopathy level (P = 0.031), but less significantly so if baseline retinopathy keyed to the worse eye was used as a covariate (P = 0.08). Worsening occurred more frequently in those patients starting with the lower retinopathy levels. Progression was associated with the appearance of retinal infarcts (cotton-wool spots, soft exudates) and/or intraretinal microvascular abnormalities, with the pump patients showing a significant increase in these individual retinal lesions compared with the conventionally treated patients over 8 mo (P < 0.025).

A major goal of the study was to assess the methodologies available for the quantification of retinal lesions suitable for application in trials of metabolic management. We describe the methods used for grading stereoscopic color fundus photographs. Overall retinopathy severity level for each eye ranging from normal (level 10) to high-risk category (level 70) was assigned on the basis of gradings of individual lesions. Change in retinopathy severity level over the 8-mo period was detected in 3–62% of patients, depending on the method used and the definition of change. Lesions responsible for change in level were mainly retinal infarcts (soft exudates) and intraretinal microvascular abnormalities.

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.

Ketone bodies have been suggested to have a proteinsparing effect, since infusion of Na-β-hydroxybutyrate in man decreases plasma alanine concentrations and urinary nitrogen (N) excretion. To test this hypothesis, six normal postabsorptive volunteers were infused with Na-β-hydroxybutyrate for 3 h. Rates of glucose, leucine carbon, and alanine appearance and disappearance from the plasma space were traced with [3-3H]glucose, L-[6,6,6-2H3]leucine, and [2,3,3,3-2H4]alanine. Rates of leucine N appearance and disappearance and the rate of transfer of leucine N to alanine were assessed with [15N]leucine. During ketone body infusion, plasma alanine decreased (P < 0.05), whereas plasma leucine increased (P < 0.05). Rates of alanine appearance increased (5.3 ± 0.3 to 7.8 ± 0.6 μmol/kg · min), but the increase in its rate of disappearance was sightly greater, accounting for the decrease in plasma alanine concentration. Leucine N flux and the rate and percent of leucine N transferred to alanine increased, whereas leucine carbon flux was unchanged. To determine the effect of the alkalemia induced by Na-β-hydroxybutyrate, four additional subjects were infused with NaHCO3. Alkalemia had no effect on leucine N or carbon flux or on the rate of appearance of alanine, but increased the rate of alanine disappearance, resulting in a decrease in the plasma alanine concentration. Since the rate of appearance of leucine carbon was unaltered during the infusion of Na-β-hydroxybutyrate, it is unlikely that hyperketonemia per se decreases proteolysis in postabsorptive man.

To evaluate the roles of counterregulatory hormones and insulin antibodies in the impairment of plasma glucose recovery from hypoglycemia in diabetes mellitus, and to assess the relationship between the glucagon response and duration of the disease, 21 insulin-dependent diabetic patients and 10 nondiabetic subjects were studied. The diabetics consisted of 5 patients with recent onset of diabetes (< 1 mo); 11 with 2.6 ± 0.3 (mean ± SEM) yr duration of diabetes, 5 of whom had insulin antibodies; and 5 patients with long-term diabetes (21 ± 3 yr), insulin antibodies, and autonomic neuropathy. During insulin-induced hypoglycemia (28 mU/m2 × min for 60 min) in patients with recent-onset diabetes, plasma free insulin, glucose, and counterregulatory hormone concentrations did not differ from those of nondiabetic subjects. In patients with insulin antibodies, the disappearance of insulin after insulin infusion was delayed, and both restitution of normoglycemia and plasma glucagon response were blunted compared with patients without antibodies. When glucagon was infused (80–130 ng/m2 × min) during hypoglycemia in diabetics with impaired glucagon responses in order to simulate normal glucagon responses, plasma glucose recovery was normalized in patients without antibodies but not in those with antibodies. In patients with long-standing diabetes, restitution of normoglycemia was further impaired and this was associated with an absent plasma glucagon response and a diminished plasma epinephrine response. Plasma glucagon responses to hypoglycemia were inversely correlated to the duration of diabetes (r = −0.943; P < 0.0005). It is concluded that impaired A-cell secretion is the predominant mechanism for the delayed glucose recovery after hypoglycemia in diabetic patients without insulin antibodies and normal epinephrine responses. Slowed disappearance of insulin due to the presence of insulin antibodies further delays the restoration of normoglycemia. Patients with long-standing diabetes and autonomic neuropathy exhibit decreased epinephrine secretion, which leads to an additional retardation of glucose recovery. Since plasma glucagon and epinephrine responses to hypoglycemia were normal at the onset of diabetes but diminished in long-term diabetes, it appears that the impaired glucagon and epinephrine responses to hypoglycemia are acquired defects that develop subsequent to B-cell failure.

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.