Citations

Clinical risk factors for nephropathy were assessed in a population-based study of Rochester, Minnesota, residents with diabetes mellitus initially diagnosed between 1945 and 1969 (incidence cohort). The 1031 Rochester residents with non-insulin-dependent diabetes mellitus (NIDDM) were followed through their complete medical records in the community to 1 January 1982. The prevalence of persistent proteinuria was 8.2% at the diagnosis of NIDDM. Among those initially free of persistent proteinuria, the subsequent incidence was 15.3/1000 person-yr. Twenty years after the diagnosis of diabetes, the cumulative incidence of persistent proteinuria was 24.6%. A proportional hazards model identified the following risk factors for persistent proteinuria in NIDDM: elevated initial fasting blood glucose (P < .01); older age at onset of diabetes (P < .01); male gender (P = .05); and presence of macrovascular disease (P = .05), diabetic retinopathy (P = .05), or glycosuria (P = .07) at the diagnosis of diabetes. Separate analyses controlling for attained age indicated no association between duration of NIDDM and the incidence of persistent proteinuria. Stratified analysis of the two most significant risk factors (fasting blood glucose and age) indicated that hyperglycemia was a stronger risk factor for proteinuria in younger diabetic subjects, perhaps because of a competing risk of death in the elderly diabetic patient. In contrast to a recently described decreasing secular trend of proteinuria in Danish insulin-dependent diabetes mellitus patients, there was no decrease over the past 40 yr in proteinuria risk in this NIDDM incidence cohort.

To assess the possible influence of moderate titer insulin antibodies on diabetic glycemic control, we examined insulin-antibody equilibrium binding characteristics, postprandial glucose tolerance, and plasma free-insulin profiles after subcutaneous injection of both porcine and human insulin (0.15 U/kg) in 12 patients with insulin-dependent diabetes mellitus under conditions simulating intensive insulin therapy. The patients' antibodies bound porcine and human insulin indistinguishably, and their plasma glucose and freeinsulin profiles after ingestion of a standard meal were similar with both insulins. Initial increases in plasma free-insulin levels after injection of both insulins were negatively correlated with both insulin-antibody binding (r = −.55, P < .006) and postprandial hyperglycemia (peak level r = −.56, P < .006); the latter was positively correlated with insulin-antibody binding (r = .48, P < .02). The effects of insulin antibodies on postprandial plasma free-insulin and glucose levels could be accounted for substantially by the association constant of the high-affinity insulin-antibody binding sites (K1); patients in the highest quartile for K1 had significantly slower initial increments in plasma free insulin (0.31 ± 0.04 vs. 0.46 ± 0.06 μU/min, P < .05) and greater postprandial hyperglycemia (peak value 237 ± 10 vs. 166 ± 12 mg/dl, P < .001) than patients in the lowest quartile. We conclude that moderate insulin-antibody titers commonly found in insulin-treated patients can slow the early increase in plasma free insulin after subcutaneous injection and that this impairs postprandial glucose tolerance; such an effect may Received for publication 22 April 1986 and accepted in revised form 18 September 1986. limit the effectiveness of intensive insulin therapy.

Competition between glucose and free fatty acids as metabolic fuels is supported by both in vitro and in vivo data, but whether amino acids can also compete with glucose as a source of energy in vivo remains to be established. To determine the effect of increased availability of an amino acid on whole-body glucose flux and glucose carbon uptake by the human forearm, five groups of overnight-fasted normal subjects were infused with either saline, leucine (at 0.5 or 1.0μmol · kg−1 · min−1), isoleucine (0.5 μmol · kg−1 · min−1), or threonine (0.5 μmol · kg−1 · min−1). Plasma glucose concentrations and glucose flux decreased similarly in all groups. No significant changes in forearm output of leucine carbon, isoleucine carbon, or threonine were seen during saline infusion. In contrast, during leucine infusion there was a dose-dependent increase (r = .86, P < .001) in leucine carbon uptake with increased arterial leucine and a-ketoisocaproate concentrations. During infusions of isoleucine and threonine, increases (P < .05) in isoleucine carbon uptake and threonine uptake, respectively, were observed. Glucose uptake by forearm tissues did not change during the saline infusion, but it decreased (P < .05) in all four groups receiving an amino acid infusion. Changes in leucine carbon uptake were strongly correlated (r = −.76, P < .001) with changes in glucose uptake. Therefore, amino acids affect glucose uptake in human forearm tissue and presumably compete as oxidative fuels.

To determine whether therapy with exogenous insulin or sulfonylureas results in a postprandial pattern of carbohydrate metabolism in patients with non-insulin-dependent diabetes mellitus (NIDDM) that resembles that in nondiabetic individuals, we employed a dual-isotope technique combined with forearm catheterization to examine meal disposition in NIDDM patients, before and after 3 mo of therapy with tolazamide and after 3 mo of therapy with exogenous insulin, with a randomized crossover design. Results were compared with those observed in nondiabetic subjects. Although both forms of therapy improved chronic glycemic control (glycosylated hemoglobin concentration went from 9.6 ± 0.7 to 7.6 ± 0.5 and 7.1 ± 0.2%, respectively, P <.01), exogenous insulin resulted in a lower postprandial glycemic response than tolazamide (P <.001). Both agents comparably increased (P <.01) fasting and integrated postprandial insulin concentrations. However, the initial rate of postprandial increase was greater with exogenous insulin (P <.05). Tolazamide (P <.05) but not exogenous insulin increased postprandial C-peptide concentrations. However, tolazamide did not improve the deficient early insulin release. Both agents (P <.05) lowered postabsorptive hepatic glucose release (from 2.8 ± 0.3 to 2.3 ± 0.2 mg · kg−1 · min−1), but not to normal rates (1.8 ± 0.1 mg · kg−1 · min−1). Endogenous glucose release after carbohydrate ingestion was lowered (P <.001) by insulin (from 633 ± 52 to 460 ± 41 mg kg−1 7 h−1) but not by tolazamide (625 ± 62 mg · kg−1 · 7 h−1) to rates observed in nondiabetic subjects (470 ± 32 mg · kg−1 · 7 h−1). Unmetabolized meal glucose reaching the systemic circulation did not differ before or after therapy with either insulin or tolazamide. Total postprandial glucose uptake was not changed by tolazamide (1308 ± 85 mg kg−1 · 7 h−1) but was lowered (P <.01) by exogenous insulin (from 1269 ± 57 to 1088 ± 67 mg · kg−1 · 7 h−1) to normal rates (1023 ± 64 mg kg−1 7 h−1). Forearm glucose uptakedid not differ among any group. We conclude that, although tolazamide and exogenous insulin, as administered in this study, both improve carbohydrate tolerance, therapy with exogenous insulin results in a pattern of postprandial carbohydrate metabolism that more closely approximates that observed in nondiabetic subjects.

To assess the possible role of increased insulin clearance in the pathogenesis of the dawn phenomenon, we compared plasma free-insulin concentrations, free-insulin clearance rates, and plasma glucose concentrations in eight subjects with insulin-dependent diabetes mellitus (IDDM) during infusion of insulin from midnight to 0800 h (0.15 mU · kg−1 · min−1) with a Biostator and a Harvard pump. During infusion of insulin with the Biostator, plasma free insulin decreased 40% (from 14 ± 1 to 9 ± 1 μU/ml, P < .01), insulin clearance increased 54% (from 11 ± 1 to 17 ± 2 ml/min, P < .05), and plasma glucose increased from 101 ± 4 to 217 ± 27 mg/dl, P < .01. During infusion of insulin with the Harvard pump, neither plasma free insulin (14 ± vs. 13 ± 1 μU/ml) nor free-insulin clearance (12 ± 2 vs. 13 ± 2 ml/min) changed significantly, but plasma glucose increased from 100 ± 3 to 167 ± 21 mg/dl, P < .01. The increases in plasma glucose during infusion of insulin with the Biostator and the Harvard pump were not significantly different (t = 1.44, P = .19). When insulin was delivered directly into test tubes with the Biostator and the Harvard pump, insulin concentrations in the test tubes decreased 46% over 8 h (P < .05) with the Biostator, whereas no decrease was observed with the Harvard pump. We conclude that the dawn phenomenon can occur without an increase in insulin clearance and that the apparent overnight increase in insulin clearance observed in studies with the Biostator iS artifactual.

Studies with tritiated isotopes of glucose have demonstrated that hyperglycemia per se stimulates glucos utilization and suppresses glucose production in humans. These conclusions rely on the assumption that tritiated glucose provides an accurate measure of glucose turnover. However, if in the presence of hyperglycemia the isotope either loses its label during “futile” cycling or retains its label during cycling through glycogen, then this assumption is not valid. To examine this question, glucose utilization and glucose production rates were measuredin nine normal subjects with a simultaneous infusion of [23H]glucose, an isotope that may undergo futile cycling but does not cycle through glycogen; [614C]glucose, an isotope that may cycle through glycogen but does not futile cycle; and [33H]glucose, an isotope that can both undergo futile cycling and cycle through glycogen. In the postabsorptive state at plasma glucose concentration of 95 mg dl−1, glucose turnover determined with [614C]glucose (2.3 ±0.1 mg kg−1 min−1) was greater than that determined with [33H]glucose (2.1 ± 0.1 mg kg−1 min−1 P = 0.002) and slightly less than that determined with [23H]glucose (2.7 ± 0.2 mg kg−1 min−1 P = 0.08). Plasma glucose was then raised from 95 to 135 to 175 mg dl−1 while insulin secretion was inhibited, and circulating insulin, glucagon, and growth hormone concentrations were maintained constant by infusion of these hormones and somatostatin. Glucose production and utilization rates determined with [614C]-glucose continued to be less than those determined with [23H]glucose and greater than those seen with [33H]glucose. However, the decrements in glucose production and increments in glucose utilization were identical with all isotopes. Glucagon was then infused at a high rate to stimulate endogenous glucose release. This resulted in a significant (P < 0.05) increase in both [614C]- and [33H]- but not [23H]giucose, indicating release of the former two isotopes from glycogen. This resulted in a significantly lower (P < 0.04) estimate of glucose production and utilization during the glucagon infusion determined with [614C]- and [33H]glucose compared with that determined with [23H]glucose. Thus, whereas neither [23H]- nor [33H]glucose precisely reflect glucose turnover measured by [614C]glucose, all three isotopes provide an equivalent assessment of the effects of hyperglycemia on glucose production and utilization in humans. However, release of either [614C]- or [33H]glucose from glycogen may result in an underestimate Of glucose turnover.

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.

In man, a decrease in plasma glucose concentration results in a compensatory increase in hepatic glucose release. Studies in vitro have suggested that a low glucose concentration per se may directly stimulate hepatic glucose release, an effect often referred to as autoregulation. Whether autoregulation occurs in man in response to a physiologic decrement in blood glucose is not known. Therefore, seven healthy, nonobese subjects were studied on two occasions to determine the role of autoregulation in mediating the increase in glucose production that accompanies a physiologic decrement in plasma glucose concentration. On both occasions, plasma glucose concentrations were clamped successively at 95, 65, and 95 mg/dl for 2 h each. Insulin (∼14 μU/ml) and glucagon (∼70 pg/ml) were maintained constant on both occasions by an infusion of somatostatin and insulin. Phentolamine and propranolol also were infused on one occasion to produce combined alpha- and beta-adrenergic blockade. In the absence of adrenergic blockade, glucose production increased by approximately 1.3 mg/kg min when the plasma glucose concentration was decreased from 95 to 65 mg/dl and decreased by approximately 1.5 mg/kg min when glucose was increased from 65 to 95 mg/dl. In the presence of adrenergic blockade, the increase and decrease in glucose production averaged 0 and 0.5 mg/kg·min, respectively, representing 70–100% inhibition. We conclude that, in the presence of low physiologic insulin concentrations, autoregulation is not a major contributor to the hepatic response to a physiologic decrement in plasma glucose concentration in man.

Type A insulin resistance, associated with acanthosis nigricans and menstrual irregularity, has been ascribed to a decreased concentration of insulin receptors. We now report four affected females from one family, a mother and three daughters (including identical twins) who appear to have the type A syndrome. Two of the kindred had no apparent ovarian dysfunction, while the other two had hyperprolactinemia without other findings of polycystic ovary disease, suggesting a genetic disease with variable penetrance. All had normal erythrocyte and monocyte insulin binding. Insulin dose-response studies to assess glucose metabolism and insulinsensitivity were performed in the affected twins. The dose response to insulin was shifted to the right with a decrease in maximal response. These results are consistent with a postbinding defect in insulin action in these patients.

To determine whether glucose-mediated as well as insulin-mediated regulation of glucose utilization and glucose production is impaired in patients with insulindependent diabetes mellitus (IDDM), six nonobese, diabetic patients and seven age-, sex-, and weightmatched nondiabetic subjects were studied. Despite slightly higher free insulin concentrations in the diabetic patients than in the nondiabetic subjects during 0.2 mU/kg · min (22 ± 3 versus 15 ± 2 μU'ml) and 1.0 mU'kg · min (98 ± 10 versus 75 μU/ml) insulin infusions, glucose utilization at plasma glucose concentrations of 95, 135, and 175 mg/dl was lower in the diabetic patients than in the nondiabetic subjects. The increment in glucose utilization per increment in plasma glucose (i.e., slope) in the diabetic and nondiabetic subjects, respectively, did not differ significantly during either the 0.2 (1.7 ±1.3 versus 1.4 ± 0.5 dl/kg · min) or 1.0 (4.4 ±1.1 versus 6.2 ±1.0 dl/kg · min) mU/kg · min insulin infusions, although they tended to be higher in the nondiabetic subjects during the latter infusion. Thus, although stimulation of glucose utilization by insulin is impaired in patients with IDDM, the ability of an increase in glucose concentration to increase glucose utilization does not appear to differ from that present in nondiabetic subjects, at insulin concentrations in the low physiologic range. Whether differences exist in the high physiologic range remains to be determined.