Iatrogenic hypoglycemia causes recurrent morbidity in most people with type 1 diabetes and many with type 2 diabetes, and it is sometimes fatal. The barrier of hypoglycemia generally precludes maintenance of euglycemia over a lifetime of diabetes and thus precludes full realization of euglycemia's long-term benefits. While the clinical presentation is often characteristic, particularly for the experienced individual with diabetes, the neurogenic and neuroglycopenic symptoms of hypoglycemia are nonspecific and relatively insensitive; therefore, many episodes are not recognized. Hypoglycemia can result from exogenous or endogenous insulin excess alone. However, iatrogenic hypoglycemia is typically the result of the interplay of absolute or relative insulin excess and compromised glucose counterregulation in type 1 and advanced type 2 diabetes. Decrements in insulin, increments in glucagon, and, absent the latter, increments in epinephrine stand high in the hierarchy of redundant glucose counterregulatory factors that normally prevent or rapidly correct hypoglycemia. In insulin-deficient diabetes (exogenous) insulin levels do not decrease as glucose levels fall, and the combination of deficient glucagon and epinephrine responses causes defective glucose counterregulation. Reduced sympathoadrenal responses cause hypoglycemia unawareness. The concept of hypoglycemia-associated autonomic failure in diabetes posits that recent antecedent hypoglycemia causes both defective glucose counterregulation and hypoglycemia unawareness. By shifting glycemic thresholds for the sympathoadrenal (including epinephrine) and the resulting neurogenic responses to lower plasma glucose concentrations, antecedent hypoglycemia leads to a vicious cycle of recurrent hypoglycemia and further impairment of glucose counterregulation. Thus, short-term avoidance of hypoglycemia reverses hypoglycemia unawareness in most affected patients. The clinical approach to minimizing hypoglycemia while improving glycemic control includes 1) addressing the issue, 2) applying the principles of aggressive glycemic therapy, including flexible and individualized drug regimens, and 3) considering the risk factors for iatrogenic hypoglycemia. The latter include factors that result in absolute or relative insulin excess: drug dose, timing, and type; patterns of food ingestion and exercise; interactions with alcohol and other drugs; and altered sensitivity to or clearance of insulin. They also include factors that are clinical surrogates of compromised glucose counterregulation: endogenous insulin deficiency; history of severe hypoglycemia, hypoglycemia unawareness, or both; and aggressive glycemic therapy per se, as evidenced by lower HbA 1c levels, lower glycemic goals, or both. In a patient with hypoglycemia unawareness (which implies recurrent hypoglycemia) a 2-to 3-week period of scrupulous avoidance of hypoglycemia is advisable. Pending the prevention and cure of diabetes or the development of methods that provide glucose-regulated insulin replacement or secre...
We examined the in vivo metabolic effects of vanadyl sulfate (VS) in non-insulin-dependent diabetes mellitus (NIDDM). Six NIDDM subjects treated with diet and/or sulfonylureas were examined at the end of three consecutive periods: placebo for 2 wk, VS (100 mg/d) for 3 wk, and placebo for 2 wk. Euglycemic hyperinsulinemic (30 mU/ m2 * min) clamps and oral glucose tolerance tests were performed at the end of each study period. Glycemic control at baseline was poor (fasting plasma glucose 210±19 mg/ dl; HbAlc 9.6±0.6%) and improved after treatment (181±14 mg/dl [P < 0.05],8.8±0.6%, [P < 0.002]); fasting and post-glucose tolerance test plasma insulin concentrations were unchanged. After VS, the glucose infusion rate during the clamp was increased (by -88%, from 1.80 to 3.38 mg/kg* min, P < 0.0001). This improvement was due to both enhanced insulin-mediated stimulation of glucose uptake (rate of glucose disposal [Rd.], +0.89 mg/kg min) and increased inhibition of HGP (-0.74 mg/kg r min) (P < 0.0001 for both). Increased insulin-stimulated glycogen synthesis (+0.74 mg/kg min, P < 0.0003) accounted for > 80% of the increased Rd after VS, and the improvement in insulin sensitivity was maintained after the second placebo period. The K. of skeletal muscle glycogen synthase was lowered by -30% after VS treatment (P < 0.05).These results indicate that 3 wk of treatment with VS improves hepatic and peripheral insulin sensitivity in insulin-resistant NIDDM humans. These effects were sustained for up to 2 wk after discontinuation of VS. (J. Clin. Invest. 1995. 95:2501-2509
Insulin resistance and -cell dysfunction, two factors central to the pathogenesis of type 2 diabetes, were studied in relation to the development of diabetes in a group of participants with impaired glucose tolerance in the Diabetes Prevention Program (DPP) at baseline and after specific interventions designed to prevent diabetes. Participants were randomly assigned to placebo (n ؍ 1,082), metformin (850 mg twice a day) (n ؍ 1,073), or intensive lifestyle intervention (n ؍ 1,079). The diabetes hazard rate was negatively associated with baseline insulin sensitivity (hazard rate ratio ؍ 0.62-0.94 per SD difference, depending on treatment group and measure of sensitivity) and with baseline insulin secretion (hazard rate ratio ؍ 0.57-0.76 per SD). Improvements in insulin secretion and insulin sensitivity were associated with lower hazard rates in all treatment arms (hazard rate ratio ؍ 0.46 -0.95 per SD increase and 0.29 -0.79 per SD increase, respectively). In multivariate models that included the three metabolic variables (changes in body weight, insulin sensitivity, and insulin secretion) each significantly and independently predicted progression to diabetes when adjusted for the other two variables. The intensive lifestyle intervention, which elicited the greatest reduction in diabetes incidence, produced the greatest improvement in insulin sensitivity and the best preservation of -cell function after 1 year, whereas the placebo group, which had the highest diabetes incidence, had no significant change in insulin sensitivity and -cell function after 1 year. In the metformin group, diabetes risk, insulin sensitivity, and -cell function at 1 year were intermediate between those in the intensive lifestyle and placebo groups. In conclusion, higher insulin secretion and sensitivity at baseline and improvements in response to treatment were associated with lower diabetes risk in the DPP. The better preventive effectiveness of intensive lifestyle may be due to improved insulin sensitivity concomitant with preservation of -cell function.
We evaluated the effect of antecedent hypoglycemia on glucose counterregulation during hypoglycemia in non-diabetic human subjects. In single hypoglycemia studies, glucose production [( 3H]3-glucose) and counterregulatory hormone concentrations were measured (after a 3.5-h baseline period of euglycemia) during 120 min of hypoglycemia (glucose clamped at 3.0 mmol/L). During the final 60 min of hypoglycemia, counterregulation resulted in significant increments in glucose production (12.88 +/- 0.83 mumol/kg.min), and plasma glucagon (IRG; 185 +/- 22 ng/L), GH (29.3 +/- 7.0 micrograms/L), cortisol (630 +/- 100 nmol/L), epinephrine (3.44 +/- 0.76 nmol/L), and norepinephrine (2.02 +/- 0.21 nmol/L). In the recurrent hypoglycemia experiment, an antecedent period of identical hypoglycemia was induced. Glucose counterregulation during the second of two periods of hypoglycemia (HYPO 2) was then compared to that in single hypoglycemia studies. During HYPO 2, there were decreased responses in Ra (by 32%; P less than 0.03), GH (by 67%; P less than 0.05), F (by 41%; P less than 0.03), and norepinephrine (by 20%; P = 0.03) compared to those in the single hypoglycemia study. In contrast, plasma IRG values were similar in the single hypoglycemia studies and HYPO 2, but were reduced relative to those during the first hypoglycemic period of recurrent hypoglycemia (IRG, 263 +/- 18 ng/L; P less than 0.025 vs. HYPO 2 and P less than 0.05 vs. single hypoglycemia). Our results suggest that 1) antecedent hypoglycemia may alter glucose counterregulation during hypoglycemia; and 2) recurrent hypoglycemia may result in alterations in reduction of hepatic glucose production.
We infused epinephrine, glucagon, and cortisol in combination into health overnight-fasted subjects in doses designed to simulate changes in severe stress. When all three hormones were infused simultaneously, glucose levels rose above 200 mg/dl in spite of a 100-200% increase in plasma insulin. In contrast, infusion of each hormone individually produced either a mild (less than 120 mg/dl) or a transient elevation in the plasma glucose concentration. With the combined hormone infusion, the increment in plasma glucose was 3-fold greater than the sum of the responses to the individual hormones (P less than 0.001). The marked hyperglycemia in this setting is a result of ongoing glucose overproduction which is stimulated by epinephrine and glucagon and sustained by cortisol. Furthermore, epinephrine (and possibly cortisol) inhibited glucose disposal despite concomitant hyperinsulinemia. In contrast to their effects on glucose regulation, the simultaneous infusion of epinephrine, glucagon, and cortisol failed to cause hyperketonemia. We conclude that the combined infusion of epinephrine, glucagon, and cortisol produces a greater than additive hyperglycemic response in normal humans. These data suggest that the clinical occurrence of fasting hyperglycemia in a setting of hypersecretion of multiple antiinsulin hormones (stress hyperglycemia) may result, at least in part, from synergistic interactions among these hormones.
Objective: To examine the persistence of the original treatment effects 10 years after the Diabetes Control and Complications Trial (DCCT) in the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study. In the DCCT, intensive therapy aimed at nearnormal glycemia reduced the risk of microvascular complications of type 1 diabetes mellitus compared with conventional therapy.Methods: Retinopathy was evaluated by fundus photography in 1211 subjects at EDIC year 10. Further 3-step progression on the Early Treatment Diabetic Retinopathy Study scale from DCCT closeout was the primary outcome.Results: After 10 years of EDIC follow-up, there was no significant difference in mean glycated hemoglobin levels (8.07% vs 7.98%) between the original treatment groups. Nevertheless, compared with the former conven-tional treatment group, the former intensive group had significantly lower incidences from DCCT close of further retinopathy progression and proliferative retinopathy or worse (hazard reductions, 53%-56%; PϽ.001). The risk (hazard) reductions at 10 years of EDIC were attenuated compared with the 70% to 71% over the first 4 years of EDIC (PϽ.001). The persistent beneficial effects of former intensive therapy were largely explained by the difference in glycated hemoglobin levels during DCCT. Conclusion:The persistent difference in diabetic retinopathy between former intensive and conventional therapy ("metabolic memory") continues for at least 10 years but may be waning.
We examined the ability of an equivalent increase in circulating glucose concentrations to inhibit endogenous glucose production (EGP) and to stimulate glucose metabolism in patients with Type 2 diabetes mellitus (DM2). Somatostatin was infused in the presence of basal replacements of glucoregulatory hormones and plasma glucose was maintained either at 90 or 180 mg/dl. Overnight low-dose insulin was used to normalize the plasma glucose levels in DM2 before initiation of the study protocol. In the presence of identical and constant plasma insulin, glucagon, and growth hormone concentrations, a doubling of the plasma glucose levels inhibited EGP by 42% and stimulated peripheral glucose uptake by 69% in nondiabetic subjects. However, the same increment in the plasma glucose concentrations failed to lower EGP, and stimulated glucose uptake by only 49% in patients with DM2. The rate of glucose infusion required to maintain the same hyperglycemic plateau was 58% lower in DM2 than in nondiabetic individuals. Despite diminished rates of total glucose uptake during hyperglycemia, the ability of glucose per se (at basal insulin) to stimulate whole body glycogen synthesis (glucose uptake minus glycolysis) was comparable in DM2 and in nondiabetic subjects. To examine the mechanisms responsible for the lack of inhibition of EGP by hyperglycemia in DM2 we also assessed the rates of total glucose output (TGO), i.e., flux through glucose-6-phosphatase, and the rate of glucose cycling in a subgroup of the study subjects. In the nondiabetic group, hyperglycemia inhibited TGO by 35%, while glucose cycling did not change significantly. In DM2, neither TGO or glucose cycling was affected by hyperglycemia. The lack of increase in glucose cycling in the face of a doubling in circulating glucose concentrations suggested that hyperglycemia at basal insulin inhibits glucose-6-phosphatase activity in vivo. Conversely, the lack of increase in glucose cycling in the presence of hyperglycemia and unchanged TGO suggest that the increase in the plasma glucose concentration failed to enhance the flux through glucokinase in DM2.In summary, both lack of inhibition of EGP and diminished stimulation of glucose uptake contribute to impaired glucose effectiveness in DM2. The abilities of glucose at basal insulin to both increase the flux through glucokinase and to inhibit the flux through glucose-6-phosphatase are impaired in DM2. Conversely, glycogen synthesis is exquisitely sensitive to changes in plasma glucose in patients with DM2. ( J. Clin. Invest. 1998. 102:744-753.)
OBJECTIVE-The Diabetes Control and ComplicationsTrial (DCCT) demonstrated the powerful impact of glycemic control on the early manifestations of microvascular complications. Contemporary prospective data on the evolution of macrovascular and late microvascular complications of type 1 diabetes are limited. The Epidemiology of Diabetes Interventions and Complications (EDIC) study is a multicenter, longitudinal, observational study designed to use the well-characterized DCCT cohort of >1,400 patients to determine the long-term effects of prior separation of glycemic levels on micro-and macrovascular outcomes.RESEARCH DESIGN AND METHODS-Using a standardized annual history and physical examination, 28 EDIC clinical centers that were DCCT clinics will follow the EDIC cohort for 10 years. Annual evaluation also includes resting electrocardiogram, Doppler ultrasound measurements of ankle/arm blood pressure, and screening for nephropathy. At regular intervals, a timed 4-h urine is collected, lipid profiles are obtained, and stereoscopic fundus photographs are taken. In addition, dual B-mode Doppler ultrasound scans of the common and internal carotid arteries will be performed at years 1 and 6 and at study end.RESULTS-Written informed consent was obtained from 96% of the DCCT subjects. The participants, compared with nonparticipants, tended to have better glycemic control at the completion of the DCCT and were more likely to have their diabetes care provided by DCCT personnel. The EDIC baseline measurement stratified by sex delineates multiple cardiovascular disease risk factor differences such as age (older in men), waist-to-hip ratio (higher in men), HDL cholesterol (lower in men), hypertension (more prevalent in men), and maximum intimal-medial thickness of common and internal carotid arteries (thicker in men). Of the original conventional treatment group, 69% have changed to continuous subcutaneous insulin infusion or multiple daily injections. Although the mean HbA 1c difference between the intensive and conventional treatment groups narrowed at EDIC years 1 and 2, HbA 1c remained significantly lower in the intensive group. Of all expected clinic visits, 95% were completed, and the quality of EDIC data is very similar to that observed in the DCCT.CONCLUSIONS-Although obvious problems exist in extended follow-up studies of completed clinical trials, these are balanced by the value of continued systematic observation of the DCCT cohort. In contrast to other epidemiologic studies, EDIC will provide 1) definitive data on type 1 as distinct from type 2 diabetes; 2) reliance on prospective rather than on cross-sectional analysis; 3) long-term follow-up in a large population; 4) consistent use of objective, reliable measures of outcomes and glycemia; and 5) observation of patients from before the onset of complications. [3][4][5]. While the reduction of the earlier stages of diabetic complications could reasonably be expected to slow the evolution to end-stage complications, such as loss of vision or renal failure...
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