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Context: Short sleep duration is associated with an increased risk of type 2 diabetes. Subchronic sleep restriction (SR) causes insulin resistance, but the mechanisms and roles of specific tissues are unclear., Objective: The purpose of this article was to determine whether subchronic SR altered (1) hepatic insulin sensitivity, (2) peripheral insulin sensitivity, and (3) substrate utilization., Design: This was a randomized crossover study in which 14 subjects underwent 2 admissions separated by a washout period. Each admission had 2 acclimatization nights followed by 5 nights of either SR (4 hours time in bed) or normal sleep (8 hours time in bed). MAIN OUTCOME MEASURE/METHODS: Insulin sensitivity (measured by hyperinsulinemic-euglycemic clamp) and hepatic insulin sensitivity (measured by stable isotope techniques) were measured. In addition, we assayed stress hormone (24-hour urine free cortisol, metanephrine, and normetanephrine), nonesterified fatty acid (NEFA), and β-hydroxybutyrate (β-OH butyrate) levels. Resting energy expenditure (REE) and respiratory quotient (RQ) were measured by indirect calorimetry., Results: Compared to normal sleep, whole-body insulin sensitivity decreased by 25% (P = .008) with SR and peripheral insulin sensitivity decreased by 29% (P = .003). Whereas hepatic insulin sensitivity (endogenous glucose production) did not change significantly, percent gluconeogenesis increased (P = .03). Stress hormones increased modestly (cortisol by 21%, P = .04; metanephrine by 8%, P = .014; normetanephrine by 18%, P = .002). Fasting NEFA and β-OH butyrate levels increased substantially (62% and 55%, respectively). REE did not change (P = 0.98), but RQ decreased (0.81 ± .02 vs 0.75 ± 0.02, P = .045)., Conclusion: Subchronic SR causes unique metabolic disturbances characterized by peripheral, but not hepatic, insulin resistance; this was associated with a robust increase in fasting NEFA levels (indicative of increased lipolysis), decreased RQ, and increased β-OH butyrate levels (indicative of whole-body and hepatic fat oxidation, respectively). We postulate that elevated NEFA levels are partially responsible for the decrease in peripheral sensitivity and modulation of hepatic metabolism (ie, increase in gluconeogenesis without increase in endogenous glucose production). Elevated cortisol and metanephrine levels may contribute to insulin resistance by increasing lipolysis and NEFA levels.

Context: HIV-infected patients on antiretroviral therapy are at increased risk for excess visceral adiposity and insulin resistance. Treatment with GH decreases visceral adiposity but worsens glucose metabolism. IGF-I, which mediates many of the effects of GH, improves insulin sensitivity in HIV-negative individuals., Objective: Our objective was to determine whether IGF-I, complexed to its major binding protein, IGF-binding protein-3 (IGFBP-3), improves glucose metabolism and alters body fat distribution in HIV-infected patients with abdominal obesity and insulin resistance., Methods: We conducted a pilot, open-label study in 13 HIV-infected men with excess abdominal adiposity and insulin resistance to assess the effect of 3 months of treatment with IGF-I/IGFBP-3 on glucose metabolism and fat distribution. Glucose metabolism was assessed by oral glucose tolerance test and hyperinsulinemic-euglycemic clamp. Endogenous glucose production (EGP), gluconeogenesis, whole-body lipolysis, and de novo lipogenesis (DNL) were measured with stable isotope infusions. Body composition was assessed by dual-energy x-ray absorptiometry and abdominal computed tomography scan., Results: Glucose tolerance improved and insulin-mediated glucose uptake increased significantly during treatment. EGP increased under fasting conditions, and suppression of EGP by insulin was blunted. Fasting triglycerides decreased significantly in association with a decrease in hepatic DNL. Lean body mass increased and total body fat decreased, whereas visceral adipose tissue did not change., Conclusions: Treatment with IGF-I/IGFBP-3 improved whole-body glucose uptake and glucose tolerance, while increasing hepatic glucose production. Fasting triglycerides improved, reflecting decreased DNL, and visceral adiposity was unchanged.

Background: Some HIV protease inhibitors (PIs) have been shown to induce insulin resistance in vitro but the degree to which specific PIs affect insulin sensitivity in humans is less well understood., Methods: In two separate double-blind, randomized, cross-over studies, we assessed the effects of a single dose of ritonavir (800 mg) and amprenavir (1200 mg) on insulin sensitivity (euglycemic hyperglycemic clamp) in healthy normal volunteers., Results: Ritonavir decreased insulin sensitivity (-15%; P = 0.008 versus placebo) and non-oxidative glucose disposal (-30%; P = 0.0004), whereas neither were affected by amprenavir administration., Conclusion: Compared to previously performed studies of identical design using single doses of indinavir and lopinavir/ritonavir, a hierarchy of insulin resistance was observed with the greatest effect seen with indinavir followed by ritonavir and lopinavir/ritonavir, with little effect of amprenavir.

Posttraumatic stress disorder (PTSD) is associated with a 2–4 fold increased risk of developing Type 2 diabetes mellitus. However, detailed assessments of glucose metabolism and insulin secretion in a study designed to minimize confounders are lacking. Furthermore, few studies examine potential mechanisms involved. We analyzed data from a case–control study of medically healthy, medication-free adults to determine whether individuals with PTSD had abnormal glucose or insulin response to oral glucose tolerance test (OGTT) compared to controls. Secondarily, we assessed potential mediators such as sleep, cortisol and adiponectin. Data was analyzed from 92 age and gender-matched subjects (44 PTSD, 48 controls). Chronic PTSD was diagnosed using the Structured Clinical Interview for DSM-IV and Clinician Administered PTSD Scale. Subjects underwent 75-g OGTT, actigraphy and sleep diary (to quantify sleep duration), polysomnography (to assess slow wave sleep [SWS] and delta power), and overnight blood sampling (for cortisol and adiponectin). At baseline, individuals with PTSD had mildly increased insulin levels (by 19%, compared to controls, p = 0.048) that was mediated primarily by weight. In response to OGTT, the PTSD group had higher levels of insulin at 120 min (by 44%, p = 0.03) and insulin AUC (by 43%, p = 0.015) compared to controls, after adjusting for confounders. Glucose levels were similar in the two groups. Although self-reported sleep duration, SWS, and delta power differed between PTSD subjects and controls, they did not mediate the effects of PTSD status on insulin response.Posttraumatic stress disorder (PTSD) is associated with a 2–4 fold increased risk of developing Type 2 diabetes mellitus. However, detailed assessments of glucose metabolism and insulin secretion in a study designed to minimize confounders are lacking. Furthermore, few studies examine potential mechanisms involved. We analyzed data from a case–control study of medically healthy, medication-free adults to determine whether individuals with PTSD had abnormal glucose or insulin response to oral glucose tolerance test (OGTT) compared to controls. Secondarily, we assessed potential mediators such as sleep, cortisol and adiponectin. Data was analyzed from 92 age and gender-matched subjects (44 PTSD, 48 controls). Chronic PTSD was diagnosed using the Structured Clinical Interview for DSM-IV and Clinician Administered PTSD Scale. Subjects underwent 75-g OGTT, actigraphy and sleep diary (to quantify sleep duration), polysomnography (to assess slow wave sleep [SWS] and delta power), and overnight blood sampling (for cortisol and adiponectin). At baseline, individuals with PTSD had mildly increased insulin levels (by 19%, compared to controls, p = 0.048) that was mediated primarily by weight. In response to OGTT, the PTSD group had higher levels of insulin at 120 min (by 44%, p = 0.03) and insulin AUC (by 43%, p = 0.015) compared to controls, after adjusting for confounders. Glucose levels were similar in the two groups. Although self-reported sleep duration, SWS, and delta power differed between PTSD subjects and controls, they did not mediate the effects of PTSD status on insulin response.In this case–control study, individuals with PTSD had a hyperinsulinemic response to oral glucose challenge compared to controls, suggestive of insulin resistance.

BackgroundChanges in the multiple mechanisms that regulate glucose metabolism after gastric bypass (RYGB) are still being unveiled. The objective of this study was to compare the changes of glucose and pancreatic hormones [C-peptide, glucagon, and pancreatic polypeptide (PP)] during a meal tolerance test (MTT) and steady-state insulin and free fatty acid (FFA) concentrations during euglycemic-hyperinsulinemic clamp 14 days and 6 months after RYGB in morbidly obese nondiabetic patients.MethodsTwo groups were studied at baseline and at 14 days: the RYGB followed by caloric restriction group (RYGB, n = 12) and the equivalent caloric restriction alone group (Diet, n = 10), to control for energy intake and weight loss. The RYGB group was studied again at 6 months to assess the changes after substantial weight loss. During MTT, the early and overall changes in glucose and pancreatic hormone concentrations were determined, and during the clamp, steady-state insulin and FFA concentrations were assessed.ResultsAfter 14 days, RYGB patients had enhanced postprandial glucose, C-peptide, and glucagon responses, and decreased postprandial PP concentrations. Steady-state insulin concentrations were decreased at 14 days only in RYGB patients, and FFA increased in both groups. Six months after RYGB and substantial weight loss, the decrease in insulin concentrations during clamp persisted, and there were further changes in postprandial glucose and glucagon responses. FFA concentrations during clamp were significantly lower at 6 months, relative to presurgical values.ConclusionsIn morbidly obese nondiabetic patients, RYGB produces early changes in postmeal glucose, C-peptide, glucagon, and PP responses, and it appears to enhance insulin clearance early after RYGB and improve insulin sensitivity in adipose tissue at 6 months postsurgery. The early changes cannot be explained by caloric restriction alone.

Altered gut and pancreatic hormone secretion may bolster resolution of insulin resistance after Roux-en-Y gastric bypass (RYGB), but the independent effects of weight loss and hormonal secretion on peripheral glucose disposal are unknown.Two groups of nondiabetic morbidly obese patients were studied: RYGB followed by standardized caloric restriction (RYGB, n = 12) or caloric restriction alone (diet, n = 10). Metabolic evaluations (euglycemic–hyperinsulinemic clamp, meal tolerance test) were done at baseline and 14 days (both groups) and 6 months after RYGB.At baseline, body composition, fasting insulin, and glucose and peripheral glucose disposal did not differ between groups. At 14 days, excess weight loss (EWL) was similar (RYGB, 12.7% vs. diet, 10.9%; p = 0.12), fasting insulin and glucose decreased to a similar extent, and RYGB subjects had altered postmeal patterns of gut and pancreatic hormone secretion. However, peripheral glucose uptake (M value) was unchanged in both groups. Six months after RYGB, EWL was 49.7%. The changes in fasting glucose and insulin levels and gut hormone secretion persisted. M values improved significantly, and changes in M values correlated with the % EWL (r = 0.68, p = 0.02).Improvement in peripheral glucose uptake following RYGB was observed only after substantial weight loss had occurred and correlated with the magnitude of weight lost.