Kristina I. Rother

Efficacy and Safety of Troglitazone in the Treatment of Lipodystrophy Syndromes

Obesity causes insulin resistance, a central feature in the pathogenesis of type 2 diabetes (1). Paradoxically, the absence of adipose tissue also causes insulin resistance and diabetes in humans (2, 3) and genetically engineered animal models (4-6). Lipoatrophy and lipodystrophy are features of a group of heterogeneous syndromes characterized by a paucity of fat, insulin resistance, and hypertriglyceridemia (7). If patients develop diabetes, the syndrome is referred to as lipoatrophic diabetes. The disease has several genetic forms, including face-sparing partial lipoatrophy (the Dunnigan syndrome or the KoberlingDunnigan syndrome, OMIM [Online Mendelian Inheritance in Man] 308980), an autosomal dominant form caused by mutations in the lamin A/C gene (8), and congenital generalized lipoatrophy (the SeipBerardinelli syndrome, OMIM 269700), an autosomal recessive form mapping to chromosome 9q34 in some pedigrees (9). These diseases are rare; reported estimated prevalences are less than 1 in 10 million (10), although our experience suggests that the actual prevalences may be somewhat higher. An association between lipoatrophy and autoimmune disease, such as juvenile dermatomyositis, has also been described (11), suggesting that autoimmune destruction of adipose tissue results in a form of lipoatrophy. Thiazolidinediones, a new class of antidiabetic drugs (12), are ligands for peroxisome proliferatoractivated receptor- (PPAR-), a nuclear receptor expressed predominantly in adipose tissue (13). Thiazolidinediones are believed to exert their primary actions in adipose tissue and to indirectly increase insulin sensitivity in other tissues (14). Because thiazolidinediones have been reported to both increase insulin sensitivity (15, 16) and promote adipocyte development (17), these drugs seemed ideally suited to treat lipoatrophic diabetes. Troglitazone, the first thiazolidinedione to be approved for therapeutic use in the United States, has been shown to improve glycemic control and ameliorate hypertriglyceridemia in patients with type 2 diabetes (18). However, the use of troglitazone is complicated by a rare form of severe, irreversible hepatotoxicity. Two additional thiazolidinediones, rosiglitazone and pioglitazone, were recently approved for use. These drugs are also effective in improving glycemic control in patients with type 2 diabetes (19). Although initial studies of rosiglitazone and pioglitazone suggested that they might not be toxic to the liver, recent reports have raised the possibility that rosiglitazone may rarely cause hepatotoxicity (19, 20). Because PPAR- ligands promote adipocyte differentiation in vitro (13), we hypothesized that troglitazone would promote adipocyte development in patients with various forms of lipoatrophy. This hypothesis implicitly assumes that some lipoatrophic patients possess pre-adipocytes that could be stimulated by troglitazone to complete adipocyte differentiation. In addition, we sought to determine whether troglitazone therapy would improve metabolic control in patients with various forms of lipoatrophy. In light of data suggesting that troglitazone exerts its primary effects on adipocytes, it was uncertain whether the drug would be effective in such patients. Methods Patients Potential study participants were referred by multiple physicians in the United States and Canada in response to advertisements placed in medical journals, notices on the Internet, or word-of-mouth. Some patients had been followed at the National Institutes of Health for varying periods of time (up to 20 years). Because of the rarity of the syndrome, it was not practical to conduct population-based recruitment. To be eligible for the study, patients had to have both insulin resistance and lipoatrophy. For our purposes, insulin resistance was defined as either a fasting plasma insulin level greater than 143 pmol/L or impaired response to intravenous insulin (0.15 U/kg). The latter criterion was defined as a decrease in plasma glucose of less than 50% in patients with fasting glucose levels of 11 mmol/L or less ( 200 mg/dL) or a decrease of 5.5 mmol/L or less (<100 mg/dL) in patients with fasting glucose levels greater than 11.1 mmol/L (>200 mg/dL). Of 33 patients screened for this study, 8 were excluded because serum aminotransferase concentrations were abnormal (range, 833 to 6666 nkat/L) and liver biopsies showed steatohepatitis with varying degrees of fibrosis. Five patients were excluded for various reasons, such as the inability to give informed consent or adhere to the study follow-up schedule. The remaining 20 patients were recruited into the study (Table). Table. Characteristics of the Study Patients Fat distribution was assessed by physical examination and magnetic resonance imaging (MRI). A region of the body was defined as affected if MRI showed a marked decrease in fat in that region. Four patients had generalized lipoatrophy, defined as involvement of the following nine regions: face, neck, upper trunk, abdominal subcutaneous fat, visceral fat, and all four extremities. Two of these patients (U1 and P1) had near-total absence of fat throughout their bodies; the other two (A1 and A2) had a generalized decrease in fat but retained some fat in their visceral abdomen. Sixteen patients, including 7 patients with the Dunnigan syndrome, had partial lipoatrophy affecting five to eight fat depots. Six patients had accompanying autoimmune disease or results on three or more laboratory tests that suggested autoimmunity (for example, antinuclear antibody, rheumatoid factor, and elevated erythrocyte sedimentation rate); these patients therefore were presumed to have an autoimmune cause of their lipoatrophy. The cause of lipoatrophy appeared to be genetic in 10 patients; lipoatrophy appeared shortly after birth in 1 patient, and 9 patients had several affected relatives. Seven of these 9 patients had Dunnigan partial lipodystrophy (21) (Table); the 7 patients were members of three pedigrees. After completion of the study, the diagnosis of the Dunnigan syndrome was confirmed by identifying the R482Q mutation in the lamin A/C gene in all three pedigrees (22). In 4 patients, the cause of disease was unknown. Of the 20 study patients (Table), 14 had diabetes and 2 had impaired glucose tolerance according to the 1997 American Diabetes Association criteria (23). Most diabetic patients were receiving pharmacotherapy before study entry. Five patients were receiving insulin (0.5 to 2 U/kg of body weight per day) and 5 were receiving sulfonylureas; patients continued to receive these therapies during the study. Two patients were receiving metformin, but this therapy was discontinued 6 weeks before initiation of troglitazone treatment. Syndromes of lipoatrophy are associated with substantial comorbid conditions. Of the 8 patients with triglyceride levels greater than 4.5 mmol/L (400 mg/dL), 6 had a history of pancreatitis. Seventeen patients had acanthosis nigricans, a dermatologic condition associated with insulin resistance. Twelve of the 18 female participants had histories of irregular menses and polycystic ovaries as documented by ultrasonography; 6 of these women had hirsutism. Of the 6 remaining female participants, 4 were postmenopausal, 1 was perimenopausal, and 1 was prepubertal. Fatty liver is another important feature sometimes associated with lipoatrophy. To be included in the study, patients had to have normal biochemical function of the liver (Table). Nevertheless, results of ultrasonography in 12 patients suggested fatty infiltration of the liver. Lipoatrophic diabetes was associated with chronic complications of diabetes in some patients. Six patients had albuminuria, seven had diabetic polyneuropathy, and three had diabetic retinopathy (one of whom had proliferative retinopathy). One patient had three-vessel coronary artery disease. Design Patients were treated with troglitazone in an open-label prospective trial in which each patient was compared with his or her own baseline state. Because of the rarity of lipoatrophy syndromes and the variability of the clinical features, it was not feasible to use a randomized, placebo-controlled design. The study was approved by the institutional review board of the National Institute of Diabetes and Digestive and Kidney Diseases. Informed consent was obtained from the patient or his or her legal guardian. The decision to analyze the data after 6 months of therapy was made before the study was begun. Patients were evaluated as inpatients at the Clinical Center of the National Institutes of Health before treatment with troglitazone was initiated. They were admitted again after 6 weeks, 3 months, and 6 months of treatment. Before starting troglitazone therapy, diabetic patients were followed for at least 6 weeks while receiving stable doses of medication. Patients receiving insulin or sulfonylureas continued therapy with these drugs; however, metformin therapy was discontinued before troglitazone therapy was initiated. In diabetic patients, troglitazone therapy was started at a dosage of 200 mg/d and was increased to 400 to 600 mg/d over the course of 6 to 12 weeks, with the goal of optimizing glycemic control. The slow titration was chosen to minimize the risk for hypoglycemia. Doses of insulin or sulfonylureas were decreased if this was necessary to prevent hypoglycemia. Patients received stable doses of lipid-lowering medication for at least 6 weeks before starting troglitazone therapy. In nondiabetic adult participants, troglitazone was prescribed at a dosage of 400 mg/d. In one 6-year-old child weighing 15 to 18 kg, the dosage was 100 mg/d. Liver function tests and blood counts were performed every 3 to 4 weeks. Patients completed weekly questionnaires about their symptoms to identify potential side effects. Patients were instructed not to change their diet and exercise habits during this study. Information about dietary habits was collected by using

Phosphatidylinositol 3-Kinase-dependent Membrane Association of the Bruton’s Tyrosine Kinase Pleckstrin Homology Domain Visualized in Single Living Cells

Phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) has been proposed to act as a second messenger to recruit regulatory proteins to the plasma membrane via their pleckstrin homology (PH) domains. The PH domain of Bruton’s tyrosine kinase (Btk), which is mutated in the human disease X-linked agammaglobulinemia, has been shown to interact with PI(3,4,5)P3 in vitro. In this study, a fusion protein containing the PH domain of Btk and the enhanced green fluorescent protein (BtkPH-GFP) was constructed and utilized to study the ability of this PH domain to interact with membrane inositol phospholipids inside living cells. The localization of expressed BtkPH-GFP in quiescent NIH 3T3 cells was indistinguishable from that of GFP alone, both being cytosolic as assessed by confocal microscopy. In NIH 3T3 cells coexpressing BtkPH-GFP and the epidermal growth factor receptor, activation of epidermal growth factor or endogenous platelet-derived growth factor receptors caused a rapid (<3 min) translocation of the cytosolic fluorescence to ruffle-like membrane structures. This response was not observed in cells expressing GFP only and was completely inhibited by treatment with the PI 3-kinase inhibitors wortmannin and LY 292004. Membrane-targeted PI 3-kinase also caused membrane localization of BtkPH-GFP that was slowly reversed by wortmannin. When the R28C mutation of the Btk PH domain, which causes X-linked agammaglobulinemia, was introduced into the fluorescent construct, no translocation was observed after stimulation. In contrast, the E41K mutation, which confers transforming activity to native Btk, caused significant membrane localization of BtkPH-GFP with characteristics indicating its possible binding to PI(4,5)P2. This mutant, but not wild-type BtkPH-GFP, interfered with agonist-induced PI(4,5)P2 hydrolysis in COS-7 cells. These results show in intact cells that the PH domain of Btk binds selectively to 3-phosphorylated lipids after activation of PI 3-kinase enzymes and that losing such binding ability or specificity results in gross abnormalities in the function of the enzyme. Therefore, the interaction with PI(3,4,5)P3 is likely to be an important determinant of the physiological regulation of Btk and can be utilized to visualize the dynamics and spatiotemporal organization of changes in this phospholipid in living cells.

SGLT2 Inhibitors May Predispose to Ketoacidosis

CONTEXT Sodium glucose cotransporter 2 (SGLT2) inhibitors are antidiabetic drugs that increase urinary excretion of glucose, thereby improving glycemic control and promoting weight loss. Since approval of the first-in-class drug in 2013, data have emerged suggesting that these drugs increase the risk of diabetic ketoacidosis. In May 2015, the Food and Drug Administration issued a warning that SGLT2 inhibitors may lead to ketoacidosis. EVIDENCE ACQUISITION Using PubMed and Google, we conducted Boolean searches including terms related to ketone bodies or ketoacidosis with terms for SGLT2 inhibitors or phlorizin. Priority was assigned to publications that shed light on molecular mechanisms whereby SGLT2 inhibitors could affect ketone body metabolism. EVIDENCE SYNTHESIS SGLT2 inhibitors trigger multiple mechanisms that could predispose to diabetic ketoacidosis. When SGLT2 inhibitors are combined with insulin, it is often necessary to decrease the insulin dose to avoid hypoglycemia. The lower dose of insulin may be insufficient to suppress lipolysis and ketogenesis. Furthermore, SGLT2 is expressed in pancreatic α-cells, and SGLT2 inhibitors promote glucagon secretion. Finally, phlorizin, a nonselective inhibitor of SGLT family transporters decreases urinary excretion of ketone bodies. A decrease in the renal clearance of ketone bodies could also increase the plasma ketone body levels. CONCLUSIONS Based on the physiology of SGLT2 and the pharmacology of SGLT2 inhibitors, there are several biologically plausible mechanisms whereby this class of drugs has the potential to increase the risk of developing diabetic ketoacidosis. Future research should be directed toward identifying which patients are at greatest risk for this side effect and also to optimizing pharmacotherapy to minimize the risk to patients.

Ingestion of Diet Soda Before a Glucose Load Augments Glucagon-Like Peptide-1 Secretion

OBJECTIVE The goal of this study was to determine the effect of artificial sweeteners on glucose, insulin, and glucagon-like peptide (GLP)-1 in humans. RESEARCH DESIGN AND METHODS For this study, 22 healthy volunteers (mean age 18.5 ± 4.2 years) underwent two 75-g oral glucose tolerance tests with frequent measurements of glucose, insulin, and GLP-1 for 180 min. Subjects drank 240 ml of diet soda or carbonated water, in randomized order, 10 min prior to the glucose load. RESULTS Glucose excursions were similar after ingestion of carbonated water and diet soda. Serum insulin levels tended to be higher after diet soda, without statistical significance. GLP-1 peak and area under the curve (AUC) were significantly higher with diet soda (AUC 24.0 ± 15.2 pmol/l per 180 min) versus carbonated water (AUC 16.2 ± 9.0 pmol/l per 180 min; P = 0.003). CONCLUSIONS Artificial sweeteners synergize with glucose to enhance GLP-1 release in humans. This increase in GLP-1 secretion may be mediated via stimulation of sweet-taste receptors on L-cells by artificial sweetener.

Interacting epidemics? Sleep curtailment, insulin resistance, and obesity

In the last 50 years, the average self‐reported sleep duration in the United States has decreased by 1.5–2 hours in parallel with an increasing prevalence of obesity and diabetes. Epidemiological studies and meta‐analyses report a strong relationship between short or disturbed sleep, obesity, and abnormalities in glucose metabolism. This relationship is likely to be bidirectional and causal in nature, but many aspects remain to be elucidated. Sleep and the internal circadian clock influence a host of endocrine parameters. Sleep curtailment in humans alters multiple metabolic pathways, leading to more insulin resistance, possibly decreased energy expenditure, increased appetite, and immunological changes. On the other hand, psychological, endocrine, and anatomical abnormalities in individuals with obesity and/or diabetes can interfere with sleep duration and quality, thus creating a vicious cycle. In this review, we address mechanisms linking sleep with metabolism, highlight the need for studies conducted in real‐life settings, and explore therapeutic interventions to improve sleep, with a potential beneficial effect on obesity and its comorbidities.

Possible adverse effects of SGLT2 inhibitors on bone

SGLT2 inhibitors decrease plasma glucose concentrations by inhibiting proximal tubular reabsorption of glucose in the kidney.1 The attractive efficacy profile of glucose-lowering plus weight loss must be balanced against possible side effects, including an increase in the incidence of treatment-emergent bone fractures observed in clinical studies. In a study of moderate renal impairment, 9.4% of patients treated with dapagliflozin (10 mg) experienced bone fractures while no fractures were observed in placebo-treated patients.2 Furthermore, a ~30% increase in bone fractures was observed in canagliflozin-treated patients in eight pooled clinical trials with longer mean duration (68 weeks).3 Although these data suggest the possibility that SGLT2 inhibitors might increase the risk of bone fractures, additional data will be required before drawing a firm conclusion. SGLT2 inhibitors increase tubular reabsorption of phosphate, thereby increasing serum phosphate levels3,4 (Fig. 1A). The body has evolved complex homeostatic mechanisms to regulate phosphate, and an increase in serum phosphate has the potential to exert an adverse impact upon bone (Fig. 1B). For example, phosphate administration increases PTH secretion.6 Furthermore, SGLT2 inhibitors increase levels of both phosphate and PTH.3,4 While canagliflozin caused a small increase in mean PTH (+7.9%), the standard deviation (SD) was relatively large (39.3%).3 Thus, a substantial number of canagliflozin-treated patients might experience a >50% increase in PTH levels – a change that could be clinically significant. In addition, phosphate administration has been reported to increase FGF23 levels in healthy volunteers,7 which would decrease 1,25-dihydroxyvitamin D levels. However, the mechanisms whereby phosphate regulates FGF23 remain controversial.8 In in vitro studies, phosphate exerts a direct effect to increase FGF23 mRNA levels in primary human fetal bone cells.9 In contrast, some evidence suggests phosphate decreases FGF23 expression by an indirect mechanism – possibly mediated by PTH.8 In light of the controversy, it is critical to conduct clinical studies to assess the effect of SGLT2 inhibitors upon FGF23 levels. Figure 1 Proposed mechanisms whereby SGTL2 inhibitors exert adverse effects on bone Phosphate administration increases both PTH and FGF23, two hormones that exert opposing effects upon vitamin D metabolism8 with PTH increasing and FGF23 decreasing 1,25-dihydroxyvitamin D levels. Accordingly, if SGLT2 inhibitors increase levels of both PTH and FGF23, one could not predict a priori the net impact upon 1,25-dihydroxyvitamin D. Nevertheless, available data suggest that SGLT2 inhibitors decrease mean 1,25-dihydroxyvitamin D levels.3 Canagliflozin caused a small decrease in mean 1,25-dihydroxyvitamin D levels (−12%), but the SD was relatively large (42.4%).3 Thus, a significant percentage of canagliflozin-treated patients could experience a clinically significant ~50% decrease in 1,25-dihydroxyvitamin D levels. In contrast to clinical data suggesting an increase in PTH, suprapharmacological doses of dapagliflozin decreased PTH in rats.10 An investigative toxicology study elucidated the mechanism.10 Dapagliflozin is relatively selective for SGLT2, but high doses administered in toxicology experiments were sufficient to inhibit intestinal SGLT1, which led to glucose malabsorption. Colonic bacteria fermented the unabsorbed glucose, which acidified the intestinal contents. Acid pH increased solubility of calcium, promoted calcium absorption, suppressed PTH, and promoted ectopic calcification. These suprapharmacologic doses of SGLT2 inhibitor are unlikely to be relevant to human pharmacology with approved doses of selective SGLT2 inhbitors.10 Sustained increases in PTH enhance bone resorption, and increase the risk of bone fractures. Similarly, increased levels of FGF23 have been associated with bone disease.8 Finally, decreased levels of 1,25-dihydroxyvitamin D may decrease absorption of Ca+2 from the GI tract, and impair bone calcification. Consistent with these mechanisms, canagliflozin was observed to increase bone turnover as reflected by increases in levels of both collagen type 1 beta-carboxy-telopeptide levels and osteocalcin (biomarkers for bone resorption and bone formation, respectively). In addition, both DXA and quantitative CT detected a decrease in bone mineral density in the lumbar spine and total hip after 52 weeks of therapy with canagliflozin (300 mg).3 In contrast, there was no statistically significant change in bone mineral density at the distal forearm and femoral neck. Additional data could place these observations into context – including a correlation of clinical outcomes (i.e., fractures) with changes in bone biomarkers and bone mineral density in individual patients. The existence of numerous homeostatic mechanisms creates challenges in interpretation of studies of mechanisms whereby SGLT2 inhibitors could affect bone health. For example, an increase in serum phosphate is predicted to increase FGF23 and PTH – both of which promote phosphaturia. Because of this negative feedback, the maximum increase in mean serum phosphate may be transient and/or small in magnitude. Nevertheless, even small changes may significantly affect bone health over years of drug exposure. Finally, it is important to recognize that most drug-treated patients do not experience bone fractures. Bone fractures may be most likely to occur in the subpopulation of “outlier” patients with above average changes in bone-related parameters. In short, mean data may not provide a full picture of the impact upon bone. Patients with type 2 diabetes are especially susceptible to adverse effects of drugs upon bone because of coexisting bone diseases (including post-menopausal osteoporosis, renal osteodystrophy, and diabetes-associated bone fragility). As reported in the ADOPT trial, thiazolidinediones increase the risk of bone fractures.11 After a one year lag, rosiglitazone-treated patients experienced an increase in bone fractures (hazard ratio, 1.6). Similarly, the fracture rate was not increased during the first year of treatment with canagliflozin, but patients experienced more fractures during the second year of therapy.3 The median follow-up for rosiglitazone-treated patients was four years, suggesting that the average duration of the pooled canagliflozin studies (68 weeks) was likely too short to provide conclusive data on fracture risk. Fortunately, ongoing FDA-mandated cardiovascular outcome studies with SGLT2 inhibitors are of sufficient size and duration to assess the risk of bone fractures. Several arguments have been advanced suggesting that the observed increase in fracture rate might be a “chance phenomenon”.2 For example, some fractures occur in the feet, hands, and patella, which were stated not to be associated with bone health.2,3 At the time of the FDA’s Dapagliflozin Advisory Committee, eight fractures had been observed among patients treated with dapagliflozin (10 mg) in the special study of patients with moderate renal impairment. These included one patient with a fractured patella and one with a foot fracture. It is impossible to draw firm conclusions based upon these two patients – either about the distribution of fractures among anatomical sites or whether the increased number of fractures will ultimately be confirmed as a toxicity associated with SGLT2 inhibitors. In contrast to biomarker data suggesting canagliflozin increases bone turnover,3 it has been reported that dapagliflozin does not affect mean bone mineral density or biomarkers of bone turnover in patients with normal to mildly impaired renal function.3,4 These obervations raise the question of whether the bone effects might be a compound-specific rather than mechanism-based. However, the literature suggests that any differences among compounds may be the consequence of dose selection rather than an intrinsic difference between the two compounds. Whereas the 300 mg dose of canagliflozin delivers maximal inhibition of SGLT2,3 the 10 mg dose of dapagliflozin delivers only sub-maximal inhibition.12 Specifically, the 10 mg dose was reported to cause ~35 g/day of urinary glucose excretion – approximately 35% less than the urinary glucose excretion caused by maximally effective doses of dapagliflozin (50–100 mg).4 Thus, canagliflozin (300 mg) might be more efficacious than dapagliflozin (10 mg) with respect to all mechanism-based pharmacology (both mechanism-based toxicity and glucose-lowering). It would require head-to-head trials to draw firm conclusions about comparative benefit:risk profiles of individual SGLT2 inhibitors. In conclusion, SGLT2 inhibitors have been observed to increase the incidence of treatment-emergent bone fractures, and the risk of fractures appears to increase over time. We have hypothesized plausible pathophysiologic mechanisms with potential to mediate adverse effects upon bone. Future mechanistic research may identify patients who are most vulnerable to develop drug-induced bone fractures (e.g., post-menopausal women), and may suggest therapeutic approaches to minimize the risk.

Artificial Sweeteners: A systematic review of metabolic effects in youth

Epidemiological data have demonstrated an association between artificial sweetener use and weight gain. Evidence of a causal relationship linking artificial sweetener use to weight gain and other metabolic health effects is limited. However, recent animal studies provide intriguing information that supports an active metabolic role of artificial sweeteners. This systematic review examines the current literature on artificial sweetener consumption in children and its health effects. Eighteen studies were identified. Data from large, epidemiologic studies support the existence of an association between artificially-sweetened beverage consumption and weight gain in children. Randomized controlled trials in children are very limited, and do not clearly demonstrate either beneficial or adverse metabolic effects of artificial sweeteners. Presently, there is no strong clinical evidence for causality regarding artificial sweetener use and metabolic health effects, but it is important to examine possible contributions of these common food additives to the global rise in pediatric obesity and diabetes.

Effects of Exenatide Alone and in Combination With Daclizumab on β-Cell Function in Long-Standing Type 1 Diabetes

OBJECTIVE In patients with long-standing type 1 diabetes, we investigated whether improved β-cell function can be achieved by combining intensive insulin therapy with agents that may 1) promote β-cell growth and/or limit β-cell apoptosis and 2) weaken the anti–β-cell autoimmunity. RESEARCH DESIGN AND METHODS For this study, 20 individuals (mean age 39.5 ± 11.1 years) with long-standing type 1 diabetes (21.3 ± 10.7 years) were enrolled in this prospective open-label crossover trial. After achieving optimal blood glucose control, 16 subjects were randomized to exenatide with or without daclizumab. Endogenous insulin production was determined by repeatedly measuring serum C-peptide. RESULTS In 85% of individuals with long-standing type 1 diabetes who were screened for participation in this trial, C-peptide levels ≥0.05 ng/ml (0.02 nmol/l) were found. Residual β-cells responded to physiological (mixed-meal) and pharmacological (arginine) stimuli. During exenatide treatment, patients lost 4.1 ± 2.9 kg body wt and insulin requirements declined significantly (total daily dose on exenatide 0.48 ± 0.11 vs. 0.55 ± 0.13 units · kg−1 · day−1 without exenatide; P = 0.0062). No signs of further activation of the underlying autoimmune disease were observed. Exenatide delayed gastric emptying, suppressed endogenous incretin levels, but did not increase C-peptide secretion. CONCLUSIONS In long-standing type 1 diabetes, which remains an active autoimmune disease even decades after its onset, surviving β-cells secrete insulin in a physiologically regulated manner. However, the combination of intensified insulin therapy, exenatide, and daclizumab did not induce improved function of these remaining β-cells.

Rise of Oxyntomodulin in Response to Oral Glucose after Gastric Bypass Surgery in Patients with Type 2 Diabetes

CONTEXT The mechanisms by which Roux-en-Y gastric bypass surgery (GBP) results in sustained weight loss and remission of type 2 diabetes are not fully understood. OBJECTIVE We hypothesized that the anorexic hormone oxyntomodulin (OXM) might contribute to the marked weight reduction and the rapid improvement in glucose metabolism observed in morbidly obese diabetic patients after GBP. METHODS Twenty obese women with type 2 diabetes were studied before and 1 month after GBP (n=10) or after a diet-induced equivalent weight loss (n=10). Patients from both groups were matched for age, body weight, body mass index, and diabetes duration and control. OXM concentrations were measured during a 50-g oral glucose challenge before and after weight loss. RESULTS At baseline, OXM levels (fasting and stimulated values) were indistinguishable between the GBP and the diet group. However, OXM levels rose remarkably in response to an oral glucose load more than 2-fold (peak, 5.25+/-1.31 to13.8+/-16.2 pmol/liter; P=0.025) after GBP but not after diet. The peak of OXM after glucose was significantly correlated with glucagon-like peptide-1 and peptide YY3-36. CONCLUSIONS Our data suggest that the observed changes in OXM primarily occur in response to GBP and not as a consequence of weight loss. These changes were observed early after surgery and occurred in parallel with previously reported increases in incretins and peptide YY. We speculate that the combination of gut hormone changes is essential for the improved glucose homeostasis and may partially explain the success of this surgery on diabetes resolution and weight loss.

Evening Chronotype Is Associated with Changes in Eating Behavior, More Sleep Apnea, and Increased Stress Hormones in Short Sleeping Obese Individuals

Background Short sleep duration and decreased sleep quality are emerging risk factors for obesity and its associated morbidities. Chronotype, an attribute that reflects individual preferences in the timing of sleep and other behaviors, is a continuum from morningness to eveningness. The importance of chronotype in relation to obesity is mostly unknown. Evening types tend to have unhealthy eating habits and suffer from psychological problems more frequently than Morning types, thus we hypothesized that eveningness may affect health parameters in a cohort of obese individuals reporting sleeping less than 6.5 hours per night. Methodology and Principal Findings Baseline data from obese (BMI: 38.5±6.4 kg/m2) and short sleeping (5.8±0.8 h/night by actigraphy) participants (n = 119) of the Sleep Extension Study were analyzed (www.ClinicalTrials.gov, identifier NCT00261898). Assessments included the Horne and Ostberg Morningness-Eveningness questionnaire, a three-day dietary intake diary, a 14-day sleep diary, 14 days of actigraphy, and measurements of sleep apnea. Twenty-four hour urinary free cortisol, 24 h urinary norepinephrine and epinephrine levels, morning plasma ACTH and serum cortisol, fasting glucose and insulin, and lipid parameters were determined. Eveningness was associated with eating later in the day on both working and non-working days. Progression towards eveningness was associated with an increase in BMI, resting heart rate, food portion size, and a decrease in the number of eating occasions and HDL-cholesterol. Evening types had overtly higher 24 h urinary epinephrine and morning plasma ACTH levels, and higher morning resting heart rate than Morning types. In addition, Evening types more often had sleep apnea, independent of BMI or neck circumference. Conclusions Eveningness was associated with eating later and a tendency towards fewer and larger meals and lower HDL-cholesterol levels. In addition, Evening types had more sleep apnea and higher stress hormones. Thus, eveningness in obese, chronically sleep-deprived individuals compounds the cardiovascular risk associated with obesity.