Search

The contribution of endogenous glucagon-like peptide (GLP)-1 to β-cell function after Roux-en-Y gastric bypass surgery (RYGB) is well established in normoglycaemic individuals, but not in those with postoperative hyperglycaemia. We, therefore, studied the effect of GLP-1 on β-cell function in individuals with varying degrees of type 2 diabetes mellitus (T2D) control after RYGB.Glucose, insulin secretion rates, β-cell glucose sensitivity and glucagon were measured during an oral glucose tolerance test before (saline only) and at 3, 12 and 24 months after RYGB with and without infusion of the GLP-1 receptor blocker exendinEX9 blunted the increase in β-cell glucose sensitivity at 3 months (-44.1%, p .001) and 12 months (-43.3%, p .001), but not at 24 months (-12.4%, p = .243). EX9 enhanced postprandial glucagon concentrations by 62.0% at 3 months (p = .008), 46.5% at 12 months (p = .055), and 30.4% at 24 months (p = .017). EX9 counterintuitively decreased glucose concentrations at 3 months in the entire cohort (p .001) but had no effect on glycaemia at 12 and 24 months in persistent T2D and impaired glucose tolerance; it minimally worsened glycaemia in REM at 12 months.GLP-1 blockade reversed the improvement in β-cell function observed after RYGB, but this effect varied temporally and by REM status. GLP-1 blockade transiently and minimally worsened glycaemia only in REM, and lowered postprandial glucose values at 3 months, regardless of REM status.

International audience; Background: A novel data-driven classification of type 2 diabetes has been proposed to personalise anti-diabetic treatment according to phenotype. One subgroup, severe insulin-resistant diabetes (SIRD), is characterised by mild hyperglycaemia but marked hyperinsulinaemia, and presents an increased risk of diabetic nephropathy. We hypothesised that patients with SIRD could particularly benefit from metabolic surgery.Methods: We retrospectively related the newly defined clusters with the response to metabolic surgery in participants with type 2 diabetes from independent cohorts in France (the Atlas Biologique de l'Obésite Sévère [ABOS] cohort, n=368; participants underwent Roux-en-Y gastric bypass or sleeve gastrectomy between Jan 1, 2006, and Dec 12, 2017) and Brazil (the metabolic surgery cohort of the German Hospital of San Paulo, n=121; participants underwent Roux-en-Y gastric bypass between April 1, 2008, and March 20, 2016). The study outcomes were type 2 diabetes remission and improvement of estimated glomerular filtration rate (eGFR).Findings: At baseline, 34 (9%) of 368 patients, 314 (85%) of 368 patients, and 17 (5%) of 368 patients were classified as having SIRD, mild obesity-related diabetes (MOD), and severe insulin deficient diabetes (SIDD) in the ABOS cohort, respectively, and in the São Paulo cohort, ten (8%) of 121 patients, 83 (69%) of 121 patients, and 25 (21%) of 121 patients were classified as having SIRD, MOD, and SIDD, respectively. At 1 year, type 2 diabetes remission was reported in 26 (81%) of 32 and nine (90%) of ten patients with SIRD, 167 (55%) of 306 and 42 (51%) of 83 patients with MOD, and two (13%) of 16 and nine (36%) of 25 patients with SIDD, in the ABOS and São Paulo cohorts, respectively. The mean eGFR was lower in patients with SIRD at baseline and increased postoperatively in these patients in both cohorts. In multivariable analysis, SIRD was associated with more frequent type 2 diabetes remission (odds ratio 4·3, 95% CI 1·8-11·2; p=0·0015), and an increase in eGFR (mean effect size 13·1 ml/min per 1·73 m2, 95% CI 3·6-22·7; p=0·0070).Interpretation: Patients in the SIRD subgroup had better outcomes after metabolic surgery, both in terms of type 2 diabetes remission and renal function, with no additional surgical risk. Data-driven classification might help to refine the indications for metabolic surgery.Funding: Agence Nationale de la Recherche, Investissement d'Avenir, Innovative Medecines Initiative, Fondation Cœur et Artères, and Fondation Francophone pour la Recherche sur le Diabète.

Objective The Action for Health in Diabetes (Look AHEAD) study previously reported that intensive lifestyle intervention (ILI) reduced incident depressive symptoms and improved health-related quality of life (HRQOL) over nearly 10 years of intervention compared with a control group (the diabetes support and education group [DSE]) in participants with type 2 diabetes and overweight or obesity. The present study compared incident depressive symptoms and changes in HRQOL in these groups for an additional 6 years following termination of the ILI in September 2012. Methods A total of 1,945 ILI participants and 1,900 DSE participants completed at least one of four planned postintervention assessments at which weight, mood (via the Patient Health Questionnaire-9), antidepressant medication use, and HRQOL (via the Medical Outcomes Scale, Short Form-36) were measured. Results ILI participants and DSE participants lost 3.1 (0.3) and 3.8 (0.3) kg [represented as mean (SE); p = 0.10], respectively, during the 6-year postintervention follow-up. No significant differences were observed between groups during this time in incident mild or greater symptoms of depression, antidepressant medication use, or in changes on the physical component summary or mental component summary scores of the Short Form-36. In both groups, mental component summary scores were higher than physical component summary scores. Conclusions Prior participation in the ILI, compared with the DSE group, did not appear to improve subsequent mood or HRQOL during 6 years of postintervention follow-up.

The alimentary limb has been proposed to be a key driver of the weight-loss-independent metabolic improvements that occur upon bariatric surgery. However, the one anastomosis gastric bypass (OAGB) procedure, consisting of one long biliary limb and a short common limb, induces similar beneficial metabolic effects compared to Roux-en-Y Gastric Bypass (RYGB) in humans, despite the lack of an alimentary limb. The aim of this study was to assess the role of the length of biliary and common limbs in the weight loss and metabolic effects that occur upon OAGB. OAGB and sham surgery, with or without modifications of the length of either the biliary limb or the common limb, were performed in Gottingen minipigs. Weight loss, metabolic changes, and the effects on plasma and intestinal bile acids (BAs) were assessed 15 days after surgery. OAGB significantly decreased body weight, improved glucose homeostasis, increased postprandial GLP-1 and fasting plasma BAs, and qualitatively changed the intestinal BA species composition. Resection of the biliary limb prevented the body weight loss effects of OAGB and attenuated the postprandial GLP-1 increase. Improvements in glucose homeostasis along with changes in plasma and intestinal BAs occurred after OAGB regardless of the biliary limb length. Resection of only the common limb reproduced the glucose homeostasis effects and the changes in intestinal BAs. Our results suggest that the changes in glucose metabolism and BAs after OAGB are mainly mediated by the length of the common limb, whereas the length of the biliary limb contributes to body weight loss. NEW & NOTEWORTHY Common limb mediates postprandial glucose metabolism change after gastric bypass whereas biliary limb contributes to weight loss.

This study aimed to measure the impact of the COVID-19 pandemic on self-reported life experiences in older adults with diabetes and obesity.Participants were surveyed in 2020 regarding negative and positive impacts of the pandemic across domains of personal, social, and physical experiences. A cumulative negative risk index (a count of all reported negative impacts of 46 items) and a positive risk index (5 items) were characterized in relation to age, sex, race/ethnicity, BMI, and multimorbidity.Response rate was high (2950/3193, 92%), average age was 76 years, 63% were women, and 39% were from underrepresented populations. Women reported more negative impacts than men (6.8 vs. 5.6; p0.001 [of 46 items]) as did persons with a greater multimorbidity index (p0.001). Participants reporting African American/Black race reported fewer negative impacts than White participants. Women also reported more positive impacts than men (1.9 vs. 1.6; p0.001 [of 5 items]).Older adults with diabetes and obesity reported more positive impacts of the pandemic than negative impacts, relative to the number of positive (or negative) items presented. Some subgroups experienced greater negative impacts (e.g., for women, a greater multimorbidity index). Efforts to reestablish personal, social, and physical health after the pandemic could target certain groups.

OBJECTIVE: To examine whether breakfast consumption frequency (BCF) is associated with weight loss outcomes in the Look AHEAD (Action for Health in Diabetes) trial. METHODS: Data from a subset of participants (n = 3,915) from Look AHEAD, a randomized trial comparing intensive lifestyle intervention (ILI) to diabetes support and education (DSE) in adults with overweight/obesity and type 2 diabetes, were analyzed. BCF was collected by yearly questionnaire. Multivariable linear regression models were used to estimate the association between average BCF and percentage weight change over 4 years, controlling for baseline sociodemographic, anthropometric, and diabetes-related variables. In separate models, adjustment for diet (n = 915) and physical activity level (n = 837) were performed in a subset of participants. RESULTS: 4-year average BCF was similar in DSE (n=1916) and ILI (n=1999) arms (p=0.14). Each 1-day higher average BCF was associated with an additional 0.5% weight loss in the ILI arm (p

Time-restricted feeding (TRF, animal-based studies) and time-restricted eating (TRE, humans) are an emerging behavioral intervention approach based on the understanding of the role of circadian rhythms in physiology and metabolism. In this approach, all calorie intake is restricted within a consistent interval of less than 12 hours without overtly attempting to reduce calories. This article will summarize the origin of TRF/TRE starting with concept of circadian rhythms and the role of chronic circadian rhythm disruption in increasing the risk for chronic metabolic diseases. Circadian rhythms are usually perceived as the sleep-wake cycle and dependent rhythms arising from the central nervous system. However, the recent discovery of circadian rhythms in peripheral organs and the plasticity of these rhythms in response to changes in nutrition availability raised the possibility that adopting a consistent daily short window of feeding can sustain robust circadian rhythm. Preclinical animal studies have demonstrated proof of concept and identified potential mechanisms driving TRF-related benefits. Pilot human intervention studies have reported promising results in reducing the risk for obesity, diabetes, and cardiovascular diseases. Epidemiological studies have indicated that maintaining a consistent long overnight fast, which is similar to TRE, can significantly reduce risks for chronic diseases. Despite these early successes, more clinical and mechanistic studies are needed to implement TRE alone or as adjuvant lifestyle intervention for the prevention and management of chronic metabolic diseases.

OBJECTIVE Equations for predicting body surface area (BSA) produce flawed estimates, especially for individuals with obesity. This study aimed to compare BSA measured by a three-dimensional photonic scanner (3DPS) with BSA predicted by six commonly cited prediction equations and to develop new prediction equations if warranted. METHODS The 3DPS was validated against manual measurements by breadth caliper for body thicknesses measured at three anatomical sites on a mannequin. BSA was derived from 3DPS whole-body scans of 67 males and 201 females, aged 18 to 83 years, with BMI between 17.8 and 77.8 kg/m2 and varied races/ethnicities. RESULTS Width and depth measurements by 3DPS and caliper were within 1%, except for hip, with an error of 1.8%. BSA3DPS differed from BSA predicted by each equation (P

The determinants of type 2 diabetes (T2D) remission and/or relapse after gastric bypass (RYGB) remain fully unknown. This study characterized β- and α-cell function, in cretin hormone release and insulin sensitivity in individuals with (remitters) or without (non-remitters) diabetes remission after RYGB.This is a cross-sectional study of two distinct cohorts of individuals with or without diabetes remission at least 2 years after RYGB. Each individual underwent-either an oral glucose (remitters) or a mixed meal (non-remitters) test; glucose, proinsulin, insulin, C-peptide, glucagon, incretins and leptin were measured.Compared to remitters (n = 23), non-remitters (n = 31) were older (mean [±SD] age 56.1 ± 8.2 vs. 46.0 ± 8.9 years, P 0.001), had longer diabetes duration (13.1 ± 10.1 vs. 2.2 ± 2.4 years, P 0.001), were further out from the surgery (5.6 ± 3.3 vs. 3.5 ± 1.7 years, P 0.01), were more insulin resistant (HOMA-IR 4.01 ± 3.65 vs. 2.08 ± 1.22, P 0.001), but did not differ for body weight. As predicted, remitters had higher β-cell glucose sensitivity (1.95 ± 1.23 vs. 0.86 ± 0.55 pmol/kg/min/mmol, P 0.001) and disposition index (1.55 ± 1.75 vs 0.33 ± 0.27, P = 0.003), compared to non-remitters, who showed non-suppressibility of glucagon during the oral challenge (time × group P = 0.001). Higher proinsulin (16.55 ± 10.45 vs. 6.62 ± 3.50 PM, P 0.0001), and proinsulin: C-peptide (40.83 ± 29.43 vs. 17.13 ± 7.16, P 0.001) were strongly associated with non-remission status, while differences in incretins between remitters and non-remitters were minimal.Individual without diabetes remission after gastric bypass have poorer β-cell response and lesser suppression of glucagon to an oral challenge; body weight and incretins differ minimally according to remission status.背景: 目前尚未完全明确2型糖尿病(T2D)患者接受胃旁路术(RYGB)后病情缓解或复发的决定因素。这项研究描述了RYGB术后糖尿病缓解或未缓解个体的β-与α-细胞功能、肠促胰岛素激素释放及胰岛素敏感性。 方法: 这是一项横断面研究, 对RYGB术后至少2年后糖尿病缓解或未缓解的不同队列个体进行了研究。每个个体均进行口服葡萄糖(缓解者)或者混合餐(非缓解者)耐量试验；测量血糖、胰岛素原、胰岛素、C肽、胰高血糖素、肠促胰岛素以及瘦素水平。 结果: 与缓解者(n=23)相比, 未缓解者(n=31)年龄更大(平均[±SD]年龄56.1±8.2 vs. 46.0±8.9岁, P0.001)、糖尿病病程更长(13.1±10.1 vs. 2.2±2.4年, P0.001)、距离手术时间更长(5.6±3.3 vs. 3.5±1.7年, P0.01)、胰岛素抵抗更严重(HOMA-IR为4.01±3.65 vs. 2.08±1.22, P0.001), 但体重无差异。正如预期, 与未缓解者相比, 缓解者具有较高的β细胞葡萄糖敏感性(1.95±1.23 vs. 0.86±0.55 pmol/kg/min/mmol, P0.001)以及处置指数(1.55±1.75 vs. 0.33±0.27, P=0.003), 后者在口服耐量试验期间的胰高血糖素水平并未受到抑制(时间×分组, P=0.001)。较高水平的胰岛素原(16.55±10.45 vs. 6.62±3.50PM, P0.0001)以及胰岛素原:C肽比值(40.83±29.43与17.13±7.16, P0.001)与未缓解状态密切相关, 但是缓解者与未缓解者之间的肠促胰岛素差异非常小。 结论: 胃旁路术后糖尿病无缓解的个体对口服耐量试验中β细胞的应答较差, 对胰高血糖素的抑制也较小；根据糖尿病缓解状态进行分组, 发现体重与肠促胰岛素的差异非常小。.

Context The independent contribution of young adult exposure to overweight and obesity to later-life incident diabetes is not well studied. Objective To assess the associations of exposures to elevated body mass index (BMI) and waist circumference (WC) in young adulthood (ages 18-39 years) with incident diabetes later in life (≥40 years). Design Pooled data from 6 US prospective cohorts (Atherosclerosis Risk in Communities Study, Cardiovascular Risk Development in Young Adults Study, Cardiovascular Health Study, (4) Framingham Heart Study Offspring Cohort, (5) Health, Aging and Body Composition Study, and (6) Multi-Ethnic Study of Atherosclerosis. Setting Population-based cohort studies. Participants 30 780 participants (56.1% female, 69.8% non-Hispanic white) without a diagnosis of diabetes by age 40. Interventions We imputed BMI and WC trajectories from age 18 for every participant and estimated time-weighted average exposures to BMI or WC during young adulthood and later life. Main Outcome Measure(s) Incident diabetes defined as fasting glucose ≥126 mg/dL, nonfasting glucose ≥200 mg/dL, or use of diabetes medications. Results During a 9-year median follow-up, 4323 participants developed incident diabetes. Young adult BMI and WC were associated with later-life incident diabetes after controlling for later-life exposures [hazard ratios (HR) 1.99 for BMI ≥ 30 kg/m2 and 2.13 for WC > 88cm (women)/>102cm (men) compared to normal ranges]. Young adult homeostatic model of insulin resistance mediated 49% and 44% of the association between BMI and WC with later-life incident diabetes. High-density lipoproteins and triglycerides mediated a smaller proportion of these associations. Conclusions Elevated BMI and WC during young adulthood were independently associated with later-life incident diabetes. Insulin resistance may be a key mediator.

Obesity is an epidemic internationally. While weight loss interventions are efficacious, they are compounded by heterogeneity with regards to clinically relevant metabolic responses. Thus, we sought to identify metabolic biomarkers that are associated with beneficial metabolic changes to weight loss and which distinguish individuals with obesity who would most benefit from a given type of intervention. Liquid chromatography mass spectrometry-based profiling was used to measure 765 metabolites in baseline plasma from three different weight loss studies: WLM (behavioral intervention, N = 443), STRRIDE-PD (exercise intervention, N = 163), and CBD (surgical cohort, N = 125). The primary outcome was percent change in insulin resistance (as measured by the Homeostatic Model Assessment of Insulin Resistance [%ΔHOMA-IR]) over the intervention. Overall, 92 individual metabolites were associated with %ΔHOMA-IR after adjustment for multiple comparisons. Concordantly, the most significant metabolites were triacylglycerols (TAGs; p = 2.3e-5) and diacylglycerols (DAGs; p = 1.6e-4), with higher baseline TAG and DAG levels associated with a greater improvement in insulin resistance with weight loss. In tests of heterogeneity, 50 metabolites changed differently between weight loss interventions; we found amino acids, peptides, and their analogues to be most significant (4.7e-3) in this category. Our results highlight novel metabolic pathways associated with heterogeneity in response to weight loss interventions, and related biomarkers which could be used in future studies of personalized approaches to weight loss interventions.

Background: Per- and polyfluoroalkyl substances (PFAS) are widely used chemicals, some of which have been linked to type 2 diabetes. We tested whether PFAS concentrations were cross-sectionally associated with metabolites previously shown to predict incident type 2 diabetes using the Diabetes Prevention Program (DPP), a trial of individuals at high risk of type 2 diabetes. Methods: We evaluated 691 participants enrolled in the DPP with baseline measures of 10 PFAS (including total perfluorooctanesulfonic acid (PFOS), total perfluorooctanoic acid (PFOA), and Sb-PFOA [branched isomers of PFOA]) and 77 metabolites. We used log2-transformed PFAS concentrations as exposures and standardized metabolite concentrations as outcomes in linear regression models adjusted for age, sex, race/ethnicity, use of anti-hyperlipidemic or triglyceride-lowering medication, income, years of education, marital status, smoking, and family history of diabetes, with Benjamini-Hochberg linear step-up false discovery rate correction. Results: Sb-PFOA was associated with the largest number of tested metabolites (29 of 77). Each doubling in Sb-PFOA was associated with higher leucine (β=0.07 [95%CI: 0.02, 0.11] SD) and lower glycine (-0.08 [95%CI: -0.03, -0.13] SD). Each doubling of either total PFOA or n-PFOA was associated with -0.13 [95%CI: -0.04, -0.22] SD lower glycine. PFOA and Sb-PFOA were positively associated with multiple triacylglycerols and diacylglycerols, and total PFOS, total PFOA, and Sb-PFOA were positively associated with phosphatidylethanolamines.Conclusions: PFAS concentrations are associated with metabolites linked to type 2 diabetes (particularly amino acid, glycerolipid and glycerophospholipid pathways). Further prospective research is needed to test whether these metabolites mediate associations of PFAS and type 2 diabetes.

Context Few studies have examined the clinical characteristics that predict durable, long-term diabetes remission after bariatric surgery. Objective To compare diabetes prevalence and remission rates during 7-year follow-up after Roux-en-Y gastric bypass (RYGB) and laparoscopic gastric banding (LAGB). Design An observational cohort of adults with severe obesity recruited between 2006 and 2009 who completed annual research assessments for up to 7 years after RYGB or LAGB. Setting Ten US hospitals. Participants A total sample of 2256 participants, 827 with known diabetes status at both baseline and at least 1 follow-up visit. Interventions Roux-en-Y gastric bypass or LAGB. Main Outcome Measures Diabetes rates and associations of patient characteristics with remission status. Results Diabetes remission occurred in 57% (46% complete, 11% partial) after RYGB and 22.5% (16.9% complete, 5.6% partial) after LAGB. Following both procedures, remission was greater in younger participants and those with shorter diabetes duration, higher C-peptide levels, higher homeostatic model assessment of β-cell function (HOMA %B), and lower insulin usage at baseline, and with greater postsurgical weight loss. After LAGB, reduced HOMA insulin resistance (IR) was associated with a greater likelihood of diabetes remission, whereas increased HOMA-%B predicted remission after RYGB. Controlling for weight lost, diabetes remission remained nearly 4-fold higher compared with LAGB. Conclusions Durable, long-term diabetes remission following bariatric surgery is more likely when performed soon after diagnosis when diabetes medication burden is low and beta-cell function is preserved. A greater weight-independent likelihood of diabetes remission after RYGB than LAGB suggests mechanisms beyond weight loss contribute to improved beta-cell function after RYGB. Trial Registration clinicaltrials.gov Identifier: NCT00465829.

The present study was a 4-week randomized trial to assess the efficacy and safety of sitagliptin, a dipeptidyl-peptidase-4 inhibitor, in persistent or recurring type 2 diabetes after Roux-en-Y gastric bypass surgery (RYGB). Participants (n = 32) completed a mixed meal test (MMT) and self-monitoring of plasma glucose (SMPG) before and 4 weeks after randomization to either sitagliptin 100 mg daily or placebo daily. Questionnaires were administered to assess gastrointestinal discomfort. Outcome variables were glucose, active glucagon-like peptide-1 and β-cell function during the MMT, and glucose levels during SMPG. Age (56.3 ± 8.2 years), body mass index (34.4 ± 6.7 kg/m2 ), glycated haemoglobin (7.21 ± 0.77%), diabetes duration (12.9 ± 10.0 years), years since RYGB (5.6 ± 3.3 years) and β-cell function did not differ between the placebo and sitagliptin groups at pre-intervention. Sitagliptin was well tolerated, decreased postprandial glucose levels during the MMT (from 8.31 ± 1.92 mmol/L to 7.67 ± 1.59 mmol/L, P = 0.03) and mean SMPG levels, but had no effect on β-cell function. In patients with diabetes and mild hyperglycemia after RYGB, a short course of sitagliptin provided a small but significant glucose-lowering effect, with no identified improvement in β-cell function.

Bariatric surgery has now emerged as an effective means of glycemic control in individuals with diabetes and obesity. However, long-term data show recurrence of hyperglycemia years after the procedure. Although the exact prevalence of diabetes relapse is unknown because of attrition and limited data on long-term follow up after the surgery, a significant percentage of patients experience relapse of diabetes. The mechanism of diabetes relapse is not completely understood and is not always linked to weight regain. The clinical implications of hyperglycemia after bariatric surgery for patients and healthcare providers is reviewed.

In a previous study (Kissileff HR, Carretta JC, Geliebter A, Pi-Sunyer FX. Am J Physiol Regul Integr Comp Physiol 285: R992–R998, 2003), when subthreshold gastric distension (300 ml) and a low dose of cholecystokinin octapeptide (CCK-8) (112 ng/min for 21 min) were concurrently administered to human participants, intake of a test meal was significantly reduced. However, the supra-additive interaction of CCK-8 and gastric distension was not significant. The purpose of the present study was to determine whether a significant interaction would be obtained when CCK-8 and gastric distension were each increased by 50% above levels used in the previous study. Twelve normal-weight, healthy participants were tested four times each with either CCK-8 (168 ng/min for 30 min) or saline infusion crossed with gastric distension (450 ml) or no distension. The combination of CCK-8 and gastric distension reduced food intake by a mean of 405 ± 86 g (SE) in comparison with the saline nondistension condition ( P < 0.001), which is a 51% reduction. Although there were some differences in the protocols, the combined effect was double that seen in the previous study. Although the interactive effect was larger [118 ± 109 g (SE)] than it was previously [73 ± 86 (SE)], it was not significant ( P = 0.29). There were also reports of a short-lived sick feeling after CCK-8, with and without distension, that was not observed in the previous study. Thus the combination of CCK-8 at 1.5 times threshold and gastric distension at 450 ml (increased from 300 ml) resulted in a combined effect to reduce food intake, which was also 1.5 times its previous value, and thus appears linear.

OBJECTIVE Hepatic insulin clearance is a significant regulator of glucose homestasis. We hypothesized that the improvement in insulin clearance rates (ICRs) under fasting conditions and in response to oral and intravenous (IV) glucose would improve similarly after Roux-en-Y gastric bypass (RYGB) and adjustable gastric banding (AGB) as a function of weight loss; the difference in ICR after oral and IV glucose stimulation will be enhanced after RYGB compared with AGB, an effect mediated by glucagon-like peptide 1 (GLP-1). RESEARCH DESIGN AND METHODS In study 1, the ICR was calculated under fasting condition (F-ICR), after oral glucose (O-ICR), and after an isoglycemic IV glucose clamp (IV-ICR) in individuals from an established cohort with type 2 diabetes mellitus (T2DM) before, after 10% matched weight loss, and 1 year after either RYGB (n = 22) or AGB (n = 12). In study 2, O-ICR was studied in a separate cohort of individuals with T2DM (n = 22), before and 3 months after RYGB, with and without exendin(9-39) infusion. RESULTS In study 1, age, BMI, T2DM duration and control, and ICR did not differ between RYGB and AGB preintervention. Weight loss at 1 year was two times greater after RYGB than after AGB (31.6 ± 5.9% vs. 16.6 ± 9.8%; P < 0.05). RYGB and AGB both significantly increased F-ICR, O-ICR, and IV-ICR at 1 year. ICR was inversely associated with insulinemia. The difference between IV-ICR and O-ICR was significantly greater after RYGB versus AGB. GLP-1 antagonism with exendin(9-39) led to an increase in O-ICR in subjects post-RYGB. CONCLUSIONS Weight loss increased ICR, an effect more pronounced after RYGB compared with AGB. Our data support a potential role for endogenous GLP-1 in the control of postprandial ICR after RYGB.

Background Medium chain triglycerides (MCT) enhance thermogenesis and may reduce food intake relative to long chain triglycerides (LCT). The goal of this study was to establish the effects of MCT on appetite and food intake and determine whether differences were due to differences in hormone concentrations. Methods Two randomized, crossover studies were conducted in which overweight men consumed 20 g of MCT or corn oil (LCT) at breakfast. Blood samples were obtained over 3 h. In Study 1 (n=10), an ad lib lunch was served after 3 h. In Study 2 (n=7), a pre-load containing 10 g of test oil was given at 3 h and lunch was served 1 h later. Linear mixed model analyses were performed to determine the effects of MCT and LCT oil on change in hormones and metabolites from fasting, adjusting for body weight. Correlations were computed between differences in hormones just before the test meals and differences in intakes after the two oils for Study 1 only. Results Food intake at the lunch test meal after the MCT pre-load (Study 2) was (mean ± SEM) 532 ± 389 kcal vs. 804 ± 486 kcal after LCT (P < 0.05). MCT consumption resulted in a lower rise in triglycerides (P = 0.014) and glucose (P = 0.066) and a higher rise in peptide YY (P = 0.017) and leptin (P = 0.036) compared to LCT (combined data). Correlations between differences in hormone levels (GLP-1, PYY) and differences in food intake were in the opposite direction to expectations. Conclusions MCT consumption reduced food intake acutely but this does not seem to be mediated by changes in GLP-1, PYY, and insulin.

The mechanisms responsible for the remarkable remission of type 2 diabetes after Roux-en-Y gastric bypass (RYGBP) are still puzzling. To elucidate the role of the gut, we compared β-cell function assessed during an oral glucose tolerance test (OGTT) and an isoglycemic intravenous glucose clamp (iso-IVGC) in: 1) 16 severely obese patients with type 2 diabetes, up to 3 years post-RYGBP; 2) 11 severely obese normal glucose-tolerant control subjects; and 3) 7 lean control subjects. Diabetes remission was observed after RYGBP. β-Cell function during the OGTT, significantly blunted prior to RYGBP, normalized to levels of both control groups after RYGBP. In contrast, during the iso-IVGC, β-cell function improved minimally and remained significantly impaired compared with lean control subjects up to 3 years post-RYGBP. Presurgery, β-cell function, weight loss, and glucagon-like peptide 1 response were all predictors of postsurgery β-cell function, although weight loss appeared to be the strongest predictor. These data show that β-cell dysfunction persists after RYGBP, even in patients in clinical diabetes remission. This impairment can be rescued by oral glucose stimulation, suggesting that RYGBP leads to an important gastrointestinal effect, critical for improved β-cell function after surgery.

OBJECTIVE To investigate glucose-dependent insulinotropic polypeptide (GIP) secretion in patients with type 2 diabetes and nondiabetic control subjects during oral glucose or meal tests. RESEARCH DESIGN AND METHODS Eligible trials were identified by The Cochrane Library, MEDLINE, Embase, and Web of Science. Data were retrieved and random-effects models for the primary meta-analysis, random-effects meta-regression, and subgroup and regression analyses were applied. RESULTS Random-effects meta-analysis of GIP responses in 23 trials during 28 different stimulation tests showed that patients with type 2 diabetes (n = 363) exhibited no significant differences (P = not significant) in peak plasma GIP, total area under the curve (tAUC), time-corrected tAUC (tAUC × min−1), and time-corrected incremental area under the curve (iAUC × min−1) in comparison with nondiabetic control subjects (n = 325) but had lower GIP responses as evaluated from iAUC (weighted mean difference, −648 pmol/L × min; 95% CI, −1,276 to −21). Fixed-effects models meta-analyses confirmed most of the results of the primary meta-analysis but showed iAUC × min−1 to be reduced and showed tAUC and tAUC × min−1 to be higher in diabetic patients. Random-effects meta-regression of the primary meta-analysis showed that age (peak GIP, tAUC, iAUC, and iAUC × min−1), BMI (tAUC, iAUC, and iAUC × min−1), and HbA1c (iAUC and iAUC × min−1) predicted some of the GIP outcomes. Post hoc subgroup analysis showed a negative influence of age and of HbA1c on GIP responses and showed a positive influence of BMI on GIP responses. CONCLUSIONS Our results suggest that patients with type 2 diabetes are characterized by preserved GIP secretion in response to oral glucose and meal tests. They also suggest that high BMI is associated with increased GIP responses but increasing age and HbA1c are associated with reduced GIP secretion.

Summary Background & aims Zinc, magnesium and vitamin D are trace minerals and vitamins of importance to human biology and health and increasing evidences suggest that these minerals and vitamin play an important role in glucose metabolism. The aim of the study was to summarize the current evidences that links mineral deficiencies and alterations in glucose metabolism Methods A systematic review of PubMed database was conducted from September 1983 to September 2011 to identify literature related to zinc, magnesium and vitamin D deficiencies and glucose metabolism. Results Accumulating data from clinical studies suggest that zinc, magnesium and vitamin D deficiencies are independently associated with alterations in glucose metabolism. Deficiencies may increase risk of the development of insulin resistance and T2DM. However, there is inadequate evidence based data available to inform public health strategies. Conclusions Clearly, there is a need for further research, using well-designed studies and long-term follow-up, to fully demonstrate a causal role for these nutritional deficiencies in the development of insulin resistance and T2DM and the beneficial role of these vitamin and minerals supplementation in disorders of glucose metabolism, and/or in patients with or at risk of developing nutritional deficiencies.

Despite the beneficial effect of bariatric surgery (BS) on overall health, this therapeutic approach may compromise protein status (PS). BS decreases food and protein intake (PI) and changes the gastrointestinal tract, which may result in maldigestion and malabsorption. Both factors can compromise PS. Changes in PS may have a negative impact on several systems of body functions, such as skeletal muscle mass, protein turnover, resting energy expenditure, bone density, branched-chain amino acid circulating levels, the immune system, and satiety. In this chapter we will review the mechanisms by which BS alters PS, and the resulting health consequences. In a more translational approach, the methods to perform a quantitative and qualitative PS assessment will be briefly reviewed.

We carried out a systematic review of clinical studies investigating glucagon-like peptide-1 (GLP-1) secretion in patients with type 2 diabetes and non-diabetic controls and performed meta-analyses of plasma total GLP-1 concentrations during an OGTT and/or meal test.Random effects models for the primary meta-analysis and random effects meta-regression, subgroup and regression analyses were applied.Random effects meta-analysis of GLP-1 responses in 22 trials during 29 different stimulation tests showed that patients with type 2 diabetes (n = 275) and controls without type 2 diabetes (n = 279) exhibited similar responses of total GLP-1 (p = NS) as evaluated from peak plasma concentrations (weighted mean difference [95% CI] 1.09 pmol/l [-2.50, 4.67]), total AUC (tAUC) (159 pmol/l × min [-270, 589]), time-corrected tAUC (tAUC min⁻¹) (0.99 pmol/l [-1.28, 3.27]), incremental AUC (iAUC) (-122 pmol/l × min [-410, 165]) and time-corrected iAUC (iAUC min⁻¹) (-0.49 pmol/l [-2.16, 1.17]). Fixed effects meta-analysis revealed higher peak plasma GLP-1 concentrations in patients with type 2 diabetes. Subgroup analysis showed increased responses after a liquid mixed meal test (peak, tAUC and tAUC min⁻¹) and after a 50 g OGTT (AUC and tAUC min⁻¹), and reduced responses after a solid mixed meal test (tAUC min⁻¹) among patients with type 2 diabetes. Meta-regression analyses showed that HbA1c and fasting plasma glucose predicted the outcomes iAUC and iAUC min⁻¹, respectively.The present analysis suggests that patients with type 2 diabetes, in general, do not exhibit reduced GLP-1 secretion in response to an OGTT or meal test, and that deteriorating glycaemic control may be associated with reduced GLP-1 secretion.

OBJECTIVE The superior effect of Roux-en-Y gastric bypass (RYGB) on glucose control compared with laparoscopic adjustable gastric banding (LAGB) is confounded by the greater weight loss after RYGB. We therefore examined the effect of these two surgeries on metabolic parameters matched on small and large amounts of weight loss. RESEARCH DESIGN AND METHODS Severely obese individuals with type 2 diabetes were tested for glucose metabolism, β-cell function, and insulin sensitivity after oral and intravenous glucose stimuli, before and 1 year after RYGB and LAGB, and at 10% and 20% weight loss after each surgery. RESULTS RYGB resulted in greater glucagon-like peptide 1 release and incretin effect, compared with LAGB, at any level of weight loss. RYGB decreased glucose levels (120 min and area under the curve for glucose) more than LAGB at 10% weight loss. However, the improvement in glucose metabolism, the rate of diabetes remission and use of diabetes medications, insulin sensitivity, and β-cell function were similar after the two types of surgery after 20% equivalent weight loss. CONCLUSIONS Although RYGB retained its unique effect on incretins, the superiority of the effect of RYGB over that of LAGB on glucose metabolism, which is apparent after 10% weight loss, was attenuated after larger weight loss.

Following gastric bypass surgery (GBP), there is a post-prandial rise of incretin and satiety gut peptides. The mechanisms of enhanced incretin release in response to nutrients after GBP is not elucidated and may be in relation to altered nutrient transit time and/or malabsorption.Seven morbidly obese subjects (BMI = 44.5 ± 2.8 kg/m(2)) were studied before and 1 year after GBP with a D: -xylose test. After ingestion of 25 g of D: -xylose in 200 mL of non-carbonated water, blood samples were collected at frequent time intervals to determine gastric emptying (time to appearance of D: -xylose) and carbohydrate absorption using standard criteria.One year after GBP, subjects lost 45.0 ± 9.7 kg and had a BMI of 27.1 ± 4.7 kg/m(2). Gastric emptying was more rapid after GBP. The mean time to appearance of D: -xylose in serum decreased from 18.6 ± 6.9 min prior to GBP to 7.9 ± 2.7 min after GBP (p = 0.006). There was no significant difference in absorption before (serum D: -xylose concentrations = 35.6 ± 12.6 mg/dL at 60 min and 33.9 ± 9.1 mg/dL at 180 min) or 1 year after GBP (serum D: -xylose = 31.5 ± 18.1 mg/dL at 60 min and 27.2 ± 11.9 mg/dL at 180 min).These data confirm the acceleration of gastric emptying for liquid and the absence of carbohydrate malabsorption 1 year after GBP. Rapid gastric emptying may play a role in incretin response after GBP and the resulting improved glucose homeostasis.

OBJECTIVE To characterize the magnitude and variance of the change of glucose and glucagon-like peptide-1 (GLP-1) concentrations, and to identify determinants of glucose control up to 2 years after gastric bypass (GBP). RESEARCH DESIGN AND METHODS Glucose and GLP-1 concentrations were measured during an oral glucose challenge before and 1, 12, and 24 months after GBP in 15 severely obese patients with type 2 diabetes. RESULTS Glucose area under the curve from 0 to 180 min (AUC0–180) started decreasing in magnitude (P < 0.05) 1 month after surgery. GLP-1 AUC0–180 increased in magnitude 1 month after GBP (P < 0.05), with increased variance only after 1 year (Pσ2 ≤ 0.001). GLP-1 AUC0–180 was positively associated with insulin AUC0–180 (P = 0.025). CONCLUSIONS The increase in variance of GLP-1 at 1 and 2 years after GBP suggests mechanisms other than proximal gut bypass to explain the enhancement of GLP-1 secretion. The association between GLP-1 and insulin concentrations supports the idea that the incretins are involved in glucose control after GBP.

Insulin resistance (IR) improves with weight loss, but this response is heterogeneous. We hypothesised that metabolomic profiling would identify biomarkers predicting changes in IR with weight loss.Targeted mass spectrometry-based profiling of 60 metabolites, plus biochemical assays of NEFA, β-hydroxybutyrate, ketones, insulin and glucose were performed in baseline and 6 month plasma samples from 500 participants who had lost ≥4 kg during Phase I of the Weight Loss Maintenance (WLM) trial. Homeostatic model assessment of insulin resistance (HOMA-IR) and change in HOMA-IR with weight loss (∆HOMA-IR) were calculated. Principal components analysis (PCA) and mixed models adjusted for race, sex, baseline weight, and amount of weight loss were used; findings were validated in an independent cohort of patients (n = 22).Mean weight loss was 8.67 ± 4.28 kg; mean ∆HOMA-IR was -0.80 ± 1.73, range -28.9 to 4.82). Baseline PCA-derived factor 3 (branched chain amino acids [BCAAs] and associated catabolites) correlated with baseline HOMA-IR (r = 0.50, p0.0001) and independently associated with ∆HOMA-IR (p0.0001). ∆HOMA-IR increased in a linear fashion with increasing baseline factor 3 quartiles. Amount of weight loss was only modestly correlated with ∆HOMA-IR (r = 0.24). These findings were validated in the independent cohort, with a factor composed of BCAAs and related metabolites predicting ∆HOMA-IR (p = 0.007).A cluster of metabolites comprising BCAAs and related analytes predicts improvement in HOMA-IR independent of the amount of weight lost. These results may help identify individuals most likely to benefit from moderate weight loss and elucidate novel mechanisms of IR in obesity.

Gastric bypass surgery (GBP) results in important and sustained weight loss and remarkable improvement of Type 2 diabetes. The favorable change in the incretin gut hormones is thought to be responsible, in part, for diabetes remission after GBP, independent of weight loss. However, the relative role of the change in incretins and of weight loss is difficult to differentiate. After GBP, the plasma concentrations of the incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide increase postprandially by three- to fivefold. The postprandial incretin effect on insulin secretion, blunted in diabetes, improves rapidly after the surgery. In addition to the change in incretins, the pattern of insulin secretion in response to oral glucose changes after GBP, with recovery of the early phase and significant decrease in postprandial glucose levels. These changes were not seen after an equivalent weight loss by diet. The improved insulin release and glucose tolerance after GBP were shown by others to be blocked by the administration of a GLP-1 antagonist, demonstrating that the favorable metabolic changes after GBP are, in part, GLP-1 dependent. The improved incretin levels and effect persist years after GBP, but their long-term effect on glucose metabolism, and on hypoglycemia post GBP are yet unknown. Understanding the mechanisms by which incretin release is exaggerated postprandially after GBP may help develop new less invasive treatment options for obesity and diabetes. Changes in rate of eating, gastric emptying, intestinal transit time, nutrient absorption and sensing, as well as bile acid metabolism, may all be implicated.

Background: The aim of the present study was to determine the mechanisms underlying Type 2 diabetes remission after gastric bypass (GBP) surgery by characterizing the short- and long-term changes in hormonal determinants of blood glucose. Methods: Eleven morbidly obese women with diabetes were studied before and 1, 6, and 12 months after GBP; eight non-diabetic morbidly obese women were used as controls. The incretin effect was measured as the difference in insulin levels in response to oral glucose and to an isoglycemic intravenous challenge. Outcome measures were glucose, insulin, C-peptide, proinsulin, amylin, glucagon, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) levels and the incretin effect on insulin secretion. Results: The decrease in fasting glucose (r = 0.724) and insulin (r = 0.576) was associated with weight loss up to 12 months after GBP. In contrast, the blunted incretin effect (calculated at 22%) that improved at 1 month remained unchanged with further weight loss at 6 (52%) and 12 (52%) months. The blunted incretin (GLP-1 and GIP) levels, early phase insulin secretion, and other parameters of β-cell function (amylin, proinsulin/insulin) followed the same pattern, with rapid improvement at 1 month that remained unchanged at 1 year. Conclusions: The data suggest that weight loss and incretins may contribute independently to improved glucose levels in the first year after GBP surgery.

Weight loss by diet is often of small magnitude and difficult to sustain over time. On the contrary, bariatric surgery, particularly Roux-en-Y gastric bypass (GBP), typically results in loss of 50% excess body weight within the first year, and the effect is often sustained at 10 years. The rapid and dramatic resolution of type 2 diabetes mellitus (T2DM) after GBP has led to the hypothesis that some of the metabolic effects of the surgery may be independent of weight loss1–3 and may be related to the changes in incretins, gut hormones that stimulate insulin secretion.4,5 The mechanisms by which GBP suppresses appetite are not clear. The marked increase in levels of 2 anorexigenic hormones, peptide YY (PYY),6–10 and glucagon-like peptide 1 (GLP-1),4,7 could explain the increased satiety after GBP. A greater PYY release is associated with greater weight loss after GBP11 and weight regain has been shown with lower PYY levels in a rodent model.12 Previous reports on change in PYY levels after diet intervention are scarce, report only fasting levels, and are inconsistent.13,14 The gastric hormone ghrelin may also be implicated in meal-to-meal regulation.15 Its levels increase in anticipation of a meal and decrease after feeding, suggesting a role in short-term meal-to-meal regulation.16 Ghrelin levels vary as a function of body mass index (BMI) and are low in obese individuals.17 The increase in ghrelin levels may explain weight regain after a diet-induced weight loss.18 Contrary to weight loss by diet, most studies agree that ghrelin levels decrease18,19 or do not increase in proportion to weight loss after GBP,6,20 an effect that could favor a better control of appetite and the decreased food intake observed after this surgery. In addition to gut hormones, the adipocyte-secreted hormone, leptin, is also an important regulator of energy balance in humans.21 Restriction of food intake or diet-induced weight loss decreases plasma leptin levels. This decrease in leptin signals the hypothalamus a state of negative energy balance and thus triggers food intake.22 After GBP, leptin levels have been found to be lower than expected for a given BMI.6 The first goal of this study was to examine the effect of a short-term equivalent weight loss, by GBP or by diet, on PYY3–36, ghrelin, and leptin levels. Our secondary goal was to determine the effect of BMI and diabetes status on PYY3–36 levels. Partial data on GLP-1 levels after GBP and diet have been published before.2

To investigate the influence of age, sex, ethnicity and total fatness on central obesity in four ethnic populations.Cross-sectional analysis of study subjects enrolled from 1993 to 2005.A multi-ethnic (Caucasian (CA), African-American (AA), Hispanic-American (HA) and Asian (As)) convenience sample of 604 men and 1192 women (aged 18-96 years, body mass index 15.93-45.80 kg/m(2)).Total body fat (TBF) and truncal fat were measured by dual-energy X-ray absorptiometry. General linear regression models were used to test for independent associations with log(10)-transformed truncal fat.For all ethnicities, men had a lower percent body fat and more truncal fat than women. Log(10-)transformed truncal fat increased with TBF approximately as a square root function. At older ages, there was a greater amount of truncal fat in CA, HA and As men (approximately 0.20-0.25 kg/decade) with the effect more pronounced in AA men ( approximately 0.33 kg/decade). For women, the increment of truncal fat per decade was reduced in CA and AA women (approximately 0.07 kg) compared with As and HA women (approximately 0.33 kg). Adjusted for mean values of covariates in our sample, AA had less truncal fat than As.The accumulation of truncal fat is strongly related to age, ethnicity and total fatness in both men and women.

Administration of glucocorticoids increases serum leptin levels in lean and obese individuals. A morning meal produces an increase in insulin, a cortisol peak, and an increase in leptin; these changes do not occur during fasting.The objective of this study was to investigate whether inhibiting endogenous cortisol secretion with metyrapone decreases 24-h serum leptin levels and to determine whether a meal-related midmorning surge in cortisol is a prerequisite for the meal-entrained nocturnal rise in leptin.This was a randomized, cross-over study.The study was performed at the General Clinical Research Center.Lean males were studied.In study 1, seven lean men were studied for 24 h while their endogenous cortisol secretions were manipulated as follows: 1) CONTROL; 2) cortisol suppression by metyrapone (MET); and 3) MET and oral hydrocortisone (at 0900 h) (MET + CORT). Subjects were all fed a eucaloric diet (two meals at 1100 and 1700 h). In study 2, six men were studied without pharmacological intervention for 24 h on two occasions: once under a complete fast (FAST) and once in a feeding condition (one meal at 1100 h; FED).The main outcome measure was serum leptin.MET significantly suppressed serum cortisol at 0800 h, midmorning, and over the 24-h period. As a result of cortisol suppression, 24-h serum leptin levels were decreased vs. control values despite similar insulin responses to meals. Administering a single dose of hydrocortisone to MET subjects potently stimulated serum leptin compared with the effect of MET alone.Our data demonstrate that endogenous cortisol secretion is necessary for the maintenance of serum leptin levels over 24 h in lean, normally fed males.

The aim of the study was to investigate in premenopausal women whether the relationship between percentage body fat (PBF) and body mass index (BMI; in kg/m2) differs between Korean Asians (Ko-As) living in Seoul, South Korea, and Caucasians (Ca) living in New York City. Healthy premenopausal women (50 Ko-As; 38 Ca), ages 22–50 yr, were studied. Weight, height, and PBF by dual-energy X-ray absorptiometry were measured. Total body dual-energy X-ray absorptiometry data were collected using GE-Lunar systems (Prodigy-Korea and DPXL-New York), and all scan analyses were performed by one technician in New York. Similar soft tissue phantoms were used for daily instrument calibrations at both sites. The relationship between PBF and BMI was assessed by multiple regression analysis with race, age, reciprocal of BMI (1/BMI), and a race-by-age interaction as the final independent variables. Race ( P = 0.003) and 1/BMI ( P < 0.001) were significantly related to PBF in this model. A significant race-by-age interaction ( P = 0.039) indicated that the slope of the lines for PBF vs. age differed between Ko-As and Ca. This study demonstrates in a Ko-As sample that the BMI-fat relationship differs significantly from that in a comparable group of Caucasian women. Investigators who use BMI as an index of fatness should be aware of the well documented differences in the relationship of BMI and fatness across race/ethnic groups.

GHRP-2 is a synthetic agonist of ghrelin, the newly-discovered gut peptide which binds to the growth hormone (GH) secretagogue receptor. Ghrelin has two major effects, stimulating both GH secretion and appetite/meal initiation. GHRP-2 has been extensively studied for its utility as a growth hormone secretagogue (GHS). Animal studies have shown its effect on food intake. However, whether GHRP-2 can also stimulate appetite in humans when administered acutely is not known. We subcutaneously infused 7 lean, healthy males with GHRP-2 (1 microg/kg/h) or saline for 270 minutes and then measured their intake of an ad libitum, buffet-style meal. Similar to what has been reported for ghrelin administration, our subjects ate 35.9 +/- 10.9% more when infused with GHRP-2 vs. saline, with every subject increasing their intake even when calculated per kg body weight (136.0 +/- 13.0 kJ/kg [32.5 +/- 3.1 kcal/kg] vs. 101.3 +/- 10.5 kJ/kg [24.2 +/- 2.5 kcal/kg], p = 0.008). The macronutrient composition of consumed food was not different between conditions. As expected, serum GH levels rose significantly during GHRP-2 infusion (AUC 5550 +/- 1090 microg/L/240 min vs. 412 +/- 161 microg/L/240 min, p = 0.003). These data are the first to demonstrate that GHRP-2, like ghrelin, increases food intake, suggesting that GHRP-2 is a valuable tool for investigating ghrelin effects on eating behavior in humans.

With anthropometric models using skinfolds and circumferences, we studied changes in the percentage of subcutaneous fat in the total cross-sectional area (SF%) at four body sites in obese women, before and after weight loss induced by 6 months of caloric restriction.In 61 obese women [31 African Americans and 30 whites; ages, 24 to 68 years; body mass index (BMI),or =28 kg/m(2)], we measured SF% at the midpoint of the upper arm and thigh and the waistline and hipline, and we measured the percentage of total body fat by DXA before (Obs#1) and after (Obs#2) a 6-month nonintervention control period and then after 6 months on a 1200 kcal/d diet (Obs#3).The mean body weight and BMI increased (1.8 kg and 0.61 kg/m(2); p = 0.0001), but there were no significant changes in any other body composition measurements from Obs#1 to Obs#2. The means of Obs#3 for weight and BMI decreased by 11%, and the percentage of total body fat decreased by 13% of Obs#2 mean values (p = 0.0001). The mean SF% at each site decreased 7.6% to 18.0% of the Obs#2 mean values (p0.001). The SF% decreases were greater at mid-arm and mid-thigh than in the cross-sectional regions at the waistline and hipline (p = 0.05). There was no interaction between age or ethnicity (p0.2).In obese women, caloric restriction alone reduces anthropometrically measured subcutaneous fat proportionally more in peripheral than in central regions.

Food intake suppresses plasma levels of the gastric peptide ghrelin in humans. We hypothesize that the food intake- suppression of ghrelin could be secondary to the plasma glucose and insulin changes after a meal. The aim of this study was to compare the effect of the administration of a combined pulse of glucose and insulin to the effect of one meal on plasma ghrelin in human subjects. A secondary aim was to study the effect of an oral glucose load on ghrelin levels.Experiment 1 (n = 10) studied plasma glucose, insulin, leptin and ghrelin for 6 hours after a 790 kcal liquid meal. In Experiment 2 (n = 7), a subcutaneous pulse of insulin (Humalog 0.03U/kg) and an I.V. infusion of glucose were administered in order to mimic the plasma changes of glucose and insulin after a meal, and plasma ghrelin levels were monitored for 9 h. The OGTT data was used to study the effect of oral glucose on ghrelin.A mixed liquid meal decreased basal serum ghrelin by 26% at 40 minutes (p = 0.009). A 75 gr oral glucose load suppresses ghrelin by 28% at 30 minutes. Contrary to the meal effect, the parenteral administration of insulin and glucose did not suppress serum ghrelin.Unlike food intake, the administration of insulin and glucose does not suppress ghrelin levels. These data suggest that the suppressive effect of food intake or oral glucose on serum ghrelin is unlikely mediated by the changes of plasma insulin and glucose observed after the ingestion.

The combination of decreased physical activity and over nutrition has resulted in a worldwide increase in the prevalence of obesity and its associated complications. In the United States, about 2/3rd of adults are overweight [with body mass index (BMI) ≥25 kg/m2] and 1/3rd adults are obese (BMI ≥30 kg/m2) [1]. Obesity is often associated with insulin resistance, and with increased incidence of type 2 diabetes (T2DM), cardiovascular disease, hypertension, and cancer [2]. Weight loss reduces insulin resistance, prevents and/or treats diabetes [3], and decreases cardiovascular risk [4]. The biological factors that link excess weight, insulin resistance, and weight loss with improved health and metabolic status are not completely understood. Studies on insulin resistance and T2DM have focused on disordered glucose and lipid metabolism and insulin signaling, however protein metabolism is also altered in the state of insulin resistance at the whole body level as well as at the muscle level [5]. Elevated amino acid (AA) has long been associated with obesity and insulin resistance [6] and recently, circulating branched chain amino acids (BCAA) have been identified as early biomarker predictors of diabetes risk in obese insulin resistant subjects [7]. This chapter will review the effect of weight loss on BCAA metabolism in obesity and diabetes.

We thank Dr. Pontiroli, and agree with his commentary (1). Dr. Pontiroli provides an interesting observation regarding change in β-cell function following weight loss by gastric banding in subjects with type 2 diabetes. His data show minimal improvement in insulin release, as assessed by the Δinsulin/Δglucose during an oral glucose tolerance test (OGTT), but a significant improvement in insulin sensitivity by homeostasis model assessment, 18 months after gastric banding (1,2). In our study …

Serum levels of the adipocyte hormone leptin are increased in proportion to body fat stores as a result of increased production in enlarged fat cells from obese subjects. In vitro studies indicate that insulin and glucocorticoids work directly on adipose tissue to upregulate in a synergistic manner leptin mRNA levels and rates of leptin secretion in human adipose tissue over the long term. Thus, the increased leptin expression observed in obesity could result from the chronic hyperinsulinemia and increased cortisol turnover. Superimposed upon the long-term regulation, nutritional status can influence serum leptin over the short term, independent of adiposity. Fasting leads to a gradual decline in serum leptin that is probably attributable to the decline in insulin and the ability of catecholamines to decrease leptin expression, as observed in both in vivo and in vitro studies. In addition, increases in serum leptin occur approximately 4-7 h after meals. Increasing evidence indicates that insulin, in concert with permissive effects of cortisol, can increase serum leptin over this time frame and likely contributes to meal-induced increases in serum leptin. Further research is required to elucidate the cellular and molecular mechanisms underlying short- and long-term nutritional and hormonal regulation of leptin production and secretion.

While the hyperleptinemia of obesity is likely to be associated with the metabolic complications of obesity/hyperinsulinemia/insulin resistance, it is not associated with diabetes, with the relative hypercortisolism of upper body obesity, with hypertension in women, (it is in men), or with dyslipidemia. Overall, the correlations between leptin and the metabolic diseases associated with obesity are weak. The equivocal results of an association of leptin with components of the metabolic syndrome make it unlikely that leptin affects these directly. (On the other hand, these correlations, when found, preclude any causal relationship between leptin and metabolic diseases.) There are experimental data showing a definite role for insulin and glucocorticoids in the regulation of leptin, and of leptin in the regulation of insulin. More data are required on the effects of leptin, but it is likely that leptin will not be a major link between obesity and the metabolic syndrome. Certainly, however, when leptin is available for clinical use, its effect on different aspects of the metabolic syndrome will be worth studying.

The objectives of this study were to determine the time course of the stimulatory effect of dexamethasone on serum leptin and whether it depends on food intake. Dexamethasone (4mg) was administered I.V. over 1 minute to healthy human volunteers (n=8) under fasting and feeding conditions (2000 kcal given at three meals over 7 hours). At 10 hours, serum leptin levels were increased only in the fed subjects (delta leptin 10.6+/-1.6 vs -2.4+/-1.9 ng/ml, p=0.01, n=8). To assess the interactive effect of food and dexamethasone on serum leptin, a subgroup (n=4) was studied under 4 conditions: 1) dexamethasone/fast; 2) dexamethasone/food; 3) saline/fast; 4) saline/food. Serum leptin declined from baseline under the fasting conditions, with or without dexamethasone. Feeding prevented the drop in serum leptin. In the dexamethasone/food condition, leptin levels rose from baseline after 7 hours and doubled after 10 hours (p

OPPERT, JEAN-MICHEL, NAJIBA LAHLOU, BLANDINE LAFERRERE, MARC ROGER, ARNAUD BASDEVANT, BERNARD GUY-GRAND. Plasma leptin and acute serotoninergic stimulation of the corticotropic axis in women who are normal weight or obese. In some recent studies, glucocorticoid treatment was associated with rapid induction of obese (ob) gene expression in adipose tissue of normal rats and in isolated adipocytes. We studied the effect of acute stimulation of the corticotropic axis on plasma leptin, the ob gene product, in 7 women of normal weight and 12 women with obesity. Under double-blind, placebo-controlled conditions, a single 12.5-mg dose of clomipramine, a serotonin uptake inhibitor, was administered intravenously in 15 minutes. Mean basal plasma leptin was increased more than 3-fold in subjects with obesity compared with subjects of normal weight (35.1 ± 4.9 ng/mL vs. 8.9 ± 1.4 ng/mL, p=0.001). Whereas corticotropin (ACTH) and Cortisol responses were increased in women who were obese compared with women who were lean, no significant effect of clomipramine infusion was found on plasma leptin concentrations measured during the following 150 minutes in both groups. There was a strong positive correlation between basal plasma leptin concentrations and body mass index (r=0.92, p

Severe obesity is a preeminent health care problem that impacts overall health and survival. The most effective treatment for severe obesity is bariatric surgery, an intervention that not only maintains long-term weight loss but also is associated with improvement or remission of several comorbidies including type 2 diabetes mellitus. Some weight loss surgeries modify the gastrointestinal anatomy and physiology, including the secretions and actions of gut peptides. This review describes how bariatric surgery alters the patterns of gastrointestinal motility, nutrient digestion and absorption, gut peptide release, bile acids and the gut microflora, and how these changes alter energy homeostasis and glucose metabolism.

Weight regain after gastric bypass (GBP) can be associated with a gastrogastric fistula (GGF), in which a channel forms between the gastric pouch and gastric remnant, allowing nutrients to pass through the “old route” rather than bypassing the duodenum. To further understand the mechanisms by which GGF may lead to weight regain, we investigated gut hormone levels in GBP patients with a GGF, before and after repair. Seven post-GBP subjects diagnosed with GGF were studied before and 4 months after GGF repair. Another cohort of 22 GBP control subjects without GGF complication were studied before and 1 year post-GBP. All subjects underwent a 50-g oral glucose tolerance test and blood was collected from 0–120 min for glucose, insulin, ghrelin, PYY3-36, GIP, and GLP-1 levels. Four months after GGF repair subjects lost 6.0 ± 3.9 kg and had significantly increased postprandial PYY3-36 levels. After GGF repair, fasting and postprandial ghrelin levels decreased and were strongly correlated with weight loss. The insulin response to glucose also tended to be increased after GGF repair, however no concomitant increase in GLP-1 was observed. Compared to the post-GBP group, GLP-1 and PYY3-36 levels were significantly lower before GGF repair; however, after GGF repair, PYY3-36 levels were no longer lower than the post-GBP group. These data utilize the GGF model to highlight the possible role of duodenal shunting as a mechanism of sustained weight loss after GBP, and lend support to the potential link between blunted satiety peptide release and weight regain.

Erratum: In the original publication, an erroneous date is given in the information on Prior Presentations in the Acknowledgements section. The correct date for the AHRQ Health Information Technology conference is June 2-4, 2010 as opposed to September 27, 2010. In the original publication, the given and surnames of the fourth and fifth authors were reversed. The correct names are Béatrice Morio (B. Morio) and Yves Boirie (Y. Boirie). (Erratum to: Surgical Weight Loss: Impact on Energy Expenditure, Obesity Surgery, Volume 23, Issue 5, p 734, doi: 10.1007/s11695-013-0870-x); International audience; Diet-induced weight loss is often limited in its magnitude and often of short duration, followed by weight regain. On the contrary, bariatric surgery now commonly used in the treatment of severe obesity favors large and sustained weight loss, with resolution or improvement of most obesity-associated comorbidities. The mechanisms of sustained weight loss are not well understood. Whether changes in the various components of energy expenditure favor weight maintenance after bariatric surgery is unclear. While the impact of diet-induced weight loss on energy expenditure has been widely studied and reviewed, the impact of bariatric surgery on total energy expenditure, resting energy expenditure, and diet-induced thermogenesis remains unclear. Here, we review data on energy expenditure after bariatric surgery from animal and human studies. Bariatric surgery results in decreased total energy expenditure, mainly due to reduced resting energy expenditure and explained by a decreased in both fat-free mass and fat mass. Limited data suggest increased diet-induced thermogenesis after gastric bypass, a surgery that results in gut anatomical changes and modified the digestion processes. Physical activity and sustained intakes of dietary protein may be the best strategies available to increase non-resting and then total energy expenditure, as well as to prevent the decline in lean mass and resting energy expenditure.

Study objective To determine the hormonal effects of reducing sleep duration under controlled feeding conditions. Design Randomized, crossover study. Setting Inpatient. Participants Twenty-seven normal weight, 30- to 45-yr-old men and women habitually sleeping 7-9 hr/night. Intervention PARTICIPANTS WERE STUDIED UNDER TWO SLEEP CONDITIONS: short (4 hr in bed) or habitual (9 hr in bed) sleep. A controlled diet was provided for each 4-day study period. Measurements and results Fasting blood samples were obtained daily and frequent blood samples were obtained throughout day 4. The main outcomes measures included glucose, insulin, leptin, ghrelin, adiponectin, total glucagon-like peptide 1 (GLP-1) and peptide YY(3-36) (PYY(3-36)) concentrations. Body weights were reduced by 2.2 ± 0.4 lb and 1.7 ± 0.4 lb during the habitual and short sleep phases, respectively (both P 0.05). Ghrelin and GLP-1 responses differed by sex. Short sleep increased fasting (P = 0.054) and morning (08:00-12:00) (P = 0.042) total ghrelin in men but not women. The reverse was observed for GLP-1: afternoon levels (12:30-19:00) were lower (P = 0.016) after short sleep compared with habitual sleep in women but not men. Conclusions These data suggest that, in the context of negative energy balance, short sleep does not lead to a state of increased insulin resistance, but may predispose to overeating via separate mechanisms in men and women. Clinical trial information Trial registration on http://www.clinicaltrials.gov. #NCT00935402.

A closer look at diabetes remission after gastric bypass surgery: a case study Katrina Brakoniecki, B.A., Christine Ren-Fielding, M.D., Blandine Laferrere, M.D.* New York Obesity Nutrition Research Center, Department of Medicine, St. Luke’s-Roosevelt Hospital Center, New York, New York New York University Bariatric Associates, New York University Langone Medical Center, New York, New York Columbia University College of Physicians and Surgeons, New York, New York Received May 1, 2012; accepted July 15, 2012

Reductions in mesolimbic responsivity have been noted following Roux-en-Y gastric bypass (RYGB; Ochner et al., 2011a). Given potential for postoperative increases in postprandial gut (satiety) peptides to affect mesolimbic neural responsivity, we hypothesized that: (1) post RYGB changes in mesolimbic responsivity would be greater in the fed relative to the fasted state and; (2) fasted vs. fed state differences in mesolimbic responsivity would be greater post-relative to pre-surgery. fMRI was used to asses neural responsivity to high- and low-calorie food cues in five women 1 mo pre- and 1 mo post-RYGB. Scans were repeated in fasted and fed states. Significant post RYGB decreases in the insula, ventromedial prefrontal cortex (vmPFC) and dorsolateral prefrontal cortex (dlPFC) responsivity were found in the fasted state. These changes were larger than neural changes in the fed state, which were non-significant. Preoperatively, fasted vs. fed differences in neural responsivity were greater in the precuneus, with large but nonsignificant clusters in the vmPFC and dlPFC. Postoperatively, however, no fasted vs. fed differences in neural responsivity were noted. Results were opposite to that predicted and appear inconsistent with the initial hypothesis that postoperative increases in postprandial gut peptides are the primary driver of postoperative changes in neural responsivity.