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OBJECTIVE The role of the gut in diabetes remission after Roux-en-Y gastric bypass (RYGB) is incompletely understood. We assessed the temporal change in insulin secretory capacity after RYGB, using oral and intravenous (IV) glucose, in individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS Longitudinal, prospective measures of β-cell function were assessed after oral glucose intake and graded glucose infusion in individuals with severe obesity and diabetes studied at 0, 3 (n = 29), 12 (n = 24), and 24 (n = 20) months after RYGB. Data were collected between 2015 and 2019 in an academic clinical research center. RESULTS The decreases in body weight, fat mass, waist circumference, and insulin resistance after surgery (all P < 0.001 at 12 and 24 months) did not differ according to diabetes remission status. In contrast, both the magnitude and temporal changes in β-cell glucose sensitivity after oral glucose intake differed by remission status (P = 0.04): greater (6.5-fold; P < 0.01) and sustained in those in full remission, moderate and not sustained past 12 months in those with partial remission (3.3-fold; P < 0.001), and minimal in those not experiencing remission (2.7-fold; P = not significant). The improvement in β-cell function after IV glucose administration was not apparent until 12 months, significant only in those in full remission, and only ∼33% of that observed after oral glucose intake. Preintervention β-cell function and its change after surgery predicted remission; weight loss and insulin sensitivity did not. CONCLUSIONS Our data show the time course of changes in β-cell function after RYGB. The improvement in β-cell function after RYGB, but not changes in weight loss or insulin sensitivity, drives diabetes remission.

Background Some of the metabolic effects of bariatric surgery may be mediated by the gut microbiome. Objectives To study the effect of bariatric surgery on changes to gut microbiota composition and bacterial pathways, and their relation to metabolic parameters after bariatric surgery. Settings University hospitals in the United States and Spain. Methods Microbial diversity and composition by 16 S rRNA sequencing, putative bacterial pathways, and targeted circulating metabolites were studied in 26 individuals with severe obesity, with and without type 2 diabetes, before and at 3, 6, and 12 months after either gastric bypass or sleeve gastrectomy. Results Bariatric surgery tended to increase alpha diversity, and significantly altered beta diversity, microbiota composition, and function up to 6 months after surgery, but these changes tend to regress to presurgery levels by 12 months. Twelve of 15 bacterial pathways enriched after surgery also regressed to presurgery levels at 12 months. Network analysis identified groups of bacteria significantly correlated with levels of circulating metabolites over time. There were no differences between study sites, surgery type, or diabetes status in terms of microbial diversity and composition at baseline and after surgery. Conclusions The association among changes in microbiome with decreased circulating biomarkers of inflammation, increased bile acids, and products of choline metabolism and other bacterial pathways suggest that the microbiome partially mediates improvement of metabolism during the first year after bariatric surgery.

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.

β-cell glucose sensitivity (BCGS) improves after gastric bypass (RYGB) in individuals in diabetes (DM2) remission. We sought to assess BCGS (pmol/kg/min/mM) after an oral glucose test (OGT) and an IV graded glucose infusion (GGI) in subjects with and without DM2 remission after RYGB. Twenty five subjects with DM2 were studied with GGI and 75g-OGT before and 3 months after RYGB. Glucose, insulin, C-peptide, insulin secretion rate, GLP-1 and BCGS were assessed during the OGT and the GGI. Data are presented as mean±SD. Within and between group comparisons with paired and unpaired t-test; GLM with repeated measure to assess change during OGT or GGI were (SPSS 24). Of the 25 subjects studied pre-surgery, 10 experienced DM2 remission (REM), 9 remained with DM2 (N-REM) at 3 months; 6 remained glucose intolerant and were not included in the analysis. Pre-surgery BMI (41.5±4.7 kg/m2), weight (108.3±15.9 kg), age (43.8±8.8 years), gender (95% female), HOMA-IR (12.1±6.7) and Matsuda index did not differ between groups; N-REM had longer DM2 duration (14 vs. 2.5 y p Weight loss did not differ for REM and N-REM (17±5%). HOMA-IR, GLP-1 and GGI-BCGS improved similarly in both groups. OGT-BCGS increased in both groups, but more in REM vs. N-REM (+1.31±1.0 vs. +0.30±0.28, p=0.01). The difference between OGT-BCGS and GGI-BCGS observed pre-RYGB (0.58±0.54 vs. 0.38±.035, p=ns) was exaggerated at 3 months by 4x in REM (2.13±1.vs. 0.58±0.15, p=0.001) and ∼2.5x in N-REM (0.60±.0.43 vs. 0.24±0.17, p=0.07). In conclusion, β-cell function assessed during an IV GGI improves by the same magnitude regardless of DM2 remission status after RYGB. However, β-cell function improved more in REM than N-REM after oral glucose, suggesting a greater incretin effect, or other gut-related mechanisms, in REM after RYGB. Disclosure A. Shah: Employee; Spouse/Partner; Daiichi Sankyo Company, Limited. K. Levesque: None. M. Ahlers: None. M.M. Holter: None. F. Alam: None. E. Pierini: None. B.L. Rojas: None. V. Mark: None. K. Patel: None. R. Dutia: None. E.J. Harvey: None. K. Park: None. N. Koshy: None. S.J. Belsley: None. J.J. Mcginty: None. B. Laferrere: None.

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.

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 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.

Proopiomelanocortin (POMC) is posttranslationally processed to several peptides including α-MSH, a primary regulator of energy balance that inhibits food intake and stimulates energy expenditure. However, another POMC-derived peptide, β-endorphin (β-EP), has been shown to stimulate food intake. In this study we examined the effects of intracerebroventricular (icv) β-EP on food intake and its ability to antagonize the negative effects of α-MSH on energy balance in male rats. A single icv injection of β-EP stimulated food intake over a 2- to 6-h period during both the light and dark cycles. This effect was, however, not sustained with chronic icv β-EP infusion. In the next study, a subthreshold dose of β-EP was injected together with Nle4, d-Phe7 (NDP)-MSH after a 16-h fast, and the negative effects of NDP-MSH on refeeding and body weight gain were partially reversed. Finally, peptide interactions were studied in a chronic icv infusion model. Weight gain and food intake were significantly suppressed in the NDP-MSH group during the entire study. A subthreshold dose of β-EP antagonized these suppressive effects on food intake and weight gain for the first 3 d. However on d 4–7, β-EP no longer blocked these effects. Of note, the stimulatory effect of β-EP on feeding and its ability to antagonize MSH were specific for β-EP1–31 and were not observed with β-EP1–27. This study highlights the importance of understanding how the balance between α-MSH and β-EP is maintained and the potential role of differential POMC processing in regulating energy balance.

INTRODUCTION:We investigated the effect of parity on induction of labor (IOL) outcomes in women treated with either misoprostol (MVI) or dinoprostone vaginal inserts (DVI).METHODS:Pooled IOL outcome data were analyzed from 3 phase II/III trials using DVI 10mg and MVI 200µg in nulliparous (DVI n=715/

Hypothalamic proopiomelanocortin (POMC)-derived MSH peptides and the melanocortin receptor antagonist, agouti-related protein (AgRP), interact to regulate energy balance. Both POMC and AgRP neurons express estrogen receptors, but little is known about estrogen regulation of the melanocortin system in the primate. We have therefore examined the effects of physiological doses of estradiol (E2) on POMC and AgRP in lumbar cerebrospinal fluid (CSF) of ovariectomized monkeys. POMC prohormone was measured by ELISA. AgRP was measured by RIA (sensitive for the more biologically active C-terminal AgRP83-132 but also detects full-length AgRP) and by ELISA (measures primarily full length AgRP). In the first experiment, 14 animals were studied before and after 3 wk of E2. CSF POMC did not change, but AgRP(RIA) decreased from 7.9 ± 1.2 to 4.7 ± 1.2 fmol/ml after E2 (P = 0.03) and the POMC/AgRP(RIA) ratio increased from 4.2 ± 0.89 to 6.8 ± 1.04 (P = 0.04). AgRP(ELISA) did not change, but the ratio of AgRP(RIA) compared with AgRP(ELISA) was reduced after E2 (P = 0.02). In the second experiment, 11 animals were studied after 6 wk of E2, and similar changes were noted. The degree of AgRP(RIA) suppression with E2 was inversely related to body mass index (r = 0.569; P = 0.03). These results show for the first time that E2 suppresses AgRP(C-terminal) in CSF, increases the POMC to AgRP ratio, and may decrease AgRP processing, thus leading to increased melanocortin signaling. Furthermore, obesity was associated with resistance to the suppressive effects of E2 on AgRP, analogous to what is seen with obesity and leptin resistance.

Cells acquire cholesterol either by de novo synthesis in the endoplasmic reticulum or by internalization of cholesterol-containing lipoproteins, particularly low density lipoprotein (LDL), via receptor-mediated endocytosis. The inherited disorder Niemann-Pick type C (NPC), in which abnormal LDL-cholesterol trafficking from the endo/lysosomal compartment leads to substantial cholesterol and glycolipid accumulation in lysosomes, is caused by defects in either of two genes that encode for proteins designated as NPC1 and NPC2. NPC2 is a small intralysosomal protein that has been characterized biochemically as a cholesterol binding protein. We determined the rate and mechanism by which NPC2 delivers cholesterol to model phospholipid membranes. A fluorescence dequenching assay was used to monitor the kinetics of cholesterol transfer from the protein to membranes. The endogenous tryptophan fluorescence of the NPC2 was quenched upon binding of cholesterol, and the subsequent addition of acceptor vesicles resulted in dequenching of the tryptophan signal, enabling the monitoring of cholesterol transfer to membranes. The rates of cholesterol transfer were evaluated as a function of acceptor vesicle concentration, acceptor vesicle phospholipid headgroup composition, and aqueous phase properties. The results suggest that NPC2 rapidly transports cholesterol to phospholipid vesicles via a collisional mechanism which involves a direct interaction with the acceptor membrane. Transfer of cholesterol to membranes is faster in an acidic environment and is greatly enhanced by the presence of the unique lysosomal/late endosomal phospholipid lyso-bisphosphatidic acid (LBPA) (also known as bismonoacylglycerol phosphate). Finally, we found that the rate of transfer of cholesterol from vesicles to NPC2 was dramatically increased by the presence of lyso-bisphosphatidic acid in the donor vesicles. These results support a role for the NPC2 protein in the egress of LDL derived cholesterol out of the endosomal/lysosomal compartment.

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 …

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.

e18008Background: ~1 in 10 cancer cases occur in adults of reproductive age.* ASCO guidelines encourage oncologists to discuss the possibility of infertility with patients of reproductive age or wi...

Activation of brain melanocortin-4 receptors (MC4-R) by α-melanocyte-stimulating hormone (MSH) or inhibition by agouti-related protein (AgRP) regulates food intake and energy expenditure and can modulate neuroendocrine responses to changes in energy balance. To examine the effects of AgRP inhibition on energy balance, a small molecule, non-peptide compound, TTP2515, developed by TransTech Pharma, Inc., was studied in vitro and in rodent models in vivo. TTP2515 prevented AgRP from antagonizing α-MSH-induced increases in cAMP in HEK 293 cells overexpressing the human MC4-R. When administered to rats by oral gavage TTP2515 blocked icv AgRP-induced increases in food intake, weight gain and adiposity and suppression of T4 levels. In both diet-induced obese (DIO) and leptin-deficient mice, TTP2515 decreased food intake, weight gain, adiposity and respiratory quotient. TTP2515 potently suppressed food intake and weight gain in lean mice immediately after initiation of a high fat diet (HFD) but had no effect on these parameters in lean chow-fed mice. However, when tested in AgRP KO mice, TTP2515 also suppressed food intake and weight gain during HFD feeding. In several studies TTP2515 increased T4 but not T3 levels, however this was also observed in AgRP KO mice. TTP2515 also attenuated refeeding and weight gain after fasting, an effect not evident in AgRP KO mice when administered at moderate doses. This study shows that TTP2515 exerts many effects consistent with AgRP inhibition however experiments in AgRP KO mice indicate some off-target effects of this drug. TTP2515 was particularly effective during fasting and in mice with leptin deficiency, conditions in which AgRP is elevated, as well as during acute and chronic HFD feeding. Thus the usefulness of this drug in treating obesity deserves further exploration, to define the AgRP dependent and independent mechanisms by which TTP2515 exerts its effects on energy balance.

This study used two mouse models with genetic manipulation of the melanocortin system to investigate prolactin regulation. Mice with overexpression of the melanocortin receptor (MC-R) agonist, α-melanocyte-stimulating hormone (Tg-MSH) or deletion of the MC-R antagonist agouti-related protein (AgRP KO) were studied. Male Tg-MSH mice had lower blood prolactin levels at baseline (2.9±0.3 vs 4.7±0.7 ng/ml) and after restraint stress(68 ±6.5 vs 117±22 ng/ml) versus WT (p