incretins and Obesity--Morbid

Bariatric surgery is currently the most efficacious treatment for obesity and its associated metabolic co-morbidities, such as diabetes. The metabolic improvements occur through both weight-dependent and weight-independent mechanisms. Bile acids (BAs) have emerged as key signalling molecules that have a central role in modulating many of the physiological effects seen after bariatric surgery. This systematic review assesses the evidence from both human and animal studies for the role of BAs in reducing the metabolic complications of obesity following bariatric surgery.. We conducted a systematic search of Medline and Embase databases to identify all articles investigating the role of BAs in mediating the metabolic changes observed following bariatric surgery in both animal and human studies. Boolean logic was used with relevant search terms, including the following MeSH terms: 'bile acids and salts', 'bariatric surgery', 'metabolic surgery', 'gastrointestinal tract/surgery' and 'obesity/surgery'.. Following database searches (n=1197), inclusion from bibliography searches (n=2) and de-duplication (n=197), 1002 search results were returned. Of these, 132 articles were selected for full-text review, of which 38 articles were deemed relevant and included in the review. The findings support the effects of BAs on satiety, lipid and cholesterol metabolism, incretins and glucose homoeostasis, energy metabolism, gut microbiota and endoplasmic reticulum stress following bariatric surgery. Many of these metabolic effects are modulated through the BA receptors FXR and TGR5. We also explore a possible link between BAs and carcinogenesis following bariatric surgery.. Overall there is good evidence to support the role of BAs in the metabolic effects of bariatric surgery through the above mechanisms. BAs could serve as a novel therapeutic pharmacological target for the treatment of obesity and its associated co-morbidities.

Topics: Bariatric Surgery; Bile Acids and Salts; Endoplasmic Reticulum; Energy Metabolism; Gastrointestinal Microbiome; Glucose; Homeostasis; Humans; Incretins; Lipid Metabolism; Metabolic Diseases; Obesity, Morbid; Receptors, Cytoplasmic and Nuclear; Receptors, G-Protein-Coupled; Treatment Outcome; Weight Loss

Bariatric surgery has emerged as the most durably effective treatment of type 2 diabetes (DM). However, the mechanisms governing improvement in glucose homeostasis have yet to be fully elucidated. In this review we discuss the various types of surgical interventions and the multitude of factors that potentially mediate the effects on glycemia, such as altered delivery of nutrients to the distal ileum, duodenal exclusion, gut hormone changes, bile acid reabsorption, and amino acid metabolism. Accumulating evidence that some of these changes seem to be independent of weight loss questions the rationale of using body mass index as the major indication for surgery in diabetic patients. Understanding the complex mechanisms and interactions underlying improved glycemic control could lead to novel therapeutic targets and would also allow for greater individualization of therapy and optimization of surgical outcomes.

Topics: Bariatric Surgery; Body Mass Index; Caloric Restriction; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Glucose; Glycated Hemoglobin; Homeostasis; Humans; Incretins; Insulin Resistance; Male; Obesity, Morbid; Peptide YY; Randomized Controlled Trials as Topic; Remission Induction; Treatment Outcome; Weight Loss

Glucagon like peptide-1 (GLP-1) is one of the gastrointestinal peptides implicated in glycaemic homeostasis. In non-obese individuals with normal glucose tolerance GLP-1 is secreted in response to nutrient intake. However, this GLP- 1 response is generally accepted to be significantly diminished in those with diabetes, obesity or both. Given that GLP-1 is secreted from enteroendocrine L cells in the intestine, it is not surprising that manipulation of the gastro- intestinal tract has been shown to alter GLP-1 secretion; particularly when this intestinal manipulation is designed to aid weight reduction. GLP-1 dynamics are altered by bariatric surgery, with an improved secretory response to nutrient intake. However, there remains debate on the mechanisms responsible for the alterations in GLP-1 dynamics. Here we review the evidence for GLP-1 dynamics after Roux-en-Y gastric bpyass (RYGB), adjustable gastric banding (AGB), biliopancreatic diversion (BPD) and sleeve gastrectomy (SG), and make comparisons between modalities. In addition, we review the potential mechanisms underlying these dynamics, other molecules that may add to the "incretin effect" and other possible roles for GLP-1 following bariatric surgery. Finally, we will offer our critique of the evidence base.

Topics: Animals; Biliopancreatic Diversion; Blood Glucose; Cross-Sectional Studies; Fasting; Female; Gastric Bypass; Gastroplasty; Glucagon-Like Peptide 1; Humans; Incretins; Longitudinal Studies; Male; Neural Pathways; Obesity, Morbid; Peptide YY; Prospective Studies; Rats; Weight Loss

Type 2 diabetes mellitus is increasing over time as result of the obesity epidemics. In fact, the prevalence of Type 2 diabetes across Europe in 2010 was estimated to be 8.2% of the population and its projection for 2030 sees figures of 10.1%. This increase in the number of diabetic individuals has also dramatically raised the health expense, with spending on diabetes in Europe in 2010 accounting for 10% of the total healthcare cost. A meta-analysis of the literature evidenced that the clinical and laboratory manifestations of Type 2 diabetes are resolved in 78.1%, and are improved in 86.6% of obese patients (body mass index >35 kg/m²) after bariatric surgery. However, a gradation of effects of different surgical techniques in improving glucose control does exist, with the largest and durable effects observed in prevalently malabsorptive procedures. The outcome of bariatric surgery on insulin sensitivity and secretion is different in relation to the type of operation performed. In fact, while Roux-en-Y Gastric Bypass enhances insulin secretion after a meal thus improving glucose metabolism, Bilio-Pancreatic Diversion acts through the amelioration of insulin sensitivity allowing a subsequent reduction of insulin hypersecretion, which is a typical feature of the insulin resistance state. Gastric banding action is mediated uniquely through the weight loss, and the effect of sleeve gastrectomy is still to be elucidated. Incretin secretion is dramatically increased under nutrient stimulation after gastric bypass leading, probably, to an overstimulation of pancreatic β-cells resulting in the increase of insulin secretion.

Topics: Animals; Bariatric Surgery; Body Mass Index; Diabetes Mellitus, Type 2; Gastric Mucosa; Ghrelin; Glucagon; Glucagon-Like Peptide 1; Glucagon-Secreting Cells; Humans; Incretins; Insulin Resistance; Insulin-Secreting Cells; Intestinal Mucosa; Obesity, Morbid

Roux-en-Y gastric bypass surgery (GBP) results in 30-40% sustained weight loss and improved type 2 diabetes in up to 80% of patients. The relative contribution of the gut neuroendocrine changes after GBP versus the weight loss has not been fully elucidated. There are clear differences between weight loss by GBP and by dietary intervention or gastric banding. One of them is the enhanced post-prandial release of incretin hormones and the recovery of the incretin effect on insulin secretion after GBP, not seen after diet-induced weight loss. The favorable changes in incretin hormones after GBP result in recovery of the early phase insulin secretion and lower post-prandial glucose levels during oral glucose administration. The enhanced incretin response may be related to the neuroglycopenia post-GBP. In parallel with changes of glucose metabolism, a larger decrease of circulating branched-chain amino acids in relation to improved insulin sensitivity and insulin secretion is observed after GBP compared to diet. The mechanisms of the rapid and longterm endocrine and metabolic changes after GBP are not fully elucidated. Changes in rate of eating, gastric emptying, nutrient absorption and sensing, bile acid metabolism, and microbiota may all be important. Understanding the mechanisms by which incretin release is exaggerated post-prandially after GBP may help develop new less invasive treatment options for obesity and diabetes. Equally important would be to identify biological predictors of success or failure and to understand the mechanisms of weight regain and/or diabetes relapse.

Topics: Amino Acids; Animals; Diabetes Mellitus, Type 2; Gastric Bypass; Humans; Incretins; Obesity; Obesity, Morbid; Recurrence; Severity of Illness Index; Weight Loss

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.

Topics: Bariatric Surgery; Diabetes Mellitus, Type 2; Evidence-Based Medicine; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Intestine, Small; Obesity, Morbid; Remission Induction; Weight Loss

Gastric bypass surgery (GBP), in addition to weight loss, results in dramatic remission of type 2 diabetes (T2DM). The mechanisms by which this remission occurs are unclear. Besides weight loss and caloric restriction, the changes in gut hormones that occur after GBP are increasingly gaining recognition as key players in glucose control. Incretins are gut peptides that stimulate insulin secretion postprandially; the levels of these hormones, particularly glucagon-like peptide-1, increase after GBP in response to nutrient stimulation. Whether these changes are causal to changes in glucose homeostasis remain to be determined. The purpose of this review is to assess the evidence on incretin changes and T2DM remission after GBP, and the possible mechanisms by which these changes occur. Our goals are to provide a thorough update on this field of research so that recommendations for future research and criteria for bariatric surgery can be evaluated.

Topics: Animals; Diabetes Mellitus, Type 2; Evidence-Based Medicine; Gastric Bypass; Gastric Emptying; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon-Like Peptide 1; Gluconeogenesis; Glucose; Homeostasis; Humans; Incretins; Intestine, Small; Leptin; Liver; Obesity, Morbid; Peptide YY; Randomized Controlled Trials as Topic; Remission Induction; Weight Loss

Diabetes resolves in 80% of individuals undergoing successful Roux-en-Y gastric bypass. Absolute caloric restriction alone resulting from gastric anatomic changes indeed leads to weight loss; however, immediate effects in glycemic control often precede substantial weight loss typically associated with insulin sensitivity. One putative explanation relates to hormonal effects accompanying Roux-en-Y gastric bypass. We reviewed the existing and recent literature to investigate the hormonal changes accompanying Roux-en-Y gastric bypass.. Changes in levels of five candidate enteric hormones have been recently associated with early postoperative glycemic control following Roux-en-Y gastric bypass; the strongest effects are seen with variations in glucagon-like peptide-1, glucose-dependent insulinotropic peptide and ghrelin.. The unique hybridization of static anatomic restriction and dynamic absorptive bypass lends a duality to the beneficial effects of Roux-en-Y gastric bypass. This duality likely explains the short-term and long-term resolution of diabetes in patients undergoing Roux-en-Y gastric bypass.

Topics: Caloric Restriction; Diabetes Mellitus, Type 2; Energy Intake; Gastric Bypass; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon-Like Peptide 1; Humans; Incretins; Obesity, Morbid; Peptide Hormones; Weight Loss

There is limited literature available on the long-term effect of bariatric surgery especially laparoscopic sleeve gastrectomy (LSG) on the incretin hormone response.. Our primary aim was to investigate changes in glucose metabolism and incretin hormone responses in participants with impaired glucose regulation approximately 4 years after LSG. The secondary aim was to examine the long-term incretin hormone changes of biliopancreatic diversion (BPD).. A non-randomised prospective study comprising of 10 participants undergoing LSG and 6 participants undergoing BPD. Serial measurements of glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) were performed during an oral glucose tolerance test pre-operatively and 1 month, 6 months and at approximately 4-7 years post-operatively. Area under the curve (AUC) was examined at 60 and 120 min.. In the LSG group, a significant reduction in 2-h plasma glucose (2 h PG), HbA1c and HOMA-IR was observed at 4 years. Compared with pre-operative levels, significant increases in post-glucose GLP-1 secretion were observed at 1 and 6 months, but not maintained at 4 years. A linear increase was seen in post-glucose GIP response at 1 month and 6 months and 4 years. Within the BPD group, a reduction in HbA1c along with an increase GLP-1 response was observed at 7 years.. An increase in GLP-1 response was not preserved at 4 years, but a significant increase in GIP response was observed along with improved glycaemic control following LSG.

Topics: Adult; Blood Glucose; C-Peptide; Female; Follow-Up Studies; Gastrectomy; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Homeostasis; Humans; Incretins; Insulin; Laparoscopy; Male; Middle Aged; Obesity, Morbid; Postoperative Period; Prospective Studies; Time Factors

We aimed to explore the relationship between GLP-1 receptor (GLP-1R) expression in adipose tissue (AT) and incretin secretion, glucose homeostasis and weight loss, in patients with morbid obesity and type 2 diabetes undergoing bariatric surgery. RNA was extracted from subcutaneous (SAT) and visceral (VAT) AT biopsies from 40 patients randomized to metabolic gastric bypass, sleeve gastrectomy or greater curvature plication. Biochemical parameters, fasting plasma insulin, glucagon and area under the curve (AUC) of GLP-1 following a standard meal test were determined before and 1 year after bariatric surgery. GLP-1R expression was higher in VAT than in SAT. GLP-1R expression in VAT correlated with weight (r = -0.453, p = 0.008), waist circumference (r = -0.494, p = 0.004), plasma insulin (r = -0.466, p = 0.007), and systolic blood pressure (BP) (r = -0.410, p = 0.018). At 1 year, GLP-1R expression in VAT was negatively associated with diastolic BP (r = -0.361, p = 0.039) and, following metabolic gastric bypass, with the increase of GLP-1 AUC, (R

Topics: Adipose Tissue; Adolescent; Adult; Bariatric Surgery; Blood Glucose; Diabetes Mellitus, Type 2; Fasting; Female; Gastrectomy; Gastric Bypass; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Male; Middle Aged; Obesity, Morbid; Stomach; Weight Loss; Young Adult

To evaluate early changes in glycemia, insulin physiology and gut hormone responses to an easily tolerated and slowly ingested solid, low-carbohydrate mixed meal test (MMT) following laparoscopic adjustable gastric banding (LAGB) or Roux-en-Y gastric bypass (RYGB) surgery.. This was a prospective non-randomized study. Plasma glucose, insulin and c-peptide (to estimate hepatic insulin extraction; %HIE), incretins (GIP, aGLP-1) and pancreatic polypeptide (PP) responses to the MMT were measured at 4-8 weeks before and after surgery in obese, metabolically healthy patients (RYGB=10F or LAGB =7F/1M). Supplementary clamp data on basal endogenous glucose production (EGP) and peripheral insulin action (Rd=rate of glucose disposal) and metabolic clearance rates of insulin (MCR-INS) were available in five of the RYGB patients. Repeated measures were appropriately accounted for in the analyses.. RYGB results in distinctly different changes in plasma glucose, insulin and gut hormone response patterns to a solid, slowly ingested low-carbohydrate MMT versus LAGB. Altered nutrient delivery, along with indirect evidence for changes in hepatic and peripheral insulin physiology, are consistent with the greater early improvement in glycemia observed after RYGB versus LAGB surgery.

Topics: Adult; Blood Glucose; C-Peptide; Diet, Carbohydrate-Restricted; Female; Gastric Bypass; Glucagon-Like Peptide 1; Glucose Clamp Technique; Humans; Incretins; Insulin; Male; Meals; Obesity, Morbid; Postoperative Care; Postprandial Period; Prospective Studies; Treatment Outcome; Weight Loss

Intestinal glucose absorption is mediated by sodium-dependent glucose transporter 1 (SGLT-1) and glucose transporter 2 (GLUT2), which are linked to sweet taste receptor (STR) signaling and incretin responses.. This study aimed to examine intestinal glucose absorption in morbidly obese humans and its relationship to the expression of STR and glucose transporters, glycemia, and incretin responses.. Seventeen nondiabetic, morbidly obese subjects (body mass index [BMI], 48 ± 4 kg/m(2)) and 11 lean controls (BMI, 25 ± 1 kg/m(2)) underwent endoscopic duodenal biopsies before and after a 30-minute intraduodenal glucose infusion (30 g glucose and 3 g 3-O-methylglucose [3-OMG]).. Blood glucose and plasma concentrations of 3-OMG, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1), insulin, and glucagon were measured over 270 minutes. Expression of duodenal SGLT-1, GLUT2, and STR (T1R2) was quantified by PCR.. The increase in plasma 3-OMG (P < .001) and blood glucose (P < .0001) were greater in obese than lean subjects. Plasma 3-OMG correlated directly with blood glucose (r = 0.78, P < .01). In response to intraduodenal glucose, plasma GIP (P < .001), glucagon (P < .001), and insulin (P < .001) were higher, but GLP-1 (P < .001) was less in the obese compared with lean. Expression of SGLT-1 (P = .035), but not GLUT2 or T1R2, was higher in the obese, and related to peak plasma 3-OMG (r = 0.60, P = .01), GIP (r = 0.67, P = .003), and insulin (r = 0.58, P = .02).. In morbid obesity, proximal intestine glucose absorption is accelerated and related to increased SGLT-1 expression, leading to an incretin-glucagon profile promoting hyperinsulinemia and hyperglycemia. These findings are consistent with the concept that accelerated glucose absorption in the proximal gut underlies the foregut theory of obesity and type 2 diabetes.

Topics: 3-O-Methylglucose; Adult; Blood Glucose; Female; Gastric Inhibitory Polypeptide; Gene Expression; Glucagon; Glucagon-Like Peptide 1; Glucose; Glucose Transport Proteins, Facilitative; Humans; Incretins; Insulin; Intestinal Absorption; Male; Middle Aged; Obesity, Morbid; Time Factors

To identify the metabolic determinants of type 2 diabetes non-remission status after bariatric surgery at 12 and 24 months.. A total of 40 adults [mean ± sd body mass index 36 ± 3 kg/m(2) , age 48 ± 9 years, glycated haemoglobin (HbA1c) 9.7 ± 2%) undergoing bariatric surgery [Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG)] were enrolled in the present study, the Surgical Treatment and Medication Potentially Eradicate Diabetes Efficiently (STAMPEDE) trial. Type 2 diabetes remission was defined as HbA1c <6.5% and fasting glucose <126 mg/dl (i.e. <7 mmol/l) without antidiabetic medication. Indices of insulin secretion and sensitivity were calculated from plasma glucose, insulin and C-peptide values during a 120-min mixed-meal tolerance test. Body fat, incretins (glucagon-like polypeptide-1, gastric inhibitory peptide, ghrelin) and adipokines [adiponectin, leptin, tumour necrosis factor-α, high-sensitivity C-reactive protein (hs-CRP)] were also assessed.. At 24 months, 37 patients had available follow-up data (RYGB, n = 18; SG, n = 19). Bariatric surgery induced type 2 diabetes remission rates of 40 and 27% at 12 and 24 months, respectively. Total fat/abdominal fat loss, insulin secretion, insulin sensitivity and β-cell function (C-peptide0-120 /glucose0-120 × Matsuda index) improved more in those with remission at 12 and 24 months than in those without remission. Incretin levels were unrelated to type 2 diabetes remission, but, compared with those without remission, hs-CRP decreased and adiponectin increased more in those with remission. Only baseline adiponectin level predicted lower HbA1c levels at 12 and 24 months, and elevated adiponectin correlated with enhanced β-cell function, lower triglyceride levels and fat loss.. Smaller rises in adiponectin level, a mediator of insulin action and adipose mass, characterize type 2 diabetes non-remission up to 2 years after bariatric surgery. Adjunctive strategies promoting greater fat loss and/or raising adiponectin may be key to achieving higher type 2 diabetes remission rates after bariatric surgery.

Topics: Adiponectin; Adult; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Gastrectomy; Gastric Bypass; Glycated Hemoglobin; Humans; Incretins; Insulin Resistance; Male; Middle Aged; Obesity, Morbid; Prospective Studies; Remission Induction; Time Factors; Treatment Outcome; Weight Loss

Protein supplements are routinely used after a laparoscopic gastric bypass (LGB). The aim of this study was to evaluate the impact of an amino acid supplement on glucose homeostasis and hormonal and inflammatory markers after LGB.. Thirty patients undergoing LGB were randomized to receive or not 24 g of an oral supplement containing a leucine metabolite, glutamine, and arginine twice daily. Changes in weight, glucose, insulin, C-peptide, insulin sensitivity, interleukin (IL) 6, C-reactive protein (CRP), leptin, insulin-like growth factor (IGF) 1, ghrelin, and incretins were assessed preoperatively and 2 weeks and 8 weeks postoperatively.. Thirty patients (96.7% female, age 46.9 ± 8.4 years, body mass index 43.3 ± 4.1 kg/m(2)) were randomized. The experimental (n = 14) and control (n = 16) groups were not significantly different at baseline. Weight loss was similar for the 2 groups. Fasting glucose decreased significantly at 2 and 8 weeks compared with base line (p < 0.0001) with no difference between the experimental and control groups (p = 0.8), but insulin and calculated insulin sensitivity, which were similar at baseline, became significantly worse in the experimental group 8 weeks after surgery (p = 0.02 for insulin; p = 0.04 for the homeostasis model assessment of insulin resistance). CRP and IL-6, which were similar at baseline, were found to be significantly higher at 8 weeks in the experimental group (p = 0.018 and p = 0.05, respectively). Leptin and IGF-1 levels decreased significantly from baseline at 2 and 8 weeks (p < 0.0001), but there was no difference between the 2 groups. No significant changes in GLP-1, ghrelin, or gastric inhibitory polypeptide were noticed after 8 weeks.. An amino acid supplement had no effect on the early postoperative incretins after LGB. It may have a negative influence on glucose kinetics and degree of inflammation. Future studies are needed to clarify these effects.

Topics: Adult; Arginine; Blood Glucose; C-Reactive Protein; Dietary Supplements; Female; Gastric Bypass; Glutamine; Humans; Incretins; Interleukin-6; Laparoscopy; Male; Middle Aged; Obesity, Morbid; Pilot Projects; Treatment Outcome; Valerates

Topics: Gastrectomy; Gastric Bypass; Humans; Incretins; Obesity, Morbid; Retrospective Studies; Treatment Outcome

Exaggerated postprandial incretin and insulin responses are well documented in postbariatric surgery hypoglycemia (PBH) after Roux-en-Y gastric bypass (RYGB). However, less is known about PBH after sleeve gastrectomy (SG).. We sought to compare meal-stimulated hormonal response in those with PBH after SG vs RYGB.. We enrolled 23 post-SG (12 with and 11 without PBH) and 20 post-RYGB (7 with and 13 without PBH) individuals who underwent bariatric surgery at our institution. PBH was defined as plasma glucose less than 60 mg/dL on 4-hour mixed-meal tolerance test (MTT). Islet and incretin hormones were compared across the 4 groups.. Participants (N = 43) were on average 5 years post surgery, with a mean age of 48 years, mean preoperative body mass index of 48.4, 81% female, 61% White, and 53% post SG. Regardless of PBH, the SG group showed lower glucose, glucagon, and glucagon-like peptide 1 (GLP-1) responses to MTT and similar insulin and glucose-dependent insulinotropic polypeptide (GIP) responses compared to the RYGB group. Among those with PBH, the SG group following the MTT showed a lower peak glucose (P = .02), a similar peak insulin (90.3 mU/L vs 171mU/L; P = .18), lower glucagon (P < .01), early GLP-1 response (AUC0-60 min; P = .01), and slower time to peak GIP (P = .02) compared to PBH after RYGB.. Among individuals with PBH, those who underwent SG were significantly different compared to RYGB in meal-stimulated hormonal responses, including lower glucagon and GLP-1 responses, but similar insulin and GIP responses. Future studies are needed to better understand the differential contribution of insulin and non-insulin-mediated mechanisms behind PBH after SG vs RYGB.

Topics: Blood Glucose; Female; Gastrectomy; Gastric Bypass; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose; Humans; Hypoglycemia; Incretins; Insulin; Male; Middle Aged; Obesity, Morbid

Enteroendocrine L cells can be found in the entire gastrointestinal tract and their incretins act on glycemic control and metabolic homeostasis. Patients with severe obesity and type 2 diabetes mellitus may have lower density of L cells in the proximal intestine.. This study aimed to analyze the density of L cells in the segments of the small intestine in the late postoperative of Roux-en-Y gastric bypass in diabetic patients with standardization of 60 cm in both loops, alimentary and biliopancreatic.. Immunohistochemistry analysis assays were made from intestinal biopsies in three segments: gastrointestinal anastomosis (GIA= Point A), enteroenteral anastomosis (EEA= Point B= 60 cm distal to the GIA) and 60 cm distal to the enteroenteral anastomosis (Point C).. A higher density of L cells immunostaining the glucagon-1 peptide was observed in the distal portion (Point C) when compared to the more proximal portions (Points A and B).. The concentration of L cells is higher 60 cm distal to enteroenteral anastomosis when comparing to proximal segments and may explain the difference in intestinal lumen sensitization and enterohormonal response after Roux-en-Y gastric bypass.

Topics: Anastomosis, Roux-en-Y; Diabetes Mellitus, Type 2; Enteroendocrine Cells; Gastric Bypass; Glucagon; Humans; Incretins; Obesity, Morbid; Treatment Outcome

We aimed to investigate insulin-, mTOR- and SGK1-dependent signaling basal states in morbidly obese patients' fat. We analyzed the correlation between the signaling activity, carbohydrate metabolism, and incretin profiles of patients.. The omental and subcutaneous fat was obtained in patients with obesity. The omental study included 16 patients with normal glucose tolerance (NGT) and 17 patients with type 2 diabetes mellitus (T2DM); the subcutaneous study included 9 NGT patients and 12 T2DM patients. Insulin resistance was evaluated using the hyperinsulinemic euglycemic clamp test and HOMA-IR index. The oral glucose tolerance test (OGTT) for NGT patients and mixed meal tolerance test (MMTT) for T2DM patients were performed. The levels of incretins (GLP-1, GIP, oxyntomodulin) and glucagon were measured during the tests. Signaling was analyzed by Western blotting in adipose tissue biopsies.. We have shown equal levels of basal phosphorylation of insulin- and mTOR-dependent signaling in omental fat depot in NGT and T2DM obese patients. Nevertheless, pNDRG1-T346 was decreased in omental fat of T2DM patients. Correlation analysis has shown an inverse correlation of pNDRG1-T346 in omental fat and diabetic phenotype (HbA1c, impaired incretin profile (AUC GLP-1, glucagon)). Moreover, pNDRG1-T346 in subcutaneous fat correlated with impaired incretin levels among obese patients (inverse correlation with AUC glucagon and AUC GIP).. According to results of the present study, we hypothesize that phosphorylation of pNDRG1-T346 can be related to impairment in incretin hormone processing. pNDRG1-T346 in adipose tissue may serve as a marker of diabetes-associated impairments of the systemic incretin profile and insulin sensitivity.

Topics: Adipose Tissue; Adult; Biomarkers; Biopsy; Case-Control Studies; Cell Cycle Proteins; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Humans; Incretins; Insulin Resistance; Intracellular Signaling Peptides and Proteins; Male; Metabolome; Middle Aged; Obesity, Morbid; Phosphorylation

Intestinal electrical stimulation (IES) has been reported to reduce body weight and improve glucose tolerance in obese and diabetic rats. Our study aimed to investigate possible IES mechanisms involving incretin hormones using intraduodenal glucose infusion in rats. We hypothesized that the enhanced release of postprandial glucagon-like peptide-1 (GLP-1) at early phase by IES was mediated through neuro/paracrine mechanisms involving the vagal nerve and glucose-dependent insulinotropic peptide (GIP).. Fifteen normal male Sprague-Dawley rats chronically implanted with duodenal electrodes for IES, and an intra-duodenum catheter for the infusion of glucose were studied in a series of sessions with IES of different parameters with and without atropine and M3 receptor antagonist. Blood samples were collected via the tail vein for the measurement of blood glucose, and plasma GLP-1, and GIP.. (1) Compared to sham-IES, IES of 0.3 ms reduced blood glucose by 16.5-28.4% between 30 and 120 min (all time points p < 0.05), and IES of 3-ms reduced blood glucose at 60 (12.6%) and 90 min (11.8%). IES of 0.3 ms showed a greater hypoglycemic effect than 3 ms (p = 0.024) at 30 min. (2) IES elevated plasma GLP-1 with 0.3 ms (p = 0.001) and with 3 ms p = 0.03). (3) IES substantially elevated plasma GIP with 0.3 ms (p = 0.002) and with 3 ms (p < 0.001). (4) Pretreatment of atropine and the M3 receptor antagonist 4-DAMP blocked the effects of IES on GLP-1, GIP, and blood glucose.. IES reduces postprandial blood glucose by enhancing the release of GLP-1 and GIP mediated via the cholinergic mechanism.

Topics: Animals; Blood Glucose; Cholinergic Agents; Diabetes Mellitus, Experimental; Electric Stimulation; Gastric Inhibitory Polypeptide; Incretins; Insulin; Male; Obesity, Morbid; Rats; Rats, Sprague-Dawley

Bariatric surgery is an effective treatment for morbid obesity and glycaemic dysfunction.. The aim of the work was to examine both the static and dynamic changes of glucose-insulin homeostasis and incretin hormone response following sleeve gastrectomy (SG) in a sample of 55 participants preoperatively and 1 month and 6 months postoperatively. The focus was on a sample of patients with impaired glucose tolerance and type 2 diabetes (T2D).. Morriston Hospital, UK.. Prospective study comprising of 55 participants with impaired glucose homeostasis and T2D undergoing SG (mean body mass index [BMI] 50.4 kg/m. We observed significant improvements in measures of obesity, as well as static and dynamic measures of glucose, insulin, C-peptide and HOMA. Furthermore, significant increases in GLP-1 response as early as 6 months postoperatively were also seen.. To our knowledge, no study has examined the detailed dynamic changes in glucose and insulin homeostasis in this number of participants undergoing SG in relation to incretin hormones GIP and GLP-1. This current study supports the role of SG for the treatment of obesity-related glucose dysregulation.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Gastrectomy; Glucose; Homeostasis; Humans; Incretins; Insulin; Laparoscopy; Obesity, Morbid; Prospective Studies

To evaluate the effect of periodontitis (PD) on glucoregulatory hormones in obesity, never explored so far, a cross-sectional study was conducted in 110 severely obese, non-diabetic individuals.. We collected clinical periodontal parameters, including probing pocket depth (PPD), bleeding on probing (BOP), clinical attachment level (CAL). Insulin, glucagon, GLP-1 and GIP were measured after 3 days of standardized diet.. Forty-seven subjects had periodontitis (PD+) and 63 did not (PD-). PD+ showed 30.3% of gingival sites with PPD > 4 mm, 55.2% of BOP sites and a mean CAL loss of 4.1 mm. Compared with PD-, PD+ had higher glucagon (26.60 [25.22] vs 3.93 [7.50] ng/l, p < 0.0001) and GIP levels (10.56 [13.30] vs 6.43 [8.43] pmol/l, p < 0.001), while GLP-1 was reduced (11.78 [10.07] vs 23.34 [16.80] pmol/l, p < 0.0001). Insulin did not differ. In PD+, after adjustment for confounders, PPD was positively related to glucagon (β = 0.424, p = 0.002) and inversely to GLP-1 (β = -0.159, p = 0.044).. We describe for the first time an impaired incretin axis coupled with a relative hyperglucagonemia in obese non-diabetic individuals with PD, that might contribute to deteriorate their glucose tolerance and partially explain the higher risk of diabetes observed in these patients.

Topics: Adult; Blood Glucose; Cross-Sectional Studies; Female; Gastric Inhibitory Polypeptide; Glucagon; Humans; Incretins; Insulin; Male; Middle Aged; Obesity, Morbid; Periodontitis

Despite excellent results of bariatric surgery in the treatment of type 2 diabetes and weight loss in human subjects, some patients do not obtain desired results. One of the reasons for this is that not all patients follow caloric intake recommendations.. The aim of this study was to investigate the effect of duodenojejunal omega switch (DJOS) surgery on body weight, glucose tolerance, and incretins in rats.. DJOS and SHAM surgery were performed on rats maintained for 8 weeks on high-fat diet (HF) and control diet (CD), respectively. After surgery, four groups were kept on the same diet as before the surgery, and four groups had a changed diet (CD vs. HF and HF vs. CD) for the next 8 weeks. Glucose tolerance, insulin tolerance, glucose-stimulated insulin, glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide/glucose-dependent insulinotropic polypeptide (GIP) secretion, food intake, and body weight were measured.. A change of diet after surgery resulted in reduced glucose tolerance. Plasma insulin levels were lowered between DJOS and SHAM surgeries for the HF/HF and CD/HF groups. DJOS surgery did not reduce body weight in the studied groups, irrespective of diet. In the HF/HF group, ΔGLP-1 was lower for DJOS surgery in comparison with other groups. Differences of weight changes were observed for groups HF/HF and HF/CD. After DJOS surgery, ΔGIP was lower in the CD/HF group compared with HF/HF.. Our results show that applications of different types of diets, before and after surgery, is a sensitive method for studies of mechanism of glucose intolerance after DJOS surgery.

Topics: Anastomosis, Surgical; Animals; Bariatric Surgery; Biopsy; Blood Glucose; Diabetes Mellitus, Type 2; Diet; Diet, High-Fat; Disease Models, Animal; Duodenum; Glucose Intolerance; Glucose Tolerance Test; Incretins; Jejunum; Liver; Male; Obesity, Morbid; Rats; Rats, Sprague-Dawley

Bariatric surgery (BS) is known to favorably impact fasting lipid profile. Fasting and postprandial lipids were evaluated before and 2 years after BS in obese type 2 diabetic (T2DM) patients.. A prospective study was conducted in 19 obese T2DM patients: ten undergoing sleeve gastrectomy (SG) and nine undergoing Roux-en-Y gastric bypass (RYGB). Before and 2 years after BS, clinical parameters and the response of lipid and incretin hormones to a mixed meal (MM) were assessed.. The two groups had similar characteristics at baseline. After BS, weight loss was similar in the two groups (p ≤ 0.01). Fasting glucose, insulin, and triglycerides decreased while HDL cholesterol increased in a similar way (p < 0.05); in contrast, fasting LDL cholesterol decreased only after RYGB (p < 0.05). Post-meal glucose concentrations decreased while early insulin response significantly improved after both procedures (p < 0.001 for both). Postprandial triglycerides decreased after both procedures (p < 0.05) while postprandial LDL cholesterol decreased only after RYGB (p < 0.05). Meal-GLP-1 increased postoperatively in both groups although to a greater extent after RYGB (p < 0.001 vs. SG). GIP decreased after both procedures, especially after RYGB (p = 0.003). At multivariate analysis, GLP-1 peak was the best predictor of LDL reduction (β = -0.552, p = 0.039) while the improvement of HOMA-IR (β = 0.574, p = 0.014) and weight loss (β = 0.418, p = 0.036) predicted triglycerides reduction.. Both surgical procedures markedly reduce fasting and postprandial triglycerides and increase HDL cholesterol levels. LDL cholesterol decreases only after RYGB through a mechanism likely mediated by the restoration of GLP-1.

Topics: Adult; Aged; Blood Glucose; Body Mass Index; Cholesterol, HDL; Diabetes Mellitus, Type 2; Fasting; Female; Follow-Up Studies; Gastrectomy; Gastric Bypass; Gastric Inhibitory Polypeptide; Humans; Incretins; Insulin; Insulin Resistance; Lipids; Male; Middle Aged; Obesity, Morbid; Postprandial Period; Prospective Studies; Triglycerides

Bariatric surgery often results in remission of the diabetic state in obese patients. Increased incretin effect seems to play an important role in the glycemic improvements after Roux-en-Y gastric bypass, but the impact of biliopancreatic diversion (BPD) remains unexplored.. The objective was to elucidate the effect of BPD on the incretin effect and its interplay with beta-cell function and insulin sensitivity (IS) in obese subjects with type 2 diabetes (T2DM).. Twenty-three women were studied: a control group of 13 lean, normal glucose-tolerant women (lean NGT) studied once and 10 obese patients with T2DM studied before, 1 and 12 months after BPD.. The ObeseT2DM group underwent BPD.. The main outcome measure was the change in incretin effect as measured by the isoglycemic intravenous glucose infusion test. Secondary outcomes encompassed IS and beta-cell function.. At baseline, the incretin effect was lower in obese T2DM compared to lean NGT (P < .05). One month after BPD, the incretin effect was not changed, but at 12 months it reached the level of the lean NGT group (P > .05). IS improved (P < .05) 1 month after BPD and at 12 months it resembled the levels of the lean NGT group. Insulin secretory rate and beta-cell glucose sensitivity increased after BPD and achieved levels similar to lean NGT group 1 month after BPD and even higher levels at 12 months (P < .05).. BPD has no acute impact on the reduced incretin effect, but 12 months after surgery the incretin effect normalizes alongside normalization of glucose control, IS and beta-cell function.

Topics: Adult; Biliopancreatic Diversion; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Humans; Incretins; Insulin; Insulin Resistance; Insulin-Secreting Cells; Middle Aged; Obesity, Morbid; Treatment Outcome

Bariatric surgery (BS) is able to positively influence fasting lipid profile in obese type 2 diabetic patients (T2DM), but no data is available on the impact of BS on postprandial lipid metabolism neither on its relation with incretin hormones. We evaluated the short-term (2 weeks) effects of BS on fasting and postprandial lipid metabolism in obese T2DM patients and the contribution of changes in active GLP-1.. We studied 25 obese T2DM patients (age = 46 ± 8 years, BMI = 44 ± 7 kg/m2), of which 15 underwent sleeve gastrectomy and 10 underwent gastric bypass. Lipid and incretin hormone concentrations were evaluated for 3 h after ingestion of a liquid meal before and 2 weeks after BS.. After BS, there was a significant reduction in body weight (p < 0.001), fasting plasma glucose (p < 0.001), fasting plasma insulin (p < 0.05), HOMA-IR (p < 0.001), and fasting plasma lipids (p < 0.05). The meal response of plasma triglycerides, total cholesterol, and HDL cholesterol was significantly lower compared to pre-intervention (p < 0.05, p < 0.001). In particular, the incremental area under the curve (IAUC) of plasma triglycerides decreased by 60% (p < 0.005). The meal-stimulated response of active GLP-1 increased, reaching a statistical significance (p < 0.001).. BS leads to an early improvement of fasting and postprandial lipemia. The fall in fasting triglycerides is associated with an improvement of insulin resistance, while the reduction of postprandial lipemia is likely related to reduced intestinal lipid absorption consequent to bariatric surgery.

Topics: Adult; Bariatric Surgery; Blood Glucose; Diabetes Mellitus, Type 2; Fasting; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Homeostasis; Humans; Hyperlipidemias; Incretins; Insulin Resistance; Lipids; Male; Middle Aged; Obesity, Morbid; Postprandial Period; Treatment Outcome; Triglycerides

Morbid obesity is accompanied by platelet hyperactivity, leading to thrombotic events including myocardial infarction and stroke. Bariatric surgery is an effective intervention to reduce cardiovascular risk in obesity. However, the effect of bariatric surgery on platelet function is largely unknown. This study investigated the effects of laparoscopic Roux-en-Y gastric bypass (RYGB) and laparoscopic adjustable gastric banding (LAGB) on prothrombotic monocyte-platelet aggregates (MPAs), markers of platelet activation in vivo. MPA were measured in whole blood by flow cytometry before surgery and 1 and 3 months after surgery. In non-obese healthy controls, MPA level is 13 ± 2 %. MPAs are elevated in morbidly obese subjects. RYGB (n = 12 patients) decreases MPAs 1 month after surgery by a weight-independent mechanism (56 ± 6 % presurgically vs 26 ± 8 % at 1 month, p <0.01). LAGB (n = 5 patients) has a smaller weight-dependent effect (49 ± 8 % presurgically vs 32 ± 6 % at 1 month, p > 0.05). Bariatric surgery may reduce thrombotic events by alleviation of platelet overactivity.

Topics: Adult; Biomarkers; Female; Gastric Bypass; Gastroplasty; Humans; Incretins; Laparoscopy; Male; Middle Aged; Monocytes; Obesity, Morbid; Pilot Projects; Platelet Activation; Weight Loss

The mechanisms of the diabetes mellitus type II remission after bariatric operations were analyzed. The determinations of incretins and peculiarities of the incretins system functioning in patients, suffering diabetes mellitus type II and morbid obesity, were enlightened. The results of surgical treatment of patients, suffering morbid obesity and diabetes mellitus type II, were analyzed.

Topics: Adult; Bariatric Surgery; Blood Glucose; Diabetes Mellitus, Type 2; Female; Humans; Incretins; Male; Middle Aged; Obesity, Morbid; Treatment Outcome

The number of morbidly obese subjects submitted to bariatric surgery is rising worldwide. In a fraction of patients undergoing gastric bypass (GBP), episodes with late postprandial hypoglycemia (PPHG) develop 1-3 years after surgery. The pathogenesis of this phenomenon is not fully understood; meal-induced rapid and exaggerated increases of circulating incretins and insulin appear to be at least partially responsible. Current treatments include low-carbohydrate diets, inhibition of glucose intestinal uptake, reduction of insulin secretion with calcium channel blockers, somatostatin analogs, or diazoxide, a KATP channel opener. Even partial pancreatectomy has been advocated. In type 2 diabetes, GLP1 analogs have a well-documented effect of stabilizing glucose levels without causing hypoglycemia.. We explored GLP1 analogs as open treatment in five consecutive GBP cases seeking medical attention because of late postprandial hypoglycemic symptoms.. Glucose measured in connection with the episodes in four of the cases had been 2.7, 2.5, 1.8, and 1.6 mmol/l respectively. The patients consistently described that the analogs eliminated their symptoms, which relapsed in four of the five patients when treatment was reduced/discontinued. The drug effect was further documented in one case by repeated 24-h continuous glucose measurements.. These open, uncontrolled observations suggest that GLP1 analogs might provide a new treatment option in patients with problems of late PPHG.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Incretins; Male; Middle Aged; Obesity, Morbid; Postprandial Period; Treatment Outcome

The aim of this study was to evaluate the pathophysiological mechanisms underlying the non-remission of type 2 diabetes in Roux-en-Y gastric bypass (RYGB) patients.. A group of patients not in remission (NR) was formed (n = 13). A remission group (R) was composed of patients who had undergone normalization of fasting glycemia and A1c, without anti-diabetic drugs and matched for selected baseline characteristics (i.e., duration of disease, previous BMI, final BMI, fat distribution, and age; n = 15). A control group of lean subjects (n = 41) was formed.. The NR group had higher uric acid (5.1 vs. 3.9 mg/dL), number of leukocytes (6,866.9 vs. 5,423.6), hs-CRP (0.27 vs. 0.12 mg/dL), MCP-1 (118.4 vs. 64.4 ng/mL), HOMA-IR, and AUC(glucose) but lower adiponectin (9.4 vs. 15.4 ng/mL), leptin (12.7 vs. 20.7 ng/mL), and AUC(GLP-1) in comparison to R group; the NR group also had lower leptin and higher adiponectin, HOMA-IR, AUC(glucose), AUC(C-peptide), AUC(glucagon), and AUC(GLP-1) than controls. The R group had lower MCP-1 and higher adiponectin compared to controls. Insulin sensitivity was significantly lower in the NR group than in the R and control groups. The insulin secretion index values were lower in the NR group than in the R and control groups.. This study found greater insulin resistance, lower insulin secretion, persistent adiposopathy and chronic subclinical inflammation, and less robust incretin response in the NR group despite a similar level of weight loss. Persistently altered pathophysiological mechanisms can be related to the lack of remission of type 2 diabetes after RYGB.

Topics: Adiponectin; Adolescent; Adult; Area Under Curve; Blood Glucose; Body Mass Index; Brazil; C-Reactive Protein; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Glucagon-Like Peptide 1; Humans; Incretins; Leukocytes; Male; Middle Aged; Obesity, Morbid; Remission Induction; Retrospective Studies; Uric Acid; Weight Loss; Young Adult

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.

Topics: Adult; Dietary Carbohydrates; Female; Gastric Bypass; Gastric Emptying; Glycated Hemoglobin; Humans; Incretins; Intestinal Absorption; Intestine, Small; Malabsorption Syndromes; Male; Middle Aged; Obesity, Morbid; Postprandial Period; Weight Loss

To examine after gastric bypass the effect of peroral versus gastroduodenal feeding on glucose metabolism.. A type 2 diabetic patient was examined on 2 consecutive days 5 weeks after gastric bypass. A standard liquid meal was given on the first day into the bypassed gastric remnant and on the second day perorally. Plasma glucose, insulin, C-peptide, glucagon, incretin hormones, peptide YY, and free fatty acids were measured.. Peroral feeding reduced 2-h postprandial plasma glucose (7.8 vs. 11.1 mmol/l) and incremental area under the glucose curve (iAUC) (0.33 vs. 0.49 mmol . l(-1) . min(-1)) compared with gastroduodenal feeding. beta-Cell function (iAUC(Cpeptide/Glu)) was more than twofold improved during peroral feeding, and the glucagon-like peptide (GLP)-1 response increased nearly fivefold.. Improvement in postprandial glucose metabolism after gastric bypass is an immediate and direct consequence of the gastrointestinal rearrangement, associated with exaggerated GLP-1 release and independent of changes in insulin sensitivity, weight loss, and caloric restriction.

Topics: Area Under Curve; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Enteral Nutrition; Fatty Acids, Nonesterified; Gastric Bypass; Glucagon; Glucagon-Like Peptide 1; Humans; Incretins; Male; Middle Aged; Obesity, Morbid; Peptide YY; Postoperative Period; Postprandial Period

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.. 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.. 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.. The data suggest that weight loss and incretins may contribute independently to improved glucose levels in the first year after GBP surgery.

Topics: Adiponectin; Adult; Blood Glucose; Diabetes Mellitus, Type 2; Fasting; Female; Gastric Bypass; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Incretins; Insulin; Insulin Secretion; Leptin; Middle Aged; Obesity, Morbid; Postoperative Period; Stomach; Weight Loss

The incretin system has been shown to stimulate insulin secretion in a glucose dependent manner and currently fosters considerable hope for the treatment of diabetes. Recently, we have shown that the dipeptidylpeptidase-4 (DPP4) gene, which is responsible for incretin inactivation, was overexpressed in omental adipose tissue of obese men with the metabolic syndrome, compared to men not characterized by this condition. Since the cardiovascular disease (CVD) risk profile shows substantial inter-individual variability in obesity, this study aimed at verifying whether DPP4 polymorphisms contribute to explain such a difference. In the first step of this multi-stage study, seven tagging SNPs were genotyped in a sample of 576 obese (BMI>40 kg/m(2)) individuals and tested for their association with blood pressure and lipids, as well as diabetes-related phenotypes. Then, in an additional sample of 572 obese individuals (stage 2), SNPs showing trends (P<0.10) for an association in the first sample were genotyped and reanalyzed. Logistic regressions were used to compute odds ratio for obesity-related metabolic complications. In sample 1, homozygotes for rs17848915 and rs7608798 minor alleles were at lower risk of hyperglycemia/diabetes (P=0.002) and elevated plasma triglyceride levels (P=0.030) respectively, whereas rs1558957 heterozygotes were at higher risk to have high plasma triglyceride (P=0.040), HDL- (P=0.021), LDL- (P=0.001) and total-cholesterol (P=0.003) levels. However, none of these associations was consistently replicated in stage 2. This first comprehensive genetic analysis does not support the notion that DPP4 polymorphisms could modulate the CVD risk profile among obese patients.

Topics: Adipose Tissue; Cardiovascular Diseases; Diastole; Dipeptidyl Peptidase 4; Exons; Female; Humans; Incretins; Linkage Disequilibrium; Lipids; Lipoproteins; Male; Metabolic Syndrome; Obesity, Morbid; Polymorphism, Genetic; Quebec; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors

We tested the hypothesis that the reversibility of insulin resistance and diabetes observed after biliopancreatic diversion (BPD) is related to changes in circadian rhythms of gastrointestinal hormones.. Ten morbidly obese participants, five with normal glucose tolerance (NGT) and five with type 2 diabetes, were studied before and within 2 weeks after BPD. Within-day variations in glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP1) levels were assessed using a single cosinor model. Insulin sensitivity was assessed by euglycaemic-hyperinsulinaemic clamp.. Basal GLP1 relative amplitude (amplitude/mesor x 100) was 25.82-4.06% in NGT; it increased to 41.38-4.32% after BPD but was unchanged in diabetic patients. GLP1 and GIP mesor were shifted in time after surgery in diabetic patients but not in NGT participants. After BPD, the GLP1 AUC significantly increased from 775 +/- 94 to 846 +/- 161 pmol l(-1) min in NGT, whereas GIP AUC decreased significantly from 1,373 +/- 565 to 513 +/- 186 pmol l(-1) min in diabetic patients. Two-way ANOVA showed a strong influence of BPD on both GIP (p = 0.010) and GLP1 AUCs (p = 0.033), which was potentiated by the presence of diabetes, particularly for GIP (BPD x diabetes, p = 0.003). Insulin sensitivity was markedly improved (p < 0.01) in NGT (from 9.14 +/- 3.63 to 36.04 +/- 8.55 micromol [kg fat-free mass](-1) min(-1)) and diabetic patients (from 9.49 +/- 3.56 to 38.57 +/- 4.62 micromol [kg fat-free mass](-1) min(-1)).. An incretin circadian rhythm was shown for the first time in morbid obesity. The effect of BPD on the 24 h pattern of incretin differed between NGT and diabetic patients. GLP1 secretion impairment was reversed in NGT and could not be overcome by surgery in diabetes. On the other hand, GIP secretion was blunted after the operation only in diabetic patients, suggesting a role in insulin resistance and diabetes.

Topics: Adipose Tissue; Adult; Biliopancreatic Diversion; Blood Glucose; Body Mass Index; Circadian Rhythm; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Incretins; Insulin; Insulin Resistance; Middle Aged; Obesity, Morbid

Bariatric surgery has been shown to improve glucose tolerance, although the mechanism has not been fully elucidated. Animal studies have suggested important roles of bile acid (BA) as a regulator of energy homeostasis and glucose metabolism. However, little is known about its role in humans. We investigated the longitudinal changes of BA, incretins, and adipokines after significant weight reduction in 34 Japanese adults with morbid obesity who underwent laparoscopic bariatric surgery. In subjects who underwent malabsorptive or restrictive surgery, body mass index had markedly decreased from 43.0 +/- 6.5 (SD) to 37.8 +/- 5.7 kg/m(2) and from 45.3 +/- 11.2 to 41.5 +/- 10.5 kg/m(2), respectively, at 1 month after surgery. Glycated hemoglobin decreased from 6.1% +/- 1.5% to 5.2% +/- 0.4% and from 6.2% +/- 1.3% to 5.4% +/- 0.7%, and total BA level increased from 3.1 +/- 3.5 to 7.2 +/- 5.3 mumol/L and from 3.2 +/- 2.6 to 9.4 +/- 10.0 mumol/L, respectively. At baseline, serum concentration of primary BA was positively correlated with plasma gastric inhibitory polypeptide level (r = 0.548, P = .001); and change in primary BA level was positively correlated with changes in plasma gastric inhibitory polypeptide (r = 0.626, P = .001) and serum immunoreactive insulin level (r = 0.592, P = .002) at 1 month after surgery. Furthermore, plasma glucagon-like peptide-1 and serum high-molecular weight adiponectin levels increased in both surgeries. These hormonal changes might explain the mechanism(s) of improved glucose tolerance after bariatric surgery in morbidly obese subjects.

Topics: Adipokines; Adiponectin; Adult; Bariatric Surgery; Bile Acids and Salts; Body Mass Index; Female; Humans; Incretins; Laparoscopy; Male; Middle Aged; Molecular Weight; Obesity, Morbid

Compare the response to oral glucose of the two incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) at 1 year after restrictive vs. malabsorptive bariatric surgery.. Vertical banded gastroplasty (VBG, n = 7) or jejunoileal bypass (JIB, n = 5) was performed in 12 women, aged 26-39 years, with severe obesity [body mass index (BMI) 46.6 +/- 2.3 kg/m(2)]. After 1 year, 75 g glucose was administered and plasma levels of glucose, insulin, GIP and GLP-1 were determined regularly during the following 2 h.. At 1 year after operation, reduction in body weight, actual body weight, fasting glucose or insulin, or the glucose and insulin responses to oral glucose did not differ significantly between the groups. Similarly, fasting GIP and GLP-1 levels did not differ significantly between the groups. In contrast, the GIP and GLP-1 responses to oral glucose were different between the groups in a dissociated pattern. Thus, AUC(GIP) was significantly higher after VBG than after JIB (53 +/- 8 vs. 26 +/- 6 pmol/l/min, p = 0.003). In contrast, AUC(GLP-1) was significantly higher after JIB than after VBG (49 +/- 5 vs. 20 +/- 3 pmol/l/min, p = 0.007).. We conclude that at 1 year after bariatric surgery, the two incretins show dissociated responses in that the GIP secretion is higher after VBG whereas GLP-1 secretion is higher after JIB. This dissociated incretin response is independent from reduction in body weight, glucose tolerance or insulin secretion.

Topics: Adult; Bariatric Surgery; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Incretins; Obesity, Morbid; Prospective Studies; Time Factors; Treatment Outcome

Our studies were designed to understand the role of the gut hormones incretins GLP-1 and GIP on diabetes remission after gastric bypass surgery (GBP).. Morbidly obese patients with type 2 diabetes (T2DM) were studied before and 1, 6, 12, 24 and 36 months after GBP. A matched group of patients were studied before and after a diet-induced 10 kg weight loss, equivalent to the weight loss 1 month after GBP. All patients underwent an oral glucose tolerance test and an isoglycaemic glucose intravenous challenge to measure the incretin effect.. Post-prandial GLP-1 and GIP levels increase after GBP and the incretin effect on insulin secretion normalizes to the level of non diabetic controls. In addition, the pattern of insulin secretion in response to oral glucose changes after GBP, with recovery of the early phase, and post-prandial glucose levels decrease significantly. These changes were not seen after an equivalent weight loss by diet. The changes in incretin levels and effect observed at 1 month are long lasting and persist up to 3 years after the surgery. The improved insulin release and glucose tolerance after GBP were shown by others to be blocked by the administration of a GLP-1 antagonist in rodents, demonstrating that these metabolic changes are, in part, GLP-1 dependent.. Although sustained and significant weight loss is likely to be the key mediator of diabetes remission after GBP, the changes of incretins improve the early phase of insulin secretion and post-prandial glucose levels, and contribute to the better glucose tolerance.

Topics: Adult; Case-Control Studies; Diabetes Mellitus, Type 2; Digestive System; Female; Gastric Bypass; Humans; Incretins; Insulin; Insulin Secretion; Male; Middle Aged; Obesity, Morbid; Time Factors; Weight Loss

It has been observed, as a collateral outcome of bariatric surgery, that morbidly obese patients with frank type 2 diabetes mellitus or impaired glucose tolerance undergone Roux-en-Y Gastric Bypass (RYGB) or bilio-pancreatic diversion (BPD) became and remained euglycemic since surgery. But, most interestingly, the conversion to euglycemia happened within few days from the operation, long before a significant weight loss could intervene. The purpose of this viewpoint is to try to elucidate the mechanisms involved in the resolution/remission of diabetes after bariatric surgery, in particular highlighting the role played by the modifications in incretin secretion.. The effect of purely restrictive procedures in improving glucose control is directly proportional to the degree of weight loss. In contrast, either RYGB or BPD, the first a mainly restrictive and the second a quite purely malabsorptive bariatric technique, operate through a different mechanism, as a probable consequence of the small intestine bypass. The bypass of different intestinal portions covers a central role in the mechanisms of action of these two surgical procedures. In fact, while RYGB does not affect insulin resistance but increases insulin secretion via the stimulation of nutrient-mediated incretin secretion, BPD induces a full normalization of insulin resistance and, consequently, a significant reduction of insulin secretion. The insulin resistance reversion is only partially explained by the incretin level changes after BPD.. A role of incretins in type 2 diabetes improvement or resolution is ascertained although it is possible that other, not yet identified, hormone(s) can cooperate with them.

Topics: Bariatric Surgery; Blood Glucose; Diabetes Mellitus, Type 2; Gastric Bypass; Glucose Intolerance; Humans; Incretins; Insulin Resistance; Obesity, Morbid; Proglucagon; Remission Induction; Weight Loss

Hyperinsulinemic hypoglycemia is newly recognized as a rare but important complication after Roux-en-Y gastric bypass (GB). The etiology of the syndrome and metabolic characteristics remain incompletely understood. Recent studies suggest that levels of incretin hormones are increased after GB and may promote excessive beta-cell function and/or growth.. We performed a cross-sectional analysis of metabolic variables, in both the fasting state and after a liquid mixed-meal challenge, in four subject groups: 1) with clinically significant hypoglycemia [neuroglycopenia (NG)] after GB surgery, 2) with no symptoms of hypoglycemia at similar duration after GB surgery, 3) without GB similar to preoperative body mass index of the surgical cohorts, and 4) without GB similar to current body mass index of the surgical cohorts.. Insulin and C-peptide after the liquid mixed meal were both higher relative to the glucose level achieved in persons after GB with NG compared with asymptomatic individuals. Glucagon, glucagon-like peptide 1, and glucose-dependent insulinotropic peptide levels were higher in both post-GB surgical groups compared with both overweight and morbidly obese persons, and glucagon-like peptide 1 was markedly higher in the group with NG. Insulin resistance, assessed by homeostasis model assessment of insulin resistance, the composite insulin sensitivity index, or adiponectin, was similar in both post-GB groups. Dumping score was also higher in both GB groups but did not discriminate between asymptomatic and symptomatic patients. Notably, the frequency of asymptomatic hypoglycemia after a liquid mixed meal was high in post-GB patients.. A robust insulin secretory response was associated with postprandial hypoglycemia in patients after GB presenting with NG. Increased incretin levels may contribute to the increased insulin secretory response.

Topics: Adult; Aged; Blood Glucose; Body Mass Index; C-Peptide; Eating; Female; Food; Gastric Bypass; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Incretins; Insulin; Insulin Resistance; Male; Middle Aged; Obesity; Obesity, Morbid; Postoperative Complications