The relation between postprandial glucagon-like peptide-1 release and insulin sensitivity before and after bariatric surgery in humans with class II/III obesity

BackgroundGlucagon-like peptide-1 (GLP-1) receptor agonist treatment is beneficial for the human glucose metabolism, and GLP-1 secretion is greatly enhanced following Roux-en-Y gastric bypass (RYGB).ObjectivesTo elucidate the relationship between GLP-1 concentrations and insulin sensitivity in subjects with class II/III obesity without diabetes and to assess the relation between GLP-1 and the improvements in glucose metabolism following RYGB.SettingClinical research facility in a university hospital.MethodsWe recruited 35 patients scheduled for RYGB and assessed their plasma GLP-1, insulin, and glucose responses to a high-fat mixed meal. Basal and insulin-mediated glucose fluxes were determined during a 2-step hyperinsulinemic-euglycemic clamp with stable isotope-labeled tracers. Out of 35 subjects, 10 were studied both before surgery and at 1 year of follow-up.ResultsPlasma GLP-1 increased following the high-fat mixed meal. Postprandial GLP-1 excursions correlated positively with hepatic and peripheral insulin sensitivity, but not with body mass index. At 1 year after RYGB, participants had lost 24% ± 6% of their body weight. Plasma GLP-1, insulin, and glucose levels peaked earlier and higher after the mixed meal. The positive association between the postprandial GLP-1 response and peripheral insulin sensitivity persisted.ConclusionsPostprandial GLP-1 concentrations correlate with insulin sensitivity in subjects with class II/III obesity without diabetes before and 1 year after RYGB. Increased GLP-1 signaling in postbariatric patients may, directly or indirectly, contribute to the observed improvements in insulin sensitivity and metabolic health.     

Changes in post-prandial glucose and pancreatic hormones,and steady-state insulin and free fatty acids after gastric bypass surgery

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

Changes in gut hormone profile and glucose homeostasis after laparoscopic sleeve gastrectomy

BackgroundChanges in glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) levels after bariatric surgery have been proposed as a mechanism for long-term maintenance of weight loss and improvement in glucose homeostasis postoperatively. The objective of the present study was to assess the changes in GLP-1, PYY, insulin, and glucose levels after laparoscopic sleeve gastrectomy (SG).MethodsTen morbidly obese patients without type 2 diabetes (3 male, 7 female; body mass index [BMI] 47.92±2.06 kg/m²) were evaluated preoperatively and at 6 weeks, 6 months, and 12 months after SG. Total GLP-1, total PYY, insulin, and glucose were measured in fasting state and every 30 minutes after ingestion of 75 g glucose for a total time of 120 minutes.ResultsBMI decreased markedly postoperatively (P<.001). Postprandial total GLP-1 and total PYY responses, measured by the area under the curve (AUC), were significantly increased by the sixth postoperative week compared with preoperative period (P<.001). Fasting insulin levels were markedly decreased postoperatively at all time points (all P<.01). Insulin AUC decreased progressively throughout the first postoperative year (P = .04), whereas glucose AUC decreased significantly at 6 and 12 months postoperatively (both P<.01). Insulin sensitivity measured by the Matsuda index increased progressively postoperatively. First phase insulin secretion remained unchanged.ConclusionPostprandial total GLP-1 and total PYY levels increased significantly at 6 weeks post-SG and remained elevated for at least 1 year. These findings may indicate their involvement in better glucose homeostasis and weight loss maintenance after SG.     

Exaggerated Glucagon-Like Peptide 1 Response Is Important for Improved β-Cell Function and Glucose Tolerance After Roux-en-Y Gastric Bypass in Patients With Type 2 Diabetes

β-Cell function improves in patients with type 2 diabetes in response to an oral glucose stimulus after Roux-en-Y gastric bypass (RYGB) surgery. This has been linked to the exaggerated secretion of glucagon-like peptide 1 (GLP-1), but causality has not been established. The aim of this study was to investigate the role of GLP-1 in improving β-cell function and glucose tolerance and regulating glucagon release after RYGB using exendin(9-39) (Ex-9), a GLP-1 receptor (GLP-1R)–specific antagonist. Nine patients with type 2 diabetes were examined before and 1 week and 3 months after surgery. Each visit consisted of two experimental days, allowing a meal test with randomized infusion of saline or Ex-9. After RYGB, glucose tolerance improved, β-cell glucose sensitivity (β-GS) doubled, the GLP-1 response greatly increased, and glucagon secretion was augmented. GLP-1R blockade did not affect β-cell function or meal-induced glucagon release before the operation but did impair glucose tolerance. After RYGB, β-GS decreased to preoperative levels, glucagon secretion increased, and glucose tolerance was impaired by Ex-9 infusion. Thus, the exaggerated effect of GLP-1 after RYGB is of major importance for the improvement in β-cell function, control of glucagon release, and glucose tolerance in patients with type 2 diabetes.Hyperglycemia in patients with type 2 diabetes is resolved shortly after Roux-en-Y gastric bypass (RYGB), suggesting that mechanisms independent of weight loss contribute to the improvement in glycemic control (1–4).Within 1 month and as early as 5 days after RYGB, β-cell function in response to a meal improves in subjects with type 2 diabetes, and this is accompanied by an increased postprandial glucagon-like peptide (GLP)-1 response (3,5,6). In contrast, after intravenous infusion of glucose, which does not elicit the incretin effect, an improvement in β-cell function is absent (5,7,8). Therefore, it could be speculated that the early improvements in β-cell function after RYGB are due to the enhanced GLP-1 secretion related to eating a meal, but causality has not been established (9).In patients with type 2 diabetes, energy restriction per se is known to result in improved hepatic insulin sensitivity and decreased hepatic glucose production and, as a result, lowered fasting plasma glucose concentrations (10–12). Similar metabolic changes are seen after RYGB, when energy intake is limited (13,14), and this has led to the proposal that caloric restriction with a subsequent reduction in glucotoxicity, rather than an increased effect of GLP-1, is responsible for the improved β-cell function (14,15).The aim of this study was to investigate the role of GLP-1 in the improved β-cell function and glucose tolerance seen after RYGB in subjects with type 2 diabetes. This was accomplished by pharmacologically blocking the GLP-1 receptor (GLP-1R) during a liquid meal tolerance test before and after surgery using exendin(9-39) (Ex-9; Bachem AG, Bubendorf, Switzerland), a specific GLP-1R antagonist (16).Previous studies have documented increased meal-related glucagon secretion after RYGB despite improvements in insulin secretion and sensitivity and exaggerated GLP-1 release (3,17,18). This observation is surprising given the glucagonostatic properties of GLP-1 and insulin (19,20). Therefore, a further aim of this study was to evaluate the interaction between GLP-1 and glucagon release after RYGB in both the fasting and postprandial states.     

GLP-1 and Changes in Glucose Tolerance following Gastric Bypass Surgery in Morbidly Obese Subjects

Background: It has been proposed, that the dramatic amelioration of type 2 diabetes following Roux-en-Y gastric bypass (RYGBP) could by accounted for, at least in part, by changes in glucagon-like peptide-1 (GLP-1) secretion. However, human data supporting this hypothesis is scarce. Methods: A 12-month prospective study on the changes in glucose homeostasis, and active GLP-1 in response to a standard test meal (STM) was conducted in 34 obese subjects (BMI 49.1±1.0 kg/m²) who had different degrees of glucose tolerance: normal glucose tolerance (NGT, n=12), impaired glucose tolerance (IGT, n=12), and type 2 diabetes (n=10). Results: At 6 weeks after RYGBP, despite the subjects still being markedly obese (BMI 43.5±0.9 kg/m²), fasting plasma glucose and HbA1c decreased in the 3 study groups (P<0.05). Insulin sensitivity improved, but was still abnormal in a comparable proportion of subjects among groups (P=0.717). When insulin secretion was accounted for the prevailing insulin sensitivity, an increase was found in subjects with diabetes (P<0.05) although it remained lower compared to NGT- and IGT-subjects (P<0.01). At 12 months follow-up, no differences among groups were found in the evaluated glucose homeostasis parameters. Compared to baseline, at 6 weeks the incremental AUC_0-120' of active GLP-1 in response to the STM increased in NGT and IGT (P<0.05) but not in subjects with diabetes (P=0.285). However, the GLP-1 response to a STM was comparable among groups at 12 months follow-up (P=0.887). Conclusions: 1) RYGBP was associated with an improvement but not complete restoration of glucose homeostasis at 6 weeks after surgery. 2) GLP-1 is not a critical factor for the early changes in glucose tolerance.     

GLP-1 Plays a Limited Role in Improved Glycemia Shortly After Roux-en-Y Gastric Bypass: A Comparison With Intensive Lifestyle Modification

Rapid glycemic improvements following Roux-en-Y gastric bypass (RYGB) are frequently attributed to the enhanced GLP-1 response, but causality remains unclear. To determine the role of GLP-1 in improved glucose tolerance after surgery, we compared glucose and hormonal responses to a liquid meal test in 20 obese participants with type 2 diabetes mellitus who underwent RYGB or nonsurgical intensive lifestyle modification (ILM) (n = 10 per group) before and after equivalent short-term weight reduction. The GLP-1 receptor antagonist exendin_(9–39)-amide (Ex-9) was administered, in random order and in double-blinded fashion, with saline during two separate visits after equivalent weight loss. Despite the markedly exaggerated GLP-1 response after RYGB, changes in postprandial glucose and insulin responses did not significantly differ between groups, and glucagon secretion was paradoxically augmented after RYGB. Hepatic insulin sensitivity also increased significantly after RYGB. With Ex-9, glucose tolerance deteriorated similarly from the saline condition in both groups, but postprandial insulin release was markedly attenuated after RYGB compared with ILM. GLP-1 exerts important insulinotropic effects after RYGB and ILM, but the enhanced incretin response plays a limited role in improved glycemia shortly after surgery. Instead, enhanced hepatic metabolism, independent of GLP-1 receptor activation, may be more important for early postsurgical glycemic improvements.     

Changes in Gastrointestinal Hormone Responses, Insulin Sensitivity, and Beta-Cell Function Within 2 Weeks After Gastric Bypass in Non-diabetic Subjects

Background

Roux-en-Y gastric bypass (RYGB) surgery causes profound changes in secretion of gastrointestinal hormones and glucose metabolism. We present a detailed analysis of the early hormone changes after RYGB in response to three different oral test meals designed to provide this information without causing side effects (such as dumping).

Methods

We examined eight obese non-diabetic patients before and within 2?weeks after RYGB. On separate days, oral glucose tolerance tests (25 or 50?g glucose dissolved in 200?mL of water) and a liquid mixed meal test (200?mL 300?kcal) were performed. We measured fasting and postprandial glucose, insulin, C-peptide, glucagon, total and intact glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-2 (GLP-2), peptide YY_3-36 (PYY), cholecystokinin (CCK), total and active ghrelin, gastrin, somatostatin, pancreatic polypeptide (PP), amylin, leptin, free fatty acids (FFA), and registered postprandial dumping. Insulin sensitivity was measured by homeostasis model assessment of insulin resistance.

Results

Fasting glucose, insulin, ghrelin, and PYY were significantly decreased and FFA was elevated postoperatively. Insulin sensitivity increased after surgery. The postprandial response increased for C-peptide, GLP-1, GLP-2, PYY, CCK, and glucagon (in response to the mixed meal) and decreased for total and active ghrelin, leptin, and gastrin, but were unchanged for GIP, amylin, PP, and somatostatin after surgery. Dumping symptoms did not differ before and after the operation or between the tests.

Conclusions

Within 2?weeks after RYGB, we found an increase in insulin secretion and insulin sensitivity. Responses of appetite-regulating intestinal hormones changed dramatically, all in the direction of reducing hunger.     

Comparison Between RYGB, DS, and VSG Effect on Glucose Homeostasis

Background

Our group has reported a high incidence of reactive hypoglycemia following Roux-en-Y gastric bypass (RYGB) with specific interest in postprandial insulin and the ratio of 1- to 2-h serum glucose levels. The purpose of this study is to compare the 6-month response to oral glucose challenge in patients undergoing RYGB, duodenal switch (DS), and vertical sleeve gastrectomy (VSG).

Methods

Thirty-eight patients meeting the NIH criteria for bariatric surgery who have reached the 6-month postoperative mark are the basis of this report. Preoperatively and at 6?months follow-up, patients underwent blood draw to determine levels of fasting glucose, fasting insulin, HbA1c, C peptide, and 2?h oral liquid glucose challenge test (OGTT). HOMA-IR and 1 to 2?h ratios of glucose and fasting to 1?h ratio of insulin were calculated.

Results

All patients underwent a successful laparoscopic bariatric procedure (VSG =13, DS =13, and RYGB?=?12). All operations reduced BMI, HgbA1c, fasting glucose, and fasting insulin. HOMA IR and glucose tolerance improved with all procedures. In response to OGTT at 6?months, there was a 20-fold increase in insulin at 1?h in RYGB, which was not seen in DS. At 6?months, 1-h insulin was markedly lower in DS (p?p?p?Conclusions All operations improve insulin sensitivity and decrease HgbA1c. Six-month weight loss was substantial in all groups between 22?C29% excess body weight. RYGB results in marked rise in glucose following challenge with corresponding rise in 1-h insulin. VSG has a similar response to RYGB. In comparison, at 6?months following surgery, DS causes a much lower rise in 1-h insulin, with this difference being statistically significant at p?p?相似文献   

A novel technique of Roux-en-Y gastric bypass reversal for postprandial hyperinsulinemic hypoglycaemia: A case report

BackgroundWe describe an evaluation of the effects of partial Roux-en-Y gastric bypass (RYGB) reversal on postprandial hyperinsulinaemic hypoglycaemia, insulin and GLP-1 levels.Case summaryA 37 year old man was admitted with neuroglycopenia (plasma–glucose 1.6 mmol/l) 18 months after RYGB, with normal 72 h fasting test and abdominal CT. Despite dietary modifications and medical treatment, the hypoglycaemic episodes escalated in frequency. Feeding by a gastrostomy tube positioned in the gastric remnant did not prevent severe episodes of hypoglycaemia. A modified reversal of the RYGB was performed. Mixed meal tests were done perorally (PO), through the gastrostomy tube 1 (GT1), 4 weeks (GT2) after placement and 4 weeks after reversal (POr), with assessment of glucose, insulin and GLP-1 levels.ResultsPlasma–glucose increased to a maximum of 9.6, 5.4, 6.5 and 5.8 mmol/l at the PO, GT1, GT2 and POr tests respectively. The corresponding insulin levels were 2939, 731, 725 and 463 pmol/l. A decrease of plasma–glucose followed: 2.2, 3.0, 3.9 and 2.9 mmol/l respectively and insulin levels were suppressed at 150 min: 45, 22, 21 and 14 pmol/l, respectively. GLP-1 levels increased in the PO test (60 min: 122 pmol/l, 21 fold of basal), but was attenuated in the two latter tests (12–23 pmol/l at 60 min).ConclusionsReduction of plasma–glucose, insulin and GLP-1 excursions and symptoms were seen after gastric tube placement and partial RYGB reversal. This attenuation of GLP-1 response to feeding could reflect an adaptation to nutrients.     

Preserved Insulin Secretory Capacity and Weight Loss Are the Predominant Predictors of Glycemic Control in Patients With Type 2 Diabetes Randomized to Roux-en-Y Gastric Bypass

Improvement in type 2 diabetes after Roux-en-Y gastric bypass (RYGB) has been attributed partly to weight loss, but mechanisms beyond weight loss remain unclear. We performed an ancillary study to the Diabetes Surgery Study to assess changes in incretins, insulin sensitivity, and secretion 1 year after randomization to lifestyle modification and intensive medical management (LS/IMM) alone (n = 34) or in conjunction with RYGB (n = 34). The RYGB group lost more weight and had greater improvement in HbA_1c. Fasting glucose was lower after RYGB than after LS/IMM, although the glucose area under the curve decreased comparably for both groups. Insulin sensitivity increased in both groups. Insulin secretion was unchanged after LS/IMM but decreased after RYGB, except for a rapid increase during the first 30 min after meal ingestion. Glucagon-like peptide 1 (GLP-1) was substantially increased after RYGB, while gastric inhibitory polypeptide and glucagon decreased. Lower HbA_1c was most strongly correlated with the percentage of weight loss for both groups. At baseline, a greater C-peptide index and 90-min postprandial C-peptide level were predictive of lower HbA_1c at 1 year after RYGB. β-Cell glucose sensitivity, which improved only after RYGB, and improved disposition index were associated with lower HbA_1c in both groups, independent of weight loss. Weight loss and preserved β-cell function both predominantly determine the greatest glycemic benefit after RYGB.     

The role of GLP-1 in postprandial glucose metabolism after bariatric surgery: a narrative review of human GLP-1 receptor antagonist studies

The Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) bariatric procedures lead to remission or improvement of type 2 diabetes. A weight loss–independent augmentation of postprandial insulin secretion contributes to the improvement in glycemic control after RYGB and is associated with a ～10-fold increase in plasma concentrations of the incretin hormone glucagon-like peptide-1 (GLP-1). However, the physiologic importance of the markedly increased postprandial GLP-1 secretion after RYGB has been much debated. The effect of GLP-1 receptor blockade after RYGB has been investigated in 12 studies. The studies indicate a shift toward a more prominent role for GLP-1 in postprandial β-cell function after RYGB. The effect of GLP-1 receptor antagonism on glucose tolerance after RYGB is more complex and is associated with important methodological challenges. The postprandial GLP-1 response is less enhanced after SG compared with RYGB. However, the effect of GLP-1 receptor blockade after SG has been examined in 1 study only and needs further investigation.     

The Glucagonostatic and Insulinotropic Effects of Glucagon-Like Peptide 1 Contribute Equally to Its Glucose-Lowering Action

OBJECTIVE

Glucagon-like peptide 1 (GLP-1) exerts beneficial antidiabetic actions via effects on pancreatic β- and α-cells. Previous studies have focused on the improvements in β-cell function, while the inhibition of α-cell secretion has received less attention. The aim of this research was to quantify the glucagonostatic contribution to the glucose-lowering effect of GLP-1 infusions in patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

Ten male patients with well-regulated type 2 diabetes (A1C 6.9 ± 0.8%, age 56 ± 10 years, BMI 31 ± 3 kg/m² [means ± SD]) were subjected to five 120-min glucose clamps at fasting plasma glucose (FPG) levels. On day 1, GLP-1 was infused to stimulate endogenous insulin release and suppress endogenous glucagon. On days 2–5, pancreatic endocrine clamps were performed using somatostatin infusions of somatostatin and/or selective replacement of insulin and glucagon; day 2, GLP-1 plus basal insulin and glucagon (no glucagon suppression or insulin stimulation); day 3, basal insulin only (glucagon deficiency); day 4, basal glucagon and stimulated insulin; and day 5, stimulated insulin. The basal plasma glucagon levels were chosen to simulate portal glucagon levels.

RESULTS

Peptide infusions produced the desired hormone levels. The amount of glucose required to clamp FPG was 24.5 ± 4.1 (day 1), 0.3 ± 0.2 (day 2), 10.6 ± 1.1 (day 3), 11.5 ± 2.7 (day 4), and 24.5 ± 2.6 g (day 5) (day 2 was lower than days 3 and 4, which were both similar and lower than days 1 and 5).

CONCLUSIONS

We concluded that insulin stimulation (day 4) and glucagon inhibition (day 3) contribute equally to the effect of GLP-1 on glucose turnover in patients with type 2 diabetes, and these changes explain the glucose-lowering effect of GLP-1 (day 5 vs. day 1).The incretin hormone glucagon-like peptide 1 (GLP-1), as well as GLP-1 analogues that are now being used for the treatment of patients with type 2 diabetes, potently suppresses α-cell secretion (1–4). Despite their hyperglycemia, patients with type 2 diabetes tend to have elevated fasting glucagon levels and exaggerated glucagon responses to meal ingestion (5). Since the hyperglucagonemia is thought to contribute to the hyperglycemia of these patients by increasing hepatic glucose production (HGP) (6), it follows that the glucagonostatic effect of GLP-1 may be as important clinically as its insulinotropic effect (7). Glucose-induced inhibition of α-cell secretion may be impaired in type 2 diabetic patients, but pharmacological amounts of GLP-1 have been shown to restore α-cell sensitivity to glucose (8,9), and we recently demonstrated that the glucagon-suppressive effect of GLP-1 was similar in patients with type 2 diabetes and healthy control subjects (10).Thus GLP-1 potently influences both β- and α-cell secretion in patients with type 2 diabetes, but the relative roles of these two effects in relation to the overall glucose-lowering action of GLP-1 are unclear. In the present studies, we sought to determine the importance of the glucagonostatic effect by measuring its contribution to changes in glucose turnover induced by the infusion of GLP-1 in pharmacological doses. We employed the pancreatic clamp technique (11) using somatostatin to block the endogenous secretion from the islets while substituting insulin and/or glucagon levels by infusions designed to mimic either basal levels and/or responses to a GLP-1 infusion rate (1 pmol/kg/min) known to normalize blood glucose in patients with type 2 diabetes (4). All examinations were done in the fasting state with plasma glucose (PG) clamped at individual fasting PG (FPG) levels. The amount of glucose infused to maintain the clamp was expected to accurately reflect the influence of the endocrine perturbations on glucose turnover (decreased hepatic glucose production and increased peripheral disposal).     

β-Cell Function,Incretin Effect,and Incretin Hormones in Obese Youth Along the Span of Glucose Tolerance From Normal to Prediabetes to Type 2 Diabetes

Using the hyperglycemic and euglycemic clamp, we demonstrated impaired β-cell function in obese youth with increasing dysglycemia. Herein we describe oral glucose tolerance test (OGTT)-modeled β-cell function and incretin effect in obese adolescents spanning the range of glucose tolerance. β-Cell function parameters were derived from established mathematical models yielding β-cell glucose sensitivity (βCGS), rate sensitivity, and insulin sensitivity in 255 obese adolescents (173 with normal glucose tolerance [NGT], 48 with impaired glucose tolerance [IGT], and 34 with type 2 diabetes [T2D]). The incretin effect was calculated as the ratio of the OGTT-βCGS to the 2-h hyperglycemic clamp-βCGS. Incretin and glucagon concentrations were measured during the OGTT. Compared with NGT, βCGS was 30 and 65% lower in youth with IGT and T2D, respectively; rate sensitivity was 40% lower in T2D. Youth with IGT or T2D had 32 and 38% reduced incretin effect compared with NGT in the face of similar changes in GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) in response to oral glucose. We conclude that glucose sensitivity deteriorates progressively in obese youth across the spectrum of glucose tolerance in association with impairment in incretin effect without reduction in GLP-1 or GIP, similar to that seen in adult dysglycemia.     

Roux-en-Y gastric bypass increases hepatic and peripheral insulin sensitivity in rats with type 2 diabetes mellitus

BackgroundRoux-en-Y gastric bypass (RYGB) surgery for the treatment of obesity leads to long-term diabetes remission in approximately 80% of cases. The aim of this study was to investigate the effects of RYGB on hepatic and peripheral insulin sensitivity in type 2 diabetic rats and their possible mechanisms. We also tested the hypothesis that RYGB reduces lipid content and improves insulin sensitivity in hepatocytes and skeletal muscle cells.MethodsSprague–Dawley rats were divided into 4 groups: diabetic RYGB group (n = 18), diabetic RYGB sham group (n = 6), diabetic group (n = 6), and nondiabetic control group (n = 6). The hyperinsulinemic-euglycemic clamp with tracer infusion was completed at 2, 4, and 8 weeks postoperatively to assess insulin sensitivity. The lipid content in liver and muscle tissue was examined.ResultsPostoperatively, the diabetic RYGB group had significant decreases in weight, fat mass, and food intake. Two weeks after surgery, RYGB had significantly improved the hepatic insulin sensitivity index and decreased the hepatic triglyceride, total cholesterol, and fatty acyl-CoA content. The significantly increased insulin sensitivity and decreased lipid content in muscle were not detected until 4 weeks after RYGB surgery. The basal insulin and C-peptide concentrations were significantly lower than those in diabetic group by 2 weeks after RYGB.ConclusionThe increased insulin sensitivity after RYGB occurs earlier in the liver than in the muscle and both may contribute to long-term remission of type 2 diabetes. Reduced lipid content of hepatocytes and skeletal muscle cells after RYGB may contribute to the improved insulin sensitivity in these cells.     

Effects of Roux-en-Y gastric bypass and ileal transposition surgeries on glucose and lipid metabolism in skeletal muscle and liver

BackgroundRoux-en Y gastric bypass (RYGB) and ileal transposition (IT) surgeries produce weight loss and improve diabetic control; however, the mechanisms of glycemic improvements are largely unknown. Because skeletal muscle and liver play a key role in glucose homeostasis, we compared the effects of RYGB and IT surgeries on key molecules of glucose and lipid metabolism in muscle and liver.MethodsSprague-Dawley rats were subjected to RYGB, IT, or sham surgeries; sham-animals were ad-lib fed or pair-fed to RYGB rats (n = 7-9/group). At 8 weeks postoperatively, blood samples were collected for glucagon-like peptide-1 (GLP-1) and insulin analyses by ELISA. Leg muscle and liver tissues were analyzed for mRNA (RT-qPCR) and/or protein abundance (immuno blotting) of important molecules of glucose and lipid metabolism [glucose transporter-4 (GLUT-4), hexokinase, phosphofructokinase (PFK), adenosine monophosphate activated protein kinase-α (AMPKα), cytochrome C oxidase-IV (COX-IV), citrate synthase, carnitine palmitoyl transferase-1 (CPT-1), medium-chain acyl-CoA dehydrogenase (MCAD), peroxisome proliferator-activated receptor gamma co-activator 1 α (PGC-1 α), PGC-1-related coactivator (PRC), uncoupling protein-3 (UCP-3)].ResultsPlasma GLP-1 concentrations were increased comparably with RYGB and IT. RYGB and IT increased muscle GLUT-4 protein content, muscle hexokinase mRNA, and liver PFK mRNA. IT increased muscle AMPKα and COX-IV protein content and liver citrate synthase activity. IT increased muscle CPT-1, MCAD and PRC mRNA, whereas RYGB increased UCP-3 mRNA in muscle and liver, and PGC-1 α mRNA in liver.ConclusionThe data suggest that RYGB and IT surgeries lead to enhanced GLP-1 secretion and produce similar stimulatory effects on important molecules of glucose metabolism but differential effects on key molecules of lipid oxidation in muscle and liver.     

The effect of distal-ileal exclusion after Roux-en-Y gastric bypass on glucose tolerance and GLP-1 response in type-2 diabetes Sprague-Dawley rat model

Background

An increase in glucagon-like peptide-1 (GLP-1) mediating early diabetes remission after Roux-en-Y gastric bypass (RYGB) is believed to be associated with distal-ileal stimulation.

Exaggerated glucagon-like peptide-1 and blunted glucose-dependent insulinotropic peptide secretion are associated with Roux-en-Y gastric bypass but not adjustable gastric banding

BACKGROUND: The aim of this study was to measure the circulating levels of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and glucagon in patients who had undergone adjustable gastric banding (BND) or Roux-en-Y gastric bypass (RYGB) to understand the differences in glucose and insulin regulation after these procedures. METHODS: This was a cross-sectional study of 3 groups of women matched for age and body mass index: group 1, overweight controls (n = 13); group 2, BND (n = 10); and group 3, RYGB (n = 13). Venous blood was drawn with the patient in the fasted state and throughout a 3-hour period after a liquid meal. RESULTS: The fasting glucose level was similar between the 2 surgery groups; however, the fasting insulin concentrations were greater in the BND (10.0 microU/mL) than in the RYGB (6.2 microU/mL; P <0.05) group. The glucose level at 60 minutes was significantly lower in the RYGB group (70 mg/dL, range 38-82) than in the BND group (83 mg/dL, range 63-98). The GLP-1 levels at 30 minutes were more than threefold greater in the RYGB group (96 pmol/L) compared with the BND and overweight control (28 pmol/L) groups. The GLP-1 and insulin concentrations correlated at 30 minutes only in the RYGB group (r = .66; P = .013). The glucose-dependent insulinotropic peptide levels at 30 minutes were lower in the RYGB group (20 pmol/L) than in the BND group (31 pmol/L) or overweight control group (33 pmol/L). The peak glucagon levels were similar among the 3 groups. CONCLUSION: Exaggerated postprandial GLP-1 and blunted glucose-dependent insulinotropic peptide secretion after RYGB might contribute to the greater weight loss and improved glucose homeostasis compared with BND.     

The effect of selective gut stimulation on glucose metabolism after gastric bypass in the Zucker diabetic fatty rat model

BackgroundPotential mechanisms underlying the antidiabetic effects of Roux-en-Y gastric bypass (RYGB) include altered nutrient exposure in the gut. The aim of this study was to evaluate the effects of selective gut stimulation on glucose metabolism in an obese diabetic rat model.MethodsSixteen male Zucker diabetic fatty rats were randomly assigned to 1 of 2 groups: RYGB with gastrostomy tube (GT) insertion into the excluded stomach or a control group with GT insertion into the stomach. An insulin tolerance test (ITT), oral glucose tolerance test (OGTT), and mixed meal tolerance test (MMTT) were performed before and 14–28 days after surgery. A glucose tolerance test via GT (GTT-GT) and MMTT via GT were performed postoperatively.ResultsPostoperatively, the RYGB group had significant decreases in weight and food intake. Both the ITT and OGTT tests revealed significantly improved glucose tolerance after RYGB. The GTT-GT showed a reversal of the improved glucose tolerance in the RYGB group. In response to meal stimulation, postoperatively, the RYGB group increased glucagon-like peptide 1 (GLP-1) secretion via the oral route and peptide YY secretion by both oral and GT routes.ConclusionWhen foregut exposure to nutrients was reversed after RYGB, the improvement in glucose metabolism was abrogated. This model can be extended to identify the role of gut in glucose homeostasis in type 2 diabetes.     

Antidiabetic actions of endogenous and exogenous GLP-1 in type 1 diabetic patients with and without residual β-cell function

OBJECTIVE

To investigate the effect of exogenous as well as endogenous glucagon-like peptide 1 (GLP-1) on postprandial glucose excursions and to characterize the secretion of incretin hormones in type 1 diabetic patients with and without residual β-cell function.

RESEARCH DESIGN AND METHODS

Eight type 1 diabetic patients with (T1D+), eight without (T1D−) residual β-cell function, and eight healthy matched control subjects were studied during a mixed meal with concomitant infusion of GLP-1 (1.2 pmol/kg/min), saline, or exendin 9-39 (300 pmol/kg/min). Before the meal, half dose of usual fast-acting insulin was injected. Plasma glucose (PG), glucagon, C-peptide, total GLP-1, intact glucose-dependent insulinotropic polypeptide (GIP), free fatty acids, triglycerides, and gastric emptying rate (GE) by plasma acetaminophen were measured.

RESULTS

Incretin responses did not differ between patients and control subjects. Infusion of GLP-1 decreased peak PG by 45% in both groups of type 1 diabetic patients. In T1D+ patients, postprandial PG decreased below fasting levels and was indistinguishable from control subjects infused with saline. In T1D− patients, postprandial PG remained at fasting levels. GLP-1 infusion reduced GE and glucagon levels in all groups and increased fasting C-peptide in T1D+ patients and control subjects. Blocking endogenous GLP-1 receptor action increased endogenous GLP-1 secretion in all groups and increased postprandial glucose, glucagon, and GE in T1D+ and T1D− patients. The insulinogenic index (the ratio of insulin to glucose) decreased in T1D+ patients during blockade of endogenous GLP-1 receptor action.

CONCLUSIONS

Type 1 diabetic patients have normal incretin responses to meals. In type 1 diabetic patients, exogenous GLP-1 decreases peak postprandial glucose by 45% regardless of residual β-cell function. Endogenous GLP-1 regulates postprandial glucose excursions by modulating glucagon levels, GE, and β-cell responsiveness to glucose. Long-term effects of GLP-1 in type 1 diabetic patients should be investigated in future clinical trials.At time of diagnosis and during the first year, prevalence of residual β-cell function in patients with type 1 diabetes is nearly 100% (1,2). After alleviation of initial hyperglycemia with exogenous insulin, patients enter a remission period with improved β-cell function, where insulin treatment can be paused in up to 20–30% of the patients without loss of target glycemic control (3). Persistence of residual insulin secretion is associated with reduced risk of ketosis (4), lower HbA_1c levels (5), lower insulin doses, less risk of hypoglycemia, and reduced long-term complications (2,6). However, after disease duration of 5–10 years, the prevalence of residual β-cell function has declined to about 15% (2). Even though lack of insulin is considered to be the most important factor for the hyperglycemia in type 1 diabetic patients, other metabolic disturbances may also play a role: the glucagon response to carbohydrate and protein ingestion has been shown to be abnormal (7) and there is evidence that postprandial hyperglycemia is because of lack of insulin as well as inappropriately elevated glucagon levels (8,9). The gut hormone, glucagon-like peptide 1 (GLP-1), reduces glucagon levels, increases insulin secretion (10), and inhibits gastric emptying rate (GE), thereby reducing postprandial glucose excursions (11). The insulinotropic and the glucagonostatic properties of GLP-1 are glucose dependent (12), and exogenous GLP-1, therefore, does not produce hypoglycemia. Several studies have found lowering of fasting and postprandial glucose by GLP-1 or GLP-1 agonists in type 1 diabetic patients with (13–15) as well as without (16–19) residual β-cell function. Some studies suggested that the glucose lowering effect was because of the enhancement of insulin sensitivity (19), whereas others concluded that delay of gastric emptying (13,14) or reduction of glucagon levels (17) was the most important mechanism. In animal studies, treatment with GLP-1 or GLP-1 agonists has been shown to delay diabetes development or reverse recent onset diabetes in NOD mice (20), ascribed to an improved function of existing β-cells rather than through increments in β-cell mass. However, there is also evidence that GLP-1, in combination with gastrin, increases β-cell mass and restores normoglycemia in recent onset diabetic NOD mice (21) and that GLP-1 combined with gastrin is able to expand β-cell mass of human islets implanted under the renal capsule of immunodeficient diabetic NOD mice (22). In freshly isolated human islets, GLP-1 has been reported to inhibit β-cell apoptosis (23). However, in C-peptide–positive subjects with longstanding type 1 diabetes treated with exenatide for 6 to 9 months with or without daclizumab, insulin dose was significantly reduced, primarily because of the reduction of prandial insulin, but β-cell function was not improved (15). Four weeks of treatment with vildagliptin (a DPP-4 inhibitor that increases endogenous GLP-1 levels) in 11 well-controlled type 1 diabetic patients with longstanding disease decreased postmeal glucagon and glucose levels (24), and in adolescents with minimal or no endogenous insulin secretion treated with exenatide, postprandial glucose excursions were reduced despite 20% reduction of insulin dose (25). Therefore, GLP-1–based therapies have potential for treatment of type 1 diabetes alone or—more likely—in combination with insulin.Because of controversies regarding secretion of incretin hormones in type 1 diabetes (26,27), assessment of the meal-related GLP-1 secretory responses in patients with diabetes is of interest (28). We therefore studied incretin secretion as well as the antidiabetic actions of both endogenously secreted and exogenously infused GLP-1 during a mixed meal in type 1 diabetic patients with and without residual β-cell function.     

Relationships among tonic and episodic aspects of motivation to eat,gut peptides,and weight before and after bariatric surgery

BackgroundThe interaction between motivation to eat, eating behavior traits, and gut peptides after Roux-en-Y gastric bypass (RYGB) surgery is not fully understood.MethodsAppetite and hormone responses to a fixed liquid preload were assessed in 12 obese (body mass index 45±1.9 kg/m²) participants immediately before and 3 days, 2 months, and 1 year after RYGB surgery. Subjective appetite and plasma levels of ghrelin, leptin, insulin, and glucagon-like peptide-1 (GLP-1) were measured for a 3-hour postprandial period. Eating behavior traits were also measured using the Three Factor Eating Questionnaire 18 (TFEQR18).ResultsThere was a decrease in TFEQR18 emotional eating (EE) and uncontrolled eating (UE) from presurgery to 1 year postsurgery but no significant change in cognitive restraint (CR). These changes occurred independently of change in weight. In addition, there was a reduction in subjective appetite ratings and alterations in appetite peptides favoring an anorectic response. Presurgery EE was significantly related to fasting and area under the curve (AUC) ghrelin; UE was associated with AUC desire to eat, and there was a significant association between fasting desire to eat and ghrelin (fasting and AUC). One year postsurgery, UE was positively related to fasting insulin, and CR was negatively associated with GLP-1. UE and subjective hunger were positively correlated, while the relationship between desire to eat and ghrelin remained.ConclusionThe relationships among subjective appetite ratings, eating behavior traits, and appetite peptides in obese patients both before and at 1 year after RYGB surgery may contribute to the reduction in a propensity to overeat (as measured by TFEQR18 factors) and weight loss.