Comparable early changes in gastrointestinal hormones after sleeve gastrectomy and Roux-En-Y gastric bypass surgery for morbidly obese type 2 diabetic subjects

Background

Sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGBP) are associated with similar type 2 diabetes mellitus (T2DM) resolution rates for morbidly obese subjects. However, the mechanisms underlying the resolution of T2DM after SG have not been clarified to date. This study aimed to compare the early changes in gastrointestinal hormones involved in insulin and glucagon secretion in morbidly obese T2DM subjects undergoing SG or RYGBP.

Methods

This prospective study investigated 12 subjects with T2DM who had undergone SG (n?=?6) or RYGBP (n?=?6). Five body mass index (BMI)-matched obese non-diabetic subjects and five BMI-matched obese diabetic subjects served as control subjects. Glucose, insulin, glucagon, glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and GLP-2 were determined after a standardized mixed liquid meal before surgery and 6?weeks afterward.

Results

After 6?weeks, five of the six subjects in each surgical group presented with T2DM remission, although the area under the curve (AUC)_0–120 of glucose was greater than that of the non-diabetic control subjects (P?0–120 of GLP-1 (P?P?P?Conclusions The data show that in a cohort of morbidly obese T2DM subjects, SG and RYGBP are associated with an early improvement in glucose tolerance, similar changes in insulin and glucagon secretion, and a similar GLP-1, GIP, and GLP-2 response to a standardized mixed liquid meal.     

Gastric inhibitory polypeptide and glucagon-like peptide-1 in the pathogenesis of type 2 diabetes

The incretin effect denominates the phenomenon that oral glucose elicits a higher insulin response than does intravenous glucose. The two hormones responsible for the incretin effect, glucose-dependent insulinotropic hormone (GIP) and glucagon-like peptide-1 (GLP-1), are secreted after oral glucose loads and augment insulin secretion in response to hyperglycemia. In patients with type 2 diabetes, the incretin effect is reduced, and there is a moderate degree of GLP-1 hyposecretion. However, the insulinotropic response to GLP-1 is well maintained in type 2 diabetes. GIP is secreted normally or hypersecreted in type 2 diabetes; however, the responsiveness of the endocrine pancreas to GIP is greatly reduced. In approximately 50% of first-degree relatives of patients with type 2 diabetes, similarly reduced insulinotropic responses toward exogenous GIP can be observed, without significantly changed secretion of GIP or GLP-1 after oral glucose. This opens the possibility that a reduced responsiveness to GIP is an early step in the pathogenesis of type 2 diabetes. On the other hand, this provides a basis to use incretin hormones, especially GLP-1 and its derivatives, to replace a deficiency in incretin-mediated insulin secretion in the treatment of type 2 diabetes.     

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.     

Exogenous Glucose�CDependent Insulinotropic Polypeptide Worsens Post prandial Hyperglycemia in T ype 2 Diabetes

OBJECTIVE

Glucose-dependent insulinotropic polypeptide (GIP), unlike glucagon-like peptide (GLP)-1, lacks glucose-lowering properties in patients with type 2 diabetes. We designed this study to elucidate the underlying pathophysiology.

RESEARCH DESIGN AND METHODS

Twenty-two insulin-naïve subjects with type 2 diabetes were given either synthetic human GIP (20 ng · kg⁻¹ · min⁻¹) or placebo (normal saline) over 180 min, starting with the first bite of a mixed meal (plus 1 g of acetaminophen) on two separate occasions. Frequent blood samples were obtained over 6 h to determine plasma GIP, GLP-1, glucose, insulin, glucagon, resistin, and acetaminophen levels.

RESULTS

Compared with placebo, GIP induced an early postprandial increase in insulin levels. Intriguingly, GIP also induced an early postprandial augmentation in glucagon, a significant elevation in late postprandial glucose, and a decrease in late postprandial GLP-1 levels. Resistin and acetaminophen levels were comparable in both interventions. By immunocytochemistry, GIP receptors were present on human and mouse α-cells. In αTC1 cell line, GIP induced an increase in intracellular cAMP and glucagon secretion.

CONCLUSIONS

GIP, given to achieve supraphysiological plasma levels, still had an early, short-lived insulinotropic effect in type 2 diabetes. However, with a concomitant increase in glucagon, the glucose-lowering effect was lost. GIP infusion further worsened hyperglycemia postprandially, most likely through its suppressive effect on GLP-1. These findings make it unlikely that GIP or GIP receptor agonists will be useful in treating the hyperglycemia of patients with type 2 diabetes.In response to glucose and fat in digested food, two enteroendocrine hormones, glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP), are secreted froml- andk-cells, respectively, in the gut. GLP-1 and GIP play important roles in postprandial glucose homeostasis. In healthy individuals, the potent insulinotropic effects of GLP-1 and GIP account for up to 60% of the insulin secreted postprandially (1). Exogenous GLP-1 acts to improve glycemic control in patients with type 2 diabetes by 1) stimulating insulin secretion in a glucose concentration–dependent manner during the fasted state, 2) suppressing glucagon secretion in the presence of hyperglycemia and euglycemia but not hypoglycemia, and 3) decelerating gastric emptying, leading to a delay in the absorption of ingested nutrients and a dampening of postprandial glucose excursion (2–4). However, it is still unclear which of these properties of exogenous GLP-1 plays a more prominent role in lowering postprandial glucose (5). GIP has not been studied as extensively as GLP-1. Similar to GLP-1, the insulinotropic effect of GIP in healthy humans is glucose concentration dependent under glucose clamp conditions (6). Unlike GLP-1, the administration of GIP in healthy humans was reported to have a dose-dependent glucagonotropic effect during euglycemia and no effect during hyperglycemic clamp conditions (6–8). Also, unlike GLP-1, GIP has no effect on gastric emptying (9).In patients with type 2 diabetes compared with healthy subjects, the ability of GLP-1 to stimulate insulin was noted to be 71%, while that of GIP was 46%; however, the glucose-lowering effect of GLP-1 was relatively preserved while that of GIP was absent (7,10–12). The underlying pathophysiology associated with this loss of glucose-lowering effect of GIP in humans is not known. Some hypotheses include defective expression of GIP receptors (13), accelerated degradation of GIP receptors (14), and downregulation of GIP signaling (15). It is argued that genetic components or GIP receptor defects do not play a role in the reduced insulinotropic response to GIP because patients with different types of diabetes, such as from chronic pancreatitis, latent autoimmune diabetes in adults, maturity-onset diabetes in the young, and newly diagnosed type 1 diabetes, also have impaired insulin response to GIP, thus suggesting that metabolic abnormalities may be the cause (16).The underlying pathophysiology associated with this loss of glucose-lowering effect of GIP despite still having some insulinotropic effect in humans is not known. The aims of this study were 1) to ascertain if a dose of GIP designed to elevate plasma GIP levels to fivefold of that observed postmeal might lower blood glucose in patients with type 2 diabetes and 2) to gain insight into the pathophysiology underlying the seeming lack of effects of GIP on glucose homeostasis in patients with type 2 diabetes.     

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.     

2胆胰分流术与胃旁路术治疗2型糖尿病的机制比较

临床研究发现,减重手术可以改善甚至治愈糖尿病。采用不同术式其效果不一,其中胆胰分流术（BPD）对糖尿病治愈率最高,达98％以上：其次为Roux-en-Y胃旁路术（RGBP）,可达80％。但这两种手术对于治疗糖尿病的具体作用机制尚不明确．且争议较多。BPD与RGBP术后患者体内多种激素水平、尤其是肠道激素GLP．1和GIP的变化并不一致．很难用前肠及后肠假说完全解释。本综述根据国内外最新研究结果．比较了BPD及RGBP两种术式的解剖结构及术后GLP．1和GIP的变化,并对两种术式在治疗糖尿病上可能存在的不同机制进行了探讨。     

Defective glucose-dependent insulinotropic polypeptide receptor expression in diabetic fatty Zucker rats

Glucose-dependent insulinotropic polypeptide (GIP) is a peptide hormone that is released postprandially from the small intestine and acts in concert with glucagon-like peptide (GLP)-1 to potentiate glucose-induced insulin secretion from the pancreatic beta-cell. In type 2 diabetes, there is a decreased responsiveness of the pancreas to GIP; however, the insulin response to GLP-1 remains intact. The literature suggests that the ineffectiveness of GIP in type 2 diabetes may be a result of chronic homologous desensitization of the GIP receptor. Yet, there has been no conclusive evidence suggesting that GIP levels are elevated in diabetes. The hypothesis of the present study is that one cause of decreased responsiveness to GIP in type 2 diabetes is an inappropriate expression of the GIP receptor in the pancreatic islet. This hypothesis was tested using a strain of diabetic fatty Zucker rats. The obese rats displayed basal GIP levels similar to the control animals; however, they were unresponsive to a GIP infusion (4 pmol.min(-1). kg(-1)), whereas the lean animals displayed a significant reduction in blood glucose (GIP levels, 50% control after 60 min, P < 0.05) as well as a significant increase in circulating insulin. GIP also potently stimulated first-phase insulin secretion from isolated perifused islets (10.3 +/- 3.0 x basal), and GIP and GLP-1 potentiated insulin secretion from the perfused pancreas (6 x control area under the curve [AUC]) from lean animals. GIP yielded no significant effect in the Vancouver diabetic fatty Zucker (VDF) rat pancreases, whereas GLP-1 elicited an eightfold increase of insulin secretion from the perfused VDF pancreas. Islets from lean animals subjected to static incubations with GIP showed a 2.2-fold increase in cAMP, whereas GIP failed to increase islet cAMP in the VDF islets. Finally, the expression of both GIP receptor mRNA and protein was decreased in islets from VDF rats. These data suggest that the decreased effectiveness of GIP in the VDF rat and in type 2 diabetes may be a result of a decreased receptor expression in the islet.     

Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients

Incretin hormones importantly enhance postprandial insulin secretion but are rapidly degraded to inactive metabolites by ubiquitous dipeptidyl peptidase IV. The concentrations of the intact biologically active hormones remain largely unknown. Using newly developed assays for intact glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP), we measured plasma concentrations after a mixed breakfast meal (566 kcal) in 12 type 2 diabetic patients (age 57 years [range 49-67], BMI 31 kg/m2 [27-38], and HbA1c 9.2% [7.0-12.5]) and 12 matched healthy subjects. The patients had fasting hyperglycemia (10.7 mmol/l [8.0-14.8]) increasing to 14.6 mmol/l (11.5-21.5) 75 min after meal ingestion. Fasting levels of insulin and C-peptide were similar to those of the healthy subjects, but the postprandial responses were reduced and delayed. Fasting levels and meal responses were similar between patients and healthy subjects for total GIP (intact + metabolite) as well as intact GIP, except for a small decrease in the patients at 120 min; integrated areas for intact hormone (area under the curve [AUC]INT) averaged 52 +/- 4% (for patients) versus 56 +/- 3% (for control subjects) of total hormone AUC (AUC(TOT)). AUC(INT) for GLP-1 averaged 48 +/- 2% (for patients) versus 51 +/- 5% (for control subjects) of AUC(TOT). AUC(TOT) for GLP-1 as well as AUC(INT) tended to be reduced in the patients (P = 0.2 and 0.07, respectively); but the profile of the intact GLP-1 response was characterized by a small early rise (30-45 min) and a significantly reduced late phase (75-150 min) (P < 0.02). The measurement of intact incretin hormones revealed that total as well as intact GIP responses were minimally decreased in patients with type 2 diabetes, whereas the late intact GLP-1 response was strongly reduced, supporting the hypothesis that an impaired function of GLP-1 as a transmitter in the enteroinsular axis contributes to the inappropriate insulin secretion in type 2 diabetes.     

Importance of Small Bowel Peptides for the Improved Glucose Metabolism 20 Years after Jejunoileal Bypass for Obesity

Background: Obese patients operated with jejunoileal bypass (JIB) have reduced plasma concentrations of insulin and glucose. Gastric inhibitory peptide/glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) have been found to have a profound incretin effect in humans. The aim of the present study was to examine the long-term effect of JIB on glucose metabolism. Methods: Four groups (lean, nonoperated obese, obese 9 months after JIB and obese 20 years after JIB) of six females each were given a mixed meal (280 kcal). Plasma samples were obtained every 10 min for 60 min postprandially and were analyzed for glucose, insulin, GIP and GLP-1. Results: A reduction in body mass index (kg/m²) was seen for the two patient groups operated with JIB (12.1, at 9 months post-op; 13.1, at 20 years post-op). Surgery by JIB resulted in a reduction of glucose and insulin values. Concomitantly there was an elevation of postprandial GIP and GLP-1 plasma concentrations. In the obese subjects 20 years after JIB both fasting and postprandial GIP and GLP-1 values were markedly elevated compared with the other three groups; and plasma glucose and insulin concentrations were maintained at normal levels. Conclusions: The improvement in glucose metabolism seen after JIB may be due to reduced insulin resistance after weight loss and/or increased levels of the incretin hormones GIP and GLP-1. Progressively, elevated levels of GIP and GLP-1 seem to be necessary to maintain glucose homeostasis at longterm follow-up after this procedure.     

Ilial Transposition and Enteroglucagon/GLP-1 in Obesity (and Diabetic?) Surgery

Background: This is a review of intestinal glucagon, which is released when undigested food is in the terminal ileum. Methods and Results: In the early 1980s, Koopmans and Sclafani showed in fat rats that the transposition of a short segment of ileum to the duodenum would decrease weight just as effectively as intestinal bypass. Sarson and coworkers found elevated enteroglucagon after biliopancreatic diversion (BPD). Scopinaro has observed that patients with diabetes who undergo BPD are cured of diabetes and do not experience a recurrence. N?slund and associates showed recently a high level of plasma glucagon-like peptide (GLP-1) 20 years after jejunoileal bypass. GLP-1 has been shown to be an effective medication for treatment of type 2 diabetes mellitus (DM). It must be given parenterally. It has been used only in short, well-controlled studies. Conclusions: It appears from all that is now known about GLP-1 that ileal transposition would be an ideal operation for treatment of type 2 DM. Release of enteroglucagon from the ileum has probably contributed to weight control in bypass operations for obesity, but the effect has been obscured by the associated malabsorption. The release of GLP-1 after meals has probably been beneficial to patients treated with gastric bypass who had type 2 DM. This is a recommendation for well-planned studies of ileal transposition in the treatment of type 2 DM and obesity. Ileal transposition is not recommended for general use until such studies have shown safety, efficacy, and the requirements for patient selection.     

Does Reduction in Gastric Acid Secretion in Bariatric Surgery Increase Diet-Induced Thermogenesis?

Background: Patients who have undergone gastrectomy for benign ulcer do not develop obesity. Furthermore, morbidly obese patients who undergo biliopancreatic diversion (BPD), Roux-en-Y gastric bypass (RYGBP) and vertical banded gastroplasty (VBG) plus truncal vagotomy, may lose more weight compared with patients who undergo VBG alone. A common characteristic of the above is the reduction of gastric hydrochloric acid secretion. We investigated whether reduction in gastric acid increases dietary- induced thermogenesis because of maldigestion of foods, and this may account for the greater weight loss in the above situations. Materials and Methods: 22 volunteers without symptoms from the upper gastrointestinal tract were studied. Gastric pH was measured and resting energy expenditure (MREE), using indirect calorimetry, was determined before and 8 hours after consumption of a standard meal. Parameters were measured again after 2 months administration of proton pump inhibitors in all volunteers. Results: Although significant reduction of gastric acid secretion occurred (p<0.01), following administration of proton pump inhibitors, the fasting and postprandial MREE remained unchanged (p>0.05). Conclusions: The reduction in gastric acid secretion does not increase the energy requirements for digestion of foods and thus is neither the mechanism responsible for the increased weight loss observed after RYGBP or BPD, nor the explanation for the lean appearance of gastrectomized patients.     

Does Reduction in Gastric Acid Secretion in Bariatric Surgery Increase Diet-Induced Thermogenesis?

Background: Patients who have undergone gastrectomy for benign ulcer do not develop obesity. Furthermore, morbidly obese patients who undergo biliopancreatic diversion (BPD), Roux-en-Y gastric bypass (RYGBP) and vertical banded gastroplasty (VBG) plus truncal vagotomy, may lose more weight compared with patients who undergo VBG alone. A common characteristic of the above is the reduction of gastric hydrochloric acid secretion. We investigated whether reduction in gastric acid increases dietary-induced thermogenesis because of maldigestion of foods, and this may account for the greater weight loss in the above situations. Materials and Methods: 22 volunteers without symptoms from the upper gastrointestinal tract were studied. Gastric pH was measured and resting energy expenditure (MREE), using indirect calorimetry, was determined before and 8 hours after consumption of a standard meal. Parameters were measured again after 2 months administration of proton pump inhibitors in all volunteers. Results: Although significant reduction of gastric acid secretion occurred (p<0.01), following administration of proton pump inhibitors, the fasting and postprandial MREE remained unchanged (p>0.05). Conclusions: The reduction in gastric acid secretion does not increase the energy requirements for digestion of foods and thus is neither the mechanism responsible for the increased weight loss observed after RYGBP or BPD, nor the explanation for the lean appearance of gastrectomized patients.     

Downregulation of GLP-1 and GIP receptor expression by hyperglycemia: possible contribution to impaired incretin effects in diabetes

Stimulation of insulin secretion by the incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) has been found to be diminished in type 2 diabetes. We hypothesized that this impairment is due to a defect at the receptor level induced by the diabetic state, particularly hyperglycemia. Gene expression of incretin receptors, GLP-1R and GIPR, were significantly decreased in islets of 90% pancreatectomized (Px) hyperglycemic rats, with recovery when glucose levels were normalized by phlorizin. Perifused islets isolated from hyperglycemic Px rats showed reduced insulin responses to GLP-1 and GIP. To examine the acute effect of hyperglycemia on incretin receptor expression, a hyperglycemic clamp study was performed for 96 h with reduction of GLP-1 receptor expression but increase in GIP receptor expression. Similar findings were found when islets were cultured at high glucose concentrations for 48 h. The reduction of GLP-1 receptor expression by high glucose was prevented by dominant-negative protein kinase C (PKC)alpha overexpression, whereas GLP-1 receptor expression was reduced with wild-type PKCalpha overexpression. Taken together, GLP-1 and GIP receptor expression is decreased with chronic hyperglycemia, and this decrease likely contributes to the impaired incretin effects found in diabetes.     

A Comparison of a Personal Series of Biliopancreatic Diversion and Literature Data on Gastric Bypass Help to Explain the Mechanisms of Resolution of Type 2 Diabetes by the Two Operations

BACKGROUND: Roux-en-Y gastric bypass (RYGBP) and biliopancreatic diversion (BPD) are highly beneficial operations for type 2 diabetes mellitus (T2DM) in obese patients, leading to complete T2DM resolution in 75-90 and 97-99% of cases, respectively. In both RYGBP and BPD, the foregut is excluded from the food stream and the distal small bowel receives the food stimulation, while following BPD fat intestinal absorption is also extremely limited. This study was carried out to identify clinical features that could give insight on the different mechanisms of action on diabetes resolution. METHODS: The files of 443 severely obese patients with T2DM undergoing BPD from May 1976 to May 2007 were examined, and the presence of T2DM (fasting serum glucose >125 mg/ml) at 1-2 months, at 1 year, at 10 years, and at >/=20 years following the operation was recorded. RESULTS: The percentage of patients cured (fasting serum glucose reduced to /=20 years, the 26% of uncured patients at 1 month being those with most severe preoperative T2DM. CONCLUSIONS: As the early results after BPD resemble those reported after RYGBP, it can be hypothesized that the duodenal exclusion and the distal small bowel stimulation are the first mechanisms acting in BPD, immediately after the operation, that only subsequently the myocellular fat depletion, which cannot be immediate, takes over, and that the minimal fat absorption is the mechanism accounting for the long-term results of BPD.     

Limited Recovery of β-Cell Function After Gastric Bypass Despite Clinical Diabetes Remission

The mechanisms responsible for the remarkable remission of type 2 diabetes after Roux-en-Y gastric bypass (RYGBP) are still puzzling. To elucidate the role of the gut, we compared β-cell function assessed during an oral glucose tolerance test (OGTT) and an isoglycemic intravenous glucose clamp (iso-IVGC) in: 1) 16 severely obese patients with type 2 diabetes, up to 3 years post-RYGBP; 2) 11 severely obese normal glucose-tolerant control subjects; and 3) 7 lean control subjects. Diabetes remission was observed after RYGBP. β-Cell function during the OGTT, significantly blunted prior to RYGBP, normalized to levels of both control groups after RYGBP. In contrast, during the iso-IVGC, β-cell function improved minimally and remained significantly impaired compared with lean control subjects up to 3 years post-RYGBP. Presurgery, β-cell function, weight loss, and glucagon-like peptide 1 response were all predictors of postsurgery β-cell function, although weight loss appeared to be the strongest predictor. These data show that β-cell dysfunction persists after RYGBP, even in patients in clinical diabetes remission. This impairment can be rescued by oral glucose stimulation, suggesting that RYGBP leads to an important gastrointestinal effect, critical for improved β-cell function after surgery.Roux-en-Y gastric bypass (RYGBP) remits type 2 diabetes in ∼40–80% of cases (1,2); however, mechanisms surrounding this remarkable improvement are still elusive. Although caloric restriction and weight loss are important contributors, evidence suggests that altered gut physiology, including bypass of the proximal small intestine, may also contribute. Bolus delivery of oral glucose elicits significantly lower plasma glucose excursions compared with intravenous (IV) bolus delivery, and an isoglycemic IV glucose clamp (iso-IVGC) leads to significantly lower insulin excursions than an oral glucose tolerance test (OGTT) (3). These experiments highlight the importance of gut-mediated factors in the regulation of glucose metabolism and insulin secretion. The difference in postprandial insulin excursion, or incretin effect, is severely blunted in diabetes and normalized shortly after RYGBP, in parallel with a marked increase in the incretin hormone glucagon-like peptide 1 (GLP-1) (4), which has been shown to improve glucose tolerance, insulin secretion, and β-cell glucose sensitivity (BCGS) (5–8). In fact, GLP-1 agonists are used for diabetes management.β-Cell function, often evaluated using BCGS, relating insulin secretion to plasma glucose levels, and the disposition index (DI), which also adds an insulin sensitivity component, has been shown to be an optimal predictor of diabetes risk (9–11). β-Cell function is impaired in diabetes (12,13) and significantly improved after RYGBP (13–15); evidence suggests this could be GLP-1–mediated (8,16,17). However, the contribution of the gastrointestinal tract to improvement in β-cell function after RYGBP has not been directly tested. To investigate this, we examined change in β-cell function up to 3 years after RYGBP in severely obese individuals with type 2 diabetes who experienced clinical diabetes remission post-RYGBP (OB-DM) and compared them to both nonoperated, obese normal glucose-tolerant (OB-NGT) and lean NGT (LEAN) subjects. To assess if improvements in β-cell function after RYGBP were mediated by the gut, we compared measures of β-cell function during an oral and isoglycemic glucose challenge. Lastly, we studied predictors of β-cell function and glucose control after RYGBP.     

Incretin dysfunction and hyperglycemia in cystic fibrosis: Role of acyl-ghrelin

BackgroundInsulin secretion is insufficient in cystic fibrosis (CF), even before diabetes is present, though the mechanisms involved remain unclear. Acyl-ghrelin (AG) can diminish insulin secretion and is elevated in humans with CF.MethodsWe tested the hypothesis that elevated AG contributes to reduced insulin secretion and hyperglycemia in CF ferrets.ResultsFasting AG was elevated in CF versus non-CF ferrets. Similar to its effects in other species, AG administration in non-CF ferrets acutely reduced insulin, increased growth hormone, and induced hyperglycemia. During oral glucose tolerance testing, non-CF ferrets had responsive insulin, glucagon like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) levels and maintained normal glucose levels, whereas CF ferrets had insufficient responses and became hyperglycemic. Interestingly in wild-type ferrets, the acyl-ghrelin receptor antagonist [D-Lys3]-GHRP-6 impaired glucose tolerance, and abolished insulin, GLP-1, and GIP responses during glucose tolerance testing. By contrast, in CF ferrets [D-Lys3]-GHRP-6 improved glucose tolerance, enhanced the insulin-to-glucose ratio, but did not impact the already low GLP-1 and GIP levels.ConclusionsThese results suggest a mechanism by which elevated AG contributes to CF hyperglycemia through inhibition of insulin secretion, an effect magnified by low GLP-1 and GIP. Interventions that lower ghrelin, ghrelin action, and/or raise GLP-1 or GIP might improve glycemia in CF.     

Effect of glucagon-like peptide 1(7-36) amide on glucose effectiveness and insulin action in people with type 2 diabetes

Although it is well established that glucagon-like peptide 1(7-36) amide (GLP-1) is a potent stimulator of insulin secretion, its effects on insulin action and glucose effectiveness are less clear. To determine whether GLP-1 increases insulin action and glucose effectiveness, subjects with type 2 diabetes were studied on two occasions. Insulin was infused during the night on both occasions to ensure that baseline glucose concentrations were comparable. On the morning of study, either GLP-1 (1.2 pmol x kg(-1) x min(-1)) or saline were infused along with somatostatin and replacement amounts of glucagon. Glucose also was infused in a pattern mimicking that typically observed after a carbohydrate meal. Insulin concentrations were either kept constant at basal levels (n = 6) or varied so as to create a prandial insulin profile (n = 6). The increase in glucose concentration was virtually identical on the GLP-1 and saline study days during both the basal (1.21 +/- 0.15 vs. 1.32 +/- 0.19 mol/l per 6 h) and prandial (0.56 +/- 0.14 vs. 0.56 +/- 0.10 mol/l per 6 h) insulin infusions. During both the basal and prandial insulin infusions, glucose disappearance promptly increased after initiation of the glucose infusion to rates that did not differ on the GLP-1 and saline study days. Suppression of endogenous glucose production also was comparable on the GLP-1 and saline study days during both the basal (-2.7 +/- 0.3 vs. -3.1 +/- 0.2 micromol/kg) and prandial (-3.1 +/- 0.4 vs. -3.0 +/- 0.6 pmol/kg) insulin infusions. We conclude that when insulin and glucagon concentrations are matched, GLP-1 has negligible effects on either insulin action or glucose effectiveness in people with type 2 diabetes. These data strongly support the concept that GLP-1 improves glycemic control in people with type 2 diabetes by increasing insulin secretion, by inhibiting glucagon secretion, and by delaying gastric emptying rather than by altering extrapancreatic glucose metabolism.     

Impact of biliopancreatic diversion with duodenal switch on glucose homeostasis and gut hormones and their correlations with appetite

BackgroundBiliopancreatic diversion with duodenal switch (BPD/DS) results in lifelong changes in gastrointestinal physiology with unclear associations with appetite perception.ObjectiveTo explore mixed meal–induced changes in glucose homeostasis and gut hormones and their correlations with appetite perception.SettingUniversity hospital.MethodsOf 28 patients studied preoperatively (age: 38.4 ± 11.3 years; body mass index [BMI]: 56.5 ± 5.1 kg/m²; 14 women), 19 (68%) returned for postoperative follow-up. Plasma was sampled for 180 minutes during a 260-kcal standardized mixed meal. Concentrations of leptin, glucose, insulin, triglycerides, active acyl-ghrelin, motilin, total glucose-dependent insulinotropic polypeptide (GIP), active glucagon-like peptide 1 (GLP-1), and total peptide YY (PYY) were measured. Subjective appetite sensations were scored.ResultsBPD/DS resulted in 66.1% ± 23.3% excess BMI loss. Leptin was halved. Glucose and insulin levels were reduced, blunting a preoperative peak at 30 minutes, giving a lower homeostasis model assessment for insulin resistance (HOMA-IR; 13.9 versus 4.8). In contrast, reduced ghrelin and motilin concentrations were accompanied by pronounced peaks 20–30 minutes prior to meal responses. GIP was reduced, whereas GLP-1 and PYY responses were markedly increased, with an early postprandial peak (P < .05, for all). HOMA-IR correlated with insulin (r = .72) and GIP (r = .57). Postoperatively, satiety correlated with GLP-1 (r = .56), whereas the gastric motility index correlated with the desire to eat (r = .60), percentage excess BMI loss (r = –.55), and percentage total weight loss (r = –.49). Delta insulin, GLP-1, and leptin correlated positively with percentage total weight loss (r = .51, r = .48, and r = .58, respectively).ConclusionsBPD/DS reduces leptin, HOMA-IR, and GIP while markedly increasing GLP-1 and PYY. This study marks the magnitude change in GLP-1 with additional effects of PYY as important factors for weight loss.     

Effect of Endogenous GLP-1 on Insulin Secretion in Type 2 Diabetes

OBJECTIVE

The incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) account for up to 60% of postprandial insulin release in healthy people. Previous studies showed a reduced incretin effect in patients with type 2 diabetes but a robust response to exogenous GLP-1. The primary goal of this study was to determine whether endogenous GLP-1 regulates insulin secretion in type 2 diabetes.

METHODS

Twelve patients with well-controlled type 2 diabetes and eight matched nondiabetic subjects consumed a breakfast meal containing d-xylose during fixed hyperglycemia at 5 mmol/l above fasting levels. Studies were repeated, once with infusion of the GLP-1 receptor antagonist, exendin-(9–39) (Ex-9), and once with saline.

RESULTS

The relative increase in insulin secretion after meal ingestion was comparable in diabetic and nondiabetic groups (44 ± 4% vs. 47 ± 7%). Blocking the action of GLP-1 suppressed postprandial insulin secretion similarly in the diabetic and nondiabetic subjects (25 ± 4% vs. 27 ± 8%). However, Ex-9 also reduced the insulin response to intravenous glucose (25 ± 5% vs. 26 ± 7%; diabetic vs. nondiabetic subjects), when plasma GLP-1 levels were undetectable. The appearance of postprandial ingested d-xylose in the blood was not affected by Ex-9.

CONCLUSIONS

These findings indicate that in patients with well-controlled diabetes, the relative effects of enteral stimuli and endogenous GLP-1 to enhance insulin release are retained and comparable with those in nondiabetic subjects. Surprisingly, GLP-1 receptor signaling promotes glucose-stimulated insulin secretion independent of the mode of glucose entry. Based on rates of d-xylose absorption, GLP-1 receptor blockade did not affect gastric emptying of a solid meal.Glucagon-like peptide 1 (GLP-1) is a gut-brain peptide that is a major component of the incretin effect and is essential for normal glucose tolerance (1). Based on studies in which synthetic GLP-1, or GLP-1 receptor (GLP-1r) agonists, is administered to humans, GLP-1 has a broad range of actions that promote glucose homeostasis, including stimulating insulin secretion (2), suppressing glucagon release (3–4), delaying gastric emptying (5), and increasing hepatic glucose balance (6–7). Importantly, and unlike other insulinotropic gut peptides, the effects of GLP-1 on glucose metabolism are retained in people with diabetes (8–10). This has led to the development of novel therapeutic compounds for use in diabetic patients that are based on GLP-1r signaling (11).The physiologic role of GLP-1 in individuals with diabetes has not been determined. However, there are several reasons to question whether the GLP-1 system is fully functional in this patient group. First, there is some evidence that GLP-1 secretion in response to meal ingestion in type 2 diabetes is impaired (12–15), although this finding has not been uniform (16–17). Second, the sensitivity of insulin secretion to exogenous GLP-1 is reduced in diabetic individuals (18). Finally, it has long been believed that the augmentation of glucose-stimulated insulin secretion during enteral glucose absorption, the incretin effect, is severely attenuated in type 2 diabetes, implying that incretins such as GLP-1 are not normally active in this group of subjects.In this study, we tested the hypothesis that the effect of endogenous GLP-1 to promote insulin secretion after meal ingestion is reduced in people with diabetes. Diabetic subjects and age- and weight-matched nondiabetic subjects were studied with and without infusion of the specific GLP-1r antagonist, exendin-(9–39) (Ex-9), during fixed hyperglycemia before and after a breakfast meal.