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1.
BACKGROUND: The antidiabetic effect of bariatric surgery has been interpreted as a conceivable result of surgically induced weight loss and decreased caloric intake. However, glycemic control often occurs within days, before significant weight loss has been reached. The aim of our work was to investigate the hormones that control glycemic status in diabetes mellitus after a duodenal-jejunal exclusion in an animal model of nonobese type 2 diabetes. METHODS: Twelve (12- to 14-week-old) rats (Goto-Kakizaki) randomly underwent one of the following procedures: gastrojejunal bypass (group 1, n = 6) or no intervention (controls) (group 2, n = 6). Both groups were fed with the same type and amount of diet. At basal time (preoperative) and after intervention (1 week and 1 month), weight and fasting glycemia were measured. An oral glucose tolerance test (OGTT) was realized at same times. Hormone levels (insulin, glucagons-like peptide 1 [GLP-1], glucose-dependent insulinotropic peptide [GIP], glucagon, and leptin) were measured after 20 minutes of oral glucose overload. Age-matched Goto-Kakizaki rats were used as controls for all variables. RESULTS: Rats in group 1 and group 2 remained with the same weight during the protocol. The OGTT showed an improvement in glycemic levels in group 1; glucose levels were better at 1 week and 1 month after the surgery in all times of OGTT (basal, 10 minutes, and 120 minutes). Basal glucose levels at time 0 in basal time, at 1 week, and at 1 month were lower in group 1 than group 2. Postoral glucose overload levels of glucagon, insulin, GLP-1, and GIP remained unchanged during the treatment in both groups. In group 1, leptin levels had a significant decrease at 1 week and 1 month after surgery (basal time (6.1 +/- 1.6 ng/mL) versus 1 week (0.9 +/- 0.9 ng/mL) versus 1 month (0.7 +/- 0.6 ng/mL) (P < .05). CONCLUSION: Gastrojejunal bypass in a nonobese diabetic model improves glycemic control with a significant decrease in leptin levels, without changes in enteroinsular axis (GLP-1, GIP, glucagons, and insulin levels).  相似文献   

2.
Genetic factors play an important role in the pathogenesis of type 2 diabetes. The relevance to type 2 diabetes of the common polymorphism Glu23Lys in the potassium inward rectifier 6.2 (KIR6.2) gene is still controversial. The aim of this study was to assess whether this polymorphism influences beta-cell function, alpha-cell function, or insulin action. We therefore studied 298 nondiabetic subjects using an oral glucose tolerance test (OGTT) and 75 nondiabetic subjects using a hyperglycemic clamp (10 mmol/l) with additional glucagon-like peptide (GLP)-1 and arginine stimulation. The prevalence of the Lys allele was approximately 37%, and the Lys allele was associated with higher incremental plasma glucose during the OGTT (P = 0.03, ANOVA). Neither first- nor second-phase glucose-stimulated C-peptide secretion was affected by the presence of the polymorphism; nor were maximal glucose-, GLP-1-, or arginine-induced C-peptide secretion rates; nor was insulin sensitivity (all P > 0.7). However, the relative decrease in plasma glucagon concentrations during the 10 min after the glucose challenge was reduced in carriers of the Lys allele (10 +/- 3% decrease from baseline in Lys/Lys, 18 +/- 2% in Glu/Lys, and 20 +/- 2% in Glu/Glu; P = 0.01, ANOVA). In conclusion, our findings suggest that the common Glu23Lys polymorphism in KIR6.2 is not necessarily associated with beta-cell dysfunction or insulin resistance but with diminished suppression of glucagon secretion in response to hyperglycemia. Our findings thus confirm its functional relevance for glucose metabolism in humans.  相似文献   

3.
Vella A  Shah P  Basu R  Basu A  Holst JJ  Rizza RA 《Diabetes》2000,49(4):611-617
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.  相似文献   

4.
BackgroundBiliopancreatic diversion (BPD) is the most effective bariatric procedure in terms of weight loss and remission of diabetes type 2 (T2DM), but it is accompanied by nutrient deficiencies. Sleeve gastrectomy (SG) is a relatively new operation that has shown promising results concerning T2DM resolution and weight loss. The objective of this study was to evaluate and compare prospectively the effects of BPD long limb (BPD) and laparoscopic SG on fasting, and glucose-stimulated insulin, glucagon, ghrelin, peptide YY (PYY), and glucagon-like peptide-1 (GLP-1) secretion and also on remission of T2DM, hypertension, and dyslipidemia in morbidly obese patients with T2DM.MethodsTwelve patients (body mass index [BMI] 57.6±9.9 kg/m2) underwent BPD and 12 (BMI 43.7±2.1 kg/m2) underwent SG. All patients had T2DM and underwent an oral glucose tolerance test (OGTT) before and 1, 3, and 12 months after surgery.ResultsBMI decreased more after BPD, but percent excess weight loss (%EWL) was similar in both groups (P = .8) and T2DM resolved in all patients at 12 months. Insulin sensitivity improved more after BPD than after SG (P = .003). Blood pressure, total and LDL cholesterol decreased only after BPD (P<.001). Triglycerides decreased after either operation, but HDL increased only after SG (P<.001). Fasting ghrelin did not change after BPD (P = .2), but decreased markedly after SG (P<.001). GLP-1 and PYY responses during OGTT were dramatically enhanced after either procedure (P = .001).ConclusionsSG was comparable to BPD in T2DM resolution but inferior in improving dyslipidemia and blood pressure. SG and BPD enhanced markedly PYY and GLP-1 responses but only SG suppressed ghrelin levels.  相似文献   

5.
The Roux-en-Y gastric bypass (RYGBP) and the biliopancreatic diversion (BPD) induce long-term control of type 2 diabetes in morbidly obese individuals. The reasons for such an effect on glycemic metabolism are thought to be secondary to reduced food intake, weight loss and modifications of the enteroinsular axis which is impaired in type 2 diabetic patients. Both GLP-1 and GIP have an impaired secretin effect in type 2 diabetics, and surgery can restore this function. GIP is a peptide secreted by the duodenal K-cells in response to ingested fat and carbohydrate. In obese type 2 diabetes patients, its receptor on β-cells is down-regulated. GLP-1 is a peptide secreted by the gut L-cells, and, in type 2 diabetes, its secretion is impaired. Both RYGBP and BPD provide durable GLP-1 delivery, both during fasting and after meal ingestion, inducing L-cell stimulation by early arrival of nutrients in the distal ileum. The secretion of GLP-1 influences glucose metabolism by inhibiting glucagon secretion, stimulating insulin secretion, delaying gastric emptying and stimulating glycogenogenesis. In conclusion, the early arrival of a meal in the terminal ileum seems to be the common feature of both operations that leads to an improvement in glycemic metabolism and to resolution of type 2 diabetes.  相似文献   

6.
目的 观察胃转流术对非肥胖性2型糖尿病的疗效及其对胰高血糖素样肽1(GLP-1)的影响.方法 前瞻性入选行胃转流术的32例胃溃疡合并非肥胖性2型糖尿病患者,检测术前及术后1周、1、3、6个月体质量指数(BMI)、口服葡萄糖耐量试验后0、30、60、120、180 min血糖和GLP-1水平,分析术后并发症和6个月时糖尿病转归情况.结果 术前卒腹血糖为(9.5±1.0)mmol/L,术后分别降至1周时(7.4±1.0)mmol/L、1个月时(6.5±1.2)mmol/L、3个月时(8.0±1.6)mmol/L及6个月时(5.8±1.0)mmol/L,P<0.01;术前口服葡萄糖耐量试验血糖峰值为(17.5±2.0)mmol/L,术后分别降至(12.6±1.7)mmol/L、(11.0±1.7)mmol/L、(12.4±1.7)mmol/L和(10.8±1.7)mmol/L,P<0.01;术前口服葡萄糖耐量试验血糖曲线下面积为(2455±281)mmol·min/L,术后分别降至(1842±237)mmol·min/L、(1638±261)mmol·min/L、(1828±239)mmol·min/L和(1541±253)mmol·min/L,P<0.01.术前口服葡萄糖耐量试验过程中GLP-1峰值为(20±3)pmol/L,术后分别升至(83±15)pmol/L、(86±20)pmol/L、(87±22)pmol/L和(92±20)pmol/L,P<0.01;术前口服葡萄糖耐量试验过程中GLP-1曲线下面积为(2457±395)pmol·min/L,术后分别升至(6499±1227)pmol·min/L、(7275±1475)pmol·min/L、(7307±1575)pmol·min/L和(7974±1594)pmol·min/L,P<0.01,术后各时间点BMI较术前无显著变化(P>0.05).术后出现切口感染1例,顽固性呃逆1例,术后6个月糖尿病总控制率均值为78%.结论 胃转流术可显著降低非肥胖性2型糖尿病患者血糖,改善口服葡萄糖耐量试验,胃转流术控制血糖可能与增加GLP-1释放进而促进胰岛素分泌有关,其对血糖的控制不依赖于体草的降低.  相似文献   

7.

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 (14). 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).  相似文献   

8.
BackgroundBariatric surgery is an effective treatment for morbid obesity. Current literature reports significant improvements in glucose homeostasis after malabsorptive surgery. There is limited evidence on the effects of laparoscopic sleeve gastrectomy (SG) on glucose-insulin homeostasis and postoperative incretin hormone response. The objective of this study was to examine the metabolic effects of SG on temporal changes in insulin and glucose homeostasis, incretin hormones and hepatic insulin clearance in patients with impaired glucose tolerance (IGT) and type 2 diabetes (T2 DM).MethodsA nonrandomized prospective study comprising 22 participants undergoing SG (body mass index [BMI] 50.1 kg/m2, glycated hemoglobin [HbA1c] 53 mmol/mol) and 15 participants undergoing biliopancreatic diversion (BPD) (BMI 62.1 kg/m2, HbA1c 58 mmol/mol). Serial measurements of glucose, insulin, C-peptide, glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic hormone (GIP) were performed during oral glucose tolerance testing preoperatively and 1 and 6 months postoperatively. Areas under the curve (AUC) were examined at 30, 60, and 120 minutes.ResultsWithin the SG group, significant improvements were observed respectively at 1 and 6 months in glucose control (HbA1c: −0.9%, −1.3%), measures of insulin sensitivity (fasting insulin: −4.8 mU/L, −8.5 mU/L; fasting C-peptide: −0.6 pmol/L, −1.1 pmol/L; Homeostasis Model Assessment [HOMA-IR]: −0.144, −0.174; HOMA %S:+29.6,+92.4), hepatic insulin clearance (+0.07,+0.13) and postprandial GLP-1 response (AUC0-30 pmol h L−1:+300,+331, AUC0-60:+300,+294, AUC0-120:+316,+295). These results were comparable to the BPD group.ConclusionsSG is associated with significant early improvements in insulin sensitivity and incretin hormone response and results in significant improvements in IGT/T2 DM.  相似文献   

9.
Buchanan TA  Xiang AH  Kjos SL  Trigo E  Lee WP  Peters RK 《Diabetes》1999,48(12):2430-2436
In this study, we sought to identify antepartum characteristics that predict the de novo development of diabetes 11-26 months after the index pregnancy in a carefully characterized cohort of women with gestational diabetes mellitus (GDM). Oral and frequently sampled intravenous glucose tolerance tests (OGTTs and FSIGTs), hyperinsulinemic-euglycemic clamps with labeled glucose, and body composition studies were performed on 91 islet cell antibody-negative Latino women with GDM during the third trimester of pregnancy. The women were documented to be diabetes-free within 6 months postpartum. Their diabetes status was ascertained again between 11 and 26 months postpartum. Logistic regression analysis was used to identify independent predictors of the development of diabetes within that interval. Fourteen of the women developed diabetes by World Health Organization criteria 11-26 months after delivery of the index pregnancy. Three antepartum variables were independent predictors of diabetes: the 1-h postchallenge plasma glucose concentration from the 100-g OGTT at which GDM was diagnosed (higher = increased risk; P = 0.003); an index of pancreatic beta-cell compensation for insulin resistance, defined as the product of the 30-min incremental plasma insulin:glucose ratio on a 75-g OGTT and the insulin sensitivity index from a hyperinsulinemic-euglycemic clamp (lower = increased risk, P = 0.009); and the basal glucose production rate after an overnight fast (higher = increased risk; P = 0.04). We conclude that postchallenge hyperglycemia, poor pancreatic beta-cell compensation for insulin resistance, and elevated endogenous glucose production during pregnancy precede the development of type 2 diabetes in young Latino women by at least 1-2 years.  相似文献   

10.
To determine whether nonglucose nutrient-induced insulin secretion is impaired in pre-diabetes, subjects with impaired or normal fasting glucose were studied after ingesting either a mixed meal containing 75 g glucose or 75 g glucose alone. Despite comparable glucose areas above basal, glucose-induced insulin secretion was higher (P < 0.05) and insulin action lower (P < 0.05) during the meal than the oral glucose tolerance test (OGTT) in all subgroups regardless of whether they had abnormal or normal glucose tolerance (NGT). However, the nutrient-induced delta (meal minus OGTT) in insulin secretion and glucagon concentrations did not differ among groups. Furthermore, the decrease in insulin action after meal ingestion was compensated in all groups by an appropriate increase in insulin secretion resulting in disposition indexes during meals that were equal to or greater than those present during the OGTT. In contrast, disposition indexes were reduced (P < 0.01) during the OGTT in the impaired glucose tolerance groups, indicating that reduced glucose induced insulin secretion. We conclude that, whereas glucose-induced insulin secretion is impaired in people with abnormal glucose tolerance, nonglucose nutrient-induced secretion is intact, suggesting that a glucose-specific defect in the insulin secretory pathway is an early event in the evolution of type 2 diabetes.  相似文献   

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