糖尿病患者胰高血糖素样肽-1在糖耐量试验前后的变化及意义

目的探讨2型糖尿病患者胰高血糖素样肽-1(glucagon-like peptical-1,GLP-1)水平与血糖、胰岛素及胰岛素抵抗的关系。方法 2型糖尿病患者50例(糖尿病组)及体检健康者30例(对照组),2组均禁食10h后行糖耐量试验,采集空腹及餐后2h血标本,分别检测血浆葡萄糖、胰岛素、GLP-1水平。结果糖尿病组空腹及餐后2h血糖明显高于对照组(P<0.05),餐后2hGLP-1水平明显低于对照组(P<0.05),空腹和餐后2h胰岛素水平及空腹GLP-1水平与对照组比较差异无统计学意义(P>0.05)。结论 2型糖尿病患者餐后2hGLP-1水平较正常人明显降低;餐后GLP-1分泌水平可反映2型糖尿病患者胰岛功能受损程度。     

不同糖耐量水平人群血浆胰高血糖素样肽-1和葡萄糖依赖的促胰岛素样多肽水平比较

目的 了解不同糖代谢状态的人群空腹及口服葡萄糖耐量实验(oral glucose tolerance test,OGTT)餐后胰高血糖素样态-1(GLP-1)和葡萄糖依赖的促胰岛素多态(GIP)水平.方法 将受试者根据OGTT结果分为3组:正常糖耐量组(NGT,n=61例),糖耐量受损组(IGT,n=53)和2型糖尿病...     

单纯性肥胖患者肠促胰岛素分泌激素分泌特点的研究

目的比较单纯性肥胖者和正常体重者肠促胰岛素分泌激素的分泌特点。方法选取正常葡萄糖耐量、BMI<24 kg/m2的志愿者10例作为正常对照组,以正常葡萄糖耐量、BMI≥25 kg/m2者7例为肥胖组,均进行75 g葡萄糖负荷,并检测两组受试者的0、15、30、60、90、120 min的血糖、血清胰岛素和血浆胰岛素样多肽1(GLP-1)、葡萄糖依赖促胰岛素分泌肽(GIP),并计算曲线下面积(AUCGLP-1、AUCGIP)。结果肥胖组的血糖峰值升高并后移,胰岛素分泌增加伴高峰后移。肥胖组整体GLP-1分泌水平低于正常组[AUCGLP-1差异有统计学意义(P<0.05)]。肥胖组GIP分泌模式与正常组相似,但血浆水平较正常组升高[AUCGIP差异有统计学意义(P<0.05)]。结论在胰岛素分泌增加、胰岛素抵抗存在的同时,单纯性肥胖者的GLP-1分泌减少,GIP分泌增加。提示两者在单纯性肥胖的病理生理机制中可能发挥着不同的作用。     

2型糖尿病患者葡萄糖耐量试验后胰高糖素样肽1水平变化

目的：探讨2型糖尿病(T2DM)患者葡萄糖耐量试验(OGTT,口服葡萄糖75 g)后胰高糖素样肽1(GLP-1)水平与血糖、胰岛β细胞功能、胰岛素抵抗的关系。方法 T2DM 患者35例及健康对照组30例均禁食12小时以上后行 OGTT,采集0(即空腹)、0.5、2小时血样,分别测定血浆葡萄糖、胰岛素、GLP-1浓度、糖化血红蛋白(HbA1 c)水平。结果 T2DM 患者的0、0.5、2小时血糖、空腹胰岛素及 HbA1 c 明显高于对照组(P <0.05),而T2DM 患者0.5小时胰岛素及2小时 GLP-1水平明显低于对照组(P <0.05),餐后2小时胰岛素水平及0、0.5小时GLP-1水平与对照组比较差异无统计学意义(P >0.05)。结论餐后 GLP-1水平的上升与进餐刺激有关;T2DM 患者口服葡萄糖后 GLP-1的分泌水平可能与血糖水平、胰岛功能、胰岛素抵抗相关。     

糖尿病患者胰高血糖素样肽-1在糖耐量试验前后的变化及意义

目的探讨2型糖尿病患者胰高血糖素样肽-1（glucagon-like peptical-1,GLP-1）水平与血糖、胰岛素及胰岛素抵抗的关系。方法 2型糖尿病患者50例（糖尿病组）及体检健康者30例（对照组）,2组均禁食10h后行糖耐量试验,采集空腹及餐后2h血标本,分别检测血浆葡萄糖、胰岛素、GLP-1水平。结果糖尿病组空腹及餐后2h血糖明显高于对照组（P〈0.05）,餐后2hGLP-1水平明显低于对照组（P〈0.05）,空腹和餐后2h胰岛素水平及空腹GLP-1水平与对照组比较差异无统计学意义（P〉0.05）。结论 2型糖尿病患者餐后2hGLP-1水平较正常人明显降低;餐后GLP-1分泌水平可反映2型糖尿病患者胰岛功能受损程度。     

干预高血糖人群生活方式对OGTT餐后1h血糖的影响分析

目的探讨对高血糖人群生活方式进行干预对口服葡萄糖耐量试验(OGTT)餐后1hPG水平的影响。方法选取收治的200例葡萄糖耐量减低(IGT)患者作为研究对象,按照随机数字表法分为观察组和对照组各100例,在均给予二甲双胍口服治疗的基础上观察组给予生活方式干预,干预6个月后比较两组患者的OGTT 1h PG及身体质量指数(BMI)。结果两组患者干预6个月后,OGTT 1h PG及BMI水平均有所改善,观察组OGTT 1h PG及BMI水平较对照组改善更为明显(P<0.05),具有统计学意义。其中观察组有42例患者转为正常糖耐量,对照组有18例患者转为正常糖耐量,两组患者IGT转阴率分别为42%和18%,具有显著差异(P<0.05)。结论对高血糖人群进行生活方式干预可以有效降低口服葡萄糖耐量试验(OGTT)餐后1h PG水平,改善葡萄糖负荷能力。     

空腹血糖受损与糖耐量受损者胰岛β细胞功能及胰岛素抵抗的比较

目的：比较空腹血糖受损与糖耐量受损者胰岛β细胞功能及胰岛素抵抗的不同。方法：选择正常糖耐量者40例，空腹血糖受损者32例，糖耐量受损者38例。测体重指数、血压、血脂、空腹及糖负荷后的血糖、血胰岛素。用稳态模式胰岛素抵抗指数HOMA—IR抵抗作为胰岛素抵抗指标，稳态模式HOMA—β作为基础胰岛素分泌指标，糖负荷30min净增胰岛素／净增葡萄糖作为早期胰岛素分泌指数。结果：空腹血糖受损组HOMA-IR较耐量受损组增高，差异有显著性（P〈0．05）。空腹血糖受损组HOMA—β较糖耐量受损组降低，差异有显著性（P〈0.05）。糖耐量受损组净增胰岛素／净增葡萄糖与空腹血糖受损组比较有下降，但差异无统计学意义。结论：空腹血糖受损人群较糖耐量受损人群有着更严重的胰岛素抵抗，空腹血糖受损人群基础状态下胰岛β细胞功能受损，而糖耐量受损人群的早期胰岛素分泌反应减弱。     

甲亢患者血清胰岛素的变化及其临床意义

[目的]探讨甲亢患者糖代谢紊乱的机理。[方法]用放射免疫分析(RIA)法对36例甲亢患者胰岛素的分泌情况进行了检测研究。[结果]36例甲亢病人中有44．4％的病人存在葡萄糖耐量减低(IGT)，这些病人空腹及餐后各时段的胰岛素水平明显高于正常人及葡萄糖耐量正常(NGT)的甲亢病人等时段的水平，其分泌的峰值大约在90-120min内出现。[结论]甲亢患者存在葡萄糖耐量减低。胰岛素分泌增加并延迟，是诱发糖代谢紊乱的主要因素。     

甲亢患者胰岛素、C-肽分泌水平及其临床价值

[目的]探讨甲亢患者糖代谢紊乱的机理。[方法]用放射免疫分析(RIA)法对36例甲亢患者的胰岛素和C-肽分泌情况进行了检测研究。[结果]36例甲亢病人中有44．4％的病人存在葡萄糖耐量减低(IGT)，这些病人餐后各时段的胰岛素及C-肽均明显高于正常人及葡萄糖耐量正常(NGT)的甲亢病人等时段水平，并且其C-肽分泌的峰值大约在90-120min内出现，恰与胰岛素峰值出现的时间相同。[结论]甲亢患者存在葡萄糖耐量减低，胰岛素和C-肽分泌延迟，是诱发糖尿病的主要因素。     

胃旁路术对非肥胖2型糖尿病大鼠降血糖作用机制的初步研究

目的研究胃旁路手术对非肥胖2型糖尿病大鼠降血糖作用及胰高血糖素样肽-1分泌的影响。方法将8周龄的GK大鼠72只随机分为手术组(O组)、假手术组(S组)、饮食控制组(F组)和对照组(C组),术前、术后1、24、、8W测空腹、餐后血糖和GLP-1。结果 O组术后第4、8周的空腹、餐后血糖明显低于本组术前、术后2周,差异具有统计学意义(P0.01);与相同时间点其他各组比较,差异具有统计学意义(P0.01)。O组术后第4、8周空腹、餐后GLP-1与本组术前、术后2W比较,差异具有统计学意义(P0.01);明显高于相同时间点其他各组,差异具有统计学意义(P0.01);O组空腹血糖与GLP-1相关系数(r)=-0.947(P0.05),葡萄糖灌胃后30min血糖与GLP-1相关系数(r)=-0.990(P0.01),血糖与GLP-1呈负相关,有统计学意义。结论胃旁路手术可以有效的控制非肥胖2型糖尿病大鼠的血糖,术后食物过快进入空肠下段,引起GLP-1分泌增加起重要作用。     

The Effect of Standard Versus Longer Intestinal Bypass on GLP-1 Regulation and Glucose Metabolism in Patients With Type 2 Diabetes Undergoing Roux-en-Y Gastric Bypass: The Long-Limb Study

OBJECTIVERoux-en-Y gastric bypass (RYGB) characteristically enhances postprandial levels of glucagon-like peptide 1 (GLP-1), a mechanism that contributes to its profound glucose-lowering effects. This enhancement is thought to be triggered by bypass of food to the distal small intestine with higher densities of neuroendocrine L-cells. We hypothesized that if this is the predominant mechanism behind the enhanced secretion of GLP-1, a longer intestinal bypass would potentiate the postprandial peak in GLP-1, translating into higher insulin secretion and, thus, additional improvements in glucose tolerance. To investigate this, we conducted a mechanistic study comparing two variants of RYGB that differ in the length of intestinal bypass.RESEARCH DESIGN AND METHODSA total of 53 patients with type 2 diabetes (T2D) and obesity were randomized to either standard limb RYGB (50-cm biliopancreatic limb) or long limb RYGB (150-cm biliopancreatic limb). They underwent measurements of GLP-1 and insulin secretion following a mixed meal and insulin sensitivity using euglycemic hyperinsulinemic clamps at baseline and 2 weeks and at 20% weight loss after surgery.RESULTSBoth groups exhibited enhancement in postprandial GLP-1 secretion and improvements in glycemia compared with baseline. There were no significant differences in postprandial peak concentrations of GLP-1, time to peak, insulin secretion, and insulin sensitivity.CONCLUSIONSThe findings of this study demonstrate that lengthening of the intestinal bypass in RYGB does not affect GLP-1 secretion. Thus, the characteristic enhancement of GLP-1 response after RYGB might not depend on delivery of nutrients to more distal intestinal segments.     

GLP-1 Action and Glucose Tolerance in Subjects With Remission of Type 2 Diabetes After Gastric Bypass Surgery

OBJECTIVE

Glucagon like peptide-1 (GLP-1) has been suggested as a major factor for the improved glucose tolerance ensuing after Roux-en-Y gastric bypass (RYGBP) surgery. We examined the effect of blocking endogenous GLP-1 action on glucose tolerance in subjects with sustained remission of type 2 diabetes mellitus (T2DM) present before RYGBP.

RESEARCH DESIGN AND METHODS

Blood glucose, insulin, C-peptide, glucagon, GLP-1, and glucose-dependent insulinotropic peptide levels were measured after a meal challenge with either exendin-(9–39) (a GLP-1r antagonist) or saline infusion in eight subjects with sustained remission of T2DM after RYGBP and seven healthy controls.

RESULTS

Infusion of exendin-(9–39) resulted in marginal deterioration of the 2-h plasma glucose after meal intake in RYGBP subjects [saline 78.4 ± 15.1 mg/dL compared with exendin-(9–39) 116.5 ± 22.3 mg/dL; P < 0.001]. Furthermore, glucose response to meal intake was similarly enlarged in the two study groups [percent change in the area under the curve of glucose exendin-(9–39) infusion versus saline infusion: controls 10.84 ± 8.8% versus RYGBP 9.94 ± 8.4%; P = 0.884]. In the RYGBP group, the blockade of the enlarged GLP-1 response to meal intake resulted in reduced insulin (P = 0.001) and C-peptide (P < 0.001), but no change in glucagon (P = 0.258) responses.

CONCLUSIONS

The limited deterioration of glucose tolerance on blockade of GLP-1 action in our study suggests the resolution of T2DM after RYGBP may be explained by mechanisms beyond enhancement of GLP-1 action.The beneficial effect of Roux-en-Y gastric bypass (RYGBP) surgery on glycemic control in morbidly obese subjects with type 2 diabetes mellitus (T2DM) is well established (1,2). However, the precise mechanisms mediating T2DM remission after RYGBP are not yet clear (3–5). Although it traditionally has been asserted that bariatric operations are associated with improvement of glucose tolerance merely by caloric restriction and weight loss, several lines of evidence support weight-independent mechanisms are involved (6–11). An enhanced postsurgical glucagon-like peptide-1 (GLP-1) secretion, inducing a normalized or exaggerated insulin secretion after meal intake, has been hypothesized to play a major role in the improved glucose tolerance after RYGBP (3). Association studies have demonstrated larger improvements of glucose tolerance early after RYGBP being associated with a larger GLP-1 response to nutrient intake as compared with other surgical or nonsurgical interventions resulting in equivalent weight loss (7–9). Likewise, an exaggerated GLP-1 response has been reported up to 10 years after RYGB in subjects with sustained T2DM remission, suggesting a key role of GLP-1 in maintaining normal glucose tolerance in the long term after this type of surgery (12). However, because association does not prove causation, these data do not definitely prove GLP-1 plays a critical role in T2DM remission after RYGBP.Understanding the role of endogenous GLP-1 in metabolic physiology has been greatly enhanced by the availability of a potent GLP-1 receptor antagonist, exendin-(9–39). Exendin-(9–39) blockade of GLP-1 action in healthy volunteers results in a significant enlargement of postprandial glucose excursions (13–17). Moreover, using hyperglycemic clamp technique in combination with a mixed meal test, Salehi et al. (18) demonstrated that blocking GLP-1 action results in a larger decrease in the insulin secretion rate in RYGBP-operated subjects (−33%) as compared with nonoperated controls (−16%). This study clearly supports GLP-1 as an important determinant of insulin secretion after RYGBP. However, the use of hyperglycemic clamp limited the ability of the study to investigate the relative importance of GLP-1 secretion on glucose tolerance. Furthermore, because only one-third of the study participants presented with T2DM before surgery, the study also was limited in establishing the role of GLP-1 secretion in the remission of T2DM. Of note, in Goto-Kakizaki rats (a nonobese rat model of T2DM) administration of exendin-(9–39) has been shown to totally reverse the improved glucose tolerance resulting from duodeno-jejunal exclusion surgery (an experimental metabolic surgery similar to RYGBP) (19).Against this background, the main aim of our study was to examine the effect of endogenous GLP-1 blockade by exendin-(9–39) on glucose tolerance in subjects who had undergone RYGBP and with T2DM antedating surgery that had remitted after the surgical procedure. As secondary aims, we evaluated the effect of exendin-(9–39) on the insulin, C-peptide, glucagon, GLP-1, and glucose-dependent insulinotropic peptide (GIP) responses to meal intake. We evaluated individuals during the long-term after surgery to avoid the potential confounding effect of intense caloric restriction or rapid weight loss or both on glucose tolerance.     

Acute Metabolic Effects of Exenatide in Patients With Type 1 Diabetes With and Without Residual Insulin to Oral and Intravenous Glucose Challenges

OBJECTIVE

Glucagon-like peptide 1 (GLP-1) is an incretin hormone that is released from the gastrointestinal tract. Treatment with GLP-1 analogs has proven to be of clinical use for patients with type 2 diabetes. Patients with type 1 diabetes, particularly those with residual β-cell function, may also respond to treatment, but the acute metabolic effects of GLP-1 analogs on these patients in reaction to both oral and intravenous glucose challenges are not well understood.

RESEARCH DESIGN AND METHODS

Seventeen patients with type 1 diabetes, half of whom had residual insulin production, underwent two mixed-meal tolerance tests (MMTTs) and two intravenous glucose tolerance tests (IVGTTs), with and without pretreatment with exenatide. No exogenous bolus insulin was administered for the studies. Glucose excursions, insulin secretion rates (ISRs), and levels of glucagon, endogenous GLP-1, and gastric inhibitory polypeptide were measured after the meal or glucose loads.

RESULTS

During the MMTT, glucose levels were suppressed with exenatide in patients with or without residual insulin production (P = 0.0003). Exenatide treatment did not change the absolute ISR, but the ISR to glucose levels were increased (P = 0.0078). Gastric emptying was delayed (P = 0.0017), and glucagon was suppressed (P = 0.0015). None of these hormonal or glucose changes were detected during the IVGTT with exenatide administration.

CONCLUSIONS

Exenatide showed a significant antidiabetogenic effect prior to an oral meal in patients with type 1 diabetes involving glucagon suppression and gastric emptying, while preserving increased insulin secretion. GLP-1 analogs may be useful as an adjunctive treatment in type 1 diabetes.     

Impaired incretin response after a mixed meal is associated with insulin resistance in nondiabetic men

OBJECTIVE: To investigate whether features of the insulin resistance syndrome are associated with altered incretin responses to food intake. RESEARCH DESIGN AND METHODS: From a population-based study, 35 men were recruited, representing a wide spectrum of insulin sensitivity and body weight. Each subject underwent a hyperinsulinemic-euglycemic clamp to determine insulin sensitivity. A mixed meal was given, and plasma levels of gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), as well as insulin, glucagon, and glucose were measured. RESULTS: Insulin resistance was associated with impaired GIP and GLP-1 responses to a mixed meal. The total area under the curve (AUC) of the GIP response after the mixed meal was associated with insulin sensitivity (r = 0.54, P < 0.01). There was a significant difference between the highest and the lowest tertile of insulin sensitivity (P < 0.05). GLP-1 levels 15 min after food intake were significantly lower in the most insulin-resistant tertile compared with the most insulin-sensitive tertile. During the first hour, the AUC of GLP-1 correlated significantly with insulin sensitivity (r = 0.47, P < 0.01). Multiple linear regression analysis showed that insulin resistance, but not obesity, was an independent predictor of these decreased incretin responses. CONCLUSIONS: In insulin resistance, the GIP and GLP-1 responses to a mixed meal are impaired and are related to the degree of insulin resistance. Decreased incretin responsiveness may be of importance for the development of impaired glucose tolerance.     

Pancreatic GLP-1 receptor activation is sufficient for incretin control of glucose metabolism in mice

Glucagon-like peptide-1 (GLP-1) circulates at low levels and acts as an incretin hormone, potentiating glucose-dependent insulin secretion from islet β cells. GLP-1 also modulates gastric emptying and engages neural circuits in the portal region and CNS that contribute to GLP-1 receptor-dependent (GLP-1R-dependent) regulation of glucose homeostasis. To elucidate the importance of pancreatic GLP-1R signaling for glucose homeostasis, we generated transgenic mice that expressed the human GLP-1R in islets and pancreatic ductal cells (Pdx1-hGLP1R:Glp1r-/- mice). Transgene expression restored GLP-1R-dependent stimulation of cAMP and Akt phosphorylation in isolated islets, conferred GLP-1R-dependent stimulation of β cell proliferation, and was sufficient for restoration of GLP-1-stimulated insulin secretion in perifused islets. Systemic GLP-1R activation with the GLP-1R agonist exendin-4 had no effect on food intake, hindbrain c-fos expression, or gastric emptying but improved glucose tolerance and stimulated insulin secretion in Pdx1-hGLP1R:Glp1r-/- mice. i.c.v. GLP-1R blockade with the antagonist exendin(9-39) impaired glucose tolerance in WT mice but had no effect in Pdx1-hGLP1R:Glp1r-/- mice. Nevertheless, transgenic expression of the pancreatic GLP-1R was sufficient to normalize both oral and i.p. glucose tolerance in Glp1r-/- mice. These findings illustrate that low levels of endogenous GLP-1 secreted from gut endocrine cells are capable of augmenting glucoregulatory activity via pancreatic GLP-1Rs independent of communication with neural pathways.     

Characterization of GLP-1 effects on beta-cell function after meal ingestion in humans

OBJECTIVE: Glucagon-like peptide 1 (GLP-1) is an incretin that augments insulin secretion after meal intake and is developed for treatment of type 2 diabetes. As a novel therapeutic agent, characteristics of its beta-cell effects are important to establish. Previously, beta-cell effects of GLP-1 have been characterized in humans during graded intravenous infusions of glucose, whereas its effects after more physiological stimuli, like meal intake, are not known. RESEARCH DESIGN AND METHODS: Eight women (aged 69 years, fasting glucose 3.7-10.3 mmol/l, BMI 22.4-43.9 kg/m(2)) who had fasted overnight were served a breakfast (450 kcal) with intravenous infusion of saline or synthetic GLP-1 (0.75 pmol x kg(-1) x min(-1)), and beta-cell function was evaluated by estimating the relationship between glucose concentration and insulin secretion (calculated by deconvolution of C-peptide data). RESULTS:-GLP-1 markedly augmented insulin secretion, despite lower glucose. Total insulin secretion was 29.7 +/- 4.2 nmol/m(2) with GLP-1 versus 21.0 +/- 1.6 nmol/m(2) with saline (P = 0.048). GLP-1 increased the dose-response relationship between glucose concentration and insulin secretion (70 +/- 26 with GLP-1 versus 38 +/- 16 pmol insulin. min(-1 x m(2). mmol(-1) glucose. l without, P = 0.037) and augmented the potentiation factor that modulates the dose response (2.71 +/- 0.42 with GLP-1 versus 0.97 +/- 0.17 without, P = 0.005). The potentiation factor correlated to GLP-1 concentration (r = 0.53, P < 0.001); a 10-fold increase in GLP-1 levels produced a twofold increase in the potentiation factor. These effects of GLP-1 did not correlate with fasting glucose levels or BMI. CONCLUSIONS: Administration of GLP-1 along with ingestion of a meal augments insulin secretion in humans by a dose-dependent potentiation of the dose-response relationship between plasma glucose and insulin secretion.     

Elimination of the action of glucagon-like peptide 1 causes an impairment of glucose tolerance after nutrient ingestion by healthy baboons.

Glucagon-like peptide 1 (GLP-1) is an insulinotropic hormone released after nutrient ingestion which is known to augment insulin secretion, inhibit glucagon release, and promote insulin-independent glucose disposition. To determine the overall effect of GLP-1 on glucose disposition after a meal we studied a group of healthy, conscious baboons before and after intragastric glucose administration during infusions of saline, and two treatments to eliminate the action of GLP-1: (a) exendin-[9-39] (Ex-9), a peptide receptor antagonist of GLP-1; or (b) an anti-GLP-1 mAb. Fasting concentrations of glucose were higher during infusion of Ex-9 than during saline (4.44 +/- 0.05 vs. 4.16 +/- 0.05 mM, P < 0.01), coincident with an elevation in the levels of circulating glucagon (96 +/- 10 vs. 59 +/- 3 ng/liter, P < 0.02). The postprandial glycemic excursions during administration of Ex-9 and mAb were greater than during the control studies (Ex-9 13.7 +/- 2.0 vs. saline 10.0 +/- 0.8 mM, P = 0.07; and mAb 13.6 +/- 1.2 vs. saline 10.6 +/- 0.9 mM, P = 0.044). The increments in insulin levels throughout the absorption of the glucose meal were not different for the experimental and control conditions, but the insulin response in the first 30 min after the glucose meal was diminished significantly during treatment with Ex-9 (Ex-9 761 +/- 139 vs. saline 1,089 +/- 166 pM, P = 0.044) and was delayed in three of the four animals given the neutralizing antibody (mAb 946 +/- 262 vs. saline 1,146 +/- 340 pM). Thus, elimination of the action of GLP-1 impaired the disposition of an intragastric glucose meal and this was at least partly attributable to diminished early insulin release. In addition to these postprandial effects, the concurrent elevation in fasting glucose and glucagon during GLP-1 antagonism suggests that GLP-1 may have a tonic inhibitory effect on glucagon output. These findings demonstrate the important role of GLP-1 in the assimilation of glucose absorbed from the gut.     

Glucose-dependency of the insulin stimulatory effect of glucagon-like peptide-1 (7–36) amide on the rat pancreas

The glucose-dependent action of GLP-1 (7–36) amide (GLP-1) on insulin secretion was studied in isolated islets and in the perfused rat pancreas. In islet experiments in the presence of non-stimulatory glucose levels (<3 mmol/1) a GLP-1 concentration of 10 nmol/1 increased insulin secretion by 83%. However, higher GLP-1 concentrations (25 and 100 nmol/l) could not further enhance this effect (85 and 83%, respectively). The onset of the stimulatory action of a supramaximal GLP-1-load (25 nmol/l) was at a glucose level of 3 mmol/l. In the perfused pancreas, 25 nmol/l GLP-1 induced a strong insulin release at 5 mmol/l glucose, but under basal glucose (2.8 mmol/l) only a slight enhancement of insulin secretion occurred during the late phase (30 to 54 min) of perfusion (P<0.05). In conclusion, a slight but not dose-dependent stimulation of insulin secretion by supramaximal GLP-1 loads under basal glucose levels was found. The necessary GLP-1 concentrations to achieve this in vitro effect are beyond physiological or postprandial levels.     

Gastric emptying and release of incretin hormones after glucose ingestion in humans.

This study investigated in eight healthy male volunteers (a) the gastric emptying pattern of 50 and 100 grams of glucose; (b) its relation to the phase of interdigestive motility (phase I or II) existing when glucose was ingested; and (c) the interplay between gastric emptying or duodenal perfusion of glucose (1.1 and 2.2 kcal/min; identical total glucose loads as orally given) and release of glucose-dependent insulinotropic peptide (GIP), glucagon-like peptide-1(7-36)amide (GLP-1), C-peptide, insulin, and plasma glucose. The phase of interdigestive motility existing at the time of glucose ingestion did not affect gastric emptying or any metabolic parameter. Gastric emptying of glucose displayed a power exponential pattern with a short initial lag period. Duodenal delivery of glucose was not constant but exponentially declined over time. Increasing the glucose load reduced the rate of gastric emptying by 27.5% (P < 0.05) but increased the fractional duodenal delivery of glucose. Both glucose loads induced a fed motor pattern which was terminated by an antral phase III when approximately 95% of the meal had emptied. Plasma GLP-1 rose from basal levels of approximately 1 pmol/liter of peaks of 3.2 +/- 0.6 pmol/liter with 50 grams of glucose and of 7.2 +/- 1.6 pmol/liter with 100 grams of glucose. These peaks occurred 20 min after glucose intake irrespective of the load. A duodenal delivery of glucose exceeding 1.4 kcal/min was required to maintain GLP-1 release in contrast to ongoing GIP release with negligibly low emptying of glucose. Oral administration of glucose yielded higher GLP-1 and insulin releases but an equal GIP release compared with the isocaloric duodenal perfusion. We conclude that (a) gastric emptying of glucose displays a power exponential pattern with duodenal delivery exponentially declining over time and (b) a threshold rate of gastric emptying of glucose must be exceeded to release GLP-1, whereas GIP release is not controlled by gastric emptying.