Hypersecretion of Truncated Glucagon-like Peptide-1 and Gastric Inhibitory Polypeptide in Obese Patients

Postprandial insulin secretion is modulated by both neural and humoral gastrointestinal insulinotropic factors in addition to the absorbed nutrient. To investigate the involvement of the potent insulinotropic hormones gastric inhibitory polypeptide (GIP) and truncated glucagon-like peptide-1 (tGLP-1) in the postprandial hyperinsulinaemia of obesity, we examined the changes in plasma levels of GIP and tGLP-1 by an oral glucose tolerance test (OGTT) in nine normal subjects (controls), nine obese subjects without glucose intolerance (Group A), and six obese mild diabetic patients (Group B). Following the OGTT, plasma GIP levels in Group B were increased more markedly than those in the other two groups. Plasma levels of tGLP-1 were estimated by the difference between the values measured with the N-terminal directed antiserum (GLP-1NT) and those with the C-terminal directed antiserum (GLP-1 CT). Plasma levels of GLP-1 NT were increased in Group B, but decreased in the other two groups. Plasma GLP-1 CT levels were increased in all groups with the highest response in Group B. These results suggest that the combined augmentation of plasma GIP and tGLP-1 responses were involved in the delayed and considerable increases in plasma insulin after glucose ingestion in obese diabetic patients. Since tGLP-1 is suppressed in the hyperglycaemic hyperinsulinaemic state in normal subjects, the augmented tGLP-1 response appears to be characteristic of obese Type 2 diabetes.     

Plasma gastric inhibitory polypeptide and glucagon‐like peptide‐1 levels after glucose loading are associated with different factors in Japanese subjects

Aims/Introduction: Gastric inhibitory polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) are major incretins that potentiate insulin secretion from pancreatic β‐cells. The factors responsible for incretin secretion have been reported in Caucasian subjects, but have not been thoroughly evaluated in Japanese subjects. We evaluated the factors associated with incretin secretion during oral glucose tolerance test (OGTT) in Japanese subjects with normal glucose tolerance (NGT). Materials and Methods: We measured plasma GIP and GLP‐1 levels during OGTT in 17 Japanese NGT subjects and evaluated the factors associated with GIP and GLP‐1 secretion using simple and multiple regression analyses. Results: GIP secretion (AUC‐GIP) was positively associated with body mass index (P < 0.05), and area under the curve (AUC) of C‐peptide (P < 0.05) and glucagon (P < 0.01), whereas GLP‐1 secretion (AUC‐GLP‐1) was negatively associated with AUC of plasma glucose (P < 0.05). The insulinogenic index was most strongly associated with GIP secretion (P < 0.05); homeostasis model assessment β‐cell was the most the strongly associated factor in GLP‐1 secretion (P < 0.05) among the four indices of insulin secretion and insulin sensitivity. Conclusions: Several distinct factors might be associated with GIP and GLP‐1 secretion during OGTT in Japanese subjects. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00078.x, 2011)     

Four weeks of near-normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes

Objective  The incretin effect is attenuated in patients with type 2 diabetes mellitus, partly as a result of impaired beta cell responsiveness to glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The aim of the present study was to investigate whether 4 weeks of near-normalisation of the blood glucose level could improve insulin responses to GIP and GLP-1 in patients with type 2 diabetes. Methods  Eight obese patients with type 2 diabetes with poor glycaemic control (HbA_1c 8.6 ± 1.3%), were investigated before and after 4 weeks of near-normalisation of blood glucose (mean blood glucose 7.4 ± 1.2 mmol/l) using insulin treatment. Before and after insulin treatment the participants underwent three hyperglycaemic clamps (15 mmol/l) with infusion of GLP-1, GIP or saline. Insulin responses were evaluated as the incremental area under the plasma C-peptide curve. Results  Before and after near-normalisation of blood glucose, the C-peptide responses did not differ during the early phase of insulin secretion (0–10 min). The late phase C-peptide response (10–120 min) increased during GIP infusion from 33.0 ± 8.5 to 103.9 ± 24.2 (nmol/l) × (110 min)⁻¹ (p < 0.05) and during GLP-1 infusion from 48.7 ± 11.8 to 126.6 ± 32.5 (nmol/l) × (110 min)⁻¹ (p < 0.05), whereas during saline infusion the late-phase response did not differ before vs after near-normalisation of blood glucose (40.2 ± 11.2 vs 46.5 ± 12.7 [nmol/l] × [110 min]⁻¹). Conclusions  Near-normalisation of blood glucose for 4 weeks improves beta cell responsiveness to both GLP-1 and GIP by a factor of three to four. No effect was found on beta cell responsiveness to glucose alone. ClinicalTrials.gov ID no.: NCT 00612950 Funding: This study was supported by The Novo Nordisk Foundation, The Medical Science Research Foundation for Copenhagen.     

Secretion of incretin hormones and the insulinotropic effect of gastric inhibitory polypeptide in women with a history of gestational diabetes

Aims/hypothesis The insulinotropic effect of gastric inhibitory polypeptide (GIP) is reduced in patients with type 2 diabetes and around 50% of their first-degree relatives under hyperglycaemic conditions. It is unknown whether this is a result of a specific defect in GIP action or of a general reduction in beta cell function. Moreover, impaired secretion of glucagon-like peptide 1 (GLP-1) has been described in patients with type 2 diabetes. Therefore, we studied the insulinotropic effect of GIP in women with previous gestational diabetes (pGDM) under euglycaemic fasting conditions and during a hyperglycaemic clamp experiment. The secretion of GIP and GLP-1 was assessed following oral glucose ingestion.Materials and methods On separate occasions we performed an OGTT and administered an i.v. bolus of 20 pmol GIP/kg body weight in 20 women with pGDM and 20 control women. An additional hyperglycaemic clamp experiment (140 mg/dl [7.8 mmol/l] over 120 min) with i.v. infusion of GIP (2 pmol kg^–1 min^–1; 30–90 min) was performed in 14 women in each group. Capillary and venous blood samples were drawn for the measurement of glucose (glucose oxidase), insulin, C-peptide, GIP and GLP-1 (specific immunoassays). Indices of insulin sensitivity and beta cell function were calculated. Statistical analyses were carried out using repeated measures ANOVA.Results Following oral glucose ingestion, plasma glucose, insulin and C-peptide concentrations increased to higher levels in the women with pGDM than in the control women (p<0.05). The women with pGDM were characterised by a higher degree of insulin resistance than the control women (p=0.007 for the Matsuda index), but showed no overt defects in glucose-stimulated insulin secretion (p=0.40 for the insulinogenic index following i.v. glucose). The secretion of GLP-1 and GIP was not different between the groups (p=0.87 and p=0.57, respectively). The insulin secretory response to GIP administration was similar in the two groups both after GIP bolus administration and during the hyperglycaemic clamp experiment (p=0.99 and p=0.88, respectively). A hyperbola-like relationship was found between the degree of insulin sensitivity (Matsuda index) and the insulin secretory response to GIP and i.v. glucose administration.Conclusions/interpretation These results do not support the hypothesis of an early defect in GIP action as a risk factor for subsequent development of diabetes in women with previous gestational diabetes. The inverse relationship between insulin resistance and the insulin secretory response to glucose or GIP suggests that beta cell secretory function in response to different stimuli increases adaptively when insulin sensitivity is diminished.     

Harnessing the weight-regulating properties of glucagon-like peptide-1 in the treatment of type 2 diabetes

Obesity is associated with increased insulin resistance and is a well-recognized factor for the development of type 2 diabetes. Unfortunately, most diabetes therapies are associated with further weight gain, a most unwelcome characteristic, given the association of weight gain with deteriorating metabolic control, worsening cardiovascular profiles and decreased adherence to treatment. Therapies that effectively control glycaemia without weight gain or with concomitant weight loss are needed. The aim of this article was to review the existing preclinical and clinical evidences, showing that the family of glucagon-like peptide-1 (GLP-1)–based therapies fulfils these criteria by harnessing the beneficial properties of GLP-1, a naturally occurring incretin hormone with a strong blood glucose–lowering action and the ability to induce weight loss.     

Insulin sensitivity, insulin release and glucagon-like peptide-1 levels in persons with impaired fasting glucose and/or impaired glucose tolerance in the EUGENE2 study

Aims/hypothesis We examined the phenotype of individuals with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) with regard to insulin release and insulin resistance. Methods Non-diabetic offspring (n = 874; mean age 40 ± 10.4 years; BMI 26.6 ± 4.9 kg/m²) of type 2 diabetic patients from five different European Centres (Denmark, Finland, Germany, Italy and Sweden) were examined with regard to insulin sensitivity (euglycaemic clamps), insulin release (IVGTT) and glucose tolerance (OGTT). The levels of glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) were measured during the OGTT in 278 individuals. Results Normal glucose tolerance was found in 634 participants, while 110 had isolated IFG, 86 had isolated IGT and 44 had both IFG and IGT, i.e. about 28% had a form of reduced glucose tolerance. Participants with isolated IFG had lower glucose-corrected first-phase (0–10 min) and higher second-phase insulin release (10–60 min) during the IVGTT, while insulin sensitivity was reduced in all groups with abnormal glucose tolerance. Similarly, GLP-1 but not GIP levels were reduced in individuals with abnormal glucose tolerance. Conclusions/interpretation The primary mechanism leading to hyperglycaemia in participants with isolated IFG is likely to be impaired basal and first-phase insulin secretion, whereas in isolated IGT the primary mechanism leading to postglucose load hyperglycaemia is insulin resistance. Reduced GLP-1 levels were seen in all groups with abnormal glucose tolerance and were unrelated to the insulin release pattern during an IVGTT.     

Impact of glucagon-like peptide-1 on endothelial function

Cardiovascular (CV) disease is the major cause of mortality and morbidity in individuals with diabetes. Individuals with diabetes often have a variety of factors such as hyperglycaemia, dyslipidaemia, hypertension, insulin resistance and obesity, which increase their risks of endothelial dysfunction and CV disease. The incretin hormones, such as glucagon-like peptide-1 (GLP-1), induce the glucose-dependent secretion of insulin, improve beta-cell function and induce slowing of gastric emptying and feelings of satiety – which result in reduced food intake and weight loss. Therapeutic treatments targeting the incretin system, such as GLP-1 receptor agonists, offer the potential to address beta-cell dysfunction (one the underlying pathogenic mechanisms of type 2 diabetes), as well as the resulting hyperglycaemia. Initial evidence now suggests that incretins could have beneficial effects on endothelial function and the CV system through both indirect effects on the reduction of hyperglycaemia and direct effects mediated through GLP-1 receptor–dependent and –independent mechanisms. If these initial findings are confirmed in larger clinical trials, GLP-1 receptor antagonists could help to address the major CV risks faced by patients with diabetes.     

从肠促胰素分泌机制看胰升糖素样肽1在2型糖尿病治疗中的应用

近年来在2型糖尿病发病机制及治疗领域研究中,肠促胰素是一大突破.本文以肠促胰素分泌生理机制、病理变化到临床应用为线索,简要介绍了营养物质(葡萄糖、脂肪和蛋白质)触发肠促胰素分泌机制、2型糖尿病患者肠促胰素分泌障碍以及一种重要的肠促胰素--胰升糖素样肽1在2型糖尿病治疗中的应用.

Abstract：

Recently, in the field of pathogenesis and treatment of type 2 diabetes, incretin is a major breakthrough. Based on the knowledge about physiological mechanism, pathological characters, and clinical application, this review article summarized the mechanism of nutrients ( glucose, fat, and protein) mediated incretin secretion, the impairment of incretin secretion and action in type 2 diabetes and glucagon-like peptide-1 's use in type 2 diabetic patients.     

Emptying of the gastric substitute,glucagon-like peptide-1 (GLP-1), and reactive hypoglycemia after total gastrectomy

Postprandial glucagon-like peptide-1 (GLP-1), pancreatic glucagon, and insulin were measured in 27 tumor-free patients 43 months (median) after total gastrectomy and in four controls using a⁹⁹technetium-labeled 100-g carbohydrate solid test meal. Emptying of the gastric substitute was measured by scintigraphy. Fourteen patients suffered from early dumping symptoms, and five of them also reported symptoms suggestive of reactive hypoglycemia (late dumping). The median emptying half-time (T1/2) of the gastric substitute was 480 sec. Sigstad's dumping score was 8.5±1.6 (mean±se) in patients with rapid emptying (T1/2<480 sec), and 3.0±1.5 in patients with slow emptying of the gastric substitute (P=0.02). The peak postprandial concentration of GLP-1 was 44±20 pmol/liter in controls, 172±50 in patients without reactive hypoglycemia, and 502±116 in patients whose glucose fell below 3.8 mmol/liter during the second postprandial hour. Plasma GLP-1 concentrations peaked at 15 min, and insulin concentrations at 30 min after the end of the meal. A close correlation between integrated GLP-1 responses and integrated insulin responses (r=0.68) was observed. Multiple regression revealed that three factors were significantly associated with the integrated glucose concentrations during the second hour (60–120 min): Early (first 30 min) integrated GLP-1 (inverse correlation;P=0.006), age (P=0.006), and early integrated pancreatic glucagon (P=0.005). There was a close (inverse) relationship ofT1/2 with early integrated GLP-1 and pancreatic glucagon, but not with insulin. Gel filtration of pooled postprandial plasma of gastrectomized individuals revealed that all glucagon-like immunoreactivity eluted atK _d 0.30 (K _d , coefficient of distribution), the elution position of glicentin. Almost all of the GLP-1 like immunoreactivity eluted atK _d 0.60, the elution position of gut GLP-1. The authors contend that GLP-1-induced insulin release and inhibition of pancreatic glucagon both contribute to the reactive hypoglycemia encountered in some patients following gastric surgery. Rapid emptying seems to be one causative factor for the exaggerated GLP-1 release in these subjects.     

Novel glucagon-like peptide-1 analog delivered orally reduces postprandial glucose excursions in porcine and canine models

Background

Glucagon-like peptide-1 (GLP-1) and its analogs are associated with a gamut of physiological processes, including induction of insulin release, support of normoglycemia, β-cell function preservation, improved lipid profiles, and increased insulin sensitivity. Thus, GLP-1 harbors significant therapeutic potential for regulating type 2 diabetes mellitus, where its physiological impact is markedly impaired. To date, GLP-1 analogs are only available as injectable dosage forms, and its oral delivery is expected to provide physiological portal/peripheral concentration ratios while fostering patient compliance and adherence.

Methods

Healthy, fasting, enterically cannulated pigs and beagle canines were administered a single dose of the exenatide-based ORMD-0901 formulation 30 min before oral glucose challenges. Blood samples were collected every 15 min for evaluation of ORMD-0901 safety and efficacy in regulating postchallenge glucose excursions.

Results

Enterically delivered ORMD-0901 was well tolerated by all animals. ORMD-0901 formulations RG3 and AG2 led to reduced glucose excursions in pigs when delivered prior to a 5 g/kg glucose challenge, where area under the curve (AUC)_0–120 values were up to 43% lower than in control sessions. All canines challenged with a glucose load with no prior exposure to exenatide, demonstrated higher AUC_0–150 values than in their exenatide-treated sessions. Subcutaneous exenatide delivery amounted to a 51% reduction in mean glucose AUC_0–150, while formulations AG4 and AG3 prompted 43% and 29% reductions, respectively.

Conclusions

When delivered enterically, GLP-1 (ORMD-0901) is absorbed from the canine and porcine gastrointestinal tracts and retains its biological activity. Further development of this drug class in an oral dosage form is expected to enhance diabetes control and patient compliance.     

胰高血糖素样肽-1及其类似物的降糖机制

Glucagon-like peptide-1 (GLP-1) is an insulin secretagogue that secreted by intestinal L-cells. After binding with its receptor, GLP-1 stimulates glucose-dependent insulin secretion, β-cell prolifera-tion and differentiation as well as inhibits its apeptosis, decelerates gastric emptying, improves insulin sensi-tivity of periphery tissue. The long-acting GLP-1 analogues decrease hyperglycemia safely without weight gain and hypoglycemia and protect the function of pancreatic islet beta-cell. Using GLP-1 analogues at early stages of the disease,impaired beta-cell function and possibly beta-cell mass appear to be reversible. These agents axe, therefore, considered new therapeutic agents for the treatment of patients with type 2 diabetes.     

胰高血糖素样肽-1及其类似物的降糖机制

Glucagon-like peptide-1 (GLP-1) is an insulin secretagogue that secreted by intestinal L-cells. After binding with its receptor, GLP-1 stimulates glucose-dependent insulin secretion, β-cell prolifera-tion and differentiation as well as inhibits its apeptosis, decelerates gastric emptying, improves insulin sensi-tivity of periphery tissue. The long-acting GLP-1 analogues decrease hyperglycemia safely without weight gain and hypoglycemia and protect the function of pancreatic islet beta-cell. Using GLP-1 analogues at early stages of the disease,impaired beta-cell function and possibly beta-cell mass appear to be reversible. These agents axe, therefore, considered new therapeutic agents for the treatment of patients with type 2 diabetes.     

胰高血糖素样肽-1及其类似物的降糖机制

破骨细胞生成抑制因子 (OCIF) /骨保护素 (osteoprotegerin ,OPG)是一种新发现的以可溶性蛋白质形式存在的破骨细胞负性调节因子 ,属于肿瘤坏死因子受体超家族成员 ,其配基ODF/OPGL被证明是破骨细胞分化因子 ,OCIF/OPG可与其配基结合阻断其配基的信号下传而抑制破骨细胞生成、活化 ,其它骨吸收调节因子可能部分或全部通过调节OCIF/OPG生成而发挥作用。该因子的发现 ,为探讨骨质疏松的发病机制及其预防和治疗提出了新方向。     

胰高血糖素样肽-1及其类似物的降糖机制

Glucagon-like peptide-1 (GLP-1) is an insulin secretagogue that secreted by intestinal L-cells. After binding with its receptor, GLP-1 stimulates glucose-dependent insulin secretion, β-cell prolifera-tion and differentiation as well as inhibits its apeptosis, decelerates gastric emptying, improves insulin sensi-tivity of periphery tissue. The long-acting GLP-1 analogues decrease hyperglycemia safely without weight gain and hypoglycemia and protect the function of pancreatic islet beta-cell. Using GLP-1 analogues at early stages of the disease,impaired beta-cell function and possibly beta-cell mass appear to be reversible. These agents axe, therefore, considered new therapeutic agents for the treatment of patients with type 2 diabetes.     

胰高血糖素样肽-1及其类似物的降糖机制

Glucagon-like peptide-1 (GLP-1) is an insulin secretagogue that secreted by intestinal L-cells. After binding with its receptor, GLP-1 stimulates glucose-dependent insulin secretion, β-cell prolifera-tion and differentiation as well as inhibits its apeptosis, decelerates gastric emptying, improves insulin sensi-tivity of periphery tissue. The long-acting GLP-1 analogues decrease hyperglycemia safely without weight gain and hypoglycemia and protect the function of pancreatic islet beta-cell. Using GLP-1 analogues at early stages of the disease,impaired beta-cell function and possibly beta-cell mass appear to be reversible. These agents axe, therefore, considered new therapeutic agents for the treatment of patients with type 2 diabetes.     

要重视钙离子拮抗剂在代谢紊乱中的应用

长效钙拮抗剂(CCB)广泛用于治疗心绞痛、高血压、心律失常等疾病。近年来大型临床试验的结果为CCB在代谢紊乱患者中的应用提供了更充分的证据。高血压常合并脂代谢紊乱、糖代谢紊乱、胰岛素抵抗及高尿酸血症等多重代谢异常,然而CCB具有血管舒张、改善内皮功能、抗动脉粥样硬化、减少尿蛋白等作用。对这些代谢紊乱患者应用CCB会带来益处还是会增加风险?一直在不同领域(心血管及内分泌代谢研究领域)存在着疑虑。本文将着重探讨CCB在代谢紊乱中的应用。     

胰高血糖素样肽-1及其类似物的降糖机制

胰岛素为一具多种生物学效应的激素 ,在生理上保持营养物质代谢平衡 ,维持内环境恒定 ,调控细胞生长、增殖 ,保证正常的生长发育 ;在病理生理上 ,胰岛素分泌量过多或过少 ,对靶组织的敏感性加强或减弱都会造成病态 ,尤其是胰岛素抵抗及伴发的代谢综合征和 2型糖尿病已形成流行态势 ,严重危害中、老年人健康。胰岛素于 2 0世纪二十年代初问世 ,其生理作用的研究广泛而深入 ,但其确切的作用机制 ,在细胞、分子水平的生化过程多年不明。 5 0年后 ,1971年通过同位素标记的胰岛素与肝细胞膜制备物结合特性的研究 ,确定了胰岛素受体 (ＩＲ)的存在 …