白藜芦醇对原代大鼠胰岛葡萄糖刺激的胰岛素分泌的影响

分离SD大鼠胰岛接种于24孔板中,用不同浓度的葡萄糖和白藜芦醇分别培养1 h或24 h,结果表明白藜芦醇孵育大鼠胰岛1 h可呈剂苗依赖地抑制大鼠高糖刺激的胰岛素分泌,1、10和100 μmol/L白藜芦醇可以分别使胰岛素的分泌降低10%、35%(P<0.05)和80%(P<0.01).显微离子成像技术爪10μmol/L的白藜芦醇可以使高糖引起的β细胞内Ca2+浓度的升高减少60%(P<0.05).白藜芦醇可使软脂酸孵育24 h大鼠胰岛的胰岛素分泌恢复到对照组的75%(P<0.01),提示白藜芦醇短期可通过调控细胞内的Ca+浓度,而抑制原代胰岛高精刺激的胰岛素分泌,长期可改善软脂酸引起的β细胞损伤.     

Ca2+调控的胰岛素分泌

胰岛β细胞内胰岛素分泌颗粒胞裂外排,从而分泌胰岛素。该过程是由胰岛素分泌颗粒局部Ca^2＋浓度的迅速升高而触发的。胰岛β细胞内Ca^2＋浓度的迅速升高主要源于经质膜上钙通道的Ca^2＋内流和胞内钙库Ca^2＋释放。细胞外钙内流主要通过电压依赖型钙通道,而胞内Ca^2＋释放可能来自三磷酸肌醇敏感钙库、尼克酰胺腺嘌呤二核苷酸磷酸（NAADP）敏感钙库、ryanodine敏感钙库及线粒体钙库等。不同情况下的胰岛素分泌或胰岛素分泌的不同阶段可能由不同来源的Ca^2＋触发或增强,两者相互协调,在胰岛素分泌中起重要作用。因此,对β细胞内钙信号的产生及调控途径的深入研究有利于进一步阐明糖尿病的发病机制,并为糖尿病的治疗提供新思路。     

白藜芦醇对原代大鼠胰岛葡萄糖刺激的胰岛素分泌的影响

Isolated freshly rat islets were transferred to 24-well plates and incubated with different concentrations of glucose or resveratrol for 1 or 24 h.The results showed that resveratrol dose-dependently inhibited glucose-stimulated insulin secretion from isolated rat islets after 1 h incubation,with 10%,35%,and 80% (P<0.05 or P<0.01) decrease at the concentrations of 1,I0,and 100 μmol/L.10 μmol/L resveratrol decreased the intracellular calcium concentration by 60% (P<0.05).After incubation for 24 h,resveratrol increased palmitatesuppressed insulin secretion to 75% (P<0.01) of control.These results suggest that resveratrol acutely inhibits insulin secretion from primary pancreatic islet via regulating intracellular calcium ion concentration,and in the long run resveratrol may protect β-cells from lipotoxicity.     

白藜芦醇对原代大鼠胰岛葡萄糖刺激的胰岛素分泌的影响

Isolated freshly rat islets were transferred to 24-well plates and incubated with different concentrations of glucose or resveratrol for 1 or 24 h.The results showed that resveratrol dose-dependently inhibited glucose-stimulated insulin secretion from isolated rat islets after 1 h incubation,with 10%,35%,and 80% (P<0.05 or P<0.01) decrease at the concentrations of 1,I0,and 100 μmol/L.10 μmol/L resveratrol decreased the intracellular calcium concentration by 60% (P<0.05).After incubation for 24 h,resveratrol increased palmitatesuppressed insulin secretion to 75% (P<0.01) of control.These results suggest that resveratrol acutely inhibits insulin secretion from primary pancreatic islet via regulating intracellular calcium ion concentration,and in the long run resveratrol may protect β-cells from lipotoxicity.     

胰岛素分泌的细胞调控机理

本文简介胰岛素分泌的细胞调控机理的主要进展。     

胰岛素脉冲样分泌的机制及临床意义

胰岛素的分泌呈脉冲样模式,其中包括慢速脉冲和快速脉冲两种模式,本文就它们的特点、机制、临床意义作一综述。     

非磺脲类促胰岛素分泌剂对糖尿病患者心血管事件影响

<正>2型糖尿病(T2DM)的发生机制主要涉及胰岛素分泌缺陷和(或)胰岛素抵抗(IR),主要的治疗手段为提高体内胰岛素的水平和增加组织对胰岛素的敏感性,其他的治疗手段还包括延缓和减少碳水化合物的吸收等。胰岛素分泌缺陷在T2DM的发生发展过程中起着关键作用,早期表现为早时相胰岛素分泌减少或缺失。随着T2DM病程的增加,胰岛β细胞衰竭,胰岛素和胰岛素原分泌水平减少。推荐使用促胰岛素分泌剂(简     

胰岛β细胞胰岛素分泌的反馈调节

胰岛β细胞分泌的胰岛素可反馈调节其自身的分泌。胰岛素通过存在于β细胞的胰岛素受体信号转导系统直接作用于β细胞,抑制其内质网上的Ca2 -ATP酶活性,使胞浆内钙离子浓度升高,激活蛋白激酶C,诱导胰岛素分泌,对β细胞分泌起正反馈调节;还可通过旁分泌作用于β细胞周围的δ细胞及α细胞,对其自身分泌进行负反馈调节。同时,胰岛素反馈调节途径还受白细胞介素 -1β、肿瘤坏死因子-α、儿茶酚胺以及瘦素等多种因素影响。     

The mechanism of insulin secretion after oral glucose administration

Summary Previous experiments have shown that in an oral glucose tolerance test insulin is mobilized in the first phase independent of the following hyperglycemia. By giving different amounts of glucose (0.5–2.0 g/kg) in conscious trained dogs it was shown that this early phase of insulin secretion was stimulated independently of the administered glucose load by additional mechanisms. These mechanisms, at least partly, were triggered in the nerve endings of the cavity of mouth: their paralysis by mucosal anaesthesia abolished the early IRI-increase in intact animals as well as after feeding glucose to dogs bearing oesophagus fistulas. Spraying sodium cyclamate into the mouth did not produce any IRI-increase. The results indicate that the taste modality sweet is not involved in this reflex response. Conditioned reflexes as a consequence of the training programme or of the daily feeding regime were excluded by control experiments.The authors are grateful to Mrs. Karla Brüllke, Mrs. Helga Schröder, Miss Gisela Schmidt and Miss Helga Schüler for careful technical assistance.     

The mechanism of insulin secretion after oral glucose administration

Summary Concentrations of immunoreactive insulin activity and of blood glucose were measured in portal and peripheral venous blood in six conscious dogs after oral administration of 1.0 g/kg glucose. Portal venous samples were obtained either by chronic catheterization or by direct puncture of the portal vein through a London-cannula. Portal venous IRI was already significantly increased 5 min after the onset of the stimulus. Peripheral venous IRI pattern reflected this early increase, but the peripheral venous blood glucose level was unchanged. The results indicate that the early peripheral venous IRI increase reflects a pancreatic insulin secretory reflex.Investigations supported by the research project Diabetes mellitus and diseases of lipid metabolism of the Ministry of Health of the GDR     

Effectiveness of nateglinide on in vitro insulin secretion from rat pancreatic islets desensitized to sulfonylureas

Chronic exposure of pancreatic islets to sulfonylureas (SUs) is known to impair the ability of islets to respond to subsequent acute stimulation by SUs or glucose. Nateglinide (NAT) is a novel insulinotropic agent with a primarily site of action at beta-cell K(ATP) channels, which is common to the structurally diverse drugs like repaglinide (REP) and the SUs. Earlier studies on the kinetics, glucose-dependence and sensitivity to metabolic inhibitors of the interaction between NAT and K(ATP) channels suggested a distinct signaling pathways with NAT compared to REP, glyburide (GLY) or glimepiride (GLI). To obtain further evidence for this concept, the present study compared the insulin secretion in vitro from rat islets stimulated acutely by NAT, GLY, GLI or REP at equipotent concentrations during 1-hr static incubation following overnight treatment with GLY or tolbutamide (TOL). The islets fully retained the responsiveness to NAT stimulation after prolonged pretreatment with both SUs, while their acute response to REP, GLY, and GLI was markedly attenuated, confirming the desensitization of islets. The insulinotropic efficacy of NAT in islets desensitized to SUs may result from a distinct receptor/effector mechanism, which contributes to the unique pharmacological profile of NAT.     

Studies on the mechanism of xylitol-induced insulin secretion in dogs

Summary The effect of infusion of small doses of xylitol into the pancreatic artery upon insulin release was studied in anaesthetized dogs, in order to decide whether the strong insulin-releasing effect of xylitol in dogs is mediated by a direct action of xylitol upon the islets or indirectly by some of its metabolites. Xylitol or glucose was infused at 0.5–1.0 mg/kg · min either into the femoral vein or into the superior pancreaticoduodenal artery, and the changes in plasma insulin were measured in the superior pancreaticoduodenal vein. Infusion into the pancreatic artery always resulted in a sharp increase in insulin release, whereas intravenous infusion caused no or little increase. Infusion of xylitol into the superior pancreaticoduodenal artery produced a prompt increase in plasma insulin in the superior pancreaticoduodenal vein but not in the splenic vein. These data suggest that xylitol has a direct stimulatory effect upon islet cells. — During intravenous infusion of epinephrine (1.0 g/kg. min), plasma insulin did not increase despite intravenous administration of glucose or xylitol (0.4 g/kg). There was a rebound rise of plasma insulin after cessation of epinephrine infusion. Plasma insulin responses to intravenous injection of glucose or xylitol (0.4 g/kg) were inhibited also by the intravenous infusion of diazoxide (0.2 mg/kg · min), but this was somewhat variable among individual dogs. The suppression by epinephrine or diazoxide of both glucose and xylitol-induced hyperinsulinaemia may suggest that there is some common mechanism between the insulin-releasing effects of glucose and xylitol.

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Untersuchungen zum Mechanismus der verstärkten Insulinsekretion unter Xylit

Zusammenfassung An anaesthesierten Hunden wurde die Wirkung der Infusion kleiner Xylit-Mengen in die Pankreasarterie auf die Insulinfreisetzung untersucht, um zu klären, ob das Xylit direkt oder über einen seiner Metabolite auf die Insulinausschüttung wirkt. Xylit oder Glucose wurde in Mengen von 0.5–1.0 mg/kg/min entweder in die Femoralvene oder in die A.pankreaticoduodenalis sup. infundiert und die Änderung des PlasmaInsulins in der V.pankreatico-duodenalis sup. gemessen. Zufuhr über die Pankreasarterie löste immer eine abrupte Steigerung der Insulinfreisetzung aus, während intravenöse Gaben zu keinem oder nur einem geringen Anstieg führten. Die Xylit-Infusion in die A.pankreaticoduodenalis sup.bewirkte zwar eine prompte Steigerung der Plasma-Insulinspiegel in der V.pankreatico duodenalis sup., nicht aber in der Milzvene. — Diese Befunde sprechen dafür, daß Xylit die Inselzellen direkt stimuliert. Während einer i.v.Infusion von 1.0 g/kg/min Adrenalin stieg das Plasma-Insulin trotz intravenöser Zufuhr von 0.4 g/kg Glucose oder Xylit nicht an. Nach Beendigung der Adrenalin-Infusion wurde ein verstärkter Wiederanstieg des Plasma-Insulins beobachtet. Auch durch i.v.Gaben von 0.2 mg/kg/min Diazoxid ließ sich die Wirkung der Infusion von 0.4 g/kg Glucose oder Xylit unterdrükken, wobei sich jedoch Unterschiede zwischen den einzelnen Tieren ergaben. Die Aufhebung des Xylit- u. Glucose-Effektes auf die Insulinsekretion durch Adrenalin und Diazoxid könnte darauf hinweisen, daß die Steigerung der Insulinfreisetzung durch Glucose und Xylit auf einem gemeinsamen Mechanismus beruht.

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Etudes sur le mécanisme de la sécrétion d'insuline provoquée par le xylitol chez des chiens

Résumé L'effet sur la sécrétion d'insuline de l'infusion de petites doses de xylitol dans l'artère pancréatique a été étudié chez des chiens anesthésiés, afin de savoir si l'effet fortement insulino-sécréteur du xylitol chez les chiens est dû à une action directe du xylitol sur les îlots ou à une action indirecte par l'intermédiaire de certains de ses métabolites. Le xylitol ou le glucose était infusé la dose de 0.5–1.0 mg/kg. min, soit dans la veine fémorale, soit dans l'artère pancréatico-duodénale supérieure, et les variations de l'insuline plasmatique étaient mesurées dans la veine pancréatico-duodénale supérieure. L'infusion dans l'artère pancréatique provoquait toujours une rapide augmentation de la sécrétion d'insuline, tandis que l'infusion intraveineuse ne causait pas ou peu d'augmentation. L'infusion de xylitol dans l'artère pancréaticoduodénale supérieure provoquait une augmentation prompte de l'insuline plasmatique dans la veine pancréatico-duodénale supérieure, mais pas dans la veine splénique. Ces données suggèrent que le xylitol a un effet stimulateur direct sur les cellules des îlots. — Pendant l'infusion intraveineuse d'adrénaline (1.0 g/kg. min), l'insuline plasmatique n'augmentait pas malgré l'administration intraveineuse de glucose ou de xylitol (0.4 g/kg). Après l'arrêt de l'infusion d'adrénaline, l'insuline plasmatique présentait un phénomène de rebound. Les réponses de l'insuline plasmatique l'injection intraveineuse de glucose ou de xylitol (0.4 g/kg) étaient également inhibées par l'infusion intraveineuse de diazoxide (0.2 mg/ kg. min), mais ceci était un peu variable selon les chiens. La suppression par l'adrénaline ou le diazoxide de l'hyperinsulinémie provoquée par le glucose et le xylitol peut suggérer qu'il existe un mécanisme commun entre les effets insulino-sécréteurs du glucose et du xylitol.

     

The addition of glipizide to insulin therapy in type-II diabetic patients with secondary failure to sulfonylureas is useful only in the presence of a significant residual insulin secretion

The present study aimed at 1) investigating the effect of a combined insulin + glipizide treatment on the metabolic control (HbA1c levels) and insulin requirements (Biostator assessment) in ten non-obese Type-II diabetic patients with recent secondary failure to sulfonylureas; and 2) characterizing the relative contributions of changes in endogenous insulin secretion (C-peptide response) and insulin sensitivity (insulin-induced glucose disposal in clamped conditions) to this effect. The patients were treated in a randomized cross-over order with either insulin alone or insulin + glipizide (3 X 10 mg/day) during two periods averaging 6 weeks each. Mean HbA1c levels were similar in both experimental conditions (8.2 +/- 0.6 vs 7.9 +/- 0.6%, NS). In fact, during the combined therapy, HbA1c levels decreased in five subjects (from 8.6 +/- 0.7 to 7.1 +/- 0.5%; 'responder'), but not in the five others ('non-responders'); the 20-h Biostator insulin infusion was significantly decreased in the responders (29%; P less than 0.05), but not in the non-responders. Basal (0.271 +/- 0.086 vs 0.086 +/- 0.017 nmol/l; P less than 0.05) and post-glucagon (0.468 +/- 0.121 vs 0.180 +/- 0.060 nmol/l; P less than 0.05) C-peptide plasma levels were significantly higher in the responders than in the non-responders; in addition, glipizide significantly increased basal C-peptide concentrations in the responders only (+68%; P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Insulin versus insulin plus sulfonylureas in type 2 diabetic patients with secondary failure to sulfonylureas

According to the modern pathophysiological understanding of type 2 diabetes and the mechanisms of sulfonylurea action, combined insulin-sulfonylurea therapy appears to be an interesting alternative for treating diabetic patients with secondary failure to sulfonylureas. From its revival in the early 1980s, combination therapy has been shown to have a positive effect on blood glucose control although initially published clinical studies, generally open and uncontrolled, have been widely criticized. Several recent well-designed studies confirmed these favorable results, with better glucose profiles and/or decreased insulin needs, which were shown to persist after 1 year or more. Most of the studies investigating the mechanism of action indicate that the effect is mainly due to stimulation of the residual insulin secretion with minimal or no effect on insulin sensitivity. The risk of hypoglycemic episodes is rather small when insulin doses are adapted at the beginning of the combined therapy. Effects on lipid metabolism are minimal and controversial. Thus, insulin-sulfonylurea treatment may be a safe and effective solution in type 2 diabetic patients with secondary failure to sulfonylureas, particularly in those with significant residual endogenous insulin secretion. The additional cost of such combined therapy should be weighed against the potential advantages of better metabolic control.