曲格列酮对胰岛β细胞胰岛素分泌的影响及机制研究

研究曲格列酮对胰岛β细胞(MIN6细胞株)胰岛素分泌的影响,并探讨其机制.10μmol/L曲格列酮短期抑制大鼠胰岛和MIN6细胞的葡萄糖刺激的胰岛素分泌(GSIS,P<0.01),增加AMP活化的蛋白激酶(AMPK)、乙酰辅酶A羧化酶(ACC)的磷酸化水平(均P<0.01),而AMPK抑制剂复合物C可使其AMPK、ACC的磷酸化水平以及胰岛素分泌完全恢复.     

辛伐他汀抑制大鼠胰岛β细胞胰岛素分泌的机制研究

目的 观察辛伐他汀对大鼠胰岛β细胞葡萄糖刺激的胰岛素分泌(GSIS)的抑制作用及其机制.方法 8周龄健康雄性Wistar大鼠60只,体重250～300 g,饲养1周内分批处死.采用胆管注射胶原酶法提取大鼠胰岛,将新鲜分离或经24 h培养的大鼠胰岛按体积大小分为对照组(胰岛数=60)和辛伐他汀组(胰岛数=60),对照组给予Kreb-Ringer碳酸氢盐缓冲液,辛伐他汀组以100μmol/L辛伐他汀水浴30 min或过夜培养24 h.两组经2.8、5.5、11.1、16.7、25.0 mmol/L葡萄糖刺激后,采用37 ℃水浴法观测胰岛β细胞GSIS变化,选用生物化学发光法测定腺苷三磷酸(ATP)含量.两组间数据比较采用t检验.结果 100 μmol/L辛伐他汀水浴30 min后,在25.0 mmol/L葡萄糖刺激下,胰岛β细胞ATP含量较相应对照组明显下降[(9.2±1.6)vs(12.1±1.9)pmol/胰岛,t=2.97,P＜0.05],GSIS较相应对照组明显减少(2.31±0.38 vs 3.19±0.41,t=3.154,P＜0.05).100μmol/L辛伐他汀过夜培养24 h后,在11.1 mmol/L葡萄糖刺激下,胰岛β细胞ATP含量较相应对照组明显降低[(9.2±1.4)vs(11.9±2.0)pmol/胰岛,t=2.514,P＜0.05];在2.8 mmol/L葡萄糖刺激下,胰岛素分泌即已明显受到抑制(0.28±0.03 vs 0.47±0.05,t=2.460,P＜0.05).辛伐他汀浓度超过30 μmol/L时,可剂量依赖性地抑制GSIS(2.49±0.21 vs 3.17±0.23,t=2.445,P＜0.05).结论 高浓度辛伐他汀可能通过抑制胰岛β细胞ATP生成而抑制GSIS.     

游离脂肪酸对大鼠胰岛β细胞胰岛素分泌及磺脲受体1基因表达的影响

目的 研究游离脂肪酸（FFA）对体外培养的大鼠胰岛β细胞胰岛素分泌及磺脲受体1（SUR1）基因表达的影响和机制。方法 分离纯化胰岛细胞后分别与0．25mmol／L软脂酸（PA）和0．125mmol／L油酸（OA）温育48小时，放免法检测胰岛素，RT—PCR检测SUR1基因表达。结果 与对照组比较，PA使基础胰岛素分泌增加110％（P〈0．01），葡萄糖刺激的胰岛素分泌（GSIS）降低43％（P〈0．01）；OA使基础胰岛素分泌增加80％（P〈0．01），GSIS降低32％（P〈0．05）。RT—PCR示OA显著抑制了SUR1基因的mRNA表达，比对照组降低64％（P〈0．01），而PA组的表达较对照组降低15％（P〉0．05）。结论 FFA抑制GSIS可能与其对胰岛β细胞SUR1基因表达的调节有关。     

高游离脂肪酸血症通过氧化应激导致胰岛β细胞功能受损

目的 研究高游离脂肪酸(FFA)血症对胰岛β细胞功能的影响.方法 正常雄性SD大鼠随机分为3组:对照组输注生理盐水,FFA组输注脂肪乳,氮乙酰半胱氨酸(NAC)干预组在输注脂肪乳的同时加用NAC.持续输液2～4天,行静脉葡萄糖耐最试验(IVGTY)和胰腺组织表面灌注试验评价在体及离体情况下胰岛β细胞胰岛素分泌功能.结果 胰腺组织表面灌注结果显示,FFA组脂肪乳输注2天,基础状态下的胰岛素分泌较对照组增加[(55.5±19.4 vs 27.4±6.7)mIU/L,P<0.01],而葡萄糖刺激的胰岛素分泌(GSIS)与对照组并无差别;延长脂肪乳输注到4天,高FFA刺激基础胰岛素分泌的作用消失,且GSIS明显抑制[(46.8±33.0 vs 214.7±27.4)mIU/L,P<0.05].IVG3T结果亦显示脂肪乳输注4天后胰岛素分泌功能受到抑制.但在脂肪乳输注的同时加用抗氧化剂NAC可使β细胞GSIS峰值部分恢复[(165.4±14.8)mIU/L,P<0.01].结论 循环中FFA水平增高可能通过激活氧化应激导致胰岛β细胞功能受损.     

长期高浓度葡萄糖对胰岛细胞凋亡和功能相关基因表达的影响

目的　探明长期高浓度葡萄糖对体外胰岛细胞功能和凋亡相关基因表达的影响。方法应用放免法检测不同浓度葡萄糖培养后大鼠胰岛细胞和小鼠 βTc3细胞在葡萄糖刺激时培育上清液和细胞内的胰岛素水平 ;应用半定量多重RT PCR和Northern印迹法检测培养后IDX 1(Isletduodenalhomeobox 1) ,葡萄糖激酶 (GK ) ,葡萄糖转运子 2 (GLUT2 ) ,C/EBPβ和Bcl xmRNA的表达情况 ;应用TUNEL法检测培养后的细胞凋亡百分率。结果　 ( 1)长期高浓度葡萄糖培养导致大鼠胰岛细胞和小鼠βTc3细胞对葡萄糖刺激的胰岛素分泌反应降低和细胞内胰岛素含量的减少 ;( 2 )高糖培养 14天可以使大鼠胰岛细胞IDX 1和GLUT2mRNA表达明显减少 (P <0 .0 5 ) ,C/EBPβmRNA表达明显增加 ,GKmRNA表达无明显变化 ;( 3 )高糖培养可以明显增加大鼠胰岛细胞和小鼠 βTc3细胞凋亡百分率 ;( 4 )大鼠胰岛细胞高糖培养 14天后Bcl xSmRNA水平明显增加 ,Bcl xLmRNA水平无明显变化 ,Bcl xL/Bcl xSmRNA比率明显减少 (P <0 .0 5 )。结论　 ( 1)长期高糖培养可以诱导大鼠胰岛细胞和小鼠 βTc3细胞凋亡和功能缺陷 ;( 2 )IDX 1表达的变化在大鼠胰岛细胞功能缺陷中起重要作用 ;( 3 )大鼠胰岛细胞的Bcl xL/Bcl xS比率变化在高糖所致的胰岛细胞凋亡中起重要作用。     

大脑葡萄糖感受器对于胰岛葡萄糖刺激的胰岛素分泌起显著调节作用

当患者从健康状态到罹患T2DM时,葡萄糖刺激的胰岛素分泌(GSIS)明显受损。尽管GISS主要是由胰岛β细胞对于血糖升高的直接感受所驱动,但有越来越多的证据表明,下丘脑神经元控制着外周葡萄糖代谢的其他方面。本文作者对大脑在GSIS的调节作用进行了研究。为了考察下丘脑葡萄糖感应增强或减弱对于葡萄糖耐量和胰岛素分泌     

游离脂肪酸诱导的胰岛βTC3细胞缺陷与线粒体功能改变的相关性研究

目的通过研究游离脂肪酸(FFA)慢性作用对胰岛细胞解偶联蛋白2(UCP2)mRNA和蛋白表达以及线粒体膜电位的影响,探讨FFA损害胰岛功能的机制。方法将不同浓度油酸作用于胰岛βTC3细胞72h,分别分析基础和葡萄糖刺激的胰岛素分泌量(GSIS),线粒体膜电位,ATP敏感钾电流(IKATP)、UCP2mRNA和蛋白表达;再用油酸和PPARγ配体罗格列酮共同作用,观察UCP2mRNA和蛋白的表达。结果与对照组相比,油酸明显增加2·8mmol/L葡萄糖时的基础胰岛素分泌量,减少16·7mmol/L葡萄糖时的GSIS(P均<0·01),并且呈剂量依赖性。油酸可明显降低线粒体膜电位平均荧光强度(MIF)值,使IKATP外流增加,增加UCP2mRNA和蛋白表达(P均<0·01),呈剂量依赖性;与油酸组相比,油酸 罗格列酮组增加了UCP2mRNA和蛋白表达(P<0·01)。结论在胰岛βTC3细胞中,FFA对胰岛功能的损害与线粒体功能改变有关。FFA可能通过上调PPARγ增加UCP2表达,UCP2的表达与作用增加可导致线粒体膜电位降低,使线粒体功能下降,引起胰岛素分泌减少,产生对胰岛功能的损害作用。     

瘦素对离体大鼠胰岛分泌胰岛素的双向影响

目的 了解不同浓度的瘦素，在不同条件下对离体大鼠胰岛分泌胰岛素的影响。方法 利用细胞培养技术，在不同的葡萄糖浓度（5.6mmol/L或16.7mmol/L）和不同作用时间（10min或2h)下，以0,1,5,10,15,50ak 100μg/L瘦素作用大鼠胰岛，观察其对胰岛素分泌的影响；用放免法检测培养物上清液胰岛素浓度。结果 培养液葡萄糖浓度为5.6mmol/L，培养10min，1μg/L、5μg/L瘦素促进被孵育的胰岛的胰岛素分泌；培养2h,5μg/L瘦素促进基础胰岛素分泌，≥50μg/L瘦素抑制胰岛素分泌。葡萄糖浓度为16.7mmol/L，培养10min，≥50μg/L瘦素抑制胰岛素分泌；培养2h，≥5μg/L瘦素抑制胰岛素分泌。结论 重组瘦素对离体大鼠胰岛分泌胰岛素具有双向作用，并受瘦素浓度、作用时间和环境葡萄糖浓度等因素变化的影响。     

应用INGAP多肽体外分步诱导胰岛新生研究

目的 应用INGAP多肽在体外建立新的分步诱导分化体系诱导胰岛新生. 方法 分离纯化SD大鼠的胰腺导管干细胞.并体外扩增培养,取2～6代细胞进行分步诱导分化,于分化末期添加INGAP多肽,待诱导结束后收获新生类胰岛样细胞团(ILCs)分别行免疫荧光和RT-PCR检测,并通过葡萄糖刺激的胰岛素释放试验(GSIS)评价ILCs的胰岛素分泌能力. 结果 (1)分离纯化的胰腺导管干细胞经过四步诱导后最终可形成立体结构的ILCs,其insulin和glucagon染色均为阳性,RT-PCR检测该ILCs也有insulin和glucagon基因的表达.(2)GSIS结果:新生ILCs和新分离胰岛的高糖组胰岛素释放量均显著高于低糖组(P＜0.01);新生ILCs的胰岛素刺激指数接近新分离胰岛(P＞0.01). 结论 通过建立新的包含INGAP多肽的体外分步诱导分化体系,能够获得具有立体结构和一定胰岛素分泌能力的立体ILCs,为获取胰岛移植所需的β细胞提供了更有效的方法.     

棕榈酸对胰岛的脂毒性及非诺贝特的保护作用

目的　探讨棕榈酸对胰岛功能的影响和非诺贝特对棕榈酸所致胰岛脂毒性的保护作用及机制。方法　分离大鼠胰岛,分6组:对照组、棕榈酸0. 2mmol/L组(PA0. 2)和0. 4mmol/L(PA0. 4)组,非诺贝特组(FF, 5×10-6 mol/L)及PA0. 2 FF组、PA0. 4 FF组。培养24h分别测定基础胰岛素(BIS)和葡萄糖刺激的胰岛素分泌(GSIS);RT PCR或实时PCR测定胰岛素(INS)、胰腺十二指肠同源异型盒因子1 (PDX 1)、葡萄糖转运蛋白2(GLUT2)和PPARαmRNA表达。结果　(1)与对照组比较PA0. 2组和PA0. 4组BIS增加,GSIS升高倍数减少,且PA0. 4组变化幅度更明显;FF组BIS、GSIS与对照组比较差异无统计学意义;PA0. 2 FF组比PA0. 2组BIS减少31%,GSIS增加29%;PA0. 4 FF组比PA0. 4组BIS减少56%,GSIS增加121%;PA0. 2 FF组与PA0. 4 FF组GSIS增加幅度低于对照组(均P<0. 05 )。( 2 )与对照组比较,PA0. 2组和PA0. 4组PDX 1、INS和GLUT2的表达降低(P<0. 05),但PPARα表达不受影响。(3)与PA0. 2组和PA0. 4组比较,PA0. 2 FF组、PA0. 4 FF组的INS、GLUT2、PDX 1、PPARαmRNA表达增加(P<0. 05 )。结论　棕榈酸抑制胰岛GLUT2、INS、PDX 1mRNA表达,抑制胰岛素转录合成。非诺贝特增加PPARαmRNA表达,与棕榈酸共存时增强GLUT2、INS、PDX 1mRNA表达,显著改善棕榈酸对     

Effect of prolactin versus growth hormone on islet function and the importance of using homologous mammosomatotropic hormones

The purpose of this study was to determine the effects of homologous rat PRL (rPRL) and rat GH (rGH) on islet B-cell function in neonatal and adult rat islets in vitro. In neonatal rat islets, exposure to rPRL for more than 24 h was necessary for a stimulatory effect on insulin secretion. By day 4, insulin secretion was 3.8-fold greater in the islets cultured with rPRL. rGH had a modest effect on insulin secretion, and this effect was additive with that of rPRL. Both rPRL and rGH increased islet insulin content and [3H]thymidine incorporation. After removal of rPRL, more than 24 h were necessary to detect a reversal in the level of insulin secretion. In addition, even after 5 days without rPRL the previously treated islets still had elevated levels of insulin secretion. In a dose-response study of rPRL on insulin secretion, a detectable effect was observed at 62.5 ng/ml, with a half-maximal effect of approximately 100 ng/ml. Glucose oxidation by neonatal islets was enhanced by rPRL treatment, but not by rGH treatment. In adult rat islets, exposure to rPRL, but not to rGH, enhanced insulin secretion. In contrast, when using heterologous human GH, results similar to those obtained with rPRL, but not rGH, were observed. The results from these experiments indicate that rPRL and rGH have both individual and shared regulatory effects on rat islets. However, it is rPRL and not rGH that has the primary influence on insulin secretion. When interpreting studies examining the effect of GH and PRL on islet function, it is important to consider whether homologous hormones are used.     

Upregulation of β-cell genes and improved function in rodent islets following chronic glucokinase activation

Glucokinase (GK) plays a critical role in controlling blood glucose; GK activators have been shown to stimulate insulin secretion acutely both in vitro and in vivo. Sustained stimulation of insulin secretion could potentially lead to β-cell exhaustion; this study examines the effect of chronic GK activation on β-cells. Gene expression and insulin secretion were measured in rodent islets treated in vitro with GKA71 for 72 h. Key β-cell gene expression was measured in rat, mouse and global GK heterozygous knockout mouse islets (gk(del/wt)). Insulin secretion, after chronic exposure to GKA71, was measured in perifused rat islets. GKA71 acutely increased insulin secretion in rat islets in a glucose-dependent manner. Chronic culture of mouse islets with GKA71 in 5 mmol/l glucose significantly increased the expression of insulin, IAPP, GLUT2, PDX1 and PC1 and decreased the expression of C/EBPβ compared with 5 mmol/l glucose alone. Similar increases were shown for insulin, GLUT2, IAPP and PC1 in chronically treated rat islets. Insulin mRNA was also increased in GKA71-treated gk(del/wt) islets. No changes in GK mRNA were observed. Glucose-stimulated insulin secretion was improved in perifused rat islets following chronic treatment with GKA71. This was associated with a greater insulin content and GK protein level. Chronic treatment of rodent islets with GKA71 showed an upregulation of key β-cell genes including insulin and an increase in insulin content and GK protein compared with glucose alone.     

Acute effects of fatty acids on insulin secretion from rat and human islets of Langerhans

Fatty acids have both stimulatory and inhibitory effects on insulin secretion. Long-term exposure to fatty acids results in impaired insulin secretion whilst acute exposure has generally been found to enhance insulin release. However, there are conflicting data in the literature as to the relative efficacy of various fatty acids and on the glucose dependency of the stimulatory effect. Moreover, there is little information on the responses of human islets in vitro to fatty acids. We have therefore studied the acute effects of a range of fatty acids on insulin secretion from rat and human islets of Langerhans at different glucose concentrations. Fatty acids (0.5 mM) acutely stimulated insulin release from rat islets of Langerhans in static incubations in a glucose-dependent manner. The greatest effect was seen at high glucose concentration (16.7 mM) and little or no response was elicited at 3.3 or 8.7 mM glucose. Long-chain fatty acids (palmitate and stearate) were more effective than medium-chain (octanoate). Saturated fatty acids (palmitate, stearate) were more effective than unsaturated (palmitoleate, linoleate, elaidate). Stimulation of insulin secretion by fatty acids was also studied in perifused rat islets. No effects were observed at 3.3 mM glucose but fatty acids markedly potentiated the effect of 16.7 mM glucose. The combination of fatty acid plus glucose was less effective when islets had been first challenged with glucose alone. The insulin secretory responses to fatty acids of human islets in static incubations were similar to those of rat islets. In order to examine whether the responses to glucose and to fatty acids could be varied independently we used an animal model in which lactating rats are fed a low-protein diet during early lactation. Islets from rats whose mothers had been malnourished during lactation were still able to respond effectively to fatty acids despite a lowered secretory response to glucose. These data emphasise the complex interrelationships between nutrients in the control of insulin release and support the view that fatty acids play an important role in glucose homeostasis during undernutrition.     

Cellular mechanisms of insulin release: the effects of vitamin D deficiency and repletion on rat insulin secretion

To determine whether impaired insulin release from perifused rat islets of vitamin D-deficient (D-def) rats is a result of vitamin D-deficiency specifically or an associated decrease in food intake, we: 1) compared insulin release from islets of vitamin D-def rats with insulin release from islets of pair fed (pf) normal rats, and 2) measured the effects of 1,25(OH)2D3 treatment on food intake and insulin secretion from islets of D-def rats. Both vitamin D-def and pf normal rat islets showed significantly diminished insulin release in comparison with normal controls but were not different from each other. When D-def rats were repleted with 1,25(OH)2D3, food intake increased and insulin secretion improved during perifusion of rat islets. When D-def rats treated with 1,25(OH)2D3 were prevented from increasing their food intake in response to 1,25(OH)2D3 by pair feeding to a group of untreated D-def rats, insulin release from islets of treated rats was not significantly different from untreated D-def rats. To separate the effects of vitamin D deficiency from hypocalcemia, a group of vitamin D-def hypocalcemic rats was compared with a group of D-def normocalcemic rats. Normocalcemia did not reverse the defect in insulin release. In studies of cellular calcium uptake, both pf and D-def rat islets took up less calcium than normal islets but calcium uptake was not different between pf and D-def rat islets. Our studies suggest that vitamin D deficiency is associated with marked impairment of biphasic insulin release and that the decrease in food intake may account for this impairment at least in part.     

Effects of galanin on insulin and glucagon secretion in the rat

Galanin-like immunoreactivity has been visualized in nerve fibers in the islets of Langerhans, suggesting an involvement of galanin in the neural regulation of islet function. In this study, we investigated the effects of galanin on basal and stimulated insulin and glucagon secretion by infusing the peptide at three different dose rates in rats. We also studied the direct effect of galanin on insulin secretion from freshly isolated rat islets. At 320 pmol/kg/min, but not at 20 or 80 pmol/kg/min, galanin lowered basal plasma insulin levels. In contrast, basal plasma glucagon levels were lowered by galanin already at 20 and 80 pmol/kg/min. Furthermore, galanin inhibited both glucose- and arginine-induced insulin release at all three dose levels, whereas arginine-induced glucagon release was not affected by galanin. Glucose-stimulated insulin secretion from isolated rat islets was dose-dependently suppressed by galanin (10(-6)-10(-8) M). Therefore, it is concluded that galanin in rats inhibits insulin secretion, both in vivo and in vitro, and that at lower dose levels, the peptide also inhibits basal glucagon release.     

Arachidonic acid-induced insulin secretion from rat islets of Langerhans.

There is growing evidence that arachidonic acid (AA) and/or its metabolites may be involved in the control of insulin secretion. We have now investigated the effect of AA on insulin secretion from rat islets, and the possible involvement of protein kinase C (PKC) in this process. Exogenous AA stimulated insulin secretion from intact islets at a substimulatory concentration of glucose (2 mM), but did not further enhance glucose-induced (20mM) insulin secretion. AA-induced insulin secretion was temperature dependent. The secretory responses seen at 37 degrees C were totally abolished by reducing the incubation temperature to less than or equal to 34 degrees C. AA-induced insulin secretion was not dependent upon extracellular Ca2+ and was potentiated by omission of Ca2+ or bovine serum albumin from the media. PKC in rat islets can thus be stimulated by AA, but the stimulation of PKC is not required for AA-induced insulin secretion.     

The possible mechanisms by which phanoside stimulates insulin secretion from rat islets

We recently showed that phanoside, a gypenoside isolated from the plant Gynostemma pentaphyllum, stimulates insulin secretion from rat pancreatic islets. To study the mechanisms by which phanoside stimulates insulin secretion. Isolated pancreatic islets of normal Wistar (W) rats and spontaneously diabetic Goto-Kakizaki (GK) rats were batch incubated or perifused. At both 3 x 3 and 16 x 7 mM glucose, phanoside stimulated insulin secretion several fold in both W and diabetic GK rat islets. In perifusion of W islets, phanoside (75 and 150 microM) dose dependently increased insulin secretion that returned to basal levels when phanoside was omitted. When W rat islets were incubated at 3 x 3 mM glucose with 150 muM phanoside and 0 x 25 mM diazoxide to keep K-ATP channels open, insulin secretion was similar to that in islets incubated in 150 microM phanoside alone. At 16 x 7 mM glucose, phanoside-stimulated insulin secretion was reduced in the presence of 0 x 25 mM diazoxide (P<0 x 01). In W islets depolarized by 50 mM KCl and with diazoxide, phanoside stimulated insulin release twofold at 3 x 3 mM glucose but did not further increase the release at 16 x 7 mM glucose. When using nimodipine to block L-type Ca2+ channels in B-cells, phanoside-induced insulin secretion was unaffected at 3 x 3 mM glucose but decreased at 16 x 7 mM glucose (P<0 x 01). Pretreatment of islets with pertussis toxin to inhibit exocytotic Ge-protein did not affect insulin response to 150 microM phanoside. Phanoside stimulated insulin secretion from Wand GK rat islets. This effect seems to be exerted distal to K-ATP channels and L-type Ca2+ channels, which is on the exocytotic machinery of the B-cells.     

Increased insulin binding to pancreatic islets of aged rats

In rat pancreatic islets, the effect of old age (24-month-old) on [125I]insulin binding, glucose-induced insulin release and inhibition of insulin secretion by exogenous insulin were studied. The results were compared with corresponding data obtained from young (3-month-old) rats. Specifically bound [125I]insulin in islets of old rats was increased by 40% (P less than 0.02) compared to that in young rats. Scatchard plots of displacement studies indicated an increase in receptor number rather than receptor affinity. The insulin-releasing capacity of 16.7 mM glucose did not differ between islets of old and young rats when medium insulin was bound to added antiinsulin serum. In the presence of 16.7 mM glucose (without the addition of antiinsulin serum), insulin secretion was less in islets of old rats compared to that in young rats (283 +/- 38 vs. 528 +/- 29 microU/ml; P less than 0.001). Exogenous insulin inhibited glucose (16.7 mM)-induced insulin release more in islets of old rats than in those of young rats. In conclusion, the present in vitro results may be interpreted to reflect increased insulin binding to islets of aged rats and, consequently, increased inhibition of glucose-mediated insulin secretion due to increased feedback of insulin.     

Evidence for a direct inhibitory effect of PYY on insulin secretion in rats.

Peptide YY (PYY) has been shown to inhibit stimulated insulin secretion under in vivo conditions in the mouse, the rat, and the dog. In the present study, we investigated the effects of PYY on insulin secretion from the isolated perfused rat pancreas and isolated rat islets. In isolated pancreas perfused in presence of 8.3 mM glucose, PYY at 10(-10) and 10(-9) M, but not at 10(-8) M, inhibited insulin secretion. In the presence of 5.5 mM glucose, PYY (10(-9) M) did not modify basal insulin release but reduced the biphasic insulin response to arginine (10 mM). PYY also markedly reduced the pancreatic vascular flow rate; this effect was observed at all three concentrations tested in a dose-dependent manner. In isolated islets, glucose (15 mM)-stimulated insulin secretion was inhibited by PYY at 10(-7) M. We conclude that in the perfused rat pancreas, PYY inhibits insulin secretion and induces vasoconstriction without a causal relationship. In addition, our results on isolated islets suggest that the inhibitory action of PYY on insulin secretion is exerted through a direct islet action.