过氧化物酶增殖激活受体δ腺病毒对胰岛β细胞脂代谢的影响

过氧化物酶增殖激活受体δ(.Deroxisome proliferate activated receptor delta,PPARδ)是过氧化物酶增殖激活受体的亚型之一,其发现较晚,但是其分布相当广泛,如胰岛β细胞、心肌、骨骼肌、脂肪组织、皮肤、脑组织等均有较高表达.目前研究表明,在心肌、骨骼肌、脂肪组织中,PPARδ能增强脂肪酸的氧化和利用,减少脂质在这些组织中的沉积,从而明显改善机体的脂代谢.     

游离脂肪酸在糖尿病中临床意义及研究进展

游离脂肪酸是反映脂质代谢、糖代谢、内分泌机能等的非常灵敏的指标。通过检测血浆中脂肪酸水平，可研究糖尿病与脂质及脂肪酸的关系。β细胞的功能障碍和凋亡是2型糖尿病发生的重要因素，脂代谢紊乱促进β细胞凋亡在糖尿病发生中的作用日益引起关注。探讨脂代谢和胰岛素抵抗的关系对临床诊断及治疗糖尿病及降低心血管疾病的危险因素有指导意义。现就游离脂肪酸增多与胰岛素抵抗和胰岛β细胞功能障碍的关系进行讨论。     

胰岛β细胞自噬及其在糖尿病发病机制中作用研究进展

糖尿病的发生与胰岛素分泌异常密切相关,以胰岛素抵抗与胰岛β细胞功能紊乱为特点。自噬是溶酶体对细胞组分的分解代谢过程,在维持胰岛β细胞结构功能及内环境稳定上起重要作用,可改善炎症、氧化应激等对胰岛β细胞的损伤,延缓糖尿病的病程。本文就胰岛β细胞自噬及自噬在糖尿病代谢和发病机制中作用的研究进展作一综述。     

格列美脲与诺和龙治疗初发2型糖尿病的疗效比较

格列美脲是新一代的长效磺脲类降糖药物,它在胰岛β细胞表面上的作用受体与传统的磺脲类不同;而诺和龙为苯甲酸衍生物,属非磺脲类的促泌剂,它在胰岛β细胞膜上的结合位点与传统的磺脲类药物也完全不同,二者均属于快速促胰岛素分泌剂,为了比较二者的疗效及观察在初发的2型糖尿病中的作用,我们做了临床观察,现报道如下.……     

棕榈酸羟基硬脂酸抗代谢性炎症综合征作用机制的研究进展

老年代谢性炎症综合征(MIS)患病率高,患者体内普遍存在糖脂代谢紊乱和胰岛素抵抗,而新型化合物——羟基脂肪酸支链脂肪酸酯(FAHFAs)具有增强胰岛素敏感性和抗炎作用,其中棕榈酸羟基硬脂酸(PAHSA)是含量最高的一种同分异构体。体内PAHSA水平的改变主要受碳水化合物反应元件结合蛋白(CHREBP)的调节,并通过G蛋白偶联受体120(GPR120)发挥生物学效应。本文主要就PAHSA抗MIS的作用机制研究进展作一综述。     

姜黄素拮抗LPS活化巨噬细胞对胰岛β细胞的损伤

目的检测姜黄素对LPS诱导小鼠巨噬细胞极化的影响,并检测不同极化状态下细胞培养上清对小鼠胰岛β细胞的损伤作用;研究姜黄素通过拮抗LPS诱导巨噬细胞M1极化保护胰岛β细胞的效应与机制。方法体外培养小鼠小鼠巨噬细胞RAW264.7细胞,通过LPS(2μg/ml)诱导建立M1极化模型,采用姜黄素(7.5 1μmol/l)单独或与LPS共同处理细胞。通过流式细胞术检测巨噬细胞CD40、CD86和CD206表达,并通过ELISA技术检测细胞培养上清液中TNF-α含量。采用不同诱导条件下巨噬细胞培养物上清液处理小鼠胰岛β细胞,检测其细胞凋亡与细胞增殖,分析胰岛β细胞损伤的程度。结果姜黄素可拮抗LPS诱导小鼠巨噬细胞向M1极化,降低细胞培养上清中TNF-α的含量,保护M1极化细胞培养液上清中TNF-α等炎症性细胞因子对胰岛β细胞的损伤。结论姜黄素拮抗LPS活化巨噬细胞对胰岛β细胞的损伤     

IDDM胰岛β细胞损伤机制的研究进展

IDDM胰岛β细胞损伤与多种因素有关。细胞因子、链脲佐菌素可通过NO途径和非NO途径起作用;内毒素则通过NO或细胞因子起作用;NO能引起β细胞线粒体损伤、DNA断裂直到细胞死亡;自身免疫中产生针对胰岛β细胞的特异抗体损伤β细胞;胰岛β细胞自身凋亡及淋巴细胞凋亡也与IDDM胰岛β细胞损伤直接相关。     

银杏叶提取物对高脂喂养胰岛素抵抗大鼠胰岛β细胞凋亡的保护作用

目的:研究银杏叶提取物对胰岛素抵抗大鼠的胰岛β细胞凋亡的保护作用.方法:Wistar大鼠40只,随机分为对照组(NC组)、高脂对照组(HL组)、高脂+罗格列酮组(HL+RSG组)和高脂+银杏叶提取物组(HL+EGb组).实验结束后,TUNEL法检测大鼠胰岛β细胞凋亡率,胰岛β细胞抗凋亡蛋白bcl-2和促凋亡蛋白bax的表达情况.结果:与NC组比较,HL组大鼠胰岛β细胞凋亡率升高(P＜0.05),与HL组比较,HL+EGb组、HL+RSG组大鼠胰岛β细胞凋亡率降低(P＜0.05);与NC组比较,HL组大鼠胰岛β细胞bcl-2蛋白表达水平降低,而bax蛋白水平升高,与HL组比较,HL+EGb组、HL+RSG组大鼠胰岛β细胞bcl-2蛋白表达水平升高和bax蛋白水平降低.结论:银杏叶提取物通过增加抗凋亡蛋白bcl-2表达和降低促凋亡蛋白bax表达,对高脂喂养胰岛素抵抗大鼠胰岛β细胞凋亡起到保护作用.     

辛酰化和非酰化ghrelin对胰岛β细胞的作用

目的：探讨辛酰化和非酰化ghrelin对胰岛β细胞的作用及其作用途径。方法：分别用不同浓度辛酰化ghrelin及非酰化ghrelin作用于NIT-1胰岛β细胞,48 h后观察二者是否有促进胰岛β细胞增殖的作用,并随后用阻断剂NF449分别与辛酰化ghrelin及非酰化ghrelin共同作用于NIT-1胰岛β细胞,验证二者促进增殖作用途径是否为Gαs途径。结果：MTT法结果提示10^-9～10^-7mol/L ghrelin和10^-10～10^-7mol/L非酰化ghrelin均能促进胰岛β细胞增殖,并且二者都是通过Gαs途径促进胰岛β细胞增殖。结论：辛酰化ghrelin和非酰化ghrelin都通过Gαs途径促进胰岛β细胞增殖。     

EGF 与 Gastrin 联合应用对糖尿病大鼠胰岛β细胞再生的影响

表皮生长因子（EGF）是肽类生长因子,许多研究证明,EGF 参与体外诱导干细胞向胰岛样细胞分化。已有文献证实 Gastrin 是一种介导胰岛新生的生长因子［1］,观察转导胰岛素启动子调控 Gastrin 基因的小鼠,虽然没有观察到实验组小鼠胰岛细胞数量的变化,但表达 TGF、Gastrin 的胰岛细胞数增多。在大鼠的胰腺导管结扎模型中发现 Gastrin 可促进胰岛β细胞再生,推测可能在该模型中,外源性的 Gastrin 可能是促进胰岛β细胞再生必要因子［2］。本文通过联合应用 Gastrin、EGF,观察 Gastrin、EGF 对糖尿病大鼠胰岛β细胞增殖作用影响。     

DC260126, a small-molecule antagonist of GPR40, improves insulin tolerance but not glucose tolerance in obese Zucker rats

GPR40 is a G-protein-coupled receptor specifically expressed in pancreatic islets, which maybe mediate both acute and chronic effects of free fatty acids (FFAs) on β-cell function. However, it is still a matter of debate whether GPR40 represents a novel therapeutic target for type 2 diabetes. To this aim, we evaluated the effect of DC260126, a small-molecule antagonist of GPR40, on glucose and lipid metabolism in obese Zucker rats. Rats were treated intraperitoneally with 6 mg/kg of DC260126 for 8 weeks. DC260126 could significantly decrease serum insulin levels, improve insulin tolerance and increase Akt phosphorylation levels in liver, suggesting improved insulin sensitivity in DC260126-treated rats. However, DC260126 did not affect food intake, body weight, blood glucose and lipids. Throughout the experimental period, no significant difference in glucose tolerance was observed between the vehicle and DC260126-treated rats. These results indicate that GPR40 antagonists may not be beneficial for the treatment of type 2 diabetes, although GPR40 antagonists could improve insulin tolerance and increase insulin signaling in vivo.     

The effects of TAK-875, a selective G protein-coupled receptor 40/free fatty acid 1 agonist, on insulin and glucagon secretion in isolated rat and human islets

G protein-coupled receptor 40 (GPR40)/free fatty acid 1 (FFA1) is a G protein-coupled receptor involved in free fatty acid-induced insulin secretion. To analyze the effect of our novel GPR40/FFA1-selective agonist, [(3S)-6-({2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid hemi-hydrate (TAK-875), on insulin and glucagon secretion, we performed hormone secretion assays and measured intracellular Ca2? concentration ([Ca2?](i)) in both human and rat islets. Insulin and glucagon secretion were measured in static and dynamic conditions by using groups of isolated rat and human pancreatic islets. [Ca2?](i) was recorded by using confocal microscopy. GPR40/FFA1 expression was measured by quantitative polymerase chain reaction. In both human and rat islets, TAK-875 enhanced glucose-induced insulin secretion in a glucose-dependent manner. The stimulatory effect of TAK-875 was similar to that produced by glucagon-like peptide-1 and correlated with the elevation of β-cell [Ca2?](i). TAK-875 was without effect on glucagon secretion at both 1 and 16 mM glucose in human islets. These data indicate that GPR40/FFA1 influences mainly insulin secretion in a glucose-dependent manner. The β-cell-specific action of TAK-875 in human islets may represent a therapeutically useful feature that allows plasma glucose control without compromising counter-regulation of glucagon secretion, thus minimizing the risk of hypoglycemia.     

G-protein-coupled receptors and islet function-implications for treatment of type 2 diabetes

Islet function is regulated by a number of different signals. A main signal is generated by glucose, which stimulates insulin secretion and inhibits glucagon secretion. The glucose effects are modulated by many factors, including hormones, neurotransmitters and nutrients. Several of these factors signal through guanine nucleotide-binding protein (G protein)-coupled receptors (GPCR). Examples of islet GPCR are GPR40 and GPR119, which are GPCR with fatty acids as ligands, the receptors for the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), the receptors for the islet hormones glucagon and somatostatin, the receptors for the classical neurotransmittors acetylcholine (ACh; M(3) muscarinic receptors) and noradrenaline (beta(2)- and alpha(2)-adrenoceptors) and for the neuropeptides pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP; PAC(1) and VPAC(2) receptors), cholecystokinin (CCK(A) receptors) and neuropeptide Y (NPY Y1 receptors). Other islet GPCR are the cannabinoid receptor (CB(1) receptors), the vasopressin receptors (V1(B) receptors) and the purinergic receptors (P(2Y) receptors). The islet GPCR couple mainly to adenylate cyclase and to phospholipase C (PLC). Since important pharmacological strategies for treatment of type 2 diabetes are stimulation of insulin secretion and inhibition of glucagon secretion, islet GPCR are potential drug targets. This review summarizes knowledge on islet GPCR.     

TAK-875, an orally available G protein-coupled receptor 40/free fatty acid receptor 1 agonist, enhances glucose-dependent insulin secretion and improves both postprandial and fasting hyperglycemia in type 2 diabetic rats

G protein-coupled receptor 40/free fatty acid receptor 1 (GPR40/FFA(1)) is highly expressed in pancreatic β cells and mediates free fatty acid-induced insulin secretion. This study examined the pharmacological effects and potential for avoidance of lipotoxicity of [(3S)-6-({2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}meth-oxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid hemi-hydrate) (TAK-875), a novel, orally available, selective GPR40 agonist. Insulinoma cell lines and primary rat islets were used to assess the effects of TAK-875 in vitro. The in vivo effects of TAK-875 on postprandial hyperglycemia, fasting hyperglycemia, and normoglycemia were examined in type 2 diabetic and normal rats. In rat insulinoma INS-1 833/15 cells, TAK-875 increased intracellular inositol monophosphate and calcium concentration, consistent with activation of the Gqα signaling pathway. The insulinotropic action of TAK-875 (10 μM) in INS-1 833/15 and primary rat islets was glucose-dependent. Prolonged exposure of cytokine-sensitive INS-1 832/13 to TAK-875 for 72 h at pharmacologically active concentrations did not alter glucose-stimulated insulin secretion, insulin content, or caspase 3/7 activity, whereas prolonged exposure to palmitic or oleic acid impaired β cell function and survival. In an oral glucose tolerance test in type 2 diabetic N-STZ-1.5 rats, TAK-875 (1-10 mg/kg p.o.) showed a clear improvement in glucose tolerance and augmented insulin secretion. In addition, TAK-875 (10 mg/kg, p.o.) significantly augmented plasma insulin levels and reduced fasting hyperglycemia in male Zucker diabetic fatty rats, whereas in fasted normal Sprague-Dawley rats, TAK-875 neither enhanced insulin secretion nor caused hypoglycemia even at 30 mg/kg. TAK-875 enhances glucose-dependent insulin secretion and improves both postprandial and fasting hyperglycemia with a low risk of hypoglycemia and no evidence of β cell toxicity.     

Agonist-induced desensitization/resensitization of human G protein-coupled receptor 17: a functional cross-talk between purinergic and cysteinyl-leukotriene ligands

G protein-coupled receptor (GPR) 17 is a P2Y-like receptor that responds to both uracil nucleotides (as UDP-glucose) and cysteinyl-leukotrienes (cysLTs, as LTD(4)). By bioinformatic analysis, two distinct binding sites have been hypothesized to be present on GPR17, but little is known on their putative cross-regulation and on GPR17 desensitization/resensitization upon agonist exposure. In this study, we investigated in GPR17-expressing 1321N1 cells the cross-regulation between purinergic- and cysLT-mediated responses and analyzed GPR17 regulation after prolonged agonist exposure. Because GPR17 receptors couple to G(i) proteins and adenylyl cyclase inhibition, both guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPγS) binding and the cAMP assay have been used to investigate receptor functional activity. UDP-glucose was found to enhance LTD(4) potency in mediating activation of G proteins and vice versa, possibly through an allosteric mechanism. Both UDP-glucose and LTD(4) induced a time- and concentration-dependent GPR17 loss of response (homologous desensitization) with similar kinetics. GPR17 homologous desensitization was accompanied by internalization of receptors inside cells, which occurred in a time-dependent manner with similar kinetics for both agonists. Upon agonist removal, receptor resensitization occurred with the typical kinetics of G protein-coupled receptors. Finally, activation of GPR17 by UDP-glucose (but not vice versa) induced a partial heterologous desensitization of LTD(4)-mediated responses, suggesting that nucleotides have a hierarchy in producing desensitizing signals. These findings suggest a functional cross-talk between purinergic and cysLT ligands at GPR17. Because of the recently suggested key role of GPR17 in brain oligodendrogliogenesis and myelination, this cross-talk may have profound implications in fine-tuning cell responses to demyelinating and inflammatory conditions when these ligands accumulate at lesion sites.     

Immunoglobulin-like domain containing receptor 1 mediates fat-stimulated cholecystokinin secretion

Cholecystokinin (CCK) is a satiety hormone produced by discrete enteroendocrine cells scattered among absorptive cells of the small intestine. CCK is released into blood following a meal; however, the mechanisms inducing hormone secretion are largely unknown. Ingested fat is the major stimulant of CCK secretion. We recently identified a novel member of the lipoprotein remnant receptor family known as immunoglobulin-like domain containing receptor 1 (ILDR1) in intestinal CCK cells and postulated that this receptor conveyed the signal for fat-stimulated CCK secretion. In the intestine, ILDR1 is expressed exclusively in CCK cells. Orogastric administration of fatty acids elevated blood levels of CCK in wild-type mice but not Ildr1-deficient mice, although the CCK secretory response to trypsin inhibitor was retained. The uptake of fluorescently labeled lipoproteins in ILDR1-transfected CHO cells and release of CCK from isolated intestinal cells required a unique combination of fatty acid plus HDL. CCK secretion secondary to ILDR1 activation was associated with increased [Ca²⁺]_i, consistent with regulated hormone release. These findings demonstrate that ILDR1 regulates CCK release through a mechanism dependent on fatty acids and lipoproteins and that absorbed fatty acids regulate gastrointestinal hormone secretion.     

A multiple-ascending-dose study to evaluate safety, pharmacokinetics, and pharmacodynamics of a novel GPR40 agonist, TAK-875, in subjects with type 2 diabetes

G-protein-coupled receptor 40 (GPR40), highly expressed in pancreatic β-cells, mediates free fatty acid (FFA)-induced insulin secretion. This phase I, double-blind, randomized study investigated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of a novel, glucose-lowering GPR40 agonist, TAK-875 (q.d., orally × 14 days), in type 2 diabetics (placebo, n = 14; at 25, 50, 100, 200, or 400 mg, n = 45). Approximately dose-proportional increases in AUC(0-24) and C(max) occurred. TAK-875 showed good tolerability with no dose-limiting side effects. Two subjects (on TAK-875) had mild hypoglycemia, probably related to prolonged fasting after oral glucose tolerance tests (OGTTs). TAK-875 showed reductions from baseline in fasting (2 to -93 mg/dl) and post-OGTT glucose (26 to -172 mg/dl), with an apparent dose-dependent increase in post-OGTT C-peptide over 14 days. Consistent with preclinical data, TAK-875 apparently acts as a glucose-dependent insulinotropic agent with low hypoglycemic risk. Its PK is suitable for once-daily oral administration.     

Thiazolidinedione derivatives as novel GPR120 agonists for the treatment of type 2 diabetes

GPR120, also called FFAR4, is preferentially expressed in the intestines, and can be stimulated by long-chain free fatty acids to increase the secretion of glucagon-like peptide-1 (GLP-1) from intestinal endocrine cells. It is known that GLP-1, as an incretin, can promote the insulin secretion from pancreatic cells in a glucose-dependent manner. Therefore, GPR120 is a potential drug target to treat type 2 diabetes. In this study, thiazolidinedione derivatives were found to be novel potent GPR120 agonists. Compound 5g, with excellent agonistic activity, selectivity, and metabolic stability, improved oral glucose tolerance in normal C57BL/6 mice in a dose-dependent manner. Moreover, compound 5g exhibited anti-diabetic activity by promoting insulin secretion in diet-induced obese mice. In summary, compound 5g might be a promising drug candidate for the treatment of type 2 diabetes.

GPR120 has emerged as an attractive target for the treatment of type 2 diabetes and obesity. Thiazolidinedione derivatives were found to be novel potent GPR120 agonists.