DPP-4抑制剂在2型糖尿病治疗中的应用(节选)

2型糖尿病发病和进展的一个重要原因是胰岛功能的进行性衰退,包括β细胞胰岛素分泌缺陷和α细胞胰升糖素不适当的分泌增加造成的胰岛素:胰升糖素比例失调.胰升糖素样肽1(GLP-1)是一种在食物营养物质刺激下,由肠道内分泌细胞合成分泌的肠促胰素(Incretin),具有葡萄糖依赖性促胰岛素分泌的特点,可通过促进β细胞的胰岛素分泌、抑制α细胞不适当的胰升糖素分泌、延缓胃排空及抑制食欲等多个途径参与机体血糖稳态调节.     

脂联素对胰岛β细胞的保护作用

脂联素是新发现的由脂肪细胞分泌的一种糖蛋白,参与调节糖脂代谢、炎性反应等病理生理过程,并可改善胰岛素抵抗.血浆脂联素水平与胰岛β细胞功能独立相关且与第一时相胰岛素分泌呈正相关;可减少基础胰岛素释放而增加葡萄糖刺激的胰岛素分泌(GSIS),阻止胰岛β细胞功能的进一步恶化.并且还可拮抗炎性反应因子及脂肪酸诱导的胰岛β细胞凋亡和功能缺陷,从而发挥对胰岛β细胞的保护作用.本文拟对脂联素的生物学作用及新发现的其对胰岛β细胞的保护作用进行综述.     

胰高糖素样肽-1及其类似物和二肽酰肽酶-IV抑制剂对胰岛功能的保护作用

胰岛β细胞功能受损是2型糖尿病发病的中心环节。随着病程的进展,多种机制参与导致β细胞功能进行性下降。胰高糖素样肽-1(GLP-1)是由肠道内分泌细胞L细胞分泌的肠促胰岛素,可以葡萄糖依赖性地增加胰岛素分泌、促进胰岛β细胞再生并抑制胰高糖素分泌。长效GLP-1类似物和二肽酰肽酶(DPP)-IV抑制剂能够减少内源性GLP-1在体内降解,从而更有效地保护胰岛β细胞功能,对于糖尿病的防治具有重要意义。     

胰高糖素和胰高糖素瘤综合征

胰高糖素(glucagon)由胰岛A细胞所分泌,并刺激B细胞及D细胞使之分别分泌胰岛素及生长激素释放抑制因子。在正常情况下,胰高糖素与胰岛素之间保持一定的动态平衡以维持体内血糖水平。胰岛内各种分泌细胞之间通过联结复合体相互联结,此种构造有助于协调彼此间的激素分泌。1947年Becker等首先报道一例经尸检证实的可能为胰高糖素的胰岛细胞瘤患者伴对称性、红斑性皮炎和舌炎。1966年Mcgavran等证     

胰高糖素样肽-1及其类似物和二肽酰肽酶-Ⅳ抑制剂对胰岛功能的保护作用

胰岛β细胞功能受损是2型糖尿病发病的中心环节.随着病程的进展,多种机制参与导致β细胞功能进行性下降.胰高糖素样肽-1(GLP-1)是由肠道内分泌细胞L细胞分泌的肠促胰岛素,可以葡萄糖依赖性地增加胰岛素分泌、促进胰岛β细胞再生并抑制胰高糖素分泌.长效GLP-1类似物和二肽酰肽酶(DPP)-Ⅳ抑制剂能够减少内源性GLP-1在体内降解,从而更有效地保护胰岛β细胞功能,对于糖尿病的防治具有重要意义.     

软脂酸和花生四烯酸对人肝细胞瘤细胞株细胞葡萄糖摄取的影响

脂肪酸对人肝细胞瘤细胞株(HepG2)细胞葡萄糖摄取研究显示，高浓度的软脂酸可通过抑制HepG2细胞胰岛素受体和葡萄糖转运子2的表达抑制胰岛素刺激的葡萄糖摄取；花生四烯酸可通过类似机制刺激葡萄糖摄取，部分阻断软脂酸的作用。     

脂联素受体在胰岛细胞表达,脂联素促进胰岛素的分泌

目的　检测脂联素受体(AR)在大鼠胰岛细胞的表达和脂联素对体外胰岛细胞分泌胰岛素的影响。方法　RT PCR和免疫细胞化学方法检测AR1、AR2的mRNA和蛋白表达;并在体外用脂联素(100μg/L)和不同浓度葡萄糖(3. 3, 5. 6, 16. 7mmol/L)处理胰岛细胞,放免法测定上清液的胰岛素浓度。结果　RT PCR扩增出胰岛AR1和AR2基因,并经直接和亚克隆测序证实;胰岛免疫细胞化学荧光染色AR1和AR2呈阳性;经脂联素处理后的胰岛细胞,在高糖(16. 7mmol/)培养 6~24h,其胰岛素分泌持续增加(均P<0. 05)。结论　胰岛细胞上存在AR1和AR2,以前者为主。在高糖情况下,一定浓度的脂联素可在体外促进胰岛细胞的胰岛素分泌和释放。     

β细胞素对体外培养大鼠胰岛的影响

研究β细胞素(BTC)对体外培养大鼠胰岛的作用。BTC无促胰岛急性分泌作用,但对长期培养大鼠胰岛的葡萄糖刺激的胰岛素分泌(GSIS)具有一定保护效力;实时PCR及免疫荧光检测胰高血糖素、胰岛素、PDX-1、葡萄糖转运子2的表达未随培养时间延长而丰度下降,BTC可能不是通过调节上述基因的表达来维护胰岛GSIS功能的。     

GLP-1受体激动剂的胰岛素增敏效应

2型糖尿病的发病机制主要涉及胰岛素抵抗张胰岛素分泌缺乏.研究表明,胰高血糖素样肽-1受体激动剂在有效改善胰岛β细胞功能,促进胰岛素分泌的同时,还能够作用于细胞信号转导,促进脂肪细胞分化和葡萄糖摄取,并通过减轻相关炎性反应因子表达,降低体重等,改善胰岛素抵抗,增加胰岛素敏感性.     

调钙素与胰岛素分泌

胰岛素分泌是由很多内源性与外源性动因直接刺激所引起。葡萄糖可能是主要的胰岛素促分泌剂,但氨基酸、胰高糖素与胃肠激素均刺激胰岛 B 细胞释放胰岛素;药物如磺脲化合物以及细胞外液中钾离子浓度的改变亦影响胰岛素释放。这些物质刺激胰岛素分泌的机理还不完全清楚,但有证据表明环磷腺苷(cAMP)与钙离子对胰岛 B 细胞起到连系识别刺激物与胰岛素分泌的信号分子的作用。相当多的证据提示,激素如胰高糖素与胰泌素的作用是由增加细胞内 cAMP 浓度所介     

Insulin secretion is increased in pancreatic islets of neuropeptide Y-deficient mice

Neuropeptide Y (NPY), whose role in appetite regulation is well known, is also expressed in pancreatic islets. Although previous studies indicated that application of NPY to pancreatic islets inhibits insulin secretion, its physiological role in the regulation of insulin secretion is not fully understood. We hypothesized that NPY in islets tonically suppresses insulin secretion and the reduction of islet NPY increases insulin secretion. To address the hypothesis, islet function of NPY-deficient mice was analyzed. Although there was little change in glucose homeostasis in vivo, pancreatic islets from NPY-deficient mice had higher basal insulin secretion (1.5 times), glucose-stimulated insulin secretion (1.5 times), and islet mass (1.7 times), compared with wild-type mouse. Next we sought to determine whether the expression of NPY and Y(1) receptor in islets was altered in hyperinsulinemia associated with obesity. Islets from C57BL/6J mice on a high-fat diet had 1.9 times higher basal insulin secretion and 2.4 times higher glucose-stimulated insulin secretion than control mice, indicating islet adaptation to obesity. Expression of NPY and Y(1) receptor mRNA levels was decreased by 70 and 64%, respectively, in high-fat diet islets, compared with controls. NPY and Y(1) receptor in islets were also reduced by 91 and 80%, respectively, in leptin-deficient ob/ob mice that showed marked hyperinsulinemia. Together these results suggest that endogenous NPY tonically inhibits insulin secretion from islets and a reduction of islet NPY may serve as one of the mechanisms to increase insulin secretion when islets compensate for insulin resistance associated with obesity.     

Secretory regulation of endocrine pancreas: Cyclic AMP and glucagon secretion.

Activation of adrenergic beta receptors has been found to stimulate insulin release in vitro that may be mediated through the augmentation of cyclic AMP in the beta cell. The activation of adrenergic alpha receptors in the beta cell inhibits the insulin release. The present studies have shown that isoproterenol (0.62 mug/ml) and sodium dibutyryl cyclic AMP (50 mug/ml) stimulate the insulin secretion and inhibit the glucagon secretion in the presence of 50 mg/100 ml glucose by the isolated pancreatic perfusion of the rat, while norepinephrine (0.5 mug/ml) inhibits the insulin secretion induced by 150 mg/100 ml glucose and stimulates the glucaton secretion. Theophylline (50 mug/ml) does not stimulate the insulin and the glucagon secretion. When norepinephrine is added to theophylline, the output of glucagon does not occur. From these results it can be deduced that the pancreatic alpha cell function may be inhibited by elevation of intracellular cyclic AMP, in contrast to the beta cell function which is stimulated by an increment of cyclic AMP.     

Glucose Intolerance in Patients with Chronic Inflammatory Diseases Is Normalized by Glucocorticoids

ABSTRACT Nine of 16 patients with inflammatory connective tissue diseases (rheumatoid arthritis, polymyalgia rheumatica, scleroderma and mixed connective tissue disease) had glucose intolerance defined a a K-rate less than one but a normal early insulin response to intravenous glucose loading. The degree of the impaired glucose handling was related to the degree of inflammatory activity as defined by acute phase reactants. Glucocorticoid therapy induced within three days an improved and normalized glucose tolerance and an augmented early insulin response (p<0.001). The glucocorticoid effect was still present up to six months of ongoing therapy. It is suggested that glucose intolerance in chronic inflammation is a consequence of a peripheral insulin antagonism and an inhibition of insulin secretion. This inhibition may be mediated directly or indirectly by inflammatory cell products and may be sensitive to glucocorticoids.     

L-arginine stimulation of glucose-induced insulin secretion through membrane depolarization and independent of nitric oxide

The mechanism of L-arginine stimulation of glucose-induced insulin secretion from mouse pancreatic islets was studied. At 16.7 mmol/l glucose, L-arginine (10 mmol/l) potentiated both phases 1 and 2 of glucose-induced insulin secretion. This potentiation of glucose-induced insulin secretion was mimicked by the membrane depolarizing agents tetraethylammonium (TEA, 20 mmol/l) and K+ (60 mmol/l), which at 16.7 mmol/l glucose obliterated L-arginine (10 mmol/l) modulation of insulin secretion. Thus L-arginine may potentiate glucose-induced insulin secretion by stimulation of membrane depolarization. At 3.3 mmol/l glucose, L-arginine (10 mmol/l) failed to stimulate insulin secretion. In accordance with membrane depolarization by the electrogenic transport of L-arginine, however, L-arginine (10 mmol/l) stimulation of insulin secretion was enabled by the K+ channel inhibitor TEA (20 mmol/l), which potentiates membrane depolarization by L-arginine. Furthermore, L-arginine (10 mmol/l) stimulation of insulin secretion was permitted by forskolin (10 micromol/l) or tetradecanoylphorbol 13-acetate (0.16 micromol/l), which, by activation of protein kinases A and C respectively sensitize the exocytotic machinery to L-arginine-induced Ca2+ influx. Thus glucose may sensitize L-arginine stimulation of insulin secretion by potentiation of membrane depolarization and by activation of protein kinase A or protein kinase C. Finally, L-arginine stimulation of glucose-induced insulin secretion was mimicked by NG-nitro-L-arginine methyl ester (10 mmol/l), which stimulates membrane depolarization but inhibits nitric oxide synthase, suggesting that L-arginine-derived nitric oxide neither inhibits nor stimulates insulin secretion. In conclusion, it is suggested that L-arginine potentiation of glucose-induced insulin secretion occurs independently of nitric oxide, but is mediated by membrane depolarization, which stimulates insulin secretion through protein kinase A- and C-sensitive mechanisms.     

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.     

糖皮质激素与2型糖尿病

糖皮质激素与2型糖尿病的发生、发展密切相关,但其诱导2型糖尿病发生的具体机制尚不明确.研究认为,糖皮质激素可能通过对胰岛β细胞增殖和发育、分泌功能的作用,以及对胰岛素信号转导通路、糖、脂代谢、葡萄糖转运和吸收等方面的影响,参与2型糖尿病的发生.11β-羟类固醇脱氢酶、糖皮质激素受体、热休克蛋白等通过影响糖皮质激素的作用,成为治疗2型糖尿病的新靶点.     

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^-8M). 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.     

Attenuation of insulin secretion by insulin-like growth factor 1 is mediated through activation of phosphodiesterase 3B

Both insulin and insulin-like growth factor 1 (IGF-1) are known to reduce glucose-dependent insulin secretion from the β cells of pancreatic islets. In this paper we show that the mechanism by which IGF-1 mediates this effect is in large part through activation of a specific cyclic nucleotide phosphodiesterase, phosphodiesterase 3B (PDE3B). More specifically, in both isolated pancreatic islets and insulin-secreting HIT-T15 cells, IGF-1 inhibits insulin secretion that has been increased by glucose and glucagonlike peptide 1 (GLP-1). Moreover, IGF-1 decreases cAMP levels in parallel to the reduction of insulin secretion. Insulin secretion stimulated by cAMP analogs that activate protein kinase A and also are substrates for PDE3B is also inhibited by IGF-1. However, IGF-1 does not inhibit insulin secretion stimulated by nonhydrolyzable cAMP analogs. In addition, selective inhibitors of PDE3B completely block the ability of IGF-1 to inhibit insulin secretion. Finally, PDE3B activity measured in vitro after immunoprecipitation from cells treated with IGF-1 is higher than the activity from control cells. Taken together with the fact that pancreatic β cells express little or no insulin receptor but large amounts of IGF-1 receptor, these data strongly suggest a new regulatory feedback loop model for the control of insulin secretion. In this model, increased insulin secretion in vivo will stimulate IGF-1 synthesis by the liver, and the secreted IGF-1 in turn feedback inhibits insulin secretion from the β cells through an IGF-1 receptor-mediated pathway. This pathway is likely to be particularly important when levels of both glucose and secretagogues such as GLP-1 are elevated.     

Inhibition of glucose stimulated insulin secretion by neuropeptide Y is mediated via the Y1 receptor and inhibition of adenylyl cyclase in RIN 5AH rat insulinoma cells

Summary Neuropeptide Y (NPY) has been shown to inhibit insulin secretion from the islets of Langerhans. We show that insulin secretion in the insulinoma cell line RIN 5AH is inhibited by NPY. ¹²⁵I-Peptide YY (PYY) saturation and competition-binding studies using NPY fragments and analogues on membranes prepared from this cell line show the presence of a single class of NPY receptor with a Y1 receptor subtype-like profile. Inhibition of insulin secretion in this cell line by NPY fragments and analogues also shows a Y1 receptor-like profile. Both receptor binding and inhibition of insulin secretion showed the same orders of potency with NPY > [Pro³⁴]-NPY > NPY 3–36 > > NPY 13–36. The Y1 receptor antagonist, BIBP 3226, blocks NPY inhibition of insulin secretion from, and inhibits ¹²⁵I-PYY binding to, RIN 5AH cells. Northern blot analysis using a Y1-receptor specific probe shows that NPY Y1 receptors are expressed by RIN 5AH cells. Y5 receptors are not expressed in this cell line. Neuropeptide Y inhibition of insulin secretion is blocked by incubation with pertussis toxin, implying that the effect is via a G-protein (G_i or G_o) coupled receptor. Neuropeptide Y inhibits the activation of adenylyl cyclase by isoprenaline in RIN 5AH cell lysates, and the stimulation of cAMP by glucagon-like peptide-1 (7–36) amide (GLP-1). It also blocks insulin secretion stimulated by GLP-1, but not by dibutyryl cyclic AMP. Hence, we suggest that NPY inhibits insulin secretion from RIN 5AH cells via a Y1 receptor linked through G_i to the inhibition of adenylyl cyclase. [Diabetologia (1998) 41: 1482–1491] Received: 10 November 1997 and in final revised form: 16 June 1998     

GPR54 peptide agonists stimulate insulin secretion from murine,porcine and human islets

This study was designed to determine the effects of 10 and 13 amino acid forms of kisspeptin on dynamic insulin secretion from mammalian islets since it is not clear from published data whether the shorter peptide is stimulatory while the longer peptide inhibits insulin release. Insulin secretion was measured by radioimmunoassay following perifusion of human, pig, rat and mouse isolated islets with kisspeptin-10 or kisspeptin-13 in the presence of 20 mM glucose. Both peptides stimulated rapid, reversible potentiation of glucose-stimulated insulin secretion from islets of all species tested. These data indicate that both kisspeptin-10 and kisspeptin-13, which is an extension of kisspeptin-10 by three amino acids, act directly at islet β-cells of various species to potentiate insulin secretion, and suggest that inhibitory effects reported in earlier studies may reflect differences in experimental protocols.