DPP-Ⅳ抑制剂度格列汀酒石酸盐

进餐后,人体血糖水平受胰岛素和胰高血糖素的控制,而餐后胰岛素和胰高血糖素的释放由肠促胰岛素激素胰高血糖素样肽（GLP-1）和胃肠道抑制性多肽／葡萄糖一依赖性促胰岛素多肽（GIP）所控制。2型糖尿病患者体内餐后肠促胰岛素激素水平显著降低,血糖平衡遭到破坏。因此,阻止肠促胰岛素的失活以增加其餐后作用时间将有效降低血糖。     

DPP-4抑制剂：不仅仅是一种降糖药

二肽基肽酶4（DPP-4）抑制剂是一类新型口服降糖药物,主要通过提高胰高血糖素样肽-1（GLP-1）浓度刺激胰岛素、抑制胰高糖素分泌而控制糖尿病患者血糖,临床应用越来越广泛。除降糖作用之外,DPP-4抑制剂还显现出调节炎症反应、降低心血管危险因素、促进伤口愈合以及改善阿尔茨海默病等降糖外作用。     

不同途径解除高糖毒性后2型糖尿病患者血清胰高血糖素样肽-1水平的变化

目的观察不同途径解除2型糖尿病(T2DM)患者高糖毒性后血清中胰高血糖素样肽-1(GLP-1)水平的变化及其与血糖、C-肽的关系。方法选择空腹血糖(FBS)≥10mmol/L,病程≤2年,且排除急性应激的2型糖尿病患者90名随机分成持续性皮下胰岛素输注组(CSII组)、皮下注射胰岛素组(MSII组)、口服药组(OHD组),给予降糖治疗2周,治疗前后分别测定FBS、GLP-1、C肽。同时取健康组30人测取GLP-1正常值范围。结果①降糖治疗后,3组患者FBS≤7mmol/L,C肽、GLP-1水平较前明显升高,差异均有统计学意义。②3组GLP-1上升水平无名显差异。③GLP-1与C-肽呈正相关,与FBS呈负相关。结论 2型糖尿病患者血糖较高时对GLP-1有抑制作用,解除高糖毒性后GLP-1水平明显回升,且与降糖途径无关。     

基于肠促胰岛素治疗糖尿病的药物研究进展

肠促胰岛素包括胰高血糖素样肽-1(Glucagon-like peptide-1,GLP-1)和葡萄糖依赖性促胰岛素释放多肽(Glucose-dependent insulinotropic polypeptide, GIP)两种分子,能够在肠道摄入食物后通过血糖依赖机制促进胰岛素的分泌。胰高血糖素样肽-1受体激动剂(Glucagon-like peptide-1 receptor agonists, GLP-1RAs)类药物凭借其良好的降糖活性、显著的体重控制作用以及明显的心血管收益在糖尿病的治疗中占据重要地位,基于另一肠促胰岛素GIP的疗法能否在糖尿病患者中发挥降糖作用仍不确定。GIP/GLP-1双重受体激动剂在临床试验中展现出了较好的治疗效果,针对糖尿病这一复杂的综合代谢性疾病,单分子多重受体激动剂似乎更具有潜力。文章介绍了基于肠促胰岛素的已上市药物,综述近年来处于临床试验阶段的基于肠促胰岛素治疗糖尿病的分子,以期为基于肠促胰岛素治疗糖尿病提供更多研究思路。     

DPP-4抑制剂超药物说明书用法专家共识

中国20岁以上人口的2型糖尿病的患病率已经达到9.7%。传统降糖药物在2型糖尿病的防治中发挥了重要作用,但仍存在低血糖、体重增加、增加心血管风险以及药物继发失效使血糖控制进行性恶化等局限性。二肽基肽酶-4（dipeptidyl peptidase-4, DPP-4）抑制剂是近年研发的口服降糖药,因作用机制独特、疗效确定、低血糖发生率少、对体重中性作用或轻度降低、心血管安全性良好等特点受到普遍关注,临床应用越来越广泛。DPP-4抑制剂减少体内胰高血糖素样肽-1（glucagon-like peptide-1, GLP-1）降解而增加循环GLP-1浓度2～3倍,GLP-1通过血糖依赖性刺激胰岛β细胞分泌胰岛素,抑制胰岛α细胞分泌胰高血糖素而发挥降低血糖的作用。     

非酒精性脂肪肝患者口服葡萄糖后血浆胰高血糖素样肽和葡萄糖依赖性促胰岛素多肽水平的变化

目的 考察非酒精性脂肪肝(nonalcoholic fatty liver,NAFLD)患者口服葡萄糖后胰高血糖素样肽(glucagon- likepeptide-1,GLP-1)和葡萄糖依赖性促胰岛素多肽(glucose-dependent insulinotropic ploypeptide,GIP)分泌的特征。方法 选取34例非酒精性脂肪肝和42例健康人群,行口服糖耐量试验后在120 min内测定血GLP-1、GIP、血糖、血胰岛素、胰高血糖素含量进行比较。结果 NAFLD患者经葡萄糖诱导后GLP-1分泌量明显低于正常对照组(P<0.01),而GIP没有明显改变,但是所有患者均存在胰岛素抵抗。与正常对照组相比,NAFLD患者空腹胰岛素水平和葡萄糖诱导后的胰岛素水平均明显升高,血糖降低缓慢,而空腹胰高血糖素水平明显升高。结论 NAFLD患者经葡萄糖诱导分泌GLP-1功能缺陷,GIP分泌无异常。NAFLD患者存在胰岛素抵抗、高胰岛素血症和胰高血糖素血症。     

胰高血糖素样肽1受体激动剂的临床研究进展

2型糖尿病(T2DM)主要由胰岛素分泌缺陷以及胰岛素抵抗引起,胰高血糖素样肽1(GLP-1)通过刺激胰岛 β细胞分泌胰岛素、抑制 α细胞分泌胰高糖素从而发挥降糖作用,还能增加胰岛β细胞数量、影响机体的胰岛素敏感性.另外,特异性GLP-1受体(GLP-1R)分布广泛,能影响人体多种生理机能,GLP-1可在抑制食欲、延缓胃排空、抗炎及保护心血管、降低血脂、减轻体重等多个方面产生影响.     

健脾疏肝颗粒对链脲佐菌素所致糖尿病小鼠的抗糖尿病效应及其作用机制的研究

目的：探讨健脾疏肝颗粒对链脲佐菌素（STZ）糖尿病模型小鼠的药理作用和作用机制。方法：小鼠分为空白对照组（CNTL）、空白干预组（JPSG）、模型对照组（STZ）、药物低剂量组、高剂量组（STZ+JPSGD、STZ+JPSGG）各6,6,12,12,12只,健脾疏肝颗粒或纯化水灌胃20 d,检测小鼠空腹血糖（FBG）、胰岛素（FINS）、血脂、胰高血糖素、超氧化物歧化酶（SOD）、丙二醛（MDA）、谷胱甘肽过氧化物酶（GSH-Px）,计算胰岛素抵抗指数（HOMA-IR）,以及胰高血糖素样肽-1（GLP-1）表达情况。结果：与模型对照组比较,STZ+JPSGD组、STZ+JPSGG组小鼠FBG、FINS、HOMA-IR、血脂、胰高血糖素均显著趋于正常,SOD、MDA、GSH-Px活性明显改善,GLP-1表达接近空白对照组,差异具有统计学意义（P<0.05或P<0.01）。结论：健脾疏肝颗粒对STZ模型小鼠具有明显降糖、降脂作用,作用机制可能通过抗氧化作用、调节GLP-1表达和FINS、胰高血糖素水平来发挥作用,值得进一步研究。     

糖尿病治疗新进展

本文就糖尿病治疗领域的研究进展进行了复习,重点介绍了糖尿病口服药物领域中的新观点、新剂型。胰岛素治疗领域中有关胰岛素类似物、胰岛素注射工具及非注射式胰岛素的研究进展;非胰岛素降糖激素的研究进展,包括胰高血糖素样肽(GLP-1)激活剂依西纳肽注射剂、人工合成胰淀素类似物普兰林肽的作用机制、临床使用方法、作用和副作用等。     

GLP-1R激动剂及正变构调节剂研究进展

胰高血糖素样肽-1受体(glucagon-like peptide-1 receptor, GLP-1R)是治疗2型糖尿病的重要靶标，作为一种G蛋白偶联受体可通过胰高血糖素样肽-1介导胰岛素分泌。该文对胰高血糖素样肽-1和GLP-1R的结构与功能进行综述，并对肽类GLP-1R激动剂、非肽类小分子GLP-1R激动剂和GLP-1R正变构调节剂的设计开发进行讨论，旨在为进一步探寻2型糖尿病的治疗方案提供思路。     

A physiological role of glucagon-like peptide-1 receptors in the central nervous system of Suncus murinus (house musk shrew)

Glucagon-like peptide-1 (7-36) amide (GLP-1) is released from the gut as an incretin hormone to stimulate glucose-stimulated insulin secretion. GLP-1 is also produced in the central nervous system (CNS) as a neurotransmitter that regulates feeding behaviour. By using polyclonal antiserum against GLP-1 and GLP-1 receptors, we identified the distribution of GLP-1 immunoreactive fibres and GLP-1 receptor immunoreactivity in the ventromedial hypothalamus of Suncus murinus (house musk shrew). In functional studies, subcutaneous administration of exendin-4 (1 - 30 nmol/kg) reduced blood glucose levels dose-dependently by up to 49% during an intraperitoneal glucose tolerance test (P<0.001). The glucose-lowering effects were also observed after an intracerebroventricular (i.c.v.; 0.3 - 3 nmol) or intracerebral ventromedial hypothalamic microinfusion (iVMH; 0.3 - 3 pmol) of exendin-4. The area under the curve values for glucose after i.c.v. and iVMH administrations of exendin-4 were reduced by up to 53% (P<0.01) and 46% (P<0.01), respectively. Exendin-4 (i.c.v.; 3 nmol) also increased glucose-stimulated insulin secretion by 20% compared to controls (P<0.05). The GLP-1 receptor antagonist, exendin (9-39) (10 nmol, i.c.v.) did not modify blood glucose levels but it antagonized the glucose-lowering effect of exendin-4 (1 nmol, i.c.v.; P<0.05). The data suggests that the central GLP-1 system may regulate glucose homeostasis by increasing insulin secretion. Further, GLP-1 receptors in the ventromedial hypothalamus appear to play an important role in the regulation of glucose homeostasis in S. murinus.     

1,5-Anhydro-D-fructose increases glucose tolerance by increasing glucagon-like peptide-1 and insulin in mice

Besides being degraded to glucose-6-phosphate and to free glucose, glycogen is degraded by alpha-1,4-glucan lyase to 1, 5-anhydro-D-fructose. We examined the influence of 1, 5-anhydro-D-fructose on glucose-stimulated insulin secretion in vivo and in vitro in mice. When administered together with i.v. glucose (1 g/kg), 1,5-anhydro-D-fructose did not affect (at 0.2 g/kg) or inhibited (at 1 g/kg) insulin secretion without affecting glucose elimination. When incubated with isolated islets, 1, 5-anhydro-D-fructose at <16.7 mmol/l, did not affect glucose (11.1 mM)-stimulated insulin secretion but inhibited insulin secretion at 16.7 mmol/l. When given through a gastric gavage (150 mg/mouse) together with glucose (150 mg/mouse), 1,5-anhydro-D-fructose increased glucose tolerance and insulin secretion. Furthermore, 1, 5-anhydro-D-fructose potentiated the increase in plasma levels of the gut hormone, glucagon-like peptide-1 (GLP-1). We therefore conclude that when given enterally, but not parenterally, 1, 5-anhydro-D-fructose increases glucose tolerance in mice by increasing insulin secretion due to increased plasma levels of GLP-1. The sugar may therefore be explored for increasing endogenous GLP-1 secretion in the treatment of type 2 diabetes.     

Improved glucose tolerance and insulin secretion by inhibition of dipeptidyl peptidase IV in mice

We explored whether inhibition of the enzyme dipeptidyl peptidase IV (DPP IV) increases endogenous levels of glucagon-like peptide-1 (GLP-1) and improves glucose tolerance and insulin secretion in mice. Glucose (150 mg) was administered through a gastric gavage with or without the inhibitor of dipeptidyl peptidase IV, valine-pyrrolidide (100 micromol/kg), in high-fat fed glucose intolerant or control C57BL/6J mice. The increase in plasma GLP-1 after gastric glucose was potentiated by dipeptidyl peptidase IV inhibition (P<0.05). Valine-pyrrolidide also potentiated the plasma insulin response to gastric glucose and improved the glucose tolerance in both groups of mice (P<0.001). In contrast, valine-pyrrolidide did not affect glucose-stimulated insulin secretion from isolated islets. This suggests that valine-pyrrolidide improves insulin secretion and glucose tolerance through indirect action, probably through augmentation of levels of GLP-1 and other incretin hormones. Therefore, inhibition of dipeptidyl peptidase IV activity is feasible to exploit as a treatment for glucose intolerance and type 2 diabetes.     

The major glucagon-like peptide-1 metabolite, GLP-1-(9-36)-amide, does not affect glucose or insulin levels in mice

Glucagon-like peptide-1 (GLP-1), a future treatment for type 2 diabetes, is efficiently degraded by the enzyme dipeptidyl peptidase IV (DPP IV), yielding the major metabolite GLP-1-(9-36)-amide. In this study, we examined the potential glucose lowering effect of GLP-1-(9-36)-amide in mice and found that GLP-1-(9-36)-amide (3 and 10 nmol/kg) did not affect insulin secretion or glucose elimination when administered intravenously together with glucose (1 g/kg). This was observed both in normal mice and in transgenic mice having a complete disruption of the signalling from the GLP-1 receptor. Furthermore, after blocking insulin secretion, using diazoxide (25 mg/kg), no effect on insulin-independent glucose disposal of GLP-1-(9-36)-amide was observed. Therefore, GLP-1-(9-36)-amide does not affect glucose disposal in mice either in the presence or absence of intact GLP-1-receptors or in the presence or absence of stimulated insulin levels. This suggests that the GLP-1 metabolite is not involved in the regulation of glucose homeostasis.     

灵菊七水提物的降糖作用及促胰岛素分泌作用研究

目的观察灵菊七水提物的降糖作用及对胰岛细胞分泌胰岛素的影响。方法采用四氧嘧啶（70mg·kg^-1）诱导的糖尿病模型小鼠和正常小鼠,连续给药7d后,观察灵菊七水提物（2．5mg·kg^-1、5mg·kg^-1和10mg·kg^-1）对血糖、血清胰岛素水平和糖耐量的影响;采用MIN6胰岛细胞株,观察灵菊七水提物对胰岛素分泌的影响。结果在给药7d后,灵菊七水提物可明显降低糖尿病小鼠的血糖水平,并可明显降低正常小鼠和糖尿病小鼠的糖耐量,促进胰岛素的分泌;灵菊七水提物对葡萄糖（16．7mmol·^-1）刺激下胰岛素的分泌明显具有促进作用。结论灵菊七水提物可通过促进胰岛素分泌来降低血糖。     

Hypoglycemic effect of Ganoderma lucidum polysaccharides

AIM: To investigate the hypoglycemic effect of Ganoderma lucidum polysaccharides (Gl-PS) in the normal fasted mice and its possible mechanism. METHODS: Normal fasted mice were given a single dose of Gl-PS 25, 50, and 100mg/kg by ip and the serum glucose was measured at 0, 3, and 6h after administration. Gl-PS 100mg/kg were also given by ip and the serum glucose and insulin levels were measured at 0min, 30min, 1h, 3h, 6h, and 12h Pancreatic islets were isolated and incubated with glucose 5.6mmol/L and different concentration of Gl-PS, the insulin content of islets and insulin release were examined. The islets fluorescent intensity of [Ca^2 ]i was also studied with a confocal microscope. Verapamil and egtazic acid were used to testify whether the insulin-releasing effect of Gl-PS was mediated by its ability to raise the Ca^2 influx. RESULTS: Gl-PS dose-dependently lowered the serum glucose levels at 3h and 6h after administration. Gl-PS 100mg/kg raised the circulating insulin levels at 1h after administration. In vitro, Gl-PS had no effect on islets insulin content, but it stimulated the insulin release after incubation with glucose 5.6mmol/L. Confocal microscope showed that Gl-PS 100mg/L had the capacity toraise the [Ca^2 ]i. The insulin-releasing effect of Gl-PS was inhibited by verapamil/egtazic acid. CONCLUSION:Gl-PS possesses the hypoglycemic effect on normal mice; one mechanism is through its insulin-releasing activity due to a facilitation of Ca^2 inflow to the pancreatic β cells.     

Cholinergic muscarinic effects on insulin release in mice

Insulin secretion and blood glucose homeostasis were studied in mice following administration of cholinergic agonists, antagonists and other possible modifiers of cholinergic insulin secretory mechanisms. It was observed that administration to mice of the cholinergic agonists acetylcholine, carbachol and pilocarpine resulted in an increase in plasma immuno-reactive insulin levels accompanied by a significant fall in blood glucose levels. Nicotine had no effect. Carbachol was found to enhance insulin release in a dose-dependent manner. Muscarinic blockade by atropine or methylatropine totally suppressed carbachol-induced insulin secretion. No blocking effect was accomplished by beta-adrenoceptor blockade. Glucose-induced insulin secretion was not affected by atropine in normal non-fasted mice. In mice fasted for 24 h, however, the insulin response to glucose was impaired by atropine suggesting that the nutritional state is important for cholinergic modulation of glucose-induced insulin response. Pretreatment of animals with the glycogenolytic hydrolase, acid amyloglucosidase, enhanced tolbutamide-induced insulin release but did not influence insulin secretion stimulated by carbachol. Pretreatment with the monoamine oxidase inhibitor, pargyline, plus L-dopa, leading to an intracellular accumulation of dopamine in the insulin cells, totally suppressed carbachol-induced insulin release. It is suggested that, in mice, cholinergic stimulation promotes insulin secretion through activation of muscarinic receptors on the insulin cell. Blockade of these receptors does not influence glucose-stimulated insulin release in the non-fasting state, but may impair the insulin response to glucose after fasting. Cholinergic stimulation of insulin release is inhibited after L-dopa-induced accumulation of dopamine in the insulin cells. In contrast to tolbutamide-induced insulin release cholinergic insulin release is not dependent on acid amyloglucosidase activity.     

Milrinone efficiently potentiates insulin secretion induced by orally but not intravenously administered glucose in C57BL6J mice

To study the effect of phosphodiesterase (PDE) 3 inhibition on plasma insulin and glucose levels, the selective PDE 3 inhibitor milrinone (0.25, 1.0, and 2.5 mg/kg) was given orally to anesthetized CL57Bl/6J mice 10 min before a gastric glucose gavage (150 mg/mouse). It was found that milrinone augmented the glucose-mediated increase in plasma insulin at 1.0 and 2.5 mg/kg without, however, any improvement in glucose elimination. In contrast, when given 10 min before intravenous glucose (1 g/kg), milrinone (1 mg/kg) did not affect the insulin response to glucose. The increase in glucagon-like peptide-1 (GLP-1) levels after gastric glucose was not altered by milrinone. However, the PDE3 inhibitor augmented the insulin response to intravenous GLP-1 (2.8 nmol/kg). We therefore conclude that PDE3 inhibition by milrinone augments insulin secretion in vivo in mice after oral but not after intravenous glucose, which may be explained by enhanced response to the cAMP-dependent insulinotropic action of endogenously released GLP-1.     

壳寡糖降血糖作用的实验研究

目的：探讨壳寡糖的降血糖作用.方法：以尾静脉注射四氧嘧啶建立糖尿病大鼠模型,随机分为模型对照组,壳寡糖高、中、低剂量组,二甲双胍组和正常对照组,每组6只.观察壳寡糖对糖尿病大鼠血糖、胰岛素的影响及病理改变,观察壳寡糖对正常小鼠血糖及糖耐量的影响.结果：壳寡糖中、高剂量组均有明显降低四氧嘧啶糖尿病大鼠血糖作用（P＜0.05）.壳寡糖改善模型对照组大鼠胰腺功能,3个剂量组壳寡糖使血中胰岛素有升高趋势,但与模型对照组比较差异无统计学意义.壳寡糖低、中、高剂量组与空白对照组小鼠血糖比较差异无统计学意义（P＞0.05）,中、高剂量壳寡糖使小鼠灌胃葡萄糖后0.5 h血糖降低,与空白对照组比较差异有统计学意义（P＜0.05）.结论：壳寡糖具有明显降血糖作用,对正常小鼠血糖无影响,增加小鼠糖耐量作用.     

Insulin secretion and carbohydrate metabolism in the dystrophic mouse.

Dystrophic mice were investigated with regard to their regulation of blood glucose and insulin secretion in vivo. The following were also measured: tissue glycogen levels, activity of the glycogenolytic hydrolase, acid amyloglucosidase, and in vitro glucose utilization by liver, muscle and adipose tissue. Basal levels of blood glucose and plasma insulin of dystrophic mice were essentially within the same range as in the clinically unaffected littermate controls. Dystrophic mice had a decreased tolerance to glucose and glibenclamide; the secretion of insulin in response to these secretagogues was moderately reduced. Insulin release following beta-adrenergic stimulation, however, was increased in the dystrophic mice. Glycogen levels and acid amyloglucosidase activity were increased in dystrophic muscles but were normal in liver. Acid amyloglucosidase activity in pancreatic islets was lower in the dystrophic mouse. Glucose utilization in vitro appeared normal in liver tissue from dystrophic mice; in dystrophic muscle there was a threefold increase in 14CO2-production with no concomitant increase in either glycogen or 14C-incorporation into glycogen. 14CO2 production and 14C-incorporation into lipid and glycogen were increased in dystrophic adipose tissue. We suggest that the decreased glucose tolerance, and the reduced insulin response to glucose in the dystrophic mouse are compensated by an increased glucose utilization in muscle and adipose tissue and an increased beta-adrenergic-mediated secretion of insulin.