那格列酮对不同2型糖尿病模型动物的治疗及胰岛素增敏作用(英文)

目的观察那格列酮对不同2型糖尿病模型动物的治疗及胰岛素增敏作用。方法那格列酮联合应用小剂量长效胰岛素(每只每日0.2 U,sc)治疗链佐菌素(150 mg·kg~(-1),ip)诱导的化学性糖尿病小鼠,观察那格列酮的胰岛素直接增敏作用;那格列酮ig,8 wk,分别采用ONE TOUCH稳豪型血糖测定仪及病理组织学检查,观察受试药物对自发性糖尿病小鼠(DB/DB小鼠)血糖及相关脏器(心脏、肾脏、胰腺)的影响;应用卡一介苗(BCG)每只10 mg静脉注射造成大鼠免疫性胰岛素抵抗模型,采用正糖钳技术观察那格列酮对该模型动物的葡萄糖输注速率(GIR)的回升作用。结果那格列酮(15,45,150 mg·kg~(-1)·d~(-1))合并应用胰岛素后,各剂量组动物的空腹血糖较CMC联合胰岛素对照组分别降低(14±s 4)%,(55±24)%,and(28±7)%。通过8 wk的治疗,那格列酮(15,45,150 mg·kg~(-1)·d~(-1))治疗组DB/DB小鼠的空腹血糖值与模型组相比有明显下降(P<0.01);病理组织学检查结果表明那格列酮明显改善糖尿病DB/DB小鼠肾脏和胰腺组织的损害。那格列酮(10,30,100 mg·kg~(-1)·d~(-1))连续给药2 wk,能明显升高免疫胰岛素抵抗模型大鼠高胰岛素状态下GIR(P<0.01)。结论那格列酮具有胰岛素直接增敏作用,对多种胰岛素抵抗动物模型均有治疗作用。     

Hypoglycaemic effects of antidiabetic drugs in streptozotocin-nicotinamide-induced mildly diabetic and streptozotocin-induced severely diabetic rats

In this study, streptozotocin-induced severely diabetic rats and streptozotocin-nicotinamide-induced mildly diabetic rats were established to compare their characteristics and to investigate the hypoglycaemic effects of antidiabetic drugs. Results show that in streptozotocin-induced severely diabetic rats, the pancreatic insulin content decreased to approximately 10% of that in normal rats. These severely diabetic rats also exhibited marked hyperglycaemia and impaired glucose tolerance due to insulin secretory deficiency. In contrast, the pancreatic insulin content was approximately 50% of normal levels in streptozotocin-nicotinamide-induced mildly diabetic rats. These mildly diabetic rats exhibited moderate hyperglycaemia and impaired glucose tolerance due to loss of early-phase insulin secretion. Voglibose (alpha-glucosidase inhibitor), metformin (biguanide), glibenclamide (sulfonylurea), sitagliptin (dipeptidyl peptidase-4 inhibitor) and insulin significantly improved glucose tolerance in streptozotocin-nicotinamide-induced mildly diabetic rats. In contrast, in streptozotocin-induced severely diabetic rats, voglibose, metformin and insulin significantly improved glucose tolerance, but no significant effect was observed for glibenclamide and sitagliptin due to a decreased insulinotropic effect. These results suggest that streptozotocin-nicotinamide-induced mildly diabetic rats, which exhibit a mild decline in glucose tolerance due to loss of early-phase insulin secretion, are sensitive to the hypoglycaemic effects of insulinotropic agents and have many pathological features resembling type 2 diabetes, which may be useful in the pharmacological investigation of numerous antidiabetic drugs.     

Activation of imidazoline‐I3 receptors ameliorates pancreatic damage

Agmatine, an endogenous ligand of imidazoline receptors, is reported to exhibit anti‐hyperglycaemic and many other effects. It has been established that the imidazoline I3 receptor is involved in insulin secretion. The current study characterizes the role of the imidazoline I3 receptor in the protection of pancreatic islets. The activity effect of agmatine against on streptozotocin (STZ)‐induced (5 mmol/L) rat β cell apoptosis was examined by using ApoTox‐Glo triplex assay, live/dead cell double staining assay, flow cytometric analysis, and western blot. Imidazoline I3 receptors antagonist KU14R and the phospholipase C inhibitor named U73122 were treated in β cells to investigate the potential signalling pathways. The serum glucose and recovery of insulin secretion were measured in STZ‐treated rats after continuously injected agmatine. The apoptosis in rat β cells was reduced by agmatine in a dose‐dependent manner, cell viability was improved after treatment with agmatine and these effects were suppressed after the blockade of KU14R and U73122. Western blot analysis confirmed that agmatine could decrease caspase‐3 expression and increase the p‐BAD levels. In STZ‐treated rats, injection of agmatine for 4 weeks may significantly lower the serum glucose and recovery of insulin secretion. This improvement of pancreatic islets induced by agmatine was deleted by KU14R in vivo. Agmatine can activate the imidazoline I3 receptor linked with the phospholipase C pathway to induce cell protection against apoptosis induced by a low dose of STZ. This finding provides new insight into the prevention of early stage pancreatic islet damage.     

Antidiabetic effects of chitosan oligosaccharides in neonatal streptozotocin-induced noninsulin-dependent diabetes mellitus in rats

The antidiabetic effect of chitosan oligosaccharide (COS) was investigated in neonatal streptozotocin (STZ)-induced noninsulin-dependent diabetes mellitus rats. The fasting glucose level was reduced by about 19% in diabetic rats after treatment with 0.3% COS. Glucose tolerance was lower in the diabetic group compared with the normal group. After diabetic rats had been treated with 0.3% COS for 4 weeks, glucose tolerance increased significantly versus the diabetic control group, and glucose-inducible insulin expression increased significantly. In addition, fed-triglyceride (TG) levels in diabetic rats drinking 0.3% COS were reduced by 49% compared with those in diabetic control rats. The cholesterol levels of animals treated with COS were reduced by about 10% in fed or fasting conditions versus the corresponding controls, although the difference was not statistically significant. It was found that COS has a TG-lowering effect in diabetic rats, and that COS reduces signs of diabetic cardiomyopathy such as vacuolation of mitochondria and the separation and degeneration of myofibrils. In conclusion, these results indicate that COS can be used as an antidiabetic agent because it increases glucose tolerance and insulin secretion and decreases TG.     

Sitagliptin with metformin: profile of a combination for the treatment of type 2 diabetes

Sitagliptin, a novel orally-active dipeptidyl-peptidase (DPP-4) inhibitor has been introduced into type 2 diabetes therapy. Sitagliptin inhibits the degradation of glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP), as well as that of other regulatory peptides important for glucose homeostasis. It reduces haemoglobin A1c (HbA1c), fasting and postprandial glucose by glucose- dependent stimulation of insulin secretion and inhibition of glucagon secretion. Sitagliptin is weight neutral. Indirect measures show a possible improvement of beta-cell function. Sitagliptin does not cause hypoglycemia when compared to metformin or placebo. Metformin, which has a different unique mechanism, has been used in type 2 diabetes for approximately 50 years. Metformin improves insulin resistance and is the first-line antidiabetic drug in use today. The combination of a DPP-4 inhibitor with metformin allows a broad and complementary spectrum of antidiabetic actions. This combination does not increase the risk of hypoglycaemia nor does it promote weight gain, an adverse effect of various other oral antidiabetic combinations. This article gives an overview of the data available on the combined antidiabetic effects of metformin and sitagliptin.     

PPARγ agonist pioglitazone reverses memory impairment and biochemical changes in a mouse model of type 2 diabetes

OBJECTIVE Pioglitazone,known as a peroxisome proliferator-activated receptor γ(PPARγ) agonist,is used to treat type 2 diabetes(T2DM).T2DM has been associated with reduced performance on numerous domains of cognitive function.Here,we investigated the effects of pioglitazone on memory impairment in a mouse model with defects in insulin sensitivity and secretion,namely high-fat diet(HFD) streptozotocin(STZ)-induced diabetic mice.METHODS ICR mice were fed an HFD for 4 weeks and then injected with a single low dose of STZ followed by continued HFD feeding for an additional 4 weeks.The diabetic mice were orally administered with pioglitazone(9,18 mg·kg-1) for 4-5 weeks.Y-maze test and Morris water maze test(MWM) were employed for testing learning and memory.Serum glucose,serum insulin,serum triglyceride,brain amyloid peptide-β(Aβ),brain β-site amyloid precursor protein cleaving enzyme(BACE1),brain nuclear factor κB(NF-κB),brain receptor for advanced glycation end products(RAGE) were also tested.RESULTS The STZ/HFD diabetic mice,characterized by hyperglycemia,hyperlipemia and hypoinsulinemia,performed poorly on Y-maze and MWM hence reflecting impairment of learning and memory behavior with increases of Aβ40/Aβ42,BACE1,NF-κB,and RAGE in brain.Treatment of PPARγ agonist,pioglitazone,significantly reversed diabetes-induced impairment of learning and memory behavior,which is involved in decreases of Aβ40/Aβ42 via inhibition of NF-κB,BACE1 and RAGE in brain as well as attenuation of hyperglycemia,hyperlipemia and hypoinsulinemia.CONCLUSION It is concluded that PPARγ agonist pioglitazone may be considered as potential pharmacological agents for the management of cognitive dysfunction in T2DM.     

软饮料导致的青少年糖尿病酮症的治疗及预后分析

目的研究软饮料导致的青少年糖尿病酮症的临床特点和预后情况,探讨该症的发病机制和治疗对策。方法选择10例以大量摄入含糖软饮料为明确诱因的初发2型糖尿病酮症或酮症酸中毒青少年患者,胰岛素治疗好转后跟踪随访半年,分别在入院初、血糖理想控制一周以上和出院半年后测定血糖、血清胰岛素或C-肽,以判断胰岛β细胞分泌功能,行高胰岛素正血糖钳夹试验以定量测定胰岛素抵抗程度。结果10例病例的特点是都有家族史、明显肥胖、皮肤黑棘皮病样表现,血中胰岛自身抗体阴性。入院时血清胰岛素和C-肽水平明显降低;血糖理想控制1周后水平均明显升高(P均<0.05);钳夹试验中葡萄糖输注速率(GIR)显著低于正常人。随访半年时BMI均有不同程度下降(差异不显著),全部停止口服用药,维持血糖于正常糖耐量(5例)或异常糖耐量(5例)。而空腹胰岛素/C-肽和糖负荷后2h胰岛素/C-肽水平均进一步显著升高(均P<0.01),呈现高胰岛素血症和高C肽水平。行第二次钳夹试验的病例其GIR值均比第一次钳夹试验有明显提高(P<0.01),但仍低于正常人。结论软饮料导致的糖尿病酮症预后良好的原因是虽然有严重胰岛素抵抗,但胰岛功能尚有很强的代偿能力;而大量摄入含糖软饮料导致糖毒性,使β细胞分泌功能暂时下降及胰岛素抵抗加重,引起糖尿病发病;糖毒性纠正后,β细胞分泌功能如果能足以抵消胰岛素抵抗的代偿水平,可以不引发糖尿病。     

Sulfonylurea induction of caffeine-enhanced insulin secretion and reduction of glycemic levels in diabetic rats

Context: Caffeine can stimulate insulin secretion by attenuating hyperglycemia in diabetes models with significant reduction of pancreatic functional β cells. Knowledge of these mechanisms could contribute to new strategies for treating diabetes.

Objective: This study evaluated the effects of caffeine and physical exercise on glycemic and insulin responses in diabetic rats.

Materials and methods: The diabetes model was induced by intraperitoneal administration of 60?mg/kg of streptozotocin (STZ). Animals were divided into six groups: control, caffeine, STZ control, STZ caffeine, STZ sulfonylurea, and STZ caffeine?+?sulfonylurea. Acutely, control animals received 6?mg of caffeine and 10?mg/kg sulfonylurea or 10?mg/kg saline. Animals were sacrificed after physical exercise; blood samples were collected for glucose, glycerol, lactate, and insulin analyses. Cardiovascular responses were recorded before and after treatments. A one-way ANOVA and the post hoc Student–Newman–Keuls test were used to analyze statistical differences between treatments (p?Results: About 6?mg/kg of caffeine did not alter cardiovascular responses, but promoted blood glucose reduction after 60?min of exercise when compared to animals in the control groups (387–187?mg/dL; p?p?Discussion and conclusion: Acute caffeine intake with exercise can increase glucose uptake enhancing insulin secretion stimulated by sulfonylurea in β cells-deficient pancreas. The results indicate the potential use of caffeine as a strategy for glycemic and insulin control in diabetes.     

Nelumbo nucifera leaves extract attenuate the pathological progression of diabetic nephropathy in high-fat diet-fed and streptozotocin-induced diabetic rats

Diabetic nephropathy is not only a common and severe microvascular complication of diabetes mellitus but also the leading cause of renal failure. Lotus (Nelumbo nucifera) possesses antioxidative and anticancer properties. The present study aimed to investigate the antidiabetic and renoprotective effects of N. nucifera leaf extract (NLE) in a rat model of type 2 diabetic mellitus. Male Sprague–Dawley rats with type 2 diabetes induced by a high-fat diet (HFD)/streptozotocin (STZ) were treated with NLE at dosages of 0.5% and 1% (w/w) daily for 6 weeks. At the end of the experimental period, body weight, serum glucose levels, insulin levels, and kidney function were assessed. Furthermore, antioxidant enzyme and lipid peroxide levels were determined in the kidney, and histopathological examination was performed using hematoxylin and eosin staining, periodic acid Schiff staining, and Masson trichrome staining. To shed light on the molecular mechanism underlying the functioning of NLE, mouse glomerular mesangial cells (MES-13) treated with high glucose (HG, 25 mM glucose) were chosen as a model for an examination of the signal transduction pathway of NLE. The results revealed that NLE improved diabetic kidney injury by reducing blood glucose, serum creatinine, and blood urea nitrogen levels and enhanced antioxidant enzyme activities in kidney tissue. Treatment with NLE significantly reduced the malondialdehyde and 8-hydroxy-2-deoxyguanosine levels and increased serum insulin levels; expression of renal superoxide dismutase, catalase, and glutathione peroxidase activities; and glutathione content. Histological studies have also demonstrated that NLE treatment inhibited the dilation of Bowman's capsule, which confirmed its renoprotective action in diabetes. In addition, treatment with NLE and its major component quercetin 3-glucuronide attenuated 25 mM HG-induced suppressed nuclear factor erythroid 2-related factor 2 and antioxidant enzyme expression in MES-13 cells. Collectively, these findings indicate that NLE may have antidiabetic and renoprotective effects against HFD/STZ-induced diabetes, at least in part, through antioxidative pathways.     

Effects of antidiabetic drugs in high-fat diet and streptozotocin-nicotinamide-induced type 2 diabetic mice

Based on previously established methods, we developed an easily available type 2 diabetic mouse model that exhibits obesity and insulin resistance. We investigated the effects of several antidiabetic drugs on this new model, which was induced by a high-fat diet in combination with streptozotocin and nicotinamide injection. Male ICR mice were fed a high-fat diet (45% of calories as fat) for 3weeks and then intraperitoneally administered with nicotinamide (1000mg/kg) and streptozotocin (150mg/kg). These diabetic mice exhibited hyperglycemia and glucose intolerance as a result of the loss of early-phase insulin secretion. The mice also developed significant insulin resistance, hyperlipidemia and obesity. A single dose of mitiglinide, glibenclamide, sitagliptin, insulin, metformin and voglibose significantly improved glucose tolerance during a liquid meal tolerance test. Repeated administration of sitagliptin and rosiglitazone also improved hyperglycemia and insulin resistance. These results demonstrate that a high-fat diet combined with nicotinamide and streptozotocin injection induces a diabetic mouse model that replicates the metabolic characteristics of human type 2 diabetes. This diabetic model, which exhibits impaired insulin secretion, glucose intolerance, insulin resistance, and obesity, may be suitable to evaluate antidiabetic agents for the treatment of type 2 diabetes.     

强化胰岛素治疗对糖尿病大鼠胰岛β细胞凋亡蛋白bcl-2和bax的影响

目的观察强化胰岛素治疗对糖尿病大鼠胰岛β细胞凋亡相关蛋白bcl-2和bax的影响。方法将36只Wistar大鼠随机分为对照组和高脂组,对照组给予基础饲料喂养,高脂组给予脂肪乳灌胃＋基础饲料喂养10d,然后给高脂组大鼠腹腔注射链脲佐菌素,3d后再将高脂组大鼠随机分为2个亚组,即糖尿病对照组和糖尿病治疗组,疗程4周。在脂肪乳灌胃第10天、注射STZ第3天和治疗4周末测大鼠各项指标;实验结束时用免疫组化法测大鼠胰岛β细胞凋亡相关蛋白bcl-2和bax的表达。结果大鼠在强化胰岛素治疗4周末,与糖尿病对照组相比,糖尿病治疗组的bcl-2蛋白表达升高,bax蛋白表达降低,两组差异均有统计学意义（均P〈0．05）。结论强化胰岛素治疗可增强2型糖尿病大鼠胰岛β细胞bcl-2蛋白表达,降低bax蛋白表达,减轻2型糖尿病大鼠胰岛β细胞凋亡。     

PPAR gamma agonists partially restores hyperglycemia induced aggravation of vascular dysfunction to angiotensin II in thoracic aorta isolated from rats with insulin resistance.

Altered vascular responses to various vasopressors in animal models of insulin resistance (IR) and diabetes have been well documented. However, the precise mechanisms about vascular responses in IR with or without frank hyperglycemia (prediabetic state) are not available. Moreover, recently the role of peroxisome proliferators activated receptor-gamma (PPAR gamma) has been linked to influence the vascular responses in hypertensive and diabetic state. Hence, the present study was conceived to determine the role of hyperglycemia on angiotensin II (Ang II) mediated vascular responses in the high fat diet (HFD) induced insulin resistance either with mild or frank hyperglycemia [induced by injection of low dose streptozotocin (STZ) to HFD fed rats (HFD+STZ)]. In addition, insulin-sensitizing agent such as rosiglitazone and pioglitazone were also studied on biochemical and vascular responses. Ang II-induced contractions were studied isometrically in thoracic aortic rings isolated from 4 weeks of normal pellet diet (NPD) fed control, HFD and HFD+STZ fed insulin resistant rats. Specific binding of Ang II receptors were carried out using radioligand ([(3)H]-Ang II) binding studies. After 4 weeks of HFD feeding, rats exhibited characteristics features of insulin resistance such as mild hyperglycemia, hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia and hypertension; whereas HFD+STZ treated rats showed all above parameters along with frank hyperglycemia. Maximal contractile response (E(max)) to Ang II is increased in HFD fed rats as compared to control rats. Moreover, E(max) values are further elevated in HFD+STZ group where the frank hyperglycemia was induced by low dose of streptozotocin. Rosiglitazone (5 mg kg(-1), p.o.) and pioglitazone (10 mg kg(-1), p.o.) treatment significantly lowered the plasma glucose, triglycerides, insulin and cholesterol levels in insulin resistance rats. In addition, it also restored the elevated systolic, mean arterial, diastolic blood pressure and attenuated the enhanced contractile responses to Ang II in thoracic aortic rings obtained from both HFD and HFD+STZ treated rats. Specific binding of [(3)H]-Ang II is upregulated in HFD-fed and HFD+STZ treated rats. Treatment with pioglitazone and rosiglitazone significantly decreased the AT(1)R specific binding in HFD fed rats. Our results indicate the role of hyperglycemia in the elevation of Ang II induced vascular responses in thoracic aorta isolated from insulin resistant rats and PPAR gamma agonists can attenuate these responses.     

2型糖尿病大鼠模型的建立与评价

目的：建立具有胰岛素抵抗特征、发病过程近似于人类2型糖尿病的动物模型。方法：雄性Wistar大鼠喂以富含不饱和脂肪酸的特殊高脂肪膳食5周，诱发出胰岛素抵抗．继之以小剂量链脲佐菌素（STZ，25mg／kg，腹腔注射）导致胰岛素代偿性分泌障碍，诱发高血糖症。应用正常血糖-高血浆胰岛素钳夹技术评价大鼠的胰岛素敏感性。结果：与常规饲料喂养大鼠相比，高脂膳食组的葡萄糖输注率显著降低，空腹血浆胰岛素显著升高。STZ注射后1周高脂膳食组大鼠血糖中度升高，血胰岛素下降，但仍高于普通饲料喂养组，且高脂血症和胰岛素抵抗继续存在。高脂饲料喂养组及高脂饲料＋小剂量STZ注射组大鼠的葡萄糖输注率显著低于正常对照组。结论：通过高脂膳食结合小剂量STZ注射成功复制出了实验性2型糖尿病动物模型，它是研究2型糖尿病发病机制、药物研究和胰岛素抵抗相关疾病的理想动物模型．     

Anti-diabetic effects of pentamethylquercetin in neonatally streptozotocin-induced diabetic rats

Pentamethylquercetin (PMQ), a methylated quercetin derivative, was screened for anti-diabetic effects in neonatally streptozotocin (STZ)-induced diabetic rats (n-STZ diabetic rats). Streptozotocin (90 mg/kg) was administered intraperitoneally to 2-day-old male pups to induce diabetes. PMQ was administered at doses of 2.5, 5, 10 and 20mg/kg/day orally when the rats were 6 weeks old and continued for 10 consecutive weeks. Body weights were followed. Fasting and fed glucose, triglyceride and insulin levels were monitored periodically at the 6th and 10th week after PMQ treatment. At the end of the study, oral glucose tolerance test was performed, and kidney and liver function parameters were assayed. It was found that PMQ intervention dose-dependently reduced postprandial glucose and triglyceride levels, prevented the onset of overt diabetes, ameliorated polydipsia symptom induced by diabetes, attenuated glucose intolerance, enhanced insulin sensitivity indices and decreased endogenous creatinine clearance rate, urinary albumin excretion rate and blood alanine aminotransferase levels of n-STZ diabetic rats in comparison to their diabetic counterparts. The results from the present study thus suggest that PMQ exhibits great potential as an antidiabetic agent by improving hyperglycemia and reducing the incidence of peripheral complications.     

Antihyperglycemic effect of T-1095 via inhibition of renal Na+-glucose cotransporters in streptozotocin-induced diabetic rats

T-1095, a derivative of phlorizin, is an orally active inhibitor of Na+-glucose cotransporter (SGLT). We investigated the acute antihyperglycemic effect of T-1095 in streptozotocin-induced diabetic rats (STZ rats). T-1095 and its metabolite T-1095A inhibited the SGLT activity in brush border membranes prepared from kidneys of both normal and STZ rats, but the latter agent was approximately 10 times more potent than the former. Single oral administration of T-1095 (30-100 mg/kg) dose-dependently induced glycosuria in normal rats. The fed glucose levels in STZ rats were dose-dependently suppressed by single oral administration of T-1095 (3-100 mg/kg), whereas there was only marginal hypoglycemic effect in normal rats. Since there was no effect on blood glucose in nephrectomized STZ rats, inhibition of renal glucose reabsorption rather than intestinal glucose absorption mainly contributes to the antihyperglycemic effect of T-1095. In conclusion, T-1095 is the first orally active agent which has an acute antihyperglycemic action in the absence of endogenous insulin secretion with a low risk of hypoglycemia and has therapeutic potential for treatment of diabetes mellitus.     

门冬胰岛素30强化治疗对初诊2型糖尿病患者胰岛功能的影响

目的:探讨短期门冬胰岛素30强化治疗对初诊2型糖尿病患者胰岛β细胞功能的影响。方法:对30例初诊2型糖尿病患者每日注射2次门冬胰岛素30,强化治疗2周,治疗前后分别进行口服葡萄糖耐量试验(OGTT)及胰岛素释放试验,测定0,30,120 min的血糖和胰岛素值,分别以稳态模型法β细胞功能指数(HOMA-β)评估β细胞功能,以稳态模型法胰岛素抵抗指数(HOMA-IR)评估胰岛素抵抗状况,以早相胰岛β细胞分泌指数(△I30/△G30,糖负荷30min净增胰岛素与净增葡萄糖的比值)评估早期胰岛素分泌能力。结果:经过短期门冬胰岛素30强化治疗后,患者空腹血糖(FPG)、餐后2 h血糖(2 hPG)、HOMA-IR均明显下降(P<0.05);而HOMA-β、△I30/△G30显著升高(P<0.001)。结论:短期门冬胰岛素30强化治疗能够明显改善初诊2型糖尿病患者胰岛分泌功能,减轻胰岛素抵抗,改善糖代谢。     

Effects of the combination of SGLT2 selective inhibitor ipragliflozin and various antidiabetic drugs in type 2 diabetic mice

The sodium-glucose cotransporter 2 (SGLT2) is responsible for most glucose reabsorption in the kidney and has been proposed as a novel therapeutic target for the treatment of type 2 diabetes. In the present study, the combinatory effects of SGLT2 selective inhibitor ipragliflozin and various antidiabetic drugs in high-fat diet and streptozotocin-nicotinamide-induced type 2 diabetic mice were investigated. Ipragliflozin dose-dependently increased urinary glucose excretion and improved glucose tolerance. In addition, each antidiabetic drug (mitiglinide, glibenclamide, sitagliptin, insulin, metformin, voglibose, or rosiglitazone) also significantly improved glucose tolerance without affecting urinary glucose excretion. Combination treatment of ipragliflozin with each antidiabetic drug additively improved glucose tolerance. In these experiments, ipragliflozin-induced increases in urinary glucose excretion were not influenced by combination treatment with antidiabetic drugs. Further, ipragliflozin did not affect antidiabetic drug-induced insulinotropic action (mitiglinide and glibenclamide), increases in plasma glucagon-like peptide-1 and insulin levels via inhibition of dipeptidyl peptidase 4 activity (sitagliptin), increases in plasma insulin level (insulin), decreases in hepatic phosphoenolpyruvate carboxykinase activity (metformin), inhibition of small intestinal disaccharidase activity (voglibose), or improvement of impaired insulin secretion (rosiglitazone). These results suggest that combination treatment of ipragliflozin with various antidiabetic drugs additively enhances the improvement in glucose tolerance without affecting each drug’s unique pharmacological effects. Ipragliflozin may therefore be expected to be effective when administered as part of a combination regimen in the treatment of type 2 diabetes.     

A novel long acting DPP-IV inhibitor PKF-275-055 stimulates β-cell proliferation resulting in improved glucose homeostasis in diabetic rats

The enzyme dipeptidyl peptidase-IV (DPP-4) inactivates the incretin hormone glucagon-like peptide-1 (GLP-1). GLP-1 has therapeutic effects in patients with type 2 diabetes, but its potential is limited by a short half-life, DPP-4 inhibition is a promising approach to diabetes treatment. This study examined chronic (once-a-day dosing for 8 weeks) effects of the DPP-4 inhibitor PKF-275-055 (1, 3, and 10mg/kg) on β-cell regeneration and plasma DPP-IV activity, intact GLP-1, glucose, and insulin after an oral glucose load in neonatal wistar rats injected with streptozotocin (STZ) (n2-STZ model), a recognized model of type 2 diabetes. In streptozotocin induced diabetic rats, PKF-275-055 (3, and 10mg/kg) significantly reduced glucose excursion during the oral glucose tolerance test conducted 2h and 10h after administration, with increases in plasma insulin and active glucagon-like peptide-1 (GLP-1) levels and significantly inhibited (> 50% inhibition) plasma DPP-IV activity during both the 1st and 2nd OGTT in diabetic rats. In contrast, PKF-275-055 (1-10mg/kg) did not cause hypoglycemia in fasted normal rats. Furthermore, PKF-275-055 significantly inhibited advance glycation end product (HbA1c), HOMA-Index, gastric emptying and small intestinal transit rates, with significance at doses of 1mg/kg or higher. Immunological staining showed PKF-275-055 stimulates β-cell regeneration and reduces pancreatic cell apoptosis in diabetic treated rats. The present preclinical studies indicate that PKF-275-055 is a novel selective DPP-IV inhibitor with long-acting antidiabetic effect that might be a potential agent for type 2 diabetes.     

Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: a model for type 2 diabetes and pharmacological screening.

The objective of the present study was to develop a rat model that replicates the natural history and metabolic characteristics of human type 2 diabetes and is also suitable for pharmacological screening. Male Sprague-Dawley rats (160-180 g) were divided into two groups and fed with commercially available normal pellet diet (NPD) (12% calories as fat) or in-house prepared high-fat diet (HFD) (58% calories as fat), respectively, for a period of 2 weeks. The HFD-fed rats exhibited significant increase in body weight, basal plasma glucose (PGL), insulin (PI), triglycerides (PTG) and total cholesterol (PTC) levels as compared to NPD-fed control rats. Besides, the HFD rats showed significant reduction in glucose disappearance rate (K-value) on intravenous insulin glucose tolerance test (IVIGTT). Hyperinsulinemia together with reduced glucose disappearance rate (K-value) suggested that the feeding of HFD-induced insulin resistance in rats. After 2 weeks of dietary manipulation, a subset of the rats from both groups was injected intraperitoneally with low dose of streptozotocin (STZ) (35 mg kg(-1)). Insulin-resistant HFD-fed rats developed frank hyperglycemia upon STZ injection that, however, caused only mild elevation in PGL in NPD-fed rats. Though there was significant reduction in PI level after STZ injection in HFD rats, the reduction observed was only to a level that was comparable with NPD-fed control rats. In addition, the levels of PTG and PTC were further accentuated after STZ treatment in HFD-fed rats. In contrast, STZ (35 mg kg(-1), i.p.) failed to significantly alter PI, PTG and PTC levels in NPD-fed rats. Thus, these fat-fed/STZ-treated rats simulate natural disease progression and metabolic characteristics typical of individuals at increased risk of developing type 2 diabetes because of insulin resistance and obesity. Further, the fat-fed/STZ-treated rats were found to be sensitive for glucose lowering effects of insulin sensitizing (pioglitazone) as well as insulinotropic (glipizide) agents. Besides, the effect of pioglitazone and glipizide on the plasma lipid parameters (PTG and PTC) was shown in these diabetic rats. The present study represents that the combination of HFD-fed and low-dose STZ-treated rat serves as an alternative animal model for type 2 diabetes simulating the human syndrome that is also suitable for testing anti-diabetic agents for the treatment of type 2 diabetes.     

小剂量阿司匹林对糖尿病大鼠胰腺功能和凋亡相关蛋白的研究

目的研究小剂量阿司匹林对糖尿病大鼠胰腺功能和凋亡相关蛋白的影响。方法雄性SD大鼠,尾静脉注射链脲佐菌素30mg/kg,造成1型糖尿病动物模型,随机分为糖尿病模型组和9 mg/kg阿司匹林治疗组(ASA治疗组),每组8只,另选8只健康雄性大鼠为正常对照组。各组大鼠灌服给药12周后,检测各组大鼠空腹血糖、血清胰岛素水平,免疫组化法检测分析Caspase-3、Bax和Bcl-2的表达情况。结果与正常对照组比较,糖尿病模型组大鼠空腹血糖提高、血清胰岛素水平降低,胰岛素抵抗指数升高;胰腺组织Caspase-3、Bax表达增强,Bcl-2的表达减弱,Bcl-2/Bax比值降低;ASA治疗组大鼠,血糖减低,胰岛素提高,减低Caspase-3、Bax表达,提升Bcl-2的表达,并明显提高Bcl-2/Bax比值。结论小剂量阿司匹林对糖尿病大鼠胰岛素分泌功能有保护作用,可能与调节胰腺细胞凋亡相关蛋白表达有关。