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Coagonist of glucagon-like peptide-1 and glucagon receptors ameliorates kidney injury in murine models of obesity and diabetes mellitus

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World Journal of Diabetes 2018年第6期9卷 80-91页

作者： Vishal J Patel Amit A Joharapurkar Samadhan G Kshirsagar Brijesh K Sutariya Maulik S Patel Hiren M Patel Dheerendra K Pandey Rajesh H Bahekar Mukul R Jain Department of Pharmacology and Toxicology Zydus Research CentreCadila Healthcare Limited

AIM To investigate the role of glucagon-like peptide-1(GLP-1)/glucagon receptors coagonist on renal dysfunction associated with diabetes and obesity. METHODS Chronic high-fat diet fed C57 BL/6 J mice, streptozotocintreated high-fat diet fed C57 BL/6 J mice and diabeticC57 BLKS/J db/db mice were used as models of diabetes-induced renal dysfunction. The streptozotocintreated high-fat diet fed mice and db/db mice were treated with the GLP-1 and glucagon receptors coagonist(Aib2 C24 Chimera2, 150 μg/kg, sc) for twelve weeks, while in chronic high-fat diet fed mice, coagonist(Aib2 C24 Chimera2, 150 μg/kg, sc) treatment was continued for forty weeks. Kidney function, histology, fibrosis, inflammation, and plasma biochemistry were assessed at the end of the treatment. RESULTS Coagonist treatment decreased body weight, plasma lipids, insulin resistance, creatinine, blood urea nitrogen, urinary albumin excretion rate and renal lipids. In kidney, expression of lipogenic genes(SREBP-1 C, FAS, and SCD-1) was decreased, and expression of genes involved in β-oxidation(CPT-1 and PPAR-α) was increased due to coagonist treatment. In plasma, coagonist treatment increased adiponectin and FGF21 and decreased IL-6 and TNF-?. Coagonist treatment reduced expression of inflammatory(TNF-α, MCP-1, and MMP-9) and pro-fibrotic(TGF-β, COL1 A1, and α-SMA) genes and also improved histological derangement in renal *** Coagonist of GLP-1 and glucagon receptors alleviated diabetes and obesity-induced renal dysfunction by reducing glucose intolerance, obesity, and hyperlipidemia.

关键词： Coagonist Glucagon Renal dysfunction Glucagon-like peptide-1 Insulin sensitivity

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Development of therapeutic options on type 2 diabetes in years:Glucagon-like peptide-1 receptor agonist’s role intreatment; from the past to future

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World Journal of Diabetes 2019年第8期10卷 446-453页

作者： Hakan Dogruel Mustafa Kemal Balci Department of Internal Medicine Antalya Ataturk State HospitalAntalya 07040Turkey Akdeniz University Faculty of Medicine Department of Internal MedicineDivision of Endocrinology and MetabolismAntalya 07070Turkey

Diabetes mellitus (DM) is a chronic metabolic disease characterized by *** 2 diabetes (T2DM) accounting for 90% of cases *** worldwide prevalence of DM is rising dramatically over the last decades,from 30 million cases in 1985 to 382 million cases in ***’s estimated that 451 million people had diabetes in *** the pathophysiology was understood over the years,treatment options for diabetes ***-based therapy is one of ***-like peptide-1 receptor agonist (GLP-1 RA) not only significantly lower glucose level with minimal risk of hypoglycemia but also,they have an important advantage in themanagement of cardiovascular risk and ***,we will review here GLP-1 RAsrole in the treatment of diabetes.

关键词： Incretin-basedtherapy Incretin mimetics Glucagon-like peptide-1 receptor agonist Dipeptidyl peptidase-4 inhibitor

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Exercise and glucagon-like peptide-1: Does exercise potentiate the effect of treatment?

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World Journal of Diabetes 2018年第8期9卷 138-140页

作者： Hidetaka Hamasaki Endocrinology and Metabolism Internal Medicine Hamasaki Clinic

Recently, glucagon-like peptide-1(GLP-1) receptor agonists have become a cornerstone for the treatment of obese patients with type 2 diabetes(T2D), exhibiting favorable effects on the cardiovascular outcome. In T2D, impaired GLP-1 secretion/function is observed, and gut microbiota dysbiosis is related to the GLP-1 resistance. Prior research has revealed that exercise increases GLP-1 levels in healthy and obese individuals; however, the efficacy of exercise on GLP-1 levels in patients with T2D remains unclear. Exercise may improve GLP-1 resistance rather than GLP-1 secretion in patients with T2D. Exercise increases the gut microbiota diversity, which could contribute to improving the GLP-1 resistance of T2D. Furthermore, the gut microbiota may play a role in the correlation between exercise and GLP-1. The combination of exercise and GLP-1-based therapy may have a synergistic effect on the treatment of T2D. Although the underlying mechanism remains unknown, exercise potentiates the efficacy of GLP-1 receptor agonist treatment in patients with T2D.

关键词： Type 2 diabetes Exercise Glucagon-like peptide-1 Gut microbiota Myokine

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Glucagon-like peptide-1 receptor agonists favorably address all components of metabolic syndrome

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World Journal of Diabetes 2016年第18期7卷 441-448页

作者： Sanjay Chatterjee Samit Ghosal Saurav Chatterjee Apollo Gleneagles Hospitals Kolkata 700054India Nightingale Hospital Kolkata 700071 India Cardiovascular Diseases St. Luke’s - Roosevelt Hospital Center New York NY 100019 United States

Cardiovascular death is the leading cause of mortality for patients with type 2 diabetes mellitus. The etiologyof cardiovascular disease in diabetes may be divided into hyperglycemia per se and factors operating through components of metabolic syndrome(Met S). Hyperglycemia causes direct injury to vascular endothelium and possibly on cardiac myocytes. Met S is a cluster of risk factors like obesity, hyperglycemia, hypertension and dyslipidemia. The incidence of this syndrome is rising globally. Glucagon-like peptide-1 receptor agonists(GLP-1RA) are a group of drugs, which address all components of this syndrome favorably. Experimental evidence suggests that they have favorable actions on myocardium as well. Several compounds belonging to GLP-1RA class are in market now and a large number awaiting their entry. Although, originally this class of drugs emerged as a treatment for type 2 diabetes mellitus, more recent data generated revealed beneficial effects on multiple metabolic parameters. We have studied literature published between 2000 and 2016 to look into effects of GLP-1RA on components of Met S. Results from recently concluded clinical trials suggest that some of the molecules in this class may have favorable effects on cardiovascular outcome.

关键词： Metabolic syndrome Diabetes Glucagonlike peptide-1 receptor agonists Lipids Body weight Microalbuminuria

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Glucagon-like peptide-1 analogue prevents nonalcoholic steatohepatitis in non-obese mice

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World Journal of Gastroenterology 2016年第8期22卷 2512-2523页

作者： Takaya Yamamoto Yukiomi Nakade Taeko Yamauchi Yuji Kobayashi Norimitsu Ishii Tomohiko Ohashi Kiyoaki Ito Ken Sato Yoshitaka Fukuzawa Masashi Yoneda Division of Hepatology and Pancreatology Department of Internal Medicine Aichi Medical University

AIM: To investigate whether a glucagon-like peptide-1(GLP-1) analogue inhibits nonalcoholic steatohepatitis(NASH), which is being increasingly recognized in Asia, in non-obese mice. METHODS: A methionine-choline-deficient diet(MCD) along with exendin-4(20 μg/kg per day, ip), a GLP-1 analogue, or saline was administered to male db/db mice(non-obese NASH model). Four or eight weeks after commencement of the diet, the mice were sacrificed and their livers were excised. The excised livers were examined by histochemistry for evidence of hepatic steatosis and inflammation. Hepatic triglyceride(TG) and free fatty acid(FFA) content was measured, and the expression of hepatic fat metabolism- and inflammation-related genes was evaluated. Oxidative stress-related parameters and macrophage recruitment were also examined using ***: Four weeks of MCD feeding induced hepatic steatosis and inflammation and increased the hepatic TG and FFA content. The expression of fattyacid transport protein 4(FATP4), a hepatic FFA influxrelated gene; macrophage recruitment; and the level of malondialdehyde(MDA), an oxidative stress marker, were significantly augmented by a 4-wk MCD. The levels of hepatic sterol regulatory element-binding protein-1c(SREBP-1c) m RNA(lipogenesis-related gene) and acyl-coenzyme A oxidase 1(ACOX1) m RNA(β-oxidation-related gene) had decreased at 4 wk and further decreased at 8 wk. However, the level of microsomal triglyceride transfer protein m RNA(a lipid excretion-related gene) remained unchanged. The administration of exendin-4 significantly attenuated the MCD-induced increase in hepatic steatosis, hepatic TG and FFA content, and FATP4 expression as well as the MCD-induced augmentation of hepatic inflammation, macrophage recruitment, and MDA levels. Additionally, it further decreased the hepatic SREBP-1c level and alleviated the MCD-mediated inhibition of the ACOX1 m RNA level. CONCLUSION: These results suggest that GLP-1 inhibits hepatic s

关键词： Glucagon like peptide-1 Nonalcoholic steatohepatitis Kupffer cells Free fatty acid Oxidative stress

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Berberine promotes glucagon-like.-peptide-1(7-36)amide secretion in streptozotocin-induced diabetic rats

Berberine promotes glucagon-like.-peptide-1(7-36)amide secre...

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中国药学会应用药理专业委员会第三届学术会议、中国药理学会制药工业专业委员会第十三届学术会议暨2008生物医药学术论坛

作者： Shousi Lu Yunli Yu SenYu Li Liu Yaowu Liu Lin Xie Guangii Wang Xiaodong Liu Key lab of drug metabolism & pharmacokinetics,China pharmaceutical university,Nanjing 210009 Yongge Yang Qixian people hospital Hebi district,Henan,456750,China

Objectives One of the most important challenges in diabetes mellitus treatment is to find a kind of natural product to promote biosynthesis or increase release of gut peptides such as Glucagon-like peptide-1

关键词： GLP Berberine promotes glucagon-like amide secretion in streptozotocin-induced diabetic rats peptide-1

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Elevated glucagon-like peptide-1 on a high-fat diet feeding prevents the incidence of diabetes mellitus in Spontaneously Diabetic Torii <i>Lepr<sup>fa</sup></i>rats

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Journal of Diabetes Mellitus 2012年第2期2卷 170-178页

作者： Takahiro Hata Takeshi Ohta Yukihito Ishii Tomohiko Sasase Takayuki Yamaguchi Yasuko Mera Katsuhiro Miyajima Gimpei Tanoue Eimei Sato Mutsuyoshi Matsushita Japan Tobacco Inc. Central Pharmaceutical Research Institute Osaka Japan Japan Tobacco Inc. Central Pharmaceutical Research Institute Toxicology Research Laboratories Hadano Japan Laboratory of Animal Reproduction Graduate School of Agricultural Science Tohoku University Sendai Japan

Nutritional regulation plays a critical role to reduce the incidence or progression of diabetes mellitus. In this study, we investigated the effects of a high-fat diet on Spontaneously Diabetic Torii Leprfa (SDT fatty) rats, a novel model for obese type 2 diabetes. The SDT fatty rats were divided into two dietary groups, which were fed a high-fat diet or a standard diet for 18 weeks, from 6 to 24 weeks of age. The calorie intake in the high-fat diet (HF) group was reduced after 10 weeks of age and the group inhibited an incidence of diabetes. Interestingly, the HF induced an increase of serum glucagon-like peptide-1 (GLP-1) levels in SDT fatty rats with refeeding. Fat tissue weights in the HF group increased, but the visceral fat/subcutaneous fat (V/S) ratio decreased. Moreover, histopathological observations revealed an improvement of the pancreatic abnormalities and fatty liver in the HF group. In conclusion, a preventive effect on diabetes in rats fed a high-fat diet has a relation with an increase in incretin hormone, and it might be advantageous for prevention of incidence or progression of diabetes to develop functional foods inducing an increase in incretin hormone.

关键词： Glucagon-Like peptide-1 High Fat Diets SDT Fatty Rats

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Risk of pancreatic adverse events associated with the use of glucagon-like peptide-1 receptor agonist and dipeptidyl peptidase-4 inhibitor drugs: A systematic review and metaanalysis of randomized trials

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World Journal of Meta-Analysis 2015年第6期3卷 254-283页

作者： Hasan M Shihab Tokunbo Akande Kacie Armstrong Sonal Singh Yoon K Loke Division of Acute Care Surgery Johns Hopkins University School of Medicine Department of Pediatrics Bronx-Lebanon Hospital Center Division of General Internal Medicine Johns Hopkins University School of Medicine Norwich Medical School University of East Anglia

AIM: To systematically assess risk of pancreatic adverse events with glucagon-like peptide-1(GLP-1) receptor agonist and dipeptidyl peptidase-4(DPP-4) inhibitor ***: We searched Pub Med, Embase, CINAHL, Cochrane review of clinical trials, pharmaceutical company clinical trials register, United States Food and Drug Administration website, European Medicines Agency website and Clinical *** for randomized controlled trials from inception to October 2013. Randomized control trial studies were selected for inclusion if they reported on pancreatic complication events and/or changes in pancreatic enzyme levels(serum amylase and serum lipase) as adverse events or as serious adverse events for patients who were on GLP-1 receptor agonist and DPP-4 inhibitor drugs. Two independent reviewers extracted data directly. We performed Peto odds ratio(OR) fixed effect meta-analysis of pancreatic adverse events a, and assessed heterogeneity with the I^2 ***: Sixty-eight randomized controlled trials were eligible. A total of 60720 patients were included in our analysis of the association of risk of pancreatic complication events with GLP-1 agents. A total of 89 pancreatic related adverse events occurred among the GLP-1 agents compared to 74 events among the controls. There was a statistically significant increased risk of elevation of pancreatic enzymes associated with GLP-1 agents compared with control(Peto OR = 3.15, 95%CI: 1.56-6.39, P = 0.001, I2 = 0%). There was no statistically significant difference in the risk of pancreatic adverse event associated with GLP-1 agent compared with controls(Peto OR = 1.00, 95%CI: 0.73-1.37, P = 1.00, I2 = 0%). There were a total of 71 pancreatitis events in patients on GLP-1 agents and 56 pancreatitis events occurred in the control patients. There were 36 reports of pancreatic cancer in these studies. Of these cases, 2 used linagliptin, 2 used alogliptin, 1 used vildagliptin, 7 used saxagliptin while 6 used sitaglipti

关键词： Diabetes mellitus Pancreatitis Glucagon-like peptide-1 agonists Dipeptidyl peptidase-4 inhibitors Meta-analysis

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Effects of glucagon-like peptide 1 analogs in combination with insulin on myocardial infarct size in rats with type 2 diabetes mellitus

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World Journal of Diabetes 2018年第9期9卷 149-156页

作者： Vladislav A Zykov Taisiia P Tuchina Denis A Lebedev Irina B Krylova Alina Y Babenko Elvira V Kuleshova Elena N Grineva Alekber A Bayramov Michael M Galagudza Almazov National Medical Research Centre St-Petersburg 197341Russia Institute of Experimental Medicine St-Petersburg 197376Russia

AIM To evaluate the effects of glucagon-like peptide-1 analogs(GLP-1 a) combined with insulin on myocardial ischemiareperfusion injury in diabetic *** Type 2 diabetes mellitus(T2 DM) was induced in maleWistar rats with streptozotocin(65 mg/kg) and verified using an oral glucose tolerance test. After anesthesia, the left coronary artery was occluded for 40 min followed by 80 min reperfusion. Blood glucose level was measured during surgery. Rats were randomized into six groups as follows:(1) control rats;(2) insulin(0.1 U/kg) treated rats prior to ischemia;(3) insulin(0.1 U/kg) treated rats at reperfusion;(4) GLP-1 a(140 mg/kg) treated rats prior to ischemia;(5) GLP-1 a(140 mg/kg) treated rats at reperfusion; and(6) rats treated with GLP-1 a(140 mg/kg) prior to ischemia plus insulin(0.1 U/kg) at reperfusion. Myocardial area at risk and infarct size was measured planimetrically using Evans blue and triphenyltetrazolium chloride staining, *** There was no significant difference in the myocardial area at risk among groups. Insulin treatment before ischemia resulted in a significant increase in infarct size(34.7% ± 3.4% vs 18.6% ± 3.1% in the control rats, P 1 a had no effect on infarct size. However, pre-ischemic administration of GLP-1 a reduced infarct size to 12% ± 2.2%(P 1 a prior to ischemia and insulin at reperfusion(8% ± 1.6%, P 1 a alone treated groups).CONCLUSION GLP-1 a pre-administration results in myocardial infarct size reduction in rats with T2 DM. These effects are maximal in rats treated with GLP-1 a pre-ischemia plus insulin at reperfusion.

关键词： Glucagon-like peptide-1 analog Insulin Myocardial ischemia-reperfusion injury Infarct size Type 2 diabetes mellitus Rats Experimental research

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Prediction of the effect on antihyperglycaemic action of sitagliptin by plasma active form glucagon-like peptide-1

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世界糖尿病杂志：英文版（电子版） 2016年第11期7卷 230-238页

作者： Akifumi Kushiyama Takako Kikuchi Kentaro Tanaka Tazu Tahara Toshiko Takao Yukiko Onishi Yoko Yoshida Shoji Kawazu Yasuhiko Iwamoto Division of Diabetes and Metabolism Institute for Adult Diseases Asahi Life Foundation Department of Nephrology School of Medicine Faculty of Medicine Toho University

AIM: To investigate whether active glucagon-like peptide-1(GLP-1) is a prediction Factor of Effect of sitagliptin on patients with type 2 diabetes mellitus(GLP-1 FEST:UMIN000010645). METHODS: Seventy-six patients with type 2 diabetes, who had insufficient glycemic control [Hemoglobin A1c(Hb A1c) ≥ 7%] in spite of treatment with metformin and/or sulfonylurea, were included in the investigation. Patients were divided into three groups by tertiles of fasting plasma active GLP-1 level, before the administration of 50 mg sitagliptin. RESULTS: At baseline, body mass index, serum UA, insulin and HOMA-IR were higher in the high active GLP-1 group than in the other two groups. The high active GLP-1 group did not show any decline of Hb A1c(7.6% ± 1.4% to 7.5% ± 1.5%), whereas the middle and low groups indicated significant decline of Hb A1c(7.4 ± 0.7 to 6.8 ± 0.6 and 7.4 ± 1.2 to 6.9 ± 1.3, respectively) during six months. Only the low and middle groups showed a significant increment of active GLP-1, C-peptide level, a decreased log and proinsulin/insulin ratio after administration. In logistic analysis, the low or middle group is a significantexplanatory variable for an Hb A1 c decrease of ≥ 0.5%, and its odds ratio is 4.5(1.40-17.6)(P = 0.01) against the high active GLP-1 group. This remains independent when adjusted for Hb A1 c level before administration, patients' medical history, medications, insulin secretion and insulin ***: Plasma fasting active GLP-1 is an independent predictive marker for the efficacy of dipeptidyl peptidase 4 inhibitor sitagliptin.

关键词： Dipeptidyl peptidase-4 inhibitor Active form glucagon-like peptide-1 Hemoglobin A1c Regression analysis

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