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Adropin and glucagon-like peptide-2 are associated with glucose metabolism in obese children

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World Journal of Pediatrics 2019年第6期15卷 565-571页

作者： Rui-Min Chen Xin Yuan Qian Ouyang Xiang-Quan Lin Zhuan-Zhuan Ai Ying Zhang Xiao-Hong Yang Department of Endocrinology Fuzhou Children's Hospital of Fujian ProvinceFujian Medical University Teaching HospitalNo.145817 Middle RoadFuzhou 350005China

Background The interaction of adropin,glucagon-like peptide-2(GLP2),angiopoietin-like protein 4(ANGPTL4),and with childhood obesity and glucose metabolism is *** study is to evaluate the association of the three cytokines and glucose *** This was a cross-sectional study of children with obesity ranging from 5 to 14 years compared to age-and sex-matched children of normal *** plasma glucose(FPG),oral glucose tolerance test 2-hour plasma glucose(OGT-T2hPG),and insulin(INS)were measured,and serum adropin,GLP2,and ANGPTL41evels were measured by enzyme-linked immunosorbent *** body mass index(BMI),BMI-Z scores,waist-to-hip ratio(WHR),and homeostasis model assessment of insulin resistance(HOMA-IR)were *** Thirty-nine children(9.70±1.71 years,18 females)with obesity and 29 normal weight children(8.98±1.98 years,16 females)were *** levels of INS,HOMA-IR and GLP2 of the obesity group were significantly higher than the controls(P<0.05).Pearson correlation analysis showed that serum GLP2 was positively associated with WHR,FPG,and OGTT2hPG,and adropin was negatively associated with BMI,BMI-Z,WHR,INS,and HOMA-IR(all P<0.05).Further-more,GLP2 were negatively associated with adropin and ANGPTL4(both P<0.05).By binary logistic regression,adropin and GLP2 were found to be independent markers of *** linear regression showed that GLP2 was associated with OGTT2hPG,and adropin was associated with INS and HOMA-IR(all P<0.05).Conclusions Obese children had elevated GLP2 concentrations,and adropin and GLP2 associated with both childhood obesity and glucose ***,there may be a physiologic interplay between adropin and GLP2 in obese children.

关键词： Adropin Children glucagon-like peptide-2 Glucose metabolism Obesity

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

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 < 0.05). Post-ischemic administration of insulin or GLP-1 a had no effect on infarct size. However, pre-ischemic administration of GLP-1 a reduced infarct size to 12% ± 2.2%(P < 0.05). The maximal infarct size reduction was observed in the group treated with GLP-1 a prior to ischemia and insulin at reperfusion(8% ± 1.6%, P < 0.05 vs the control and GLP-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

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

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

glucagon-like peptide 1 in the pathophysiology and pharmacotherapy of clinical obesity

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World Journal of Diabetes 2016年第20期7卷 572-598页

作者： Ananthi Anandhakrishnan Márta Korbonits Centre for Endocrinology William Harvey Research InstituteBarts and the London School of Medicine and DentistryQueen Mary University of London

Though the pathophysiology of clinical obesity is un-doubtedly multifaceted, several lines of clinical evidence implicate an important functional role for glucagon-like peptide 1(GLP-1) signalling. Clinical studies assessing GLP-1 responses in normal weight and obese subjects suggest that weight gain may induce functional deficits in GLP-1 signalling that facilitates maintenance of the obesity phenotype. In addition, genetic studies implicate a possible role for altered GLP-1 signalling as a risk factor towards the development of obesity. As reductions in functional GLP-1 signalling seem to play a role in clinical obesity, the pharmacological replenishment seems a promising target for the medical management of obesity in clinical practice. GLP-1 analogue liraglutide at a high dose(3 mg/d) has shown promising results in achieving and maintaining greater weight loss in obese individuals compared to placebo control, and currently licensed antiobesity medications. Generally well tolerated, provided that longer-term data in clinical practice supports the currently available evidence of superior short- and longterm weight loss efficacy, GLP-1 analogues provide promise towards achieving the successful, sustainable medical management of obesity that remains as yet, an unmet clinical need.

关键词： Obesity pathophysiology glucagon-like peptide 1 analogues glucagon-like peptide 1 Clinical obesity

glucagon-like peptide 1 receptor governs Wnt signaling to promote bone formation

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中国药理学通报 2015年第B11期31卷 7-7页

作者： MENGJing-ru MAXue WANGNing JIAMin ZHANGHui-nan LLUOXiao-xing DepartmentofPharmacology FourthMilitaryMedicalUniversityXi'an710032

Our previous investigation found that exendin-4 （Ex-4） , a peptide analogue of glucagon-like peptide 1 （GLP-1） , induced bone formation probably by osteoblast activation. Nevertheless, previous investigations did not observe any expression of GLP-1 receptors in osteoblasts, indicating that the direct cell target of GLP-1 and its ana- logues might not be osteoblasts but some other types of cells yet to be identified. To elucidate the underlying mecha- nisms, we performed further investigation in the present study and found that GLP-1 receptor was only identified in bone marrow mesenchymal stem cells （BMSCs）. Furthermore, activation of GLP-1 receptor by Ex-4 promoted the differentiation of B MSCs into osteoblast, which was associated with activation of PKA, nuclear translocation of [5- catenin, activation of PI3K/AKT and inhibition of GSK3β. Ex-4 also inhibited the adipocyte differentiation of BM- SCs, as evidenced by inhibition of PPARγ, lipoprotein lipase expression and lipid production. Blockade of GLP-1 receptor, PKA, PI3K or Wnt pathway, or respective knock-down of GLP-1 receptor and β-catenin in BMSCs inhib- ited the Ex-4 mediated effects. The results indicated that the GLP-1 receptor mediated osteoblastic differentiation and bone formation through stimulation of PKA/β-catenin signaling and inhibition of PKA/PI3IC/AKT/GSK3β？ signaling pathway in BMSCs. The findings reveal a new role of GLP-1 receptor for regulating osteoblastic differentia- tion of B MSCs and may provide a molecular basis for novel anabolic therapeutics against osteoporosis.

关键词： exendin-4 glucagon-like peptide 1 receptor mesenchymal stem cells osteoblast osteoporosis

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

Effects of glucagon-like peptide-1 receptor agonists on renal function

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World Journal of Diabetes 2013年第5期4卷 190-201页

作者： Theodosios D Filippatos Moses S Elisaf Department of Internal Medicine School of MedicineUniversity of Ioannina

glucagon-like peptide-1(GLP-1)receptor agonists result in greater improvements in glycemic control than placebo and promote weight loss with minimal hypoglycemia in patients with type 2 diabetes mellitus.A number of case reports show an association of GLP-1receptor agonists,mainly exenatide,with the development of acute kidney *** present review aims to present the available data regarding the effects of GLP-1 receptor agonists on renal function,their use in subjects with chronic renal failure and their possible association with acute kidney *** on the current evidence,exenatide is eliminated by renal mechanisms and should not be given in patients with severe renal impairment or end stage renal *** is not eliminated by renal or hepatic mechanisms,but it should be used with caution since there are only limited data in patients with renal or hepatic *** is evidence from animal studies that GLP-1 receptor agonists exert protective role in diabetic nephropathy with mechanisms that seem to be independent of their glucose-lowering ***,there is evidence that GLP-1 receptor agonists influence water and electrolyte *** effects may represent new ways to improve or even prevent diabetic nephropathy.

关键词： glucagon-like peptide 1 glucagon-like peptide 1 receptor agonists Exenatide Liraglutide Kidney Renal impairment Diabetic nephropathy Electrolytes