{"title":"Pharmacological effect of ZYGK1, a novel glucokinase activator, in hyperglycemic and sulfonylurea-resistant type 2 diabetes in mice models","authors":"Kalpesh Patani , Amit Joharapurkar , Rajesh Sundar , Samadhan Kshirsagar , Sunil Metiya , Ashutosh Kumar , Mukul Jain","doi":"10.1016/j.jdiacomp.2025.108977","DOIUrl":null,"url":null,"abstract":"<div><h3>Objectives</h3><div>Type 2 diabetes is caused due to inadequate glucose utilization in the liver and pancreas due to insulin resistance. Glucokinase enzyme plays a key role in metabolism of glucose and insulin release and hence glucokinase activation can be a useful therapeutic target for treatment of type 2 diabetes.</div></div><div><h3>Methods</h3><div>Present study was conducted to investigate the effect of a novel glucokinase activator ZYGK1 in the preclinical models of diabetes in mice. The activity of ZYGK1 was evaluated using recombinant glucokinase, and isolated islets and hepatocytes. Acute effect on glucose disposal was evaluated in C57 mice and repeated dose effect was assessed in db/db mice, along with the evaluation in sulfonylurea-resistance db/db mice.</div></div><div><h3>Results</h3><div>ZYGK1 has potent glucokinase stimulating activity with EC50 of 43 nM and increased glucokinase activity in islets and hepatocytes in a dose-related manner. Oral administration of ZYGK1 (0.1 to 10 mg/kg) showed dose dependently improved glucose disposal and glucose dependent insulin secretion in oral glucose tolerance test (OGTT) in C57 mice. Repeated dose administration of ZYGK1 improved glucose homeostasis and nondiabetic as well as diabetic mice and sulfonylurea-resistant db/db mice.</div></div><div><h3>Conclusion</h3><div>ZYGK1 appears to be a potential therapeutic option for the treatment of type 2 diabetes owing to its action in the liver and pancreas, and in conditions resistant to sulfonylurea therapy.</div></div>","PeriodicalId":15659,"journal":{"name":"Journal of diabetes and its complications","volume":"39 3","pages":"Article 108977"},"PeriodicalIF":3.1000,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of diabetes and its complications","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1056872725000303","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
引用次数: 0
Abstract
Objectives
Type 2 diabetes is caused due to inadequate glucose utilization in the liver and pancreas due to insulin resistance. Glucokinase enzyme plays a key role in metabolism of glucose and insulin release and hence glucokinase activation can be a useful therapeutic target for treatment of type 2 diabetes.
Methods
Present study was conducted to investigate the effect of a novel glucokinase activator ZYGK1 in the preclinical models of diabetes in mice. The activity of ZYGK1 was evaluated using recombinant glucokinase, and isolated islets and hepatocytes. Acute effect on glucose disposal was evaluated in C57 mice and repeated dose effect was assessed in db/db mice, along with the evaluation in sulfonylurea-resistance db/db mice.
Results
ZYGK1 has potent glucokinase stimulating activity with EC50 of 43 nM and increased glucokinase activity in islets and hepatocytes in a dose-related manner. Oral administration of ZYGK1 (0.1 to 10 mg/kg) showed dose dependently improved glucose disposal and glucose dependent insulin secretion in oral glucose tolerance test (OGTT) in C57 mice. Repeated dose administration of ZYGK1 improved glucose homeostasis and nondiabetic as well as diabetic mice and sulfonylurea-resistant db/db mice.
Conclusion
ZYGK1 appears to be a potential therapeutic option for the treatment of type 2 diabetes owing to its action in the liver and pancreas, and in conditions resistant to sulfonylurea therapy.
期刊介绍：
Journal of Diabetes and Its Complications (JDC) is a journal for health care practitioners and researchers, that publishes original research about the pathogenesis, diagnosis and management of diabetes mellitus and its complications. JDC also publishes articles on physiological and molecular aspects of glucose homeostasis.
The primary purpose of JDC is to act as a source of information usable by diabetes practitioners and researchers to increase their knowledge about mechanisms of diabetes and complications development, and promote better management of people with diabetes who are at risk for those complications.
Manuscripts submitted to JDC can report any aspect of basic, translational or clinical research as well as epidemiology. Topics can range broadly from early prediabetes to late-stage complicated diabetes. Topics relevant to basic/translational reports include pancreatic islet dysfunction and insulin resistance, altered adipose tissue function in diabetes, altered neuronal control of glucose homeostasis and mechanisms of drug action. Topics relevant to diabetic complications include diabetic retinopathy, neuropathy and nephropathy; peripheral vascular disease and coronary heart disease; gastrointestinal disorders, renal failure and impotence; and hypertension and hyperlipidemia.
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