Targeting alpha-cell GPCRs to stimulate glucagon and counter hypoglycemia

靶向 α 细胞 GPCR 刺激胰高血糖素并对抗低血糖

• 批准号: 10675646
• 负责人: Kimberley M El
• 金额: $ 10.57万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10675646
• 关键词: Acute; Adrenal Glands; Alanine; Alpha Cell; Amino Acids; Arginine; Automobile Driving; Awareness; Biological Assay; Biology; Blood Glucose; Brain; Carbohydrates; Carbon; Catecholamines; Cell Communication; Cell physiology; Cells; Clinical; Cognition; Complex; Complication; Dangerousness; Diabetes Mellitus; Dose; Drops; Emergency Situation; Emergency treatment; Energy-Generating Resources; Etiology; Exposure to; Foundations; Functional disorder; G-Protein-Coupled Receptors; Gastric Inhibitory Polypeptide; Generations; Glass; Glucagon; Glucose; Hepatic; Human; Hydrocortisone; Hypoglycemia; Impairment; Ingestion; Insulin; Insulin-Dependent Diabetes Mellitus; Label; Life; Measures; Metabolic; Metabolism; Methods; Modeling; Molecular; Mus; Neurons; Non obese; Pathway interactions; Patients; Persons; Physiological; Physiology; Recurrence; Research Personnel; Schedule; Serious Adverse Event; Stimulus; Strenuous Exercise; Streptozocin; System; Technical Expertise; Testing; Therapeutic; Variant; Wine; Work; career; counterregulation; design; diabetic; effective therapy; effectiveness evaluation; gastric inhibitory polypeptide receptor; glucose output; glycemic control; in vivo; insight; insulin secretion; islet; mouse model; novel; novel strategies; prevent; response; side effect

PROJECT SUMMARY Hypoglycemia is a dangerous complication of exogenous insulin therapy in Type 1 Diabetes (T1D) that is treated by exogenous glucagon secretion. However, the use of exogenous glucagon has its own side effects and can be complicated to administer in an emergency situation. As an alternative, stimuli that lead to robust endogenous glucagon secretion could be effective to counter severe hypoglycemia. Glucagon secretion can be stimulated by amino acids, like alanine and arginine, as well as by glucose-dependent insulinotropic peptide (GIP). Remarkably, we found that while alanine or GIP alone induce modest increases in glucagon secretion, the combination of alanine and GIP synergistically increase glucagon secretion in both isolated mouse and human islets, as well as mice in vivo. A better understanding of the physiology of this glucagon and the mechanism of its release is needed to determine if stimulating endogenous glucagon can treat hypoglycemia in T1D. We hypothesize that endogenous -cell stimuli, such as GIP + alanine, can counter insulin-induced hypoglycemia. The aims of this project are designed to elucidate whether -cell stimuli can mitigate severe hypoglycemia, how the effects of -cell stimulation are changed in T1D, and what is the mechanism that alanine stimulates the - cell to secrete glucagon. Successful completion of this project will enhance our understanding of the -cell and provide insight for the basis of therapeutics for hypoglycemia or insulin co-therapies. In addition, the aims will broaden the Candidate’s technical expertise and develop conceptual understanding of -cell physiology that will provide a foundation for a career as an independent investigator.

项目总结

项目成果

Discovery of a potent GIPR peptide antagonist that is effective in rodent and human systems.

• DOI: 10.1016/j.molmet.2022.101638
• 发表时间: 2022-12
• 期刊: MOLECULAR METABOLISM
• 影响因子: 8.1
• 作者: Yang, Bin;Gelfanov, Vasily M.;El, Kimberley;Chen, Alex;Rohlfs, Rebecca;DuBois, Barent;Hansen, Ann Maria Kruse;Perez-Tilve, Diego;Knerr, Patrick J.;'Alessio, David;Campbell, Jonathan E.;Douros, Jonathan D.;Finan, Brian
• 通讯作者: Finan, Brian