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mTOR signaling and regulation of alpha-cell mass and function

mTOR 信号传导以及 α 细胞质量和功能的调节

基本信息

批准号：
10620230
负责人：
Ernesto Bernal-Mizrachi
金额：
--
依托单位：
MIAMI VA HEALTH CARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10620230
关键词：
Acids Affect Alpha Cell Amino Acids Animal Experiments B-Lymphocytes Beta Cell Cell Line Cells Chronic Clinical Data Complex Data Defect Diabetes Mellitus Disease EIF4EBP1 gene Equilibrium Exhibits Eye FRAP1 gene Functional disorder Funding Generations Genetic Genetic Models Glucagon Glucagon Receptor Glucose Goals Health Human Hyperglycemia Hypoglycemia IGFBP2 gene Individual Insulin Insulin Receptor Insulin Resistance Insulin-Dependent Diabetes Mellitus Islets of Langerhans Transplantation Knowledge Liver Metformin Modeling Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Nutrient Obesity Overnutrition Pathogenesis Pathway interactions Patients Physiological Play Predisposition Publishing Receptor Signaling Regulation Research Rodent Model Role Signal Pathway Signal Transduction Sirolimus TSC1 gene TSC2 gene Testing Time Uncertainty Veterans antagonist anterior chamber blood glucose regulation design diabetes control diabetes management diabetes mellitus therapy diabetogenic drug development experimental study glucose metabolism human model hyperglucagonemia improved in vivo insight insulin secretion insulin sensitivity islet novel novel strategies novel therapeutics physiologic model prevent reconstitution response therapy design

项目摘要

Diabetes mellitus is one of the most prevalent conditions affecting human health including veterans in the 21st century. Most of the focus of our efforts to understand the pathogenesis and therapy of the disease has focused on two major components: insulin sensitivity and insulin secretion. However, dysregulation in glucagon secretion is a major component in diabetes. Hyperglucagonemia plays key roles in the pathogenesis of hyperglycemia in type 2 diabetes and has a major impact in the glycemic volatility and susceptibility to hypoglycemia in type 1 diabetes. Our observations published during the current funding period suggest that downstream of insulin/Akt, the nutrient sensitive pathway (mTOR/Raptor or mTORC1) plays a major role in regulation of alpha cell mass and glucagon secretion. However, how mTORC1 acting on key downstream targets (4E-BPs and S6K) regulates the function and mass of alpha-cells in vivo and the potential contribution of these targets to the regulation of glucose metabolism remain unclear. The long-term goal of these studies is to uncover how the nutrient sensitive insulin/Akt/mTORC1 axis regulates α-cell mass and glucagon secretion in rodent models and humans. Our studies showed that loss of mTORC1 function in alpha-cells results in major abnormalities in alpha-cell mass and glucagon secretion. We also demonstrate that gain of mTORC1 results in chronic hyperglucagonemia and alpha cell mass expansion suggesting that this signaling pathway is critical for alpha cell mass and glucagon secretion. Based on these observations, we hypothesize that mTORC1 regulates alpha-cell mass mainly by a balance between S6K and 4E-BP signaling. The specific aims will assess the individual contribution of downstream targets of mTORC1 by establishing the role of mTORC1/4E-BP/eIF4E axis in regulation of alpha-cell mass, glucagon secretion and adaptation to diabetogenic conditions using novel alpha cell specific models. In addition, we will also identify the importance of mTORC1/S6K on the control of alpha-cell mass and glucagon secretion by generation of novel models with inducible gain of S6K function in alpha cells. Finally, how mTORC1 activation alters human alpha-cell responses will be determined using a model of human islet transplantation in the anterior chamber of the mouse eye. This proposal will provide important insights into the molecular mechanisms that govern alpha-cell mass expansion by mTORC1. This information can be used to uncover novel targets that can be used for treatment of diabetes and design interventions to rescue the defects in glucagon secretion in response to hypoglycemia in patients with diabetes.

糖尿病是21世纪影响包括退伍军人在内的人类健康最普遍的疾病之一

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Hyperglucagonaemia in diabetes: altered amino acid metabolism triggers mTORC1 activation, which drives glucagon production.

糖尿病中的高胰高血糖素血症：氨基酸代谢的改变会触发 mTORC1 激活，从而驱动胰高血糖素的产生。

DOI：
10.1007/s00125-023-05967-8
发表时间：
2023
期刊：
Diabetologia
影响因子：
8.2
作者：
Riahi,Yael;Kogot-Levin,Aviram;Kadosh,Liat;Agranovich,Bella;Malka,Assaf;Assa,Michael;Piran,Ron;Avrahami,Dana;Glaser,Benjamin;Gottlieb,Eyal;Jackson3rd,Fields;Cerasi,Erol;Bernal-Mizrachi,Ernesto;Helman,Aharon;Leibowitz,Gil
通讯作者：
Leibowitz,Gil

The RNA-binding protein LARP1 is dispensable for pancreatic β-cell function and mass.

DOI：
10.1038/s41598-021-81457-4
发表时间：
2021-01-22
期刊：
Scientific reports
影响因子：
4.6
作者：
Werneck-de-Castro JP;Peçanha FLM;Silvestre DH;Bernal-Mizrachi E
通讯作者：
Bernal-Mizrachi E

Natural history of β-cell adaptation and failure in type 2 diabetes.

DOI：
10.1016/j.mam.2014.12.002
发表时间：
2015-04
期刊：
MOLECULAR ASPECTS OF MEDICINE
影响因子：
10.6
作者：
Alejandro, Emilyn U.;Gregg, Brigid;Blandino-Rosano, Manuel;Cras-Meneur, Corentin;Bernal-Mizrachi, Ernesto
通讯作者：
Bernal-Mizrachi, Ernesto

Inhibition of mTORC1 by ER stress impairs neonatal β-cell expansion and predisposes to diabetes in the Akita mouse.

DOI：
10.7554/elife.38472
发表时间：
2018-11-09
期刊：
eLife
影响因子：
7.7
作者：
Riahi Y;Israeli T;Yeroslaviz R;Chimenez S;Avrahami D;Stolovich-Rain M;Alter I;Sebag M;Polin N;Bernal-Mizrachi E;Dor Y;Cerasi E;Leibowitz G
通讯作者：
Leibowitz G

Loss of mTORC1 signalling impairs β-cell homeostasis and insulin processing.

DOI：
10.1038/ncomms16014
发表时间：
2017-07-12
期刊：
Nature communications
影响因子：
16.6
作者：
Blandino-Rosano M;Barbaresso R;Jimenez-Palomares M;Bozadjieva N;Werneck-de-Castro JP;Hatanaka M;Mirmira RG;Sonenberg N;Liu M;Rüegg MA;Hall MN;Bernal-Mizrachi E
通讯作者：
Bernal-Mizrachi E