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Hypoglycemia and alpha cell regulation

低血糖和α细胞调节

基本信息

批准号：
7922789
负责人：
Joseph Bryan
金额：
$ 21.88万
依托单位：
PACIFIC NORTHWEST RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2010-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7922789
关键词：
Address Affect Alpha Cell Amino Acid Transporter Amino Acids Biological Assay Blindness Blood Glucose Cell membrane Cell physiology Cell secretion Cells Clinical Complications of Diabetes Mellitus Data Dependence Detection Diabetes Mellitus Disease Electrophysiology (science)Epinephrine Equilibrium Erectile dysfunction Exocytosis Failure Fibrinogen Fright GCG gene GNAI2 gene Glucagon Glucose Hepatic Hormonal Hormones Human Hyperglycemia Hypoglycemia Hypothalamic structure In Vitro Insulin Insulin Resistance Insulin-Dependent Diabetes Mellitus Ion Channel Islet Cell Joints Kidney Diseases Laboratories Liver Measurement Mediating Mediator of activation protein Membrane Membrane Potentials Metabolic Metabolic Pathway Metabolism Modeling Mus Nerve Neurosecretory Systems Non-Insulin-Dependent Diabetes Mellitus Norepinephrine Pancreas Paracrine Communication Pathway interactions Physiological Physiology Plasma Play Potassium Channel Process Proteins Protocols documentation Public Health Purinoceptor Rattus Regulation Relative (related person)Reporting Rodent Role Secondary to Secretory Cell Signal Transduction Simulate Streptozocin Stroke Testing Therapeutic Tissues Wild Type Mouse Work abstracting blood glucose regulation falls gamma-Aminobutyric Acid ghrelin glucose metabolism glucose production glycemic control heart disease risk in vivo insight islet mouse model paracrine prevent receptor research study response uptake voltage

项目摘要

Project Summary/Abstract Understanding the interplay between pancreatic ¿- and ¿-cells that exerts local control on glucagon secretion is the focus of this application. Blood glucose levels are controlled primarily by two hormones, insulin, which governs tissue uptake and utilization of glucose and inhibits glucose production by the liver, and glucagon, which counteracts the inhibitory action of insulin on hepatic glucose production. Diabetes is a bi-hormonal disorder and impaired ¿-cell function, in the context of insulin deficiency or insulin resistance, contributes to the hyperglycemia that is the hallmark of the disease. In type 1 diabetes, the major clinical consequence of defective glucagon secretion is insulin-induced hypoglycemia and fear of hypoglycemia is the main limitation to achieving good glycemic control and thus preventing the secondary complications of hyperglycemia. Considerable clinical evidence shows that elevated glucagon, secondary to altered ¿-cell function, contributes to postprandial hyperglycemia in type 2 diabetes. Glucagon secretion can be suppressed by ¿-cell secretory products and paracrine control of ¿-cell function, the intra-islet insulin hypothesis, is well documented. Using a high-to-low glucose switch-off protocol we have shown that Zn2+, co-secreted with insulin, can suppress glucagon secretion during hypoglycemia and we have hypothesized that KATP channels that modulate Ca2+ signaling may be a target for Zn2+. Hyperglycemia can also suppress ¿-cell secretion potentially via a KATP channel dependent action on Ca2+ signaling. Amino acids are known to stimulate glucagon secretion via both metabolic and electrogenic effects, but the interplay between glucose and physiologic levels of amino acids is not well understood and the identity of amino acid transporters in ¿-cells is rudimentary. Glucagon secretion is potently stimulated by epinephrine and norepinephrine, but the relative importance of local control of ¿-cell function vs their response(s) to hypothalamic and other CNS inputs remains controversial. Our specific aims are to: Specific Aim #1. Specific Aim #2. Specific Aim #3. Specific Aim #4. Evaluate the role of KATP channels in the suppression of glucagon secretion by Zn2+. Determine the relative importance of ¿-cell secretory products, insulin, Zn2+, GABA and ATP, in the suppression of glucagon release. Determine the mechanism of amino acid stimulation of glucagon release from wild-type and Sur1KO islets and identify the ¿-cell transporters and/or pathways involved. Evaluate the relative importance of local vs CNS control of ¿-cell function using mice with targeted deletion of ¿-cell KATP channels.

项目总结/文摘