1. Role of KATP channels in glucose-regulated glucagon secretion and impaired counterregulation in type 2 diabetes
- Author
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Andrei I. Tarasov, Anna L. Gloyn, Carolina Lahmann, Mary E. Travers, Quan Zhang, Frances M. Ashcroft, Jonathan N. Walker, Melissa F. Brereton, Juris Galvanovskis, Albert Salehi, Fiona M. Gribble, Patrik Rorsman, Reshma Ramracheya, Paul Johnson, Orit Braha, Alejandro González, Frank Reimann, Nils J.G. Rorsman, Martin Bengtsson, Lukas N. Groschner, Stephan C. Collins, and Matthias Braun
- Subjects
medicine.medical_specialty ,endocrine system ,Patch-Clamp Techniques ,Physiology ,Tolbutamide ,030209 endocrinology & metabolism ,Type 2 diabetes ,Carbohydrate metabolism ,Biology ,Hypoglycemia ,In Vitro Techniques ,Glucagon ,Exocytosis ,Article ,Membrane Potentials ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Adenosine Triphosphate ,KATP Channels ,Internal medicine ,Diabetes mellitus ,medicine ,Animals ,Humans ,Potassium Channels, Inwardly Rectifying ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,Glucagon secretion ,Cell Biology ,medicine.disease ,Tissue Donors ,3. Good health ,Endocrinology ,Glucose ,Diabetes Mellitus, Type 2 ,Glucagon-Secreting Cells ,Mutation ,Blood sugar regulation ,Calcium ,Calcium Channels ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug - Abstract
Summary Glucagon, secreted by pancreatic islet α cells, is the principal hyperglycemic hormone. In diabetes, glucagon secretion is not suppressed at high glucose, exacerbating the consequences of insufficient insulin secretion, and is inadequate at low glucose, potentially leading to fatal hypoglycemia. The causal mechanisms remain unknown. Here we show that α cell KATP-channel activity is very low under hypoglycemic conditions and that hyperglycemia, via elevated intracellular ATP/ADP, leads to complete inhibition. This produces membrane depolarization and voltage-dependent inactivation of the Na+ channels involved in action potential firing that, via reduced action potential height and Ca2+ entry, suppresses glucagon secretion. Maneuvers that increase KATP channel activity, such as metabolic inhibition, mimic the glucagon secretory defects associated with diabetes. Low concentrations of the KATP channel blocker tolbutamide partially restore glucose-regulated glucagon secretion in islets from type 2 diabetic organ donors. These data suggest that impaired metabolic control of the KATP channels underlies the defective glucose regulation of glucagon secretion in type 2 diabetes., Graphical Abstract, Highlights • KATP channel closure stimulates insulin secretion but inhibits glucagon release • α cell depolarization reduces voltage-gated Ca2+ entry and glucagon release • An activating KATP channel mutation impairs glucagon release in mice • KATP channel closure corrects glucagon secretion defect in type 2 diabetic islets
- Published
- 2013