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Insulin signaling in alpha cells modulates glucagon secretion in vivo
| Title | Insulin signaling in alpha cells modulates glucagon secretion in vivo |
| Publication Type | Journal Article |
| Year of Publication | 2009 |
| Authors | |
| Journal | Cell Metab |
| Volume | 9 |
| Issue | 4 |
| Pagination | 350-61 |
| Date Published | Apr |
| Publication Language | eng |
| ISBN Number | 1932-7420 (Electronic) |
| Accession Number | 19356716 |
| Key Words | Animals, Arginine/pharmacology, Diabetes Mellitus, Experimental, Fasting, Feeding Behavior/drug effects, Gene Expression Regulation/drug effects, Glucagon/genetics/*secretion, Glucagon-Secreting Cells/drug effects/pathology/*secretion, Glucose Intolerance/complications, Hyperinsulinism/complications/metabolism, Hypoglycemia/complications/metabolism, Insulin/genetics/*metabolism, Insulin-Secreting Cells/drug effects/metabolism/pathology, Mice, Mice, Knockout, Organ Size/drug effects, Organ Specificity/drug effects, Receptor, Insulin/deficiency/metabolism, *Signal Transduction/drug effects, Streptozocin |
| Abstract | Glucagon plays an important role in glucose homeostasis by regulating hepatic glucose output in both normo- and hypoglycemic conditions. In this study, we created and characterized alpha cell-specific insulin receptor knockout (alphaIRKO) mice to directly explore the role of insulin signaling in the regulation of glucagon secretion in vivo. Adult male alphaIRKO mice exhibited mild glucose intolerance, hyperglycemia, and hyperglucagonemia in the fed state and enhanced glucagon secretion in response to L-arginine stimulation. Hyperinsulinemic-hypoglycemic clamp studies revealed an enhanced glucagon secretory response and an abnormal norepinephrine response to hypoglycemia in alphaIRKO mice. The mutants also exhibited an age-dependent increase in beta cell mass. Furthermore, siRNA-mediated knockdown of insulin receptor in glucagon-secreting InR1G cells promoted enhanced glucagon secretion and complemented our in vivo findings. Together, these data indicate a significant role for intraislet insulin signaling in the regulation of alpha cell function in both normo- and hypoglycemic conditions. |
| Notes | 5P30DK36836/DK/NIDDK NIH HHS/United StatesDK20593/DK/NIDDK NIH HHS/United StatesDK31842/DK/NIDDK NIH HHS/United StatesDK56341/DK/NIDDK NIH HHS/United StatesDK59637/DK/NIDDK NIH HHS/United StatesDK67536/DK/NIDDK NIH HHS/United StatesUL1RR024992/RR/NCRR NIH HHS/United StatesJournal ArticleResearch Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov'tUnited States |
| URL | http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19356716 |
| Citation Key | 564 |
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- *Signal Transduction/drug effects
- Animals
- Arginine/pharmacology
- Diabetes Mellitus, Experimental
- Fasting
- Feeding Behavior/drug effects
- Gene Expression Regulation/drug effects
- Glucagon-Secreting Cells/drug effects/pathology/*secretion
- Glucagon/genetics/*secretion
- Glucose Intolerance/complications
- Hyperinsulinism/complications/metabolism
- Hypoglycemia/complications/metabolism
- Insulin-Secreting Cells/drug effects/metabolism/pathology
- Insulin/genetics/*metabolism
- Mice
- Mice, Knockout
- Organ Size/drug effects
- Organ Specificity/drug effects
- Receptor, Insulin/deficiency/metabolism
- Streptozocin