Insulin signaling in alpha cells modulates glucagon secretion in vivo.
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.
Department of Cellular and Molecular Physiology, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
Dan
D
Kawamori
Amarnath J
AJ
Kurpad
Jiang
J
Hu
Chong Wee
CW
Liew
Judy L
JL
Shih
Eric L
EL
Ford
Pedro L
PL
Herrera
Kenneth S
KS
Polonsky
Owen P
OP
McGuinness
Rohit N
RN
Kulkarni
D000818:Animals; D001120:Arginine / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental; D005215:Fasting; D005247:Feeding Behavior / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D005934:Glucagon / Q000235:genetics / Q000378:metabolism*; D050416:Glucagon-Secreting Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018149:Glucose Intolerance / Q000150:complications; D006946:Hyperinsulinism / Q000150:complications / Q000378:metabolism; D007003:Hypoglycemia / Q000150:complications / Q000378:metabolism; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size / Q000187:drug effects; D009928:Organ Specificity / Q000187:drug effects; D011972:Receptor, Insulin / Q000172:deficiency / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013311:Streptozocin
D007328:Insulin; D013311:Streptozocin; D005934:Glucagon; D001120:Arginine; D011972:Receptor, Insulin