Pancreatic beta-cell overexpression of the glucagon receptor gene results in enhanced beta-cell function and mass.
In addition to its primary role in regulating glucose production from the liver, glucagon has many other actions, reflected by the wide tissue distribution of the glucagon receptor (Gcgr). To investigate the role of glucagon in the regulation of insulin secretion and whole body glucose homeostasis in vivo, we generated mice overexpressing the Gcgr specifically on pancreatic beta-cells (RIP-Gcgr). In vivo and in vitro insulin secretion in response to glucagon and glucose was increased 1.7- to 3.9-fold in RIP-Gcgr mice compared with controls. Consistent with the observed increase in insulin release in response to glucagon and glucose, the glucose excursion resulting from both a glucagon challenge and intraperitoneal glucose tolerance test (IPGTT) was significantly reduced in RIP-Gcgr mice compared with controls. However, RIP-Gcgr mice display similar glucose responses to an insulin challenge. beta-Cell mass and pancreatic insulin content were also increased (20 and 50%, respectively) in RIP-Gcgr mice compared with controls. When fed a high-fat diet (HFD), both control and RIP-Gcgr mice developed similar degrees of obesity and insulin resistance. However, the severity of both fasting hyperglycemia and impaired glucose tolerance (IGT) were reduced in RIP-Gcgr mice compared with controls. Furthermore, the insulin response of RIP-Gcgr mice to an IPGTT was twice that of controls when fed the HFD. These data indicate that increased pancreatic beta-cell expression of the Gcgr increased insulin secretion, pancreatic insulin content, beta-cell mass, and, when mice were fed a HFD, partially protected against hyperglycemia and IGT.
Gelling
Richard W
RW
Department of Biochemistry, Pediatric Endocrinology, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, New York, Bronx, NY 10461, USA.
Vuguin
Patricia M
PM
Du
Xiu Quan
XQ
Cui
Lingguang
L
Rømer
John
J
Pederson
Raymond A
RA
Leiser
Margarita
M
Sørensen
Heidi
H
Holst
Jens J
JJ
Fledelius
Christian
C
Johansen
Peter B
PB
Fleischer
Norman
N
McIntosh
Christopher H S
CH
Nishimura
Erica
E
Charron
Maureen J
MJ
D000818:Animals; D049109:Cell Proliferation; D048429:Cell Size; D002478:Cells, Cultured; D004036:Diet, Atherogenic; D005260:Female; D018149:Glucose Intolerance / Q000235:genetics; D006943:Hyperglycemia / Q000235:genetics; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism* / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009928:Organ Specificity / Q000235:genetics; D018027:Receptors, Glucagon / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
D007328:Insulin; D018027:Receptors, Glucagon