Hypoglycemia, defective islet glucagon secretion, but normal islet mass in mice with a disruption of the gastrin gene.
OBJECTIVE
Both cholecystokinin (CCK)-A and CCK-B receptors are expressed in the pancreas, and exogenous gastrin administration stimulates glucagon secretion from human islets. Although gastrin action has been linked to islet neogenesis, transdifferentiation, and beta-cell regeneration, an essential physiologic role(s) for gastrin in the pancreas has not been established.


METHODS
We examined glucose homeostasis, glucagon gene expression, glucagon secretion, and islet mass in mice with a targeted gastrin gene disruption.


RESULTS
Gastrin -/- mice exhibit fasting hypoglycemia and significantly reduced glycemic excursion following glucose challenge. Insulin sensitivity was normal and levels of circulating insulin and insulin messenger RNA transcripts were appropriately reduced in gastrin -/- mice. In contrast, levels of circulating glucagon and pancreatic glucagon messenger RNA transcripts were not up-regulated in hypoglycemic gastrin -/- mice. Furthermore, the glucagon response to epinephrine in isolated perifused islets was moderately impaired in gastrin -/- versus gastrin +/+ islets (40% reduction; P < 0.01, gastrin +/+ vs. gastrin -/- mice). Moreover, the glucagon response but not the epinephrine response to hypoglycemia was significantly attenuated in gastrin -/- compared with gastrin +/+ mice (P < 0.05). Despite gastrin expression in the developing fetal pancreas, beta-cell area, islet topography, and the islet proliferative response to experimental injury were normal in gastrin -/- mice.


CONCLUSIONS
These findings show an essential physiologic role for gastrin in glucose homeostasis; however, the gastrin gene is not essential for murine islet development or the adaptive islet proliferative response to beta-cell injury.
D000818:Animals; D005215:Fasting / Q000502:physiology; D005260:Female; D005755:Gastrins / Q000235:genetics* / Q000378:metabolism*; D005934:Glucagon / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology; D007003:Hypoglycemia / Q000378:metabolism* / Q000503:physiopathology*; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000254:growth & development / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000378:metabolism
D005755:Gastrins; D007328:Insulin; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; D005934:Glucagon; D005947:Glucose