Deletion of glutamate dehydrogenase in beta-cells abolishes part of the insulin secretory response not required for glucose homeostasis.
Insulin exocytosis is regulated in pancreatic ss-cells by a cascade of intracellular signals translating glucose levels into corresponding secretory responses. The mitochondrial enzyme glutamate dehydrogenase (GDH) is regarded as a major player in this process, although its abrogation has not been tested yet in animal models. Here, we generated transgenic mice, named betaGlud1(-/-), with ss-cell-specific GDH deletion. Our results show that GDH plays an essential role in the full development of the insulin secretory response. In situ pancreatic perfusion revealed that glucose-stimulated insulin secretion was reduced by 37% in betaGlud1(-/-). Furthermore, isolated islets with either constitutive or acute adenovirus-mediated knock-out of GDH showed a 49 and 38% reduction in glucose-induced insulin release, respectively. Adenovirus-mediated re-expression of GDH in betaGlud1(-/-) islets fully restored glucose-induced insulin release. Thus, GDH appears to account for about 40% of glucose-stimulated insulin secretion and to lack redundant mechanisms. In betaGlud1(-/-) mice, the reduced secretory capacity resulted in lower plasma insulin levels in response to both feeding and glucose load, while body weight gain was preserved. The results demonstrate that GDH is essential for the full development of the secretory response in beta-cells. However, maximal secretory capacity is not required for maintenance of glucose homeostasis in normo-caloric conditions.
Carobbio
Stefania
S
Department of Cell Physiology and Metabolism, Geneva, Switzerland.
Frigerio
Francesca
F
Rubi
Blanca
B
Vetterli
Laurène
L
Bloksgaard
Maria
M
Gjinovci
Asllan
A
Pournourmohammadi
Shirin
S
Herrera
Pedro L
PL
Reith
Walter
W
Mandrup
Susanne
S
Maechler
Pierre
P
D000375:Aging / Q000502:physiology; D000818:Animals; D002469:Cell Separation; D017353:Gene Deletion; D005947:Glucose / Q000378:metabolism*; D005969:Glutamate Dehydrogenase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000201:enzymology* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype
D007328:Insulin; D005969:Glutamate Dehydrogenase; D005947:Glucose