Impaired insulin secretion and excessive hepatic glucose production are both early events in the diabetic GK rat.
Adult Goto-Kakisaki Wistar (GK) rats exhibit a spontaneous non-insulin-dependent diabetes characterized by impaired glucose-induced insulin secretion, decreased beta-cell mass, hepatic glucose overproduction, and moderate insulin resistance in muscles and adipose tissues. To elucidate the pathogenesis of hyperglycemia in this animal model, we have studied insulin secretion and insulin action in 4-wk-old GK pups, just before weaning. In the postabsorptive state, their basal plasma glucose level was elevated (P < 0.001), and their tolerance to intravenous glucose was impaired. Their kinetics of insulin release in response to glucose was impaired, with a low acute phase of insulin release in vivo and in vitro (perfused pancreas). Basal glucose production was increased in the GK pups by 40% (P < 0.05). During euglycemic clamp performed at submaximal hyperinsulinemia, suppression of liver glucose production was less effective (P < 0.01) in the GK rats, whereas their overall glucose utilization was similar to that of the control group. This was correlated with a normal insulin-stimulated glucose utilization by epitrochlearis, soleus, and extensor digitorum longus muscles, diaphragm, and white adipose tissues. These data give body to the primacy of the beta-cell defects in the etiology of non-insulin-dependent diabetes mellitus in the GK rat. They also highlight a possible primary role of the liver defect. Peripheral insulin resistance does not contribute to the development of postnatal glucose intolerance in this diabetes model.
Laboratoire de Physiopathologie de la Nutrition, Centre National de la Recherche Scientifique Unité de Recherche Associée 0307, Université Paris, France.
F
F
Picarel-Blanchot
C
C
Berthelier
D
D
Bailbé
B
B
Portha
D000367:Age Factors; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001835:Body Weight; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D004195:Disease Models, Animal; D005260:Female; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D008099:Liver / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism; D051381:Rats; D011922:Rats, Mutant Strains; D017208:Rats, Wistar
D007328:Insulin; D001120:Arginine; D005947:Glucose