Glucose potentiation of arginine-induced insulin secretion is impaired in subjects with a glucokinase Glu256Lys mutation.
Insulin and glucagon release and insulin sensitivity were investigated in patients with glucokinase deficiency. Five subjects with a missense mutation (Glu256Lys) were studied. They were compared with six healthy subjects with low insulin response but normal glucose tolerance. Insulin and glucagon levels were measured at blood glucose 7.1 +/- 0.1 mmol/l and at 10.9 +/- 0.2 mmol/l with or without arginine (5 g i.v.). Insulin sensitivity was assessed as the ratio between infused glucose and the insulin level (M:I) during hyperglycemic clamps. Glu256Lys subjects were nonobese and had fasting blood glucose 6.7 +/- 0.1 mmol/l (P < 0.001 vs. control group). Insulin release was reduced in response to 11 mmol/l glucose (61% of control group, P < 0.05) as well as to arginine in the presence of 11 mmol/l glucose (54% of control group, P < 0.01). Also, the slope of potentiation, i.e., the enhancement of arginine-induced release as a function of prevailing glucose concentration, was reduced (delta insulin/delta glucose, 47% of control group, P < 0.05). As for glucagon release, the response to arginine was not inhibited normally by glucose, resulting in threefold higher levels at 11 mmol/l glucose versus control subjects. Insulin sensitivity, assessed as M:I, was significantly (P < 0.05) reduced (55% of control group). Glucokinase deficiency thus affects not only insulin responses to glucose per se but also glucose potentiation of responses to non-nutrient secretagogues. Abnormalities in glucagon release and insulin sensitivity coexist with attenuated insulin responses in glucokinase-deficient subjects.
Department of Endocrinology, Karolinska Hospital, Stockholm, Sweden.
A
A
Wajngot
M
M
Alvarsson
A
A
Glaser
S
S
Efendic
H
H
Luthman
V
V
Grill
D000328:Adult; D001120:Arginine / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D005934:Glucagon / Q000378:metabolism; D005941:Glucokinase / Q000172:deficiency* / Q000235:genetics; D005947:Glucose / Q000494:pharmacology*; D005951:Glucose Tolerance Test; D018698:Glutamic Acid / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008239:Lysine / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation
D001786:Blood Glucose; D007328:Insulin; D018698:Glutamic Acid; D005934:Glucagon; D001120:Arginine; D005941:Glucokinase; D005947:Glucose; D008239:Lysine