Counterregulatory responses to hypoglycemia in patients with glucokinase gene mutations

The glucokinase gene is expressed not only in pancreatic beta cells and in the liver, but also in pancreatic a cells, and in some cells of the central nervous system. A decreased glucokinase activity in the latter cell types may interfere with counterregulatory responses to hypoglycemia. In order to assess functional consequences of glucokinase mutations, counterregulatory hormones secretion and glucose production (6,6(-2) H glucose) were monitor ed during an hyperinsulinemic clamp at about 2.4 pmol.kg(-1).min(-1) insuli n with progressive hypoglycemia in 7 maturity onset diabetes of the young ( MODY) type 2 patients, 5 patients with type 2 diabetes, and 13 healthy subj ects. Basal glucose concentrations were significantly higher in MODY2 patie nts (7.6 +/- 0.4 mmol.l(-1)) and type 2 diabetic patients (12.4 +/- 2.3 mmo l.l(-1)) than in healthy subjects (5.3 +/- 0.1 mmol.l(-1), p < 0.01) but co unterregulatory hormones concentrations were identical. Insulin-mediated gl ucose disposal and suppression of endogenous glucose production at euglycem ia were unchanged in MODY2 patients, but were blunted in type 2 diabetes. D uring progressive hypoglycemia, the glycemic thresholds of MODY2 patients f or increasing glucose production (5.0 +/- 0.4 mmol.l(-1)) and for glucagon stimulation (4.5 +/- 0.4 mmol.l(-1))were higher than those of healthy subje cts and type 2 diabetic patients (3.9 +/- 0.1 and 4.1 +/- 0.1 mmol.l(-1) re spectively for glucose production and 3.7 +/- 0.1 and 3.5 +/- 0.1 mmol.l(-1 ) for glucagon stimulation, p < 0.02 in both cases). These results indicate that counterregulatory responses to hypoglycemia are activated at a higher plasma glucose concentration in MODY2 patients. This may he secondary to d ecreased glucokinase activity in hypothalamic neuronal cells, or to alterat ions of glucose sensing in pancreatic a cells and liver cells.