Mechanism of compensatory hyperinsulinemia in normoglycemic insulin-resistant spontaneously hypertensive rats. Augmented enzymatic activity of glucokinase in beta-cells. The Journal of clinical investigation 94

The cause of compensatory hyperinsulinemia in normogly-cemic insulin-resistant states is unknown. Using spontane-ously hypertensive rats (SHR), we tested the hypothesis that a lowered a8-cell set-point for glucose causes a hypersecre-tion of insulin at a normal glucose level. Islets isolated from normoglycemic hyperinsulinemic SHR were compared to age-matched (12 wk old) Wistar-Kyoto (WK) rats. The ED5. for glucose-induced insulin secretion was 6.6±1.0 mM glucose in SHR versus 9.6±0.5 mM glucose in WK (P < 0.02). Glucokinase enzymatic activity was increased 40% in SHR islets (P < 0.02) without any change in the glucoki-nase protein level by Western blot. The level of the p-cell glucose transporter (GLUT-2) was increased 75 % in SHR islets (P < 0.036). In summary, the P-cell sensitivity for glucose was in-creased in these normoglycemic insulin resistant rats by an enhanced catalytic activity of glucokinase. We have identi-fied a regulatory system for glucokinase in the p-cell which entails variable catalytic activity of the enzyme, is modulated in response to variations in whole-body insulin sensitivity, and is not dependent on sustained changes in the plasma glucose level. (J. Clin. Invest. 1994.94:399-404.) Key words: insulin secretion * hexokinase * glucose metabolism * islets of Langerhans * GLUT-2 * glucose transporter