MECHANISM OF COMPENSATORY HYPERINSULINEMIA IN NORMOGLYCEMIC INSULIN-RESISTANT SPONTANEOUSLY HYPERTENSIVE RATS - AUGMENTED ENZYMATIC-ACTIVITY OF GLUCOKINASE IN BETA-CELLS

The cause of compensatory hyperinsulinemia in normoglycemic insulin-re sistant states is unknown. Using spontaneously hypertensive rats (SHR) , we tested the hypothesis that a lowered beta-cell set-point for gluc ose causes a hypersecretion of insulin at a normal glucose level. Isle ts isolated from normoglycemic hyperinsulinemic SHR were compared to a ge-matched (12 wk old) Wistar-Kyoto (WK) rats. The ED(50) 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 i ncreased 40% in SHR islets (P < 0.02) without any change in the glucok inase protein level by Western blot. The level of the beta-cell glucos e transporter (GLUT-2) was increased 75% in SHR islets (P < 0.036). In summary, the beta-cell sensitivity for glucose was increased in these normoglycemic insulin resistant rats by an enhanced catalytic activit y of glucokinase. We have identified a regulatory system for glucokina se in the beta-cell which entails variable catalytic activity of the e nzyme, is modulated in response to variations in whole-body insulin se nsitivity, and is not dependent on sustained changes in the plasma glu cose level.