330 The Journal of Clinical Investigation| August 2000| Volume 106| Number 3 ated with a failure of adequate β-cell mass expansion in the face of insulin resistance. When the hypersecretion of insulin observed in perfused pancreata in ZDF and Zucker fatty rats is corrected for the increase in β-cell mass, insulin secretion rates are seen to be lower than those observed in lean control animals (6), suggesting that the increase in β-cell mass represents a functionally significant compensation. Estimated rates of β-cell proliferation, based on bromodeoxyuridine incorporation, suggest that the failure of β-cell mass to expand adequately in the ZDF rat is due not to a failure of βcell proliferation but to an enhanced rate of β-cell death, presumably resulting from apoptosis. Change in the relative activities of the two glucosephosphorylating enzymes glucokinase (GK) and hexokinase (HK) also contributes to insulin hypersecretion in insulin-resistant states. Conversion of glucose to glucose-6-phosphate is normally mediated predominantly by GK. This first, rate-limiting step in β-cell glucose metabolism represents the β cell’s glucose sensor. β-cell sensitivity to glucose and, therefore, the normal glucose–insulin secretion dose-response curve are determined predominantly by the Km of GK for glucose, which is approximately 8 mM. Insulin resistance is associated with an increase in the expression of β-cell HK, an enzyme with a significantly lower Km for glucose. Milburn et al. noted that the hypersecretion of insulin by islets from insulin-resistant Zucker fatty rats is accompanied by increased low-Km glucose metabolism, implicating upregulation of HK in this progression (7). Subsequently, Becker and colleagues (8) confirmed that experimental overexpression of HK in isolated islets induces low-Km glucose usage and insulin release at lower glucose concentration. Although overexpression of either GK or HK can enhance glucose phosphorylation, HK causes substantially more glucose-stimulated insulin secretion and overall glucose metabolism by the β-cell than does overexpression of GK (9). Cockburn et al. compared relative HK and GK activities in islets from Zucker fatty rats and lean control animals and showed that HK but not GK activity was enhanced (10). Since this induction correlated with increased basal insulin secretion rates, it appears that the selective upregulation of HK in obesity, like the increase in β-cell mass, plays an important role in the compensatory hypersecretion of insulin observed in insulin resistance.