In mice eNOS (endothelial-NO-Synthase) maintains in vivo pancreatic secretory responses to carbachol or CCK-8, maintains insulin sensitivity, and modulates pancreatic microvascular blood flow (PMBF). eNOS (-/-) mice are insulin resistant and their exocrine pancreatic secretion is impaired. We hypothesized that the reduced exocrine pancreatic secretion in eNOS (-/-) mice is due to insulin resistance or impaired PMBF. To test this hypothesis, we gave eNOS (-/-) and wild-type (WT) mice pioglitazone (20 or 50 mg/kg/d), an insulin-sensitizing peroxisome proliferator-activated receptor- (PPAR-) activator, and measured pancreatic protein secretion evoked by CCK-8 (160 pmol/kg/h, a maximal stimulus). We also measured insulin resistance, serum glucose, C-peptide, insulin, pancreatic RNA digestive enzyme expression, and PMBF (microsphere technique). In WT mice, pioglitazone did not increase CCK-8 stimulated protein output over baseline. In eNOS (-/-) mice, however, pioglitazone substantially increased the low CCK-8 stimulated protein output that is characteristic of these mutant mice (P<0.005). Pioglitazone abolished the CCK-8 evoked hyperinsulinemia (P<0.005) and increased insulin sensitivity of eNOS (-/-) mice (P<0.05), the latter based on hyperinsulinemic-euglycemic clamp studies. Pioglitazone had no effect on PMBF or pancreas mRNA expression of insulin or digestive enzymes. We conclude that in hyperinsulinemic eNOS (-/-) mice, a non-obese model of insulin resistance relevant to diabetes mellitus and possibly chronic pancreatitis, reduced pancreatic secretion is caused, at least in part, by insulin resistance. Insulin-sensitizing PPAR- agonists such as pioglitazone may thus simultaneously correct endocrine and exocrine pancreatic disorders.