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HORMONES AND SIGNALING

Pioglitazone reverses insulin resistance and impaired CCK-stimulated pancreatic secretion in eNOS(–/–) mice: therapy for exocrine pancreatic disorders?

¹Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, and ²Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan School of Medicine, Ann Arbor, Michigan

Submitted 26 September 2006 ; accepted in final form 7 May 2007

In mice, eNOS (endothelial nitric oxide synthase) maintains in vivo pancreatic secretory responses to carbachol or cholecystokinin octapeptide (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^–1·day^–1), an insulin-sensitizing peroxisome proliferator-activated receptor- (PPAR-) activator, and measured pancreatic protein secretion evoked by CCK-8 (160 pmol·kg^–1·h^–1, 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 nonobese 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.

nitric oxide; insulin; diabetes; cholecystokinin