NORMALIZATION OF INSULIN RESISTANCE & IMPAIRED CCK STIMULATED PANCREATIC SECRETION IN eNOS (???/???) MICE BY PIOGLITAZONE. POTENTIAL FOR CORRECTING HUMAN ENDOCRINE & EXOCRINE DISORDERS?

Abstract

Background: Recently we showed that eNOS (endothelial NO synthase) maintains in vivo murine pancreatic secretion response to carbachol and CCK-8. Because eNOS also maintains insulin sensitivity and modulates pancreatic blood flow (PBF), our aims were to detemine if pioglitazone (insulin sensitizer) reduces insulin resistence, improves exocrine pancreatic secretion and if changes in pancreatic secretion are coupled to PBF. Methods: WT & eNOS (−/−) mice were gavaged with pioglitazone (20 or 50 mg/kg/d) or vehicle × 5 days. Then mice were anesthetized and the bile-pancreatic duct was cannulated to collect in vivo pancreatic secretion in response to maximal stimulatory CCK-8 (160 pmol/kg/h). We measured serum glucose, parameters of insulin secretion and insulin resistance, pancreatic digestive enzyme mRNA expression, and PBF by microsphere technique. Results: In comparison to vehicle, 20 & 50 mg/kg pioglitazone increased CCK-8 stimulated output (over basal) in eNOS (−/−) mice by 195+/−29%, 266+/−39% and 357+/−47%, respectively (p < 0.005), but not in WT mice (328+/−35%, 336+/−46% and 284+/−48%, respectively, p = ns). During maximal stimulatory CCK, pioglitazone (50 mg/kg) normalized serum hyperinsulinemia in eNOS (−/−) mice receiving vehicle (p < 0.005), had no effect on pancreas insulin mRNA expression or serum c-peptide levels, but increased mRNA expression of a central hepatic insulin signaling intermediate IRS-2 by 1.6-2.0 fold vs. WT and eNOS (−/−) controls, respectively (p < 0.005). Pancreatic mRNA expression of multiple digestive enzymes was unaffected by eNOS genotype. Pioglitazone had no effect on PBF in CCK treated eNOS (−/−) mice, consistent with findings that baseline PBF in WT mice was unaffected by submaximal & maximal stimulatory CCK-8 (40-160 pmol/kg/h). Conclusion: Reduced pancreatic secretion is partially coupled to insulin resistance in eNOS (−/−) mice, and possibly in diabetes mellitus & chronic pancreatitis. Although the mechanism remains unclear, PPAR-gamma agonists may simultaneously correct endocrine & exocrine pancreas disorders.