title: Pioglitazone reverses insulin resistance and impaired CCK-stimulated pancreatic secretion in eNOS(-/-) mice: therapy for exocrine pancreatic disorders?
abstract: 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-gamma (PPAR-gamma) 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-gamma agonists such as pioglitazone may thus simultaneously correct endocrine and exocrine pancreatic disorders.
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan School of Medicine, 1150 W. Medical Center Drive, 6520 MSRB 1, Ann Arbor, MI 48109, USA.
authors.forename: Raju C
authors.initials: RC
authors.lastname: Reddy
authors.forename: Yibai
authors.initials: Y
authors.lastname: Hao
authors.forename: Sae-Hong
authors.initials: SH
authors.lastname: Lee
authors.forename: Srinivasa R
authors.initials: SR
authors.lastname: Gangireddy
authors.forename: Chung
authors.initials: C
authors.lastname: Owyang
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: DiMagno
mesh_terms: D000818:Animals; D015870:Gene Expression / Q000187:drug effects; D006946:Hyperinsulinism / Q000503:physiopathology; D007328:Insulin / Q000097:blood; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D051379:Mice; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency*; D010179:Pancreas / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism*; D010189:Pancreatic Juice / Q000378:metabolism; D010750:Phosphoproteins / Q000096:biosynthesis; D000077205:Pioglitazone; D012333:RNA, Messenger / Q000378:metabolism; D012039:Regional Blood Flow / Q000187:drug effects; D015398:Signal Transduction; D012844:Sincalide / Q000494:pharmacology; D013004:Somatostatin / Q000096:biosynthesis; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D012333:RNA, Messenger; D045162:Thiazolidinediones; D013004:Somatostatin; D052250:Nitric Oxide Synthase Type III; D012844:Sincalide; D000077205:Pioglitazone