Publications (2)12.11 Total impact
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Article: Overexpression of pituitary adenylate cyclase-activating polypeptide in islets inhibits hyperinsulinemia and islet hyperplasia in agouti yellow mice.
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ABSTRACT: Pituitary adenylate cyclase-activating polypeptide (PACAP) is an intraislet neuropeptide and shares insulinotropic and insulin-sensitizing properties with glucagon-like peptide-1 (GLP-1); however, the pathophysiological significance of PACAP in diabetes remains largely unknown. To assess this, we crossed our recently developed transgenic mice overexpressing PACAP in pancreatic beta-cells (Tg/+), with lethal yellow agouti (KKA(y)) mice (A(y)/+), a genetic model for obesity-diabetes, and examined the metabolic and morphological phenotypes of F(1) animals. Tg/+ mice with the A(y) allele (Tg/+:A(y)/+) developed maturity-onset obesity and diabetes associated with hyperglycemia, hyperlipidemia, and hyperphagia, similar to those of A(y)/+ mice, but hyperinsulinemia was significantly ameliorated in Tg/+:A(y)/+ mice. Although A(y)/+ mice exhibited a marked increase in islet mass resulting from hyperplasia and hypertrophy, this increase was significantly attenuated in Tg/+:A(y)/+ mice. Size frequency distribution analysis revealed that the very large islets comprising one-fourth of islets of A(y)/+ mice were selectively reduced in Tg/+:A(y)/+ mice. Because functional defects have been demonstrated in the large islets of obese animal models, together these findings suggest that PACAP regulates hyperinsulinemia and the abnormal increase in islet mass that occurs during the diabetic process.Journal of Pharmacology and Experimental Therapeutics 06/2004; 309(2):796-803. · 3.83 Impact Factor -
Article: Overexpression of PACAP in transgenic mouse pancreatic beta-cells enhances insulin secretion and ameliorates streptozotocin-induced diabetes.
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ABSTRACT: Pituitary adenylate cyclase-activating polypeptide (PACAP), a member of the vasoactive intestinal peptide/secretin/glucagon family, stimulates insulin secretion from islets in a glucose-dependent manner at femtomolar concentrations. To assess PACAP's pancreatic function in vivo, we generated transgenic mice overexpressing PACAP in the pancreas under the control of human insulin promoter. Northern blot and immunohistochemical analyses showed that PACAP is overexpressed in pancreatic islets, specifically in transgenic mice. Plasma glucose and glucagon levels during a glucose tolerance test were not different between PACAP transgenic mice and nontransgenic littermates. However, plasma insulin levels in transgenic mice were higher after glucose loading. Also, increases of streptozotocin-induced plasma glucose were attenuated in transgenic compared with nontransgenic mice. Notably, an increase in 5-bromo-2-deoxyuridine-positive beta-cells in the streptozotocin-treated transgenic mice was observed but without differences in the staining patterns by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. Morphometric analysis revealed that total islet mass tends to increase in 12-month-old transgenic mice but showed no difference between 12-week-old transgenic and nontransgenic littermates. This is the first time that PACAP has been observed to play an important role in the proliferation of beta-cells.Diabetes 06/2003; 52(5):1155-62. · 8.29 Impact Factor
