Glucose metabolism is impaired in the adult dopaminergic D2R knockout mouse

GARCIA-TORNADU ISABEL; ARANY EDITH; GUIDA MARIA CLARA; HILL DAVID; BECU-VILLALOBOS DAMASIA

Toronto, Canada

Congreso; Endocrine Society Anual Meeting; 2007

Endocrine Society

abel Garcia-Tornadu, Edith Arany, Clara Guida, Graciela Diaz –Torga, David J. Hill and Damasia Becu-Villalobos, Glucose metabolism is impaired in the adult dopaminergic D2R knockout mouse. In previous studies we have shown that the dopaminergic D2 receptor male knockout mouse (KO) has a lower GH secretion than their wild type (WT) counterparts during the first month of life.  These mice are growth restricted with lower serum IGF-I and have chronic hyperprolactinemia. As GH and PRL may influence pancreatic beta cell function, our aim in this study was to establish if the alteration in these hormones had any effect on glucose metabolism in adult KO male mice. Methods:At six months age, mice were subjected to an intraperitoneal glucose tolerance test (IGTT) to study beta cell response, and an insulin tolerance test (ITT) to establish insulin resistance. At this time point mice were sacrificed, pancreata was dissected and tissues were examined by immunohistochemistry for islet morphometry, abundance, insulin and glucagon cell area. Total pancreatic IGF-I content and serum insulin levels were measured by RIA.   Pancreatic Pdx-1 mRNA expression was studied by real-time PCR. Results: Overnight fasted KO mice  had higher glucose and lower insulin serum levels (KO=0.065+0.013; WT=0.123+0.022 ng/ml; p<0.05) when compared to their WT counterparts. During a glucose tolerance test KO mice demonstrated higher glucose levels at 30 min (321+20; WT=290+18mg/dl; p<0.05) and lower serum insulin (KO=0.060+0.001; WT=0.190+0.023 ng/ml; p<0.01). On the other hand insulin tolerance test was similar between genotypes. KO mice had lower HOMA â cell, and similar HOMA IR when compared to WT. Although total â cell area in the pancreas was not significantly decreased, there was a different islet size distribution with significant higher proportion of small islets (< 5000 um) in KO and large islets (> 10000 um) in WT pancreas. Pancreatic IGF-I content was reduced in KO animals, while PDX1 mRNA was increased. We conclude that D2R KO male mice with low serum GH during the neonatal period and chronic hyperprolactinemia during adult life have an impairment of insulin secretion in response to a glucose load. Neonatal GH deficiency and hyperprolactinemia might condition pancreatic development, and insulin response to glucose.