This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Google Scholar Articles by Malakauskas, S. M. Articles by Le, T. H. PubMed PubMed Citation Articles by Malakauskas, S. M. Articles by Le, T. H.

Increased Insulin Sensitivity in Mice Lacking Collectrin, a Downstream Target of HNF-1

Department of Medicine (S.M.M., W.M.K., H.E.H., T.H.L.), Department of Pharmacology and Cancer Biology (D.M.M., C.B.N.), Duke University, Durham, North Carolina 27710; Sarah W. Stedman Nutrition and Metabolism Center (D.L., R.D.S., T.R.K., H.E.H., D.M.M., C.B.N.), Duke University, Durham, North Carolina 27704; Department of Medicine (S.M.M., W.M.K., T.H.L.), Veterans Affairs Medical Centers, Durham, North Carolina 27705; and Department of Medicine (S.M.M., X.Y.Z.), University of Alabama, Birmingham, Birmingham, Alabama 35294

Address all correspondence and requests for reprints to: Sandra M. Malakauskas, Ph.D., M.D., Department of Medicine, University of Alabama at Birmingham, 701 19th Street South, LHRB 431B, Birmingham, Alabama 35294. E-mail: smalak{at}uab.edu.

Collectrin is a downstream target of the transcription factor hepatocyte nuclear factor-1 (HNF-1), which is mutated in maturity-onset diabetes of the young subtype 3 (MODY3). Evidence from transgenic mouse models with collectrin overexpression in pancreatic islets suggests divergent roles for collectrin in influencing β-cell mass and insulin exocytosis. To clarify the function of collectrin in the pancreas, we used a mouse line with targeted deletion of the gene. We examined pancreas morphology, glucose homeostasis by ip glucose tolerance testing (IPGTT) and insulin tolerance testing (IPITT), and pancreas function by in vivo acute-phase insulin response determination and glucose-stimulated insulin secretion from isolated islets. We find no difference in either pancreas morphology or function between wild-type and collectrin-deficient animals (Tmem27^–/y). However, we note that by 6 months of age, Tmem27^–/y mice exhibit increased insulin sensitivity by IPITT and decreased adiposity by dual-energy x-ray absorptiometry scanning compared with wild-type. We have previously reported that Tmem27^–/y mice exhibit profound aminoaciduria due to failed renal recovery. We now demonstrate that Tmem27^–/y animals also display inappropriate excretion of some short-chain acylcarnitines derived from amino acid and fatty acid oxidation. We provide further evidence for compensatory up-regulation of oxidative metabolism in Tmem27^–/y mice, along with enhanced protein turnover associated with preserved lean mass even out to 1.5 yr of age. Our studies suggest that collectrin-deficient mice activate a number of adaptive mechanisms to defend energy homeostasis in the setting of ongoing nutrient losses.