β-Cell Secretory Dysfunction in the Pathogenesis of Low Birth Weight–Associated Diabetes

β-Cell Secretory Dysfunction in the Pathogenesis of Low Birth Weight–Associated Diabetes A Murine Model Josep C. Jimenez-Chillaron , Marcelino Hernandez-Valencia , Carolyn Reamer , Simon Fisher , Allison Joszi , Michael Hirshman , Aysin Oge , Shana Walrond , Roberta Przybyla , Carol Boozer , Laurie J. Goodyear and Mary-Elizabeth Patti Research Division, Joslin Diabetes Center, Boston, Massachusetts Address correspondence and reprint requests to Mary Elizabeth Patti, Room 640 C, 1 Joslin Place, Boston, MA 02215. E-mail: mary.elizabeth.patti{at}joslin.harvard.edu Abstract Low birth weight (LBW) is an important risk factor for type 2 diabetes. We have developed a mouse model of LBW resulting from undernutrition during pregnancy. Restriction of maternal food intake from day 12.5 to 18.5 of pregnancy results in a 23% decrease in birth weight ( P < 0.001), with normalization after birth. However, offspring of undernutrition pregnancies develop progressive, severe glucose intolerance by 6 months. To identify early defects that are responsible for this phenotype, we analyzed mice of undernutrition pregnancies at age 2 months, before the onset of glucose intolerance. Fed insulin levels were 1.7-fold higher in mice of undernutrition pregnancies ( P = 0.01 vs. controls). However, insulin sensitivity was normal in mice of undernutrition pregnancies, with normal insulin tolerance, insulin-stimulated glucose disposal, and isolated muscle and adipose glucose uptake. Although insulin clearance was mildly impaired in mice of undernutrition pregnancies, the major metabolic phenotype in young mice of undernutrition pregnancies was dysregulation of insulin secretion. Despite normal β-cell mass, islets from normoglycemic mice of undernutrition pregnancies showed basal hypersecretion of insulin, complete lack of responsiveness to glucose, and a 2.5-fold increase in hexokinase activity. Taken together, these data suggest that, at least in mice, primary β-cell dysfunction may play a significant role in the pathogenesis of LBW-associated type 2 diabetes. Footnotes J.C.J.-C. and M.H.-V. contributed equally to this work. A.J. is employed by and holds stock in Bristol Myers Squibb. CEACAM1, cell adhesion molecule 1; KRH, Krebs-Ringer-Hepes; LBW, low birth weight. Accepted November 29, 2004. Received February 10, 2004. DIABETES