Beta-cell secretory dysfunction in the pathogenesis of low birth weight-associated diabetes: a murine model.
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 beta-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 beta-cell dysfunction may play a significant role in the pathogenesis of LBW-associated type 2 diabetes.
Jimenez-Chillaron
Josep C
JC
Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA.
Hernandez-Valencia
Marcelino
M
Reamer
Carolyn
C
Fisher
Simon
S
Joszi
Allison
A
Hirshman
Michael
M
Oge
Aysin
A
Walrond
Shana
S
Przybyla
Roberta
R
Boozer
Carol
C
Goodyear
Laurie J
LJ
Patti
Mary-Elizabeth
ME
D017667:Adipocytes / Q000378:metabolism; D000375:Aging; D000824:Animal Nutritional Physiological Phenomena; D000818:Animals; D001724:Birth Weight; D003924:Diabetes Mellitus, Type 2 / Q000196:embryology / Q000503:physiopathology*; D004195:Disease Models, Animal; D005260:Female; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007230:Infant, Low Birth Weight; D007231:Infant, Newborn; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D008813:Mice, Inbred ICR; D018482:Muscle, Skeletal / Q000378:metabolism; D011247:Pregnancy; D012307:Risk Factors
D007328:Insulin; D005947:Glucose