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

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 ␤-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 ␤-cell dysfunction may play a significant role in the pathogenesis of LBW-associated type 2 diabetes. Diabetes 54: 702-711, 2005

Genomic imprinting as an adaptative model of developmental plasticity

“…The pancreas is a plastic organ, and early life events may play a role in determining the capacity for adult pancreatic plasticity. Several animal models have demonstrated altered pancreatic development following in utero deprivation [67][68][69][70]. A group of imprinted genes including Igf2, Rasgrf, Grb10, Neuronatin and Zac1 play key roles in pancreatic development and maturation and may be involved in the pathogenesis of these defects, although direct evidence of this remains scanty.…”

Is the Fetal Origins Hypothesis of Diabetes Supported by Animal Research? A Systematic Review and Meta-Analysis of the Evidence

“…Twenty-six studies reported on protein restriction, one using a mouse model [4], and twenty-five using a rat model . Twenty-four reported on general (caloric) undernutrition, one study using guinea pigs [30] and two on a mouse model [31,32], five using a sheep model [33][34][35][36][37] and 16 studies on rats [7,8,13,[38][39][40][41][42][43][44][45][46][47][48][49][50][51] .…”

“…Randomization was reported in twenty-four studies, either randomization to the dietary regimen or randomly selecting the pups that were studied from the litters [14,15,[17][18][19][20][21][22][23][24]26,28,29,31,32,[34][35][36]39,42,44,48,50,[52][53][54]. None of the studies reported a sample size calculation or methods for concealment of allocation.…”

Epigenetics: Understanding How our Choices Lead to our Diseases

“…Self-sustaining loops and structural inheritance also impact epigenetic events but these mechanisms are less understood and will not be discussed in length in this article. Instead, the focus will remain on how DNA methylation, histone modifications, and noncoding RNA act in concert to make molecular modifications to DNA contributing to disease susceptibility and expression [10,30,31].…”