Decreased Fetal Size Is Associated With β-Cell Hyperfunction in Early Life and Failure With Age

Abstract

OBJECTIVE— Low birth weight is associated with diabetes in adult life. Accelerated or “catch-up” postnatal growth in response to small birth size is thought to presage disease years later. Whether adult disease is caused by intrauterine β-cell–specific programming or by altered metabolism associated with catch-up growth is unknown. RESEARCH DESIGN AND METHODS— We generated a new model of intrauterine growth restriction due to fatty acid synthase (FAS) haploinsufficiency (FAS deletion [FASDEL]). Developmental programming of diabetes in these mice was assessed from in utero to 1 year of age. RESULTS— FASDEL mice did not manifest catch-up growth or insulin resistance. β-Cell mass and insulin secretion were strikingly increased in young FASDEL mice, but β-cell failure and diabetes occurred with age. FASDEL β-cells had altered proliferative and apoptotic responses to the common stress of a high-fat diet. This sequence appeared to be developmentally entrained because β-cell mass was increased in utero in FASDEL mice and in another model of intrauterine growth restriction caused by ectopic expression of uncoupling protein-1. Increasing intrauterine growth in FASDEL mice by supplementing caloric intake of pregnant dams normalized β-cell mass in utero. CONCLUSIONS— Decreased intrauterine body size, independent of postnatal growth and insulin resistance, appears to regulate β-cell mass, suggesting that developing body size might represent a physiological signal that is integrated through the pancreatic β-cell to establish a template for hyperfunction in early life and β-cell failure with age.

Birth weight, current body mass index, and insulin sensitivity and secretion in young adults in two Latin American populations

“…Our study demonstrates that the association of BMI z-score with low HOMA%S and high HOMA%b may correspond to an increase of HOMA%b which compensates for the low HOMA% S. Previous studies have reported that the effect of BMI on insulin resistance is more consistent and of higher effect size than BW [10,14], as also shown in our study. Results from a study using an animal model have shown that decreased fetal size is associated with beta-cell hyperfunction in early life, which is consistent with our findings [13]. It is expected that as these cohorts become older, the compensatory increase in HOMA%b will probably decrease [13].…”

“…Results from a study using an animal model have shown that decreased fetal size is associated with beta-cell hyperfunction in early life, which is consistent with our findings [13]. It is expected that as these cohorts become older, the compensatory increase in HOMA%b will probably decrease [13]. Thus low HOMA%b could be an early warning of diabetes mellitus in a not too distant future in our population of young adults.…”

“…However, some studies have reported that current adult BMI is associated with insulin resistance regardless of BW and postnatal growth [10,11]. Studies have also assessed the effect of these factors on insulin secretion but results are not consistent [1,5,12,13].…”

Hyperinsulinemia and insulin resistance : What comes first ?

“…Beta cell expansion beginning in intrauterine life is independent of glucose, Insulin and Insulin receptors. [6] …”

“…In low birth weight neonates in humans as well as in rat models, hyperinsulinemia is found at very early stage. [6] 2. Development of insulin resistance is preceded by hyperinsulinemia in mice, rats as well as in humans.…”