In utero undernutrition reduces diabetes incidence in non-obese diabetic mice

Abstract

Aims/hypothesis Observational studies in humans suggest that low birthweight may decrease the risk of type 1 diabetes, but the mechanism is unknown. We hypothesised that antenatal undernutrition would decrease the incidence of type 1 diabetes in non-obese diabetic (NOD) mice. Materials and methods A 40% restriction of energy intake was applied to pregnant NOD dams from day 12.5 to day 18.5 of gestation, resulting in intrauterine growth retardation of offspring. All mice were fed a standard diet after weaning. Control and undernourished female offspring were followed to assess diabetes incidence. Male NOD mice were treated with cyclophosphamide to accelerate development of diabetes. Glucose homeostasis, body composition and pancreatic histology were compared in control and undernourished offspring. Results Mean birthweight was lower in undernourished than in control mice (p=0.00003). At 24 weeks of age, the cumulative incidence of spontaneous diabetes in female mice was 73% in control and 48% in undernourished mice (p=0.003). In cyclophosphamide-treated male mice, antenatal undernutrition also tended to reduce the development of diabetes (p=0.058). Maternal leptin levels were lower in undernourished dams on day 18.5 of pregnancy (p=0.039), while postnatal leptin levels were significantly higher in undernourished offspring at 4, 20 and 27 weeks of life (p<0.05). Beta cell mass was similar in both groups (control = 0.4 mg; undernourished = 0.54 mg; p=0.24). Histological evidence of apoptosis at 20 weeks was greater in control than in undernourished mice (control = 6.3± 1.4%; undernourished = 4.2±0.3%, p=0.05). Conclusions/interpretation Antenatal undernutrition reduces the incidence of diabetes in NOD mice, perhaps via alterations in apoptosis.

Maternal undernutrition increases pancreatic IGF-2 and partially suppresses the physiological wave of β-cell apoptosis during the neonatal period

“…Surprisingly, the incidence of b-cell apoptosis in food-restricted animals was significantly lower than in controls at all ages examined. Other authors have also reported that intrauterine malnutrition reduces the incidence of type 1 diabetes in non-obese diabetic mice altering b-cell apoptosis levels (Oge et al 2007). Apparently, in view of our results, even increased b-cell neogenesis and decreased b-cell apoptosis are insufficient to restore normal b-cell mass when proliferation and b-cell mass are already affected.…”

Birthweight and the risk of childhood-onset type 1 diabetes: a meta-analysis of observational studies using individual patient data

“…A recent experimental study in NOD mice demonstrated that calorific restriction during pregnancy resulted in reduced birthweight, leading to reduced risk of diabetes by 24 weeks [49]. Also an observational study in BioBreeding rats demonstrated a higher risk of diabetes with increased birthweight [50].…”

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.…”

“…Fourteen experiments were conducted in rats [7,8,12,13,38,39,[43][44][45][46][47][48][49]51], 4 in sheep [33,[35][36][37], 2 in mice [31,32] and one in guinea pigs [30]. The mean plasma insulin level was 0.03 nmol/l lower (95% CI -0.04 to -0.01) in the undernourished group compared to control animals, I² 86% ( Figure 5).…”