Diabetes Risk Begins In Utero

Woo, Melissa; Patti, Mary‐Elizabeth

doi:10.1016/j.cmet.2008.06.007

Cited by 21 publications

(17 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…First, alterations in nutrition during development can alter epigenetic marks, thus regulating gene expression through DNA methylation (12,(17)(18)(19) and/or histone modifications (17,20,21). Interestingly, such epigenetic modifications may progress with aging during postnatal life, in association with metabolic phenotypes, as recently observed at the pancreatic duodenal homeobox-1 and GLUT4 locus in rodent models of intrauterine programming (33)(34)(35). If these epigenetic changes occur in the germ line, they can be inherited through meiosis (22)(23)(24), thus providing a plausible explanation for intergenerational effects, transmitted via either maternal or paternal lines.…”

Section: Discussionmentioning

confidence: 99%

Intergenerational Transmission of Glucose Intolerance and Obesity by In Utero Undernutrition in Mice

Isganaitis²,

et al. 2009

Self Cite

View full text Add to dashboard Cite

OBJECTIVE— Low birth weight (LBW) is associated with increased risk of obesity, diabetes, and cardiovascular disease during adult life. Moreover, this programmed disease risk can progress to subsequent generations. We previously described a mouse model of LBW, produced by maternal caloric undernutrition (UN) during late gestation. LBW offspring (F 1 -UN generation) develop progressive obesity and impaired glucose tolerance (IGT) with aging. We aimed to determine whether such metabolic phenotypes can be transmitted to subsequent generations in an experimental model, even in the absence of altered nutrition during the second pregnancy. RESEARCH DESIGN AND METHODS— We intercrossed female and male F 1 adult control (C) and UN mice and characterized metabolic phenotypes in F 2 offspring. RESULTS— We demonstrate that 1 ) reduced birth weight progresses to F 2 offspring through the paternal line (C♀-C♂ = 1.64 g; C♀-UN♂ = 1.57 g, P < 0.05; UN♀-C♂ = 1.64 g; UN♀-UN♂ = 1.60 g, P < 0.05), 2 ) obesity progresses through the maternal line (percent body fat: C♀-C♂ = 22.4%; C♀-UN♂ = 22.9%; UN♀-C♂ = 25.9%, P < 0.05; UN♀-UN♂ = 27.5%, P < 0.05), and 3 ) IGT progresses through both parental lineages (glucose tolerance test area under curve C♀-C♂ = 100; C♀-UN♂ = 122, P < 0.05; UN♀-C♂ = 131, P < 0.05; UN♀-UN♂ = 151, P < 0.05). Mechanistically, IGT in both F 1 and F 2 generations is linked to impaired β-cell function, explained, in part, by dysregulation of Sur1 expression. CONCLUSIONS— Maternal undernutrition during pregnancy (F 0 ) programs reduced birth weight, IGT, and obesity in both first- and second-generation offspring. Sex-specific transmission of phenotypes implicates complex mechanisms including alterations in the maternal metabolic environment (transmaternal inheritance of obesity), gene expression mediated by developmental and epigenetic pathways (transpaternal inheritance of LBW), or both (IGT).

show abstract

Section: Discussionmentioning

confidence: 99%

Intergenerational Transmission of Glucose Intolerance and Obesity by In Utero Undernutrition in Mice

Isganaitis²,

et al. 2009

Self Cite

View full text Add to dashboard Cite

show abstract

“…In rodent models that mimic low birth weight in humans by food restriction or restriction of placental flow of pregnant dams, it has now been clearly demonstrated that not only do the low birth weight offspring have an increased risk of diabetes, but this risk is passed on to the second generation, probably through effects on intrauterine and early postnatal nutritional effects on genetic imprinting and/or epigenetic regulation of gene expression or development (Sharif et al, 2007; Ozanne and Constancia, 2007; Jimenez-Chillaron et al, 2006). Moreover, these epigenetic marks, while resulting from early life exposures, can actually progress during postnatal life and thus contribute to age-dependent transcriptional repression of key metabolic genes, as has recently been demonstrated for the β cell transcription factor PDX1 (Park et al, 2008) and the insulin-sensitive glucose transporter GLUT4 (Raychaudhuri et al, 2008, Woo and Patti, 2008). …”

Section: The Emerging Genetic Architecture Of Type 2 Diabetesmentioning

confidence: 94%

The Emerging Genetic Architecture of Type 2 Diabetes

2008

Self Cite

View full text Add to dashboard Cite

Type 2 diabetes is a genetically heterogeneous disease, with several relatively rare monogenic forms and a number of more common forms resulting from a complex interaction of genetic and environmental factors. Previous studies using a candidate gene approach, family linkage studies, and gene expression profiling uncovered a number of type 2 genes, but the genetic basis of common type 2 diabetes remained unknown. Recently, a new window has opened on defining potential type 2 diabetes genes through genome-wide SNP association studies of very large populations of individuals with diabetes. This review explores the pathway leading to discovery of these genetic effects, the impact of these genetic loci on diabetes risk, the potential mechanisms of action of the genes to alter glucose homeostasis, and the limitations of these studies in defining the role of genetics in this important disease.

show abstract

“…Person-years at risk were calculated for each employee beginning January 1, 1985, and ending at the closing date of the study (December 31,2005) or the date of death, whichever came first. Hazard ratios (HRs) for cumulative number of risk factors were calculated using a Cox proportional hazards model (SAS PHRGEG procedures) adjusted for age and gender.…”

Section: Methodsmentioning

confidence: 99%