Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis

Hales, C. N.; Barker, D. J. P.

doi:10.1007/bf00400248

Cited by 2,901 publications

(1,567 citation statements)

References 74 publications

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“…Interestingly, the impaired glucose tolerance was similar, not worse, to low protein offspring at 4 months whereby their diet was switched to 20% at weaning (Chamson-Reig et al 2009). Collectively, both studies further support of the main tenets of the Thrifty Phenotype hypothesis (Hales & Barker 1992).…”

Section: Discussionsupporting

confidence: 63%

Maternal protein restriction leads to enhanced hepatic gluconeogenic gene expression in adult male rat offspring due to impaired expression of the liver X receptor

Vo¹,

Revesz²,

Sohi³

et al. 2013

Journal of Endocrinology

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Epidemiological studies demonstrate that the link between impaired fetal development and glucose intolerance in later life is exacerbated by postnatal catch-up growth. Maternal protein restriction (MPR) during pregnancy and lactation in the rat has been previously demonstrated to lead to impaired glucose tolerance in adulthood, however the effects of protein restoration during weaning on glucose homeostasis are largely unknown. Recent in vitro studies have identified that the liver X receptor a (LXRa) maintains glucose homeostasis by inhibiting critical genes involved in gluconeogenesis including G6pase (G6pc), 11b-Hsd1 (Hsd11b1) and Pepck (Pck1). Therefore, we hypothesized that MPR with postnatal catch-up growth would impair LXRa in vivo, which in turn would lead to augmented gluconeogenic LXRa-target gene expression and glucose intolerance. To examine this hypothesis, pregnant Wistar rats were fed a control (20%) protein diet (C) or a low (8%) protein diet during pregnancy and switched to a control diet at birth (LP). At 4 months, the LP offspring had impaired glucose tolerance. In addition, LP offspring had decreased LXRa expression, while hepatic expression of 11b-HSD1 and G6Pase was significantly higher. This was concomitant with decreased binding of LXRa to the putative LXRE on 11b-Hsd1 and G6pase. Finally, we demonstrated that the acetylation of histone H3 (K9,14) surrounding the transcriptional start site of hepatic Lxra (Nr1h3) was decreased in LP offspring, suggesting MPR-induced epigenetic silencing of the Lxra promoter. In summary, our study demonstrates for the first time the important role of LXRa in mediating enhanced hepatic gluconeogenic gene expression and consequent glucose intolerance in adult MPR offspring.

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Section: Discussionsupporting

confidence: 63%

Maternal protein restriction leads to enhanced hepatic gluconeogenic gene expression in adult male rat offspring due to impaired expression of the liver X receptor

Vo¹,

Revesz²,

Sohi³

et al. 2013

Journal of Endocrinology

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“…A perinatal origin of adult disease has been suggested to contribute to the rapid rise in type 2 diabetes. This has been supported by epidemiological and animal studies, which have shown a strong relationship between poor fetal growth and subsequent development of obesity and type 2 diabetes in adult life (Hales & Barker 1992).…”

Section: Introductionmentioning

confidence: 71%

Maternal taurine supplementation in rats partially prevents the adverse effects of early-life protein deprivation on β-cell function and insulin sensitivity

Tang¹,

Marchand²,

Lam³

et al. 2013

Reproduction

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Dietary protein restriction during pregnancy and lactation in rats impairs b-cell function and mass in neonates and leads to glucose intolerance in adult offspring. Maternal taurine (Tau) supplementation during pregnancy in rats restores b-cell function and mass in neonates, but its long-term effects are unclear. The prevention of postnatal catch-up growth has been suggested to improve glucose tolerance in adult offspring of low-protein (LP)-fed mothers. The objective of this study was to examine the relative contribution of b-cell dysfunction and insulin resistance to impaired glucose tolerance in 130-day-old rat offspring of LP-fed mothers and the effects of maternal Tau supplementation on b-cell function and insulin resistance in these offspring. Pregnant rats were fed i) control, ii) LP, and iii) LPCTau diets during gestation and lactation. Offspring were given a control diet following weaning. A fourth group consisting of offspring of LP-fed mothers, maintained on a LP diet following weaning, was also studied (LP-all life). Insulin sensitivity in the offspring of LP-fed mothers was reduced in females but not in males. In both genders, LP exposure decreased b-cell function. Tau supplementation improved insulin sensitivity in females and b-cell function in males. The LP-all life diet improved b-cell function in males. We conclude that i) maternal Tau supplementation has persistent effects on improving glucose metabolism (b-cell function and insulin sensitivity) in adult rat offspring of LP-fed mothers and ii) increasing the amount of protein in the diet of offspring adapted to a LP diet after weaning may impair glucose metabolism (b-cell function) in a gender-specific manner.

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“…The relationship of IUGR and later development of components of the metabolic syndrome (MS), including obesity, diabetes, hypertension, dyslipidemia, and osteoporosis, has been thought to be an effect of programming the fetus for insulin resistance (2,19). The relationship between IUGR and adult development of glucose intolerance and the MS has been documented in numerous populations and ethnicities (20).…”

Section: Discussionmentioning

confidence: 99%

“…The most prevalent explanation for the association of decreased fetal growth and adult metabolic disease is the thrifty phenotype hypothesis (19). Fetal undernutrition is postulated to lead to selective distribution of nutrients to essential survival functions, such as brain growth, with metabolic changes that increase postnatal survival in a similarly undernourished environment.…”

Section: Discussionmentioning

confidence: 99%

Intrauterine and postnatal growth failure with normal GH/IGF1 axis and insulin-resistant diabetes in a consanguineous kinship

Guevara‐Aguirre

Hwa

et al. 2012

European Journal of Endocrinology

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Objective: To describe the clinical and biochemical features, and perform molecular analysis for candidate abnormalities in a novel familial syndrome of intrauterine growth retardation (IUGR), failure of an adolescent growth spurt with proportional adult short stature, minimal subluxation of the 5th metacarpal-phalangeal joint, and adult-onset insulin-resistant diabetes unrelated to obesity or other manifestations of metabolic syndrome (MS). Design: Detailed clinical history, auxological, biochemical, radiological, and molecular studies, including DNA analysis and in vitro study of the GH/IGF1 pathway. Materials and methods: Ten affected adults from two generations of five related families were studied in detail, and information obtained about nine other likely affected individuals. Results: Height Z-scores ranged from K7.3 to K3.8. Unaffected parents of the older generation and frequency of confirmed and suspected instances of the syndrome in the two generations studied is consistent with autosomal recessive inheritance. Insulin resistance was uniformly present in seven subjects tested who were not taking insulin. Diabetes severity did not correlate with overweight. Subjects did not have other typical manifestations of MS such as substantial hyperlipidemia, osteoporosis, or hypertension. No biochemical abnormality in the GH/IGF1 axis or molecular defect was found. Conclusions: While the association of IUGR and adult MS, including diabetes, has been well documented, these subjects did not have typical manifestations of MS. Abnormalities in common components that could result in a combination of IUGR, severe postnatal growth, and insulin resistance have been ruled out. A mutation in an unidentified gene may affect intrauterine and postnatal growth, with insulin resistance directly affected or as a result of this growth phenomenon.

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Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis

Cited by 2,901 publications

References 74 publications

Maternal protein restriction leads to enhanced hepatic gluconeogenic gene expression in adult male rat offspring due to impaired expression of the liver X receptor

Maternal protein restriction leads to enhanced hepatic gluconeogenic gene expression in adult male rat offspring due to impaired expression of the liver X receptor

Maternal taurine supplementation in rats partially prevents the adverse effects of early-life protein deprivation on β-cell function and insulin sensitivity

Intrauterine and postnatal growth failure with normal GH/IGF1 axis and insulin-resistant diabetes in a consanguineous kinship

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