Early-life programming of susceptibility to dysregulation of glucose metabolism and the development of Type 2 diabetes mellitus

Holness, Mark J.; Langdown, Maria L.; Sugden, Mary C.

doi:10.1042/bj3490657

Cited by 126 publications

(87 citation statements)

References 147 publications

(175 reference statements)

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“…Similarly, other in utero insults including glucocorticoid administration, uteroplacental insufficiency and fetal undernutrition have been shown to result in long-lasting functional deficiencies in the endocrine pancreas [19][20][21][22]. At 26 weeks of age nicotine-exposed offspring exhibit dysglycaemia and increased serum insulin concentrations.…”

Section: Discussionmentioning

confidence: 99%

Fetal and neonatal exposure to nicotine in Wistar rats results in increased beta cell apoptosis at birth and postnatal endocrine and metabolic changes associated with type 2 diabetes

et al. 2005

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Fetal and neonatal exposure to nicotine in Wistar rats results in increased beta cell apoptosis at birth and postnatal endocrine and metabolic changes associated with type 2 diabetes Abstract Aims/hypothesis: Epidemiological studies report an increased risk of obesity and type 2 diabetes in children born to women who smoked during pregnancy. This study examines the effect of fetal and neonatal exposure to nicotine, the major addictive component of cigarettes, on postnatal growth, adiposity and glucose homeostasis. Methods: Female Wistar rats were given either saline (vehicle) or nicotine (1 mg kg −1 day −1 ) during pregnancy and lactation. Serum and pancreas tissue were collected from the infant rats at birth. Postnatal growth was assessed weekly until the rats reached 26 weeks of age and glucose homeostasis was examined by OGTTs performed at 7 and 26 weeks of age. Results: Exposure to nicotine resulted in increased postnatal growth and adiposity. Nicotine exposure also resulted in dysglycaemia at 7 and 26 weeks of age. Serum insulin concentrations were decreased in the pups exposed to nicotine at birth. This was associated with increased beta cell apoptosis (pups of saline-treated mothers 8.8±1.21% apoptotic beta cells; pups of nicotine-treated mothers 27.8±3.1% apoptotic beta cells). Conclusions/interpretation: Fetal and neonatal exposure to nicotine results in metabolic changes in the offspring that are consistent with obesity and type 2 diabetes. We propose that these metabolic changes may be a consequence of the initial insult to the beta cell during fetal life and that this animal model has many characteristics of diabetes in humans.

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Section: Discussionmentioning

confidence: 99%

Fetal and neonatal exposure to nicotine in Wistar rats results in increased beta cell apoptosis at birth and postnatal endocrine and metabolic changes associated with type 2 diabetes

et al. 2005

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“…This enzyme normally protects fetal tissues from the high maternal levels of cortisol (corticosterone in rats) by catalyzing its conversion to inert cortisone (11-dehydrocorticosterone). 7 The small baby syndrome has been modelled in rats by reducing the proportion of protein in their diet (see Holness et al 10 ).…”

Section: Introductionmentioning

confidence: 99%

Modulation of susceptibility to weight gain and insulin resistance in low birthweight rats by treatment of their mothers with leptin during pregnancy and lactation

et al. 2003

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OBJECTIVES:To investigate whether administration of leptin to rats during pregnancy and lactation affects placental 11b-hydroxysteroid dehydrogenase (11b-HSD2) activity and the susceptibility of their offspring to weight gain and insulin resistance. DESIGN: Pregnant rats fed on a low-protein diet were administered leptin or saline by subcutaneous minipump from day 14 of gestation and throughout lactation. A further group was fed a normal diet and given saline. After weaning, the offspring of each group were fed on a normal diet until 6 weeks of age and then half of each group was transferred to a high-fat diet until 12 months of age. RESULTS: Plasma leptin levels were raised two-fold on days 16-18 of pregnancy in the leptin-treated dams, but, despite a constant rate of infusion, at parturition they dipped to control levels before rising again. The activity of placental 11b-HSD2 was reduced by the low-protein diet; this reduction was prevented by treating the dams with leptin. The male offspring of the salinetreated dams gained more weight and had higher plasma leptin levels on the high fat than the chow diet, but the offspring of the leptin-treated dams did not. Fasting blood glucose and intraperitoneal glucose tolerance at 6 and 12 months of age was unaffected by the high-fat diet, but only the offspring of the leptin-treated dams achieved this control without raised insulin levels. CONCLUSIONS: The rate of leptin clearance appears to increase at parturition. The administration of leptin to rats during late pregnancy and lactation makes their male offspring less susceptible to high-fat-diet-induced weight gain and insulin resistance.

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“…These observations have led to the hypothesis that events occurring before birth caused by malnutrition, or other adverse influences, can lead to persistent changes in organ structure or function that predispose to metabolic disorders in later life (Hales & Barker 2001). Two major mechanistic hypotheses have been proposed, supported by animal studies, namely maternal malnutrition, in particular protein malnutrition, and prenatal glucocorticoid exposure (Seckl 1998, Holness et al 2000. In particular, mild protein restriction when imposed during pregnancy or pregnancy and lactation elicits a profound impairment in the structural and functional development of the fetal endocrine pancreas (Dahri et al 1991) and liver (Desai et al 1997).…”

Section: Introductionmentioning

confidence: 99%

Gender-specific programming of insulin secretion and action

Sugden

Holness²

2002

Journal of Endocrinology

121

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Insulin secretion and glucose tolerance were studied in 20-week-old male and female offspring of rat dams maintained on an isocaloric 20% or 8% protein diet during pregnancy and lactation after transfer to the same diet at weaning. Protein-restricted male and female offspring were also weaned onto a 20% protein diet. In males, post-absorptive insulin concentrations were suppressed by protein restriction from conception to adulthood (by 41%; P<0·001); however, basal insulin levels were 2·6-fold higher (P<0·001) if protein restriction was limited to gestation and lactation. Post-absorptive insulinaemia in females was unaffected by early or sustained protein restriction, but was lower than for males in the control group and the group exposed to protein restriction during early life alone (by 40% (P<0·001) and 52% (P<0·001) respectively). Plasma insulin/blood glucose ratios were higher in males compared with females in both control and early protein-restricted groups (1·6-fold (P<0·05) and 2·3-fold (P<0·001) respectively). A positive linear relationship existed between mean ambient insulin and glucose concentrations in males (r=1·0) and females (r=0·9), but the gradient was 12·4-fold greater (P<0·01) in males.-Cell function was evaluated after intravenous glucose challenge. In males, the acute insulin response and the suprabasal 30-min area under the insulin curve were dramatically higher in rats exposed to protein restriction during gestation and lactation alone (2·6-and 2·8-fold respectively; P<0·001). In contrast, these parameters were lowered by extending the exposure to protein restriction to adulthood in males, and by either early or prolonged exposure to protein restriction in females. The insulin resistance index was increased (2·5-fold; P<0·001) in male, but not female, rats exposed to protein restriction during gestation and lactation alone, and was not increased by extending the period of protein restriction to adulthood in either sex. Thus the data have demonstrated genderspecific lowering of insulin sensitivity due to protein restriction during early life only. The insulinogenic index (insulin response in relation to prevailing glycaemia) was increased in male, but not female, rats exposed to protein restriction during gestation and lactation alone (3·0-fold; P<0·001). A modest decline in insulin secretion in the female groups exposed to protein restriction until either the end of lactation or adulthood was compensated by increased insulin sensitivity, as demonstrated by significant decreases in the insulin resistance index in both groups (by 48% and 52% respectively; P<0·05). Glucose disappearance rates did not differ between the male and female control or early protein-restricted groups but were higher in both male (31%; P<0·05) and female groups (46%; P<0·001) exposed to protein restriction from conception to adulthood. Marked gender differences in glucosestimulated insulin secretion were not associated with gender differences with respect to glucose tolerance. Our data therefore demonstrated...

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Early-life programming of susceptibility to dysregulation of glucose metabolism and the development of Type 2 diabetes mellitus

Cited by 126 publications

References 147 publications

Fetal and neonatal exposure to nicotine in Wistar rats results in increased beta cell apoptosis at birth and postnatal endocrine and metabolic changes associated with type 2 diabetes

Fetal and neonatal exposure to nicotine in Wistar rats results in increased beta cell apoptosis at birth and postnatal endocrine and metabolic changes associated with type 2 diabetes

Modulation of susceptibility to weight gain and insulin resistance in low birthweight rats by treatment of their mothers with leptin during pregnancy and lactation

Gender-specific programming of insulin secretion and action

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