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M J Nyirenda

Publications and source records attributed to M J Nyirenda.

8 recordsLinked to original sources
PubMed2006

Prenatal programming of hepatocyte nuclear factor 4alpha in the rat: A key mechanism in the 'foetal origins of hyperglycaemia'?

AIMS/HYPOTHESIS: Prenatal glucocorticoid exposure causes lifelong hyperglycaemia in rat offspring, associated with permanently increased hepatic phosphoenolpyruvate carboxykinase 2 (PCK2), the rate-controlling enzyme of gluconeogenesis. To elucidate the mechanisms underlying the 'programming' of PCK2, this study examined the effect of prenatal dexamethasone treatment on expression of transcription factors that regulate Pck2. MATERIALS AND METHODS: Real-time RT-PCR and in situ hybridisation were used to measure and localise hepatic mRNA transcribed from the genes for PCK2, hepatocyte nuclear factor 4, alpha (HNF4A), transcription factor 1 (TCF1), CCAAT/enhancer binding protein, alpha (CEBPA), CEBPB, the glucocorticoid receptor (NR3C1) and peroxisome proliferative activated receptor, gamma, coactivator 1 alpha (PPARGC1A) in foetal and adult offspring of dams treated with dexamethasone or vehicle during the last week of gestation. RESULTS: Prenatal dexamethasone exposure significantly elevated Hnf4a mRNA expression in foetal and adult liver. This resulted from increased expression of isoforms derived from the 'adult' (P1) Hnf4a promoter. In contrast, isoforms from the 'foetal' (P2) promoter were markedly suppressed by dexamethasone. Like Pck2, the increase in hepatic Hnf4a mRNA occurred exclusively in the periportal zone. Foetal Tcf1 expression was also increased by dexamethasone treatment, but this did not persist into adulthood. Prenatal dexamethasone did not affect the amounts of foetal and/or adult Cebpa, Cebpb, Nr3c1 or Ppargc1a mRNA. CONCLUSIONS/INTERPRETATION: Prenatal dexamethasone exposure caused a permanent increase in hepatic Hnf4a mRNA. This increase, which was associated with a premature switch from foetal to adult promoter predominance, was congruent with changes in Pck2 expression. These data suggest that HNF4A might mediate Pck2 overexpression and subsequent hyperglycaemia.

Animals↗
PubMed2006

Severe acidosis in patients taking metformin--rapid reversal and survival despite high APACHE score.

BACKGROUND: Metformin has been shown to reduce complications and mortality from Type 2 diabetes mellitus, and is increasingly used to treat this condition. This agent is, however, associated with a rare but serious risk of lactic acidosis. CASE REPORT: We present cases of 10 patients with Type 2 diabetes mellitus who developed acute renal failure and severe lactic acidosis. Despite the severity of their illness, all patients but one survived. CONCLUSIONS: The increasing prevalence of Type 2 diabetes and its treatment with metformin might result in more cases of lactic acidosis. However our case report demonstrates that early and aggressive treatment with haemofiltration can improve outcomes even in the presence of severe acidosis.

APACHE↗
PubMed2001

Programming hyperglycaemia in the rat through prenatal exposure to glucocorticoids-fetal effect or maternal influence?

In a previous study, we showed that exposure of rats to dexamethasone (Dex) selectively in late pregnancy produces permanent induction of hepatic phosphoenolpyruvate carboxykinase (PEPCK) expression and hyperglycaemia in the adult offspring. The mechanisms by which glucocorticoids cause this programming are unclear but may involve direct actions on the fetus/neonate, or glucocorticoids may act indirectly by affecting maternal postnatal nursing behaviour. Using a cross-fostering paradigm, the present data demonstrate that switching the offspring at birth from Dex-treated dams to control dams does not prevent induction of PEPCK or hyperglycaemia. Similarly, offspring born to control dams but reared by Dex-treated dams from birth maintain normal glycaemic control. During the neonatal period, injection of saline per se was sufficient to cause exaggeration in adult offspring responses to an oral glucose load, with no additional effect from Dex. However, postnatal treatment with either saline or Dex did not alter hepatic PEPCK activity. Prenatal Dex permanently raised basal plasma corticosterone levels, but under stress conditions there were no differences in circulating corticosterone levels. Likewise, Dex-exposed rats had similar plasma catecholamine concentrations to control animals. These findings show that glucocorticoids programme hyperglycaemia through mechanisms that operate on the fetus or directly on the neonate, rather than via effects that alter maternal postnatal behaviour during the suckling period. The hyperglycaemic response does not appear to result from abnormal sympathoadrenal activity or hypothalamic-pituitary-adrenal response during stress.

Animals↗
PubMed2000

Glucocorticoids, 11beta-hydroxysteroid dehydrogenase, and fetal programming.

Epidemiological studies in many distinct human populations have associated low weight or thinness at birth with a substantially increased risk of cardiovascular and metabolic disorders, including hypertension and insulin resistance/type 2 diabetes, in adult life. The concept of fetal "programming" has been advanced to explain this phenomenon. Prenatal glucocorticoid therapy reduces birthweight, and steroids are known to exert long-term organizational effects during specific "windows" of development. Therefore, we hypothesized that fetal overexposure to endogenous glucocorticoids might underpin the link between early life events and later disease. In rats, birthweight is reduced following prenatal exposure to the synthetic glucocorticoid dexamethasone, which readily crosses the placenta, or to carbenoxolone, which inhibits 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), the physiological feto-placental "barrier" to endogenous glucocorticoids. Although the offspring regain the weight deficit by weaning, as adults they exhibit permanent hypertension, hyperglycemia, and increased hypothalamic-pituitary-adrenal axis activity. Moreover, physiological variations in placental 11beta-HSD2 activity near term correlate directly with fetal weight. In humans, 11beta-HSD2 gene mutations produce a low birthweight, and some studies show reduced placental 11beta-HSD2 activity in association with intrauterine growth retardation. Moreover, low birthweight babies have higher plasma cortisol levels throughout adult life, indicating that hypothalamic-pituitary-adrenal axis programming also occurs in humans. The molecular mechanisms of glucocorticoid programming are beginning to be unraveled and involve permanent and tissue-specific changes in the expression of key genes, notably of the glucocorticoid receptor itself. Thus, glucocorticoid programming may explain, in part, the association between fetal events and subsequent disorders in adult life.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1999

Interactions between oestradiol and glucocorticoid regulatory effects on liver-specific glucocorticoid-inducible genes: possible evidence for a role of hepatic 11beta-hydroxysteroid dehydrogenase type 1.

In vitro, 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1) catalyses the interconversion of active corticosterone and inert 11-dehydrocorticosterone. 11beta-HSD-1 is highly expressed in liver, where the reaction direction is 11beta-reduction, thus potentially increasing intrahepatic active glucocorticoid levels. Inhibition of 11beta-HSD-1 increases insulin sensitivity in humans in vivo suggesting that hepatic 11beta-HSD-1 plays a role in the maintenance or control of key glucocorticoid-regulated metabolic functions. We have selectively repressed hepatic 11beta-HSD-1 in rats by oestradiol administration for 42 days. This nearly completely repressed hepatic 11beta-HSD-1 mRNA expression and enzyme activity and reduced expression of hepatic glucocorticoid-inducible genes including phosphoenolpyruvate carboxykinase (PEPCK), the rate-limiting step in gluconeogenesis. Similar effects were seen after 3 weeks of oestradiol treatment. To examine whether this was due to any direct effect of oestradiol upon PEPCK, the experiment was repeated in adrenalectomised rats+/-glucocorticoid replacement. In adrenalectomised rats, oestradiol did not attenuate hepatic PEPCK, whilst glucocorticoid replacement restored this action. Oestradiol did not alter hepatic metabolism of corticosterone by pathways other than 11beta-HSD-1. These data suggest 11beta-HSD-1 plays an important role in maintaining expression of key glucocorticoid-regulated hepatic transcripts. Enzyme inhibition may provide a useful therapeutic target for manipulating glucose homeostasis.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1998

Glucocorticoid exposure in late gestation permanently programs rat hepatic phosphoenolpyruvate carboxykinase and glucocorticoid receptor expression and causes glucose intolerance in adult offspring.

Low birth weight in humans is predictive of insulin resistance and diabetes in adult life. The molecular mechanisms underlying this link are unknown but fetal exposure to excess glucocorticoids has been implicated. The fetus is normally protected from the higher maternal levels of glucocorticoids by feto-placental 11beta-hydroxysteroid dehydrogenase type-2 (11beta-HSD2) which inactivates glucocorticoids. We have shown previously that inhibiting 11beta-HSD2 throughout pregnancy in rats reduces birth weight and causes hyperglycemia in the adult offspring. We now show that dexamethasone (a poor substrate for 11beta-HSD2) administered to pregnant rats selectively in the last week of pregnancy reduces birth weight by 10% (P < 0.05), and produces adult fasting hyperglycemia (treated 5.3+/-0.3; control 4.3+/-0.2 mmol/ liter, P = 0.04), reactive hyperglycemia (treated 8.7+/-0.4; control 7.5+/-0.2 mmol/liter, P = 0.03), and hyperinsulinemia (treated 6.1+/-0.4; control 3.8+/-0.5 ng/ml, P = 0.01) on oral glucose loading. In the adult offspring of rats exposed to dexamethasone in late pregnancy, hepatic expression of glucocorticoid receptor (GR) mRNA and phosphoenolpyruvate carboxykinase (PEPCK) mRNA (and activity) are increased by 25% (P = 0.01) and 60% (P < 0.01), respectively, while other liver enzymes (glucose-6-phosphatase, glucokinase, and 11beta-hydroxysteroid dehydrogenase type-1) are unaltered. In contrast dexamethasone, when given in the first or second week of gestation, has no effect on offspring insulin/glucose responses or hepatic PEPCK and GR expression. The increased hepatic GR expression may be crucial, since rats exposed to dexamethasone in utero showed potentiated glucose responses to exogenous corticosterone. These observations suggest that excessive glucocorticoid exposure late in pregnancy predisposes the offspring to glucose intolerance in adulthood. Programmed hepatic PEPCK overexpression, perhaps mediated by increased GR, may promote this process by increasing gluconeogenesis.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1998

Intrauterine events and the programming of adulthood disease: the role of fetal glucocorticoid exposure (Review).

There is increasing epidemiological evidence in humans which associates low birth weight with later cardiovascular and metabolic disorders including hypertension, insulin resistance, hyperlipidaemia and death from ischaemic heart disease. The molecular mechanisms underlying this link are unknown but fetal glucocorticoid exposure may play a role. In adult mammals, glucocorticoid hormones are involved in control of several physiological processes that maintain homeostasis including coordination of responses to stress. During development, glucocorticoids have important regulatory functions to prepare the organism for metabolic adaptations necessary for extrauterine life. Fetal glucocorticoid load is, in part, regulated by placental and fetal 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) which catalyses a rapid breakdown of maternal and fetal glucocorticoids into inert products. Supraphysiological doses of glucocorticoids retard fetal growth, and human intrauterine growth retardation is associated with elevated cortisol levels. Recent studies have shown that exposing rats to excessive glucocorticoids in utero reduces birth weight and causes permanent hypertension and hyperglycaemia in the adult offspring. These observations show that glucocorticoids could be the link between low birth weight and later disease. Understanding of the molecular details involved in prenatal glucocorticoid action may provide novel insights into the pathogenesis of common cardiovascular and metabolic disorders.

Adult↗