Abnormal glucose homeostasis in adult female rat offspring after intrauterine ethanol exposure

Yao, Xiaoxi; Nyomba, B. L. Grégoire

doi:10.1152/ajpregu.00822.2006

Cited by 32 publications

(45 citation statements)

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“…Both Akt and PKC are under inhibitory control by the lipid phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome ten) (7,26), whereas Akt is also negatively regulated by TRB3 (tribbles 3) (14). Although we have demonstrated that insulin stimulation of Akt and PKC is impaired along with increased expression of PTEN and TRB3 in skeletal muscle of rat offspring prenatally exposed to alcohol (11,45), mechanisms leading to hepatic insulin resistance and increased gluconeogenesis in these animals are only partially understood. Liver steatosis and increased expression of gluconeogenic genes may play a role, as previously reported (12,44).…”

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confidence: 78%

“…For example, the transcriptional coactivator peroxisome proliferator-activated receptor-␥ coactivator-1␣ (PGC-1␣), which regulates gluconeogenic enzymes, is controlled by the histone deacetylase (HDAC) SIRT1, which is posttranslationally induced by a nutrient signaling response mediated by pyruvate (32), whereas mice overexpressing HDAC1 exhibit a high incidence of hepatic steatosis (41). We have previously shown that pyruvate injection results in a dramatic blood glucose rise in alcoholexposed rat offspring (44,45), implying that PGC-1␣ deacetylation by SIRT1 is likely to be active in these animals. SIRT1 deacetylates PGC-1␣, and this, in addition to PGC-1␣ gene expression, enhances the induction of gluconeogenic genes and hepatic glucose output (32).…”

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confidence: 99%

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Hepatic insulin resistance induced by prenatal alcohol exposure is associated with reduced PTEN and TRB3 acetylation in adult rat offspring

Yao¹,

Nyomba²

2008

American Journal of Physiology-Regulatory, Integrative and Comp

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Prenatal alcohol exposure (EtOH) results in insulin resistance in rats of both sexes with increased expression of hepatic gluconeogenic genes and glucose production. To investigate whether hepatic insulin signaling is defective, we studied 3-mo-old female offspring of dams that were given EtOH during pregnancy compared with those from pair-fed and control dams. We performed an intraperitoneal pyruvate tolerance test, determined the phosphorylation status of hepatic phosphoinositide-dependent protein kinase-1 (PDK1), Akt, and PKCzeta before and after intravenous insulin bolus, and measured mRNA and in vivo acetylation of TRB3 (tribbles 3) and PTEN (phosphatase and tensin homolog deleted on chromosome ten) as well as the expression of the histone acetylase (HAT) PCAF (p300/CREB-binding protein-associated factor), histone deacetylase-1 (HDAC1), and HAT and HDAC activities. In EtOH compared with pair-fed and control offspring, basal and pyruvate-induced blood glucose was increased, insulin-induced PDK1, Akt, and PKCzeta phosphorylation was reduced, and expression of PTEN and TRB3 was increased while their acetylation status was decreased in association with increased HDAC and decreased HAT activities. Thus female adult rats prenatally exposed to EtOH have increased gluconeogenesis, reduced insulin signaling, and increased PTEN and TRB3 expression in the liver. In addition, PTEN and TRB3 are hypoacetylated, which can contribute to Akt-inhibiting activity. These results suggest that hepatic insulin resistance in rats prenatally exposed to EtOH is explained, at least in part, by increased PTEN and TRB3 activity due to both increased gene expression and reduced acetylation.

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confidence: 78%

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confidence: 99%

Hepatic insulin resistance induced by prenatal alcohol exposure is associated with reduced PTEN and TRB3 acetylation in adult rat offspring

Yao¹,

Nyomba²

2008

American Journal of Physiology-Regulatory, Integrative and Comp

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“…4). Adult rats that have in utero exposure to ethanol are predisposed to the development of diabetes, which is also associated with elevated TRIB3 in skeletal muscle and liver (20,64,65). In humans, the TRIB3 gain-offunction Q84R polymorphism is associated with insulin resistance and diabetes (41,50), early onset T2DM, and predisposition to carotid atherosclerosis (16,42).…”

Section: E571 Trib3 Impairs Insulin Action In Skeletal Musclementioning

confidence: 99%

MammalianTribbleshomolog 3 impairs insulin action in skeletal muscle: role in glucose-induced insulin resistance

Liu

Franklin

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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Tribbles homolog 3 (TRIB3) was found to inhibit insulin-stimulated Akt phosphorylation and modulate gluconeogenesis in rodent liver. Currently, we examined a role for TRIB3 in skeletal muscle insulin resistance. Ten insulin-sensitive, ten insulin-resistant, and ten untreated type 2 diabetic (T2DM) patients were metabolically characterized by hyperinsulinemic euglycemic glucose clamps, and biopsies of vastus lateralis were obtained. Skeletal muscle samples were also collected from rodent models including streptozotocin (STZ)-induced diabetic rats, db/db mice, and Zucker fatty rats. Finally, L6 muscle cells were used to examine regulation of TRIB3 by glucose, and stable cell lines hyperexpressing TRIB3 were generated to identify mechanisms underlying TRIB3-induced insulin resistance. We found that 1) skeletal muscle TRIB3 protein levels are significantly elevated in T2DM patients; 2) muscle TRIB3 protein content is inversely correlated with glucose disposal rates and positively correlated with fasting glucose; 3) skeletal muscle TRIB3 protein levels are increased in STZ-diabetic rats, db/db mice, and Zucker fatty rats; 4) stable TRIB3 hyperexpression in muscle cells blocks insulin-stimulated glucose transport and glucose transporter 4 (GLUT4) translocation and impairs phosphorylation of Akt, ERK, and insulin receptor substrate-1 in insulin signal transduction; and 5) TRIB3 mRNA and protein levels are increased by high glucose concentrations, as well as by glucose deprivation in muscle cells. These data identify TRIB3 induction as a novel molecular mechanism in human insulin resistance and diabetes. TRIB3 acts as a nutrient sensor and could mediate the component of insulin resistance attributable to hyperglycemia (i.e., glucose toxicity) in diabetes. glucose toxicity; type 2 diabetes; insulin signaling THE PREVALENCE OF TYPE 2 DIABETES MELLITUS (T2DM) is rapidly increasing in Westernized nations. Although it likely results from both genetic and environment factors, a key pathogenic characteristic of T2DM is insulin resistance, due to impaired stimulation of glucose uptake in skeletal muscle.To obtain a more comprehensive understanding of insulin resistance, we have performed cDNA microarray studies to systematically assess differential gene expression in skeletal muscle from insulin-sensitive (IS) vs. insulin-resistant (IR) humans (59, 60). These analyses identified Tribbles homolog 3 (TRIB3) as a gene with increased expression in patients with T2DM. Tribbles was first identified by Mata et al. (31) in 2000 as a regulator of germ-cell development in Drosophila (31). Tribbles inhibits mitosis and regulates DNA damage repair by promoting ubiquitination and proteasome-mediated degradation of specific cell cycle regulators early in development (17,31,46,49). Mammals express a family of three genes, TRIB1, TRIB2, and TRIB3, that are homologous to Tribbles. These family members are characterized by a variant kinase domain in the center of molecule with a high homology to serine/ threonine kinases (22). However, they app...

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“…The causal link between maternal dietary alcohol consumption and risk of metabolic complications during adulthood was evident from the data obtained in the study by Pennington et al [38], where exposure to alcohol during in utero development resulted in hypertriglyceridemia along with an increase in the very lowdensity lipoprotein fraction of serum, both known to be associated with metabolic syndrome and T2D, in adult rat offspring. The links between maternal alcohol exposure during pregnancy and beta cell dysfunction, abnormal glucose homeostasis, and insulin resistance during adulthood were evident in a line of studies [39][40][41][42][43]. In addition, insulin resistance was also evident after exposure to alcohol during lactation [42].…”

Section: Alcoholmentioning

confidence: 99%

Early-Life Exposure to Substance Abuse and Risk of Type 2 Diabetes in Adulthood

Vaiserman

2015

Curr Diab Rep

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Type 2 diabetes (T2D) is a chronic non-communicable disease that is driven by insulin resistance as a result of increasing obesity and decreasing activity levels that occur with increasing age. This disease generally develops after the age of 40, but it is now increasingly diagnosed in children and young adults. Increasing evidence, however, suggests that T2D can originate during early development. It has been repeatedly found that malnutrition during the gestational period can result in intrauterine growth restriction and low birth weight, which in combination with postnatal catch-up growth may subsequently lead to the development of T2D. There is ample evidence that T2D may also be programmed by maternal substance abuse (the harmful use of psychoactive substances such as illicit drugs or alcohol) during pregnancy and/or lactation. The research activity in this field is currently mainly focused on the childhood health problems following prenatal exposures to substance abuse. The delayed programming effects on adult-onset disorders, including metabolic syndrome and T2D, however, have been reported only rarely. This review provides animal and human evidence that early-life exposure to substance abuse, including alcohol, nicotine, and cocaine, may program not only childhood health outcomes but also life-long metabolic health status, including risk of T2D and related conditions.

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Abnormal glucose homeostasis in adult female rat offspring after intrauterine ethanol exposure

Abstract: Yao X-H, Nyomba BL. Abnormal glucose homeostasis in adult female rat offspring after intrauterine ethanol exposure.

Cited by 32 publications

References 54 publications

Hepatic insulin resistance induced by prenatal alcohol exposure is associated with reduced PTEN and TRB3 acetylation in adult rat offspring

Hepatic insulin resistance induced by prenatal alcohol exposure is associated with reduced PTEN and TRB3 acetylation in adult rat offspring

MammalianTribbleshomolog 3 impairs insulin action in skeletal muscle: role in glucose-induced insulin resistance

Early-Life Exposure to Substance Abuse and Risk of Type 2 Diabetes in Adulthood

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