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Adipocytes are the primary cells in the body that store excess energy as triglycerides. To perform this specialized function, adipocytes rely on their mitochondria; however, the role of adipocyte mitochondria in the regulation of adipose tissue homeostasis and its impact on metabolic regulation is not understood. We developed a transgenic mouse model, Mito-Ob, overexpressing prohibitin (PHB) in adipocytes. Mito-Ob mice developed obesity due to upregulation of mitochondrial biogenesis in adipocytes. Of note, Mito-Ob female mice developed more visceral fat than male mice. However, female mice exhibited no change in glucose homeostasis and had normal insulin and high adiponectin levels, whereas male mice had impaired glucose homeostasis, compromised brown adipose tissue structure, and high insulin and low adiponectin levels. Mechanistically, we found that PHB overexpression enhances the cross talk between the mitochondria and the nucleus and facilitates mitochondrial biogenesis. The data suggest a critical role of PHB and adipocyte mitochondria in adipose tissue homeostasis and reveal sex differences in the effect of PHB-induced adipocyte mitochondrial remodeling on whole-body metabolism. Targeting adipocyte mitochondria may provide new therapeutic [ABSTRACT FROM AUTHOR]

Alcohol is a potential risk factor of type 2 diabetes, but its underlying mechanism is unclear. To explore this issue,Wistar rats and mouse hepatoma cells (Hepa 1-6) were exposed to ethanol, 8 g.kg-1 .d-1 for 3 months and 100mM for 48 h, respectively. Glucose and insulin tolerance tests in vivo were performed, and protein levels of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and glucocorticoid receptor (GR) in liver and Hepa 1-6 cells were measured. Alterations of key enzymes of gluconeogenesis phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6 phosphatase (G6Pase), as well as glycogen synthase kinase 3a (GSK3α), were also examined. The results revealed that glucose levels were increased, and insulin sensitivity was impaired accompanied with liver injury in rats exposed to ethanol compared with controls. The 11β-HSD1, GR, PEPCK, G6Pase, and GSK3α proteins were increased in the liver of rats treated with ethanol compared with controls. Ethanol-exposed Hepa 1-6 cells also showed higher expression of 11β-HSD1, GR, PEPCK, G6Pase, and GSK3α proteins than control cells. After treatment of Hepa 1-6 cells exposed to ethanol with the GR inhibitor RU486, the expression of 11β-HSD1 and GR was significantly decreased. At the same time the increases in PEPCK, G6Pase, and GSK3α levels induced by ethanol in Hepa 1-6 cells were also attenuated by RU486. The results indicate that ethanol causes glucose intolerance by increasing hepatic expression of 11β-HSD1 and GR, which leads to increased expression of gluconeogenic and glycogenolytic enzymes. [ABSTRACT FROM AUTHOR]

Pancreatic β-cell dysfunction is a prerequisite for the development of type 2 diabetes. Alcoholism is a diabetes risk factor and ethanol increases oxidative stress in β-cells, whereas the mitochondrial chaperone prohibitin (PHB) has antioxidant effects in several cell types. In the present study we investigated whether PHB is expressed in β-cells and protects these cells against deleterious effects of ethanol, using INS-1E and RINm5F β-cell lines. Endogenous PHB was detected by western blot and immunocytochemistry. Reactive oxygen species were determined by 5-(and-6)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate fluorescence assay, and mitochondrial activity was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) reduction, uncoupling protein 2 expression and ATP production. Cell death was determined by Hoechst 33342 staining, cleaved caspase-3 levels and flow cytometry. PHB was expressed in β-cells under normal conditions and colocalized with Hoechst 33342 in the nucleus and with the mitochondrial probe Mitofluor in the perinuclear area. In ethanol-treated cells, MTT reduction and ATP production decreased, whereas reactive oxygen species, uncoupling protein 2 and cleaved caspase-3 levels increased. In addition, flow cytometry analysis showed an increase of apoptotic cells. Ethanol treatment increased PHB expression and induced PHB translocation from the nucleus to the mitochondria. PHB overexpression decreased the apoptotic effects of ethanol, whereas PHB knockdown enhanced these effects. The protective effects of endogenous PHB were recapitulated by incubation of the cells with recombinant human PHB. Thus, PHB is expressed in β-cells, increases with oxidative stress and protects the cells against deleterious effects of ethanol. [ABSTRACT FROM AUTHOR]

Adverse events during pregnancy, including prenatal ethanol (EtOH) exposure, are associated with insulin-resistant diabetes in male rat offspring, but it is unclear whether this is true for female offspring. We investigated whether prenatal EtOH exposure alters glucose metabolism in adult female rat offspring and whether this is associated with reduced in vivo insulin signaling in skeletal muscle. Female Sprague-Dawley rats were given EtOH, 4 g·kg-1·day-1 by gavage throughout pregnancy. Glucose tolerance test and hyperinsulinemic euglycemic clamp were performed, and insulin signaling was investigated in skeletal muscle, in adult female offspring. We gave insulin intravenously to these rats and determined the association of glucose transporter-4 with plasma membranes, as well as the phosphorylation of phosphoinositide-dependent protein kinase-1 (PDK1), Akt, and PKCζ. Although EtOH offspring had normal birth weight, they were overweight as adults and had fasting hyperglycemia, hyperinsulinemia, and reduced insulin-stimulated glucose uptake. After insulin treatment, EtOH-exposed rats had decreased membrane glucose transporter-4, PDK1, Akt, and PKCζ in the gastrocnemius muscle, com- pared with control rats. Insulin stimulation of PDK1, Akt, and PKCζ phosphorylation was also reduced. In addition, the expression of the protein tribbles-3 and the phosphatase enzyme activity of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), which prevent Akt activation, were increased in muscle from EtOH-exposed rats. Female rat offspring exposed to EtOH in utero develop insulin-resistant diabetes in association with excessive PTEN and tribbles-3 signaling downstream of the phosphatidylinositol 3-kinase pathway in skeletal muscle, which may be a mechanism for the abnormal glucose tolerance. [ABSTRACT FROM AUTHOR]

Rat offspring prenatally exposed to alcohol display features of metabolic syndrome characterized by a low birth weight, catch-up growth, dyslipidemia, and insulin-resistant diabetes with increased gluconeogenesis, during adult life. Gluconeogenesis is partly regulated by cyclic AMP- and glucocorticoid-dependent mechanisms. Glucocorticoid action at the receptor level depends on its circulating concentrations and is amplified at the prereceptor level by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which regenerates active glucocorticoids from inactive forms. To determine whether 11β-HSD1 is dysregulated in this rat model, we examined the expression and enzyme activity of 11β-HSD1 and its regulator enzyme hexose-6-phosphate dehydrogenase (H6PD) in the liver of postnatal day 7 (neonatal) and 3-mo-old (adult) rat offspring prenatally exposed to alcohol. Measurements of 11β-HSD1 and H6PD were also performed in the omental fat of adult rat offspring. In both neonatal and adult rats, prenatal alcohol exposure resulted in increased tissue corticosterone concentrations, increased expression, and oxoreductase activity of 11β-HSD1, and a parallel increase of H6PD expression. The data suggest that due to both transcriptional and posttranscriptional dysregulations, rats exposed to alcohol early in life have increased 11β-HSD1 activity, which may explain insulin-resistant diabetes in these animals later in life. [ABSTRACT FROM AUTHOR]

Rat offspring exposed to ethanol (EtOH rats) during pregnancy are insulin resistant, but it is unknown whether they have increased gluconeogenesis. To address this issue, we determined blood glucose and liver gluconeogenic genes, proteins, and enzyme activities before and after insulin administration in juvenile and adult EtOH rats and submitted adult EtOH rats to a pyruvate challenge. In juvenile rats, basal glucose; peroxisome proliferator-activated receptor-coactivator-1α protein and mRNA; and phosphoenolpyruvate carboxykinase enzyme activity, protein, and mRNA were similar between groups. After insulin injection, these parameters failed to decrease in EtOH rats, but glucose decreased by 30% and glucuneogenic enzymes, proteins, and mRNAs decreased by 50–70% in control rats. In adult offspring, basal peroxisome proliferator-activated receptor-coactivator-1α protein and mRNA levels were 40–80% higher in EtOH rats than in controls. Similarly, basal phosphoenolpyruvate carboxykinase activity, protein, and mRNA were ∼1.8-fold greater in EtOH rats than in controls. These parameters decreased by ∼50% after insulin injection in control rats, but they remained unchanged in EtOH rats. After insulin injection in the adult rats, glucose decreased by 60% in controls but did not decrease significantly in EtOH rats. A subset of adult EtOH rats had fasting hyperglycemia and an exaggerated glycemic response to pyruvate compared with controls. The data indicate that, after prenatal EtOH exposure, the expression of gluconeogenic genes is exaggerated in adult rat offspring and is insulin resistant in both juvenile and adult rats, explaining increased gluconeogenesis. These alterations persist through adulthood and may contribute to the pathogenesis of Type 2 diabetes after exposure to EtOH in utero. [ABSTRACT FROM AUTHOR]

Pancreatic β-cell failure is characterized by compromised insulin secretion in response to glucose, which ultimately results in hyperglycemia, the clinical hallmark of type 2 diabetes mellitus (T2DM). Acute exposure to plasma free fatty acids (FFAs) potentiates glucose stimulated insulin secretion (GSIS), while chronic exposure impairs GSIS, and the latter has been associated with the mechanism of β cell failure in obesity linked T2DM. By contrast, growth hormone (GH) signaling has been linked positively to GSIS in β cells. Numerous studies have examined chronic exposure of β cells to elevated FFAs both with in vivo cohorts and in vitro models. Little attention, however, has been given to the fluctuation of plasma FFA levels due to rhythmic effects that are affected by daily diet and fat intake. Mouse insulinoma Min6 cells were exposed to cyclic/daily palmitate treatment over 2 and 3 days to assess effects on GSIS. Cyclic/daily palmitate treatment with a period of recovery negatively affected GSIS in a dose-dependent manner. Removal of palmitate after two cycles/day resulted in reversal of the effect on GSIS, which was also reflected by relative gene expression involved in insulin biosynthesis (Ins1, Ins2, Pdx1, and MafA) and GSIS (glucose 2 transporter and glucokinase). Modest positive effects on GSIS and glucokinase transcript levels were also observed when Min6 cells were cotreated with human GH and palmitate. These observations indicate that like continuous palmitate treatment, cyclic exposure to palmitate can acutely impair GSIS over 48 and 72 h. However, they also suggest that the negative effects of short periods of exposure to FFAs on β cell function remain reversible.

Prohibitin (PHB) was discovered in a quest to find genes with antiproliferative functions. However, the attribute of PHB that is responsible for its antiproliferative function remains elusive. Meanwhile, recent studies have established PHB as a pleiotropic protein with roles in metabolism, immunity, and senescence. PHB has cell compartment-specific functions, acting as a scaffolding protein in mitochondria, an adaptor molecule in membrane signaling, and a transcriptional coregulator in the nucleus. However, it remains unclear whether different functions and locations of PHB are interrelated or independent from each other, or if PHB works in a tissue-specific manner. Here, we discuss new findings on the role of PHB in adipose-immune interaction and an unexpected role in sex differences in adipose and immune functions., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objective: White adipocyte metabolism is regulated by insulin-like growth factor-binding protein (IGFBP)-3, but its effect on brown adipocytes is not known. This study investigated whether IGFBP-3 influences the proliferation and differentiation of brown preadipocytes in primary culture., Methods: In vitro growth and differentiation of brown preadipocytes from wild-type mice, transgenic mice overexpressing human IGFBP-3 (PGKBP3), or its non-IGF-binding Gly56/Gly80/Gly81-mutant (PGKmutBP3), and wild-type brown preadipocytes transfected with IGFBP-3 siRNA were studied by us. In addition to IGF-I and IGFBP-3 expression, brown preadipocyte growth and differentiation were assessed by antiproliferating cell nuclear antigen, oil red O, brown fat gene expression, and phosphorylation states of Akt and ERK., Results: Akt phosphorylation and IGF-I expression were paralleled by initial growth and differentiation and were slower for PGKBP3 brown preadipocytes than PGKmutBP3 and wild-type preadipocytes. Terminal adipocyte differentiation as assessed by lipid accumulation coincided with ERK inhibition and was greatest in PGKmutBP3 cells, followed by PGKBP3 cells and then wild-type cells, whereas adipocyte differentiation was poor after IGFBP-3 siRNA treatment. Thermogenic genes were increased by IGFBP-3 overexpression, but lower in differentiated PGKmutBP3 than PGKBP3 cells., Conclusions: Brown adipocyte growth and differentiation in vitro were affected by the manipulation of IGFBP-3 expression, suggesting that IGFBP-3 is a factor regulating brown adipocyte fate., (© 2015 The Obesity Society.)

Ethnopharmacological Relevance: Several Asian plants are known for their anti-diabetic properties and produce alkaloids and flavonoids that may stimulate insulin secretion., Materials and Methods: Using Vietnamese plants (Nelumbo nucifera, Gynostemma pentaphyllum, Smilax glabra, and Stemona tuberosa), we extracted two alkaloids (neotuberostemonine, nuciferine) and four flavonoids (astilbin, engeletin, smitilbin, and 3,5,3'-trihydroxy-7,4'-dimethoxyflavone), and studied their insulin stimulatory effects., Results: Nuciferine, extracted from Nelumbo nucifera, stimulated both phases of insulin secretion in isolated islets, whereas the other compounds had no effect. The effect of nuciferine was totally abolished by diazoxide and nimodipine, and diminished by protein kinase A and protein kinase C inhibition. Nuciferine and potassium had additive effects on insulin secretion. Nuciferine also stimulated insulin secretion in INS-1E cells at both 3.3 and 16.7 mM glucose concentrations. Compared with glibenclamide, nuciferine had a stronger effect on insulin secretion and less beta-cell toxicity. However, nuciferine did not compete with glibenclamide for binding to the sulfonylurea receptor., Conclusions: Among several compounds extracted from anti-diabetic plants, nuciferine was found to stimulate insulin secretion by closing potassium-adenosine triphosphate channels, explaining anti-diabetic effects of Nelumbo nucifera., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Chronic ethanol consumption increases the risk of type 2 diabetes mellitus, and ethanol has been reported to cause insulin resistance and, inconsistently, to reduce insulin secretion. The mechanism(s) underlying the reduction of insulin secretion by ethanol is not known. We used β-cell lines and isolated murine islets to determine the effect of ethanol on insulin content and secretion at low- and high-glucose concentrations, in the presence of KCl, diazoxide, tolbutamide, and regulators of cyclic AMP and protein kinase C (PKC). We also determined the gene expression of insulin; pancreas duodenum homeobox 1; and endoplasmic reticulum (ER) stress markers, such as Chop, ERp57, glucose-regulated protein 78/binding immunoglobulin protein, and inositol 1,4,5-triphosphate receptors. Ethanol reduced insulin secretion by interfering with muscarinic signaling and PKC activation but not the K-ATP channels. In addition, ethanol reduced insulin content and caused ER stress. The deleterious effects of ethanol on β-cells were prevented by 4-methyl pyrazole, an inhibitor of alcohol dehydrogenase, suggesting that ethanol metabolism is required for these effects., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Pancreatic beta-cell dysfunction is a prerequisite for the development of type 2 diabetes. Alcoholism is a diabetes risk factor and ethanol increases oxidative stress in beta-cells, whereas the mitochondrial chaperone prohibitin (PHB) has antioxidant effects in several cell types. In the present study we investigated whether PHB is expressed in beta-cells and protects these cells against deleterious effects of ethanol, using INS-1E and RINm5F beta-cell lines. Endogenous PHB was detected by western blot and immunocytochemistry. Reactive oxygen species were determined by 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate fluorescence assay, and mitochondrial activity was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) reduction, uncoupling protein 2 expression and ATP production. Cell death was determined by Hoechst 33342 staining, cleaved caspase-3 levels and flow cytometry. PHB was expressed in beta-cells under normal conditions and colocalized with Hoechst 33342 in the nucleus and with the mitochondrial probe Mitofluor in the perinuclear area. In ethanol-treated cells, MTT reduction and ATP production decreased, whereas reactive oxygen species, uncoupling protein 2 and cleaved caspase-3 levels increased. In addition, flow cytometry analysis showed an increase of apoptotic cells. Ethanol treatment increased PHB expression and induced PHB translocation from the nucleus to the mitochondria. PHB overexpression decreased the apoptotic effects of ethanol, whereas PHB knockdown enhanced these effects. The protective effects of endogenous PHB were recapitulated by incubation of the cells with recombinant human PHB. Thus, PHB is expressed in beta-cells, increases with oxidative stress and protects the cells against deleterious effects of ethanol.

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.

Ethnic variation in soft tissue composition may contribute to observed ethnic differences in bone mineral density (BMD). This analysis was performed to determine whether ethnic differences in body composition affect differences in BMD between Canadian White and Aboriginal women. An age-stratified population-based sample of 206 Aboriginal women and 177 White women underwent multisite bone density measurements and total body soft tissue composition analysis. In univariate analyses, each kg of additional lean mass was associated with a greater increase in BMD than an equal amount of fat mass (p<.01). When models simultaneously evaluated both soft tissue measurements, lean mass (but not fat mass) was positively correlated with BMD at all measurement sites (p<.001). Aboriginal women had significantly lower weight-adjusted BMD than White women for two sites (calcaneus, p = .019; total body, p = .026) and lower BMI-adjusted for BMD three sites (calcaneus, p = .0076; distal forearm, p = .047; total body, p = .022). The ratio of lean mass to fat mass was lower in Aboriginal than White women (p<.001). When BMD was adjusted for body composition variables no significant difference was seen between Aboriginal and White women. Apparent ethnic differences in weight- and BMI-adjusted BMD between Canadian White and Aboriginal women were explained by a lower ratio of lean mass to fat mass in Aboriginal women, combined with a smaller increment in BMD from fat mass versus lean mass in both populations.

The purpose of this study was to compare patterns of adiposity and soft tissue composition in First Nations and white Canadian women. A population-based cross-sectional study was performed. A random age-stratified sample of 206 urban First Nations women and 177 white women was recruited. Soft tissue composition was analyzed with dual-energy X-ray absorptiometry. Analysis of covariance (ANCOVA) models were used to assess ethnicity in models that adjusted for body mass, body mass index (BMI), and socio-demographic factors. Obesity (BMI>or=30.0 kg/m2) was more common in First Nations women (48.1%) than in white women (36.2%, Fisher's exact test p=0.012). Mean trunk fat tissue mass fraction and total body fat mass fraction (as a percent of soft tissue) were greater in First Nations women than in white women (p<0.0001). Trunk lean tissue was also greater in First Nations women (p=0.027), but total body lean tissue was similar. The mean trunk adiposity index was strongly related to ethnicity (First Nations +0.5%+/-2.5% versus white -1.7%+/-2.6%, p<0.0001). Preferential fat accumulation in the trunk of First Nations women persisted after adjustment for body mass, BMI, and other socio-demographic variables (p<0.0001). First Nations women differ from white women in terms of fat and lean tissue mass and distribution. First Nations women had a preferential increase in trunk fat and this may contribute to high reported rates of diabetes, metabolic syndrome, and cardiovascular events.

Rat offspring prenatally exposed to alcohol display features of metabolic syndrome characterized by a low birth weight, catch-up growth, dyslipidemia, and insulin-resistant diabetes with increased gluconeogenesis, during adult life. Gluconeogenesis is partly regulated by cyclic AMP- and glucocorticoid-dependent mechanisms. Glucocorticoid action at the receptor level depends on its circulating concentrations and is amplified at the prereceptor level by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which regenerates active glucocorticoids from inactive forms. To determine whether 11beta-HSD1 is dysregulated in this rat model, we examined the expression and enzyme activity of 11beta-HSD1 and its regulator enzyme hexose-6-phosphate dehydrogenase (H6PD) in the liver of postnatal day 7 (neonatal) and 3-mo-old (adult) rat offspring prenatally exposed to alcohol. Measurements of 11beta-HSD1 and H6PD were also performed in the omental fat of adult rat offspring. In both neonatal and adult rats, prenatal alcohol exposure resulted in increased tissue corticosterone concentrations, increased expression, and oxoreductase activity of 11beta-HSD1, and a parallel increase of H6PD expression. The data suggest that due to both transcriptional and posttranscriptional dysregulations, rats exposed to alcohol early in life have increased 11beta-HSD1 activity, which may explain insulin-resistant diabetes in these animals later in life.

Prenatal ethanol (EtOH) exposure is associated with low birth weight, followed by increased appetite, catch-up growth, insulin resistance, and impaired glucose tolerance in the rat offspring. Because EtOH can induce oxidative stress, which is a putative mechanism of insulin resistance, and because of the central role of the hypothalamus in the regulation of energy homeostasis and insulin action, we investigated whether prenatal EtOH exposure causes oxidative damage to the hypothalamus, which may alter its function. Female rats were given EtOH by gavage throughout pregnancy. At birth, their offspring were smaller than those of non-EtOH rats. Markers of oxidative stress and expression of neuropeptide Y and proopiomelanocortin (POMC) were determined in hypothalami of postnatal day 7 (PD7) and 3-mo-old (adult) rat offspring. In both PD7 and adult rats, prenatal EtOH exposure was associated with decreased levels of glutathione and increased expression of MnSOD. The concentrations of lipid peroxides and protein carbonyls were normal in PD7 EtOH-exposed offspring, but were increased in adult EtOH-exposed offspring. Both PD7 and adult EtOH-exposed offspring had normal neuropeptide Y and POMC mRNA levels, but the adult offspring had reduced POMC protein concentration. Thus only adult offspring preexposed to EtOH had increased hypothalamic tissue damage and decreased levels of POMC, which could impair melanocortin signaling. We conclude that prenatal EtOH exposure causes hypothalamic oxidative stress, which persists into adult life and alters melanocortin action during adulthood. These neuroendocrine alterations may explain weight gain and insulin resistance in rats exposed to EtOH early in life.

Low birth weight in humans predisposes to obesity, cardiovascular diseases, and type 2 diabetes in adult life. Alcohol exposure during pregnancy has been associated with fetal growth restriction. We investigated the effects of prenatal exposure to alcohol on glucose metabolism later in the offspring. Female Sprague Dawley rats were given ethanol (ETOH), 4 g/kg/day by gavage throughout pregnancy. Compared with controls, newborn ETOH rats had decreased body size (5.1 +/- 0.1 v 6.3 +/- 0.1 g, P <.001), plasma insulin (0.44 +/- 0.4 v 0.67 +/- 0.1 ng/mL, P <.05), and leptin mRNA (P <.05), but they had normal beta-cell mass and elevated adipose resistin mRNA and plasma glucose (5.0 +/- 0.5 v 3.6 +/- 0.3 mmol/L, P <.01). Food intake was decreased in ETOH rats during the fourth week of life, and body weight remained decreased compared with controls until a catch-up growth occurred by 7 weeks of life. At 13 weeks of age, body weight and beta-cell mass of ETOH offspring were normal, but plasma glucose and insulin after a glucose challenge were increased compared with controls (P <.05). Adipose leptin and hypothalamic Ob-R mRNA were not different from controls, but resistin was increased (P <.05), and muscle GLUT4 content was decreased (P <.05) in ETOH offspring compared with controls. The data suggest that prenatal alcohol exposure impairs glucose tolerance in the offspring by both inducing insulin resistance and beta-cell dysfunction. The prevailing mechanism in 3-month-old rat offspring appears to be insulin resistance, manifested by glucose intolerance and decreased GLUT4 despite hyperinsulinemia., (Copyright 2003 Elsevier, Inc. All rights reserved.)