Chronic ethanol consumption is known as an independent risk factor for type 2 diabetes, which is characterized by impaired glucose homeostasis and insulin resistance; however, there is a great deal of controversy concerning the relationships between alcohol consumption and the development of type 2 diabetes. We investigated the effects of chronic ethanol consumption on pancreatic β-cell dysfunction and whether generated peroxynitrite participates in the impaired glucose homeostasis. Here we show that chronic ethanol feeding decreases the ability of pancreatic β-cells to mediate insulin secretion and ATP production in coordination with the decrease of glucokinase, Glut2, and insulin expression. Specific blockade of ATF3 using siRNA or C-terminally deleted ATF3(ΔC) attenuated ethanol-induced pancreatic β-cell apoptosis or dysfunction and restored the down-regulation of glucokinase (GCK), insulin, and pancreatic duodenal homeobox-1 induced by ethanol. GCK inactivation and down-regulation were predominantly mediated by ethanol metabolism-generated peroxynitrite, which were suppressed by the peroxynitrite scavengers N(γ)-monomethyl-L-arginine, uric acid, and deferoxamine but not by the S-nitrosylation inhibitor DTT, indicating that tyrosine nitration is the predominant modification associated with GCK down-regulation and inactivation rather than S-nitrosylation of cysteine. Tyrosine nitration of GCK prevented its association with pBad, and GCK translocation into the mitochondria results in subsequent proteasomal degradation of GCK following ubiquitination. This study identified a novel and efficient pathway by which chronic ethanol consumption may induce GCK down-regulation and inactivation by inducing tyrosine nitration of GCK, resulting in pancreatic β-cell apoptosis and dysfunction. Peroxynitrite-induced ATF3 may also serve as a potent upstream regulator of GCK down-regulation and β-cell apoptosis.
"In addition, a study by Kim et al.58 in the rat determined that chronic ethanol consumption induces glucokinase downregulation, which results in β-cell apoptosis and disrupted β-cell function.56, 57, 58 It is unknown whether CPEE disrupts β-cell structure and function via a similar mechanism. Future studies should focus on the mechanism underlying the effect of CPEE on β-cell function and the relationship between altered β-cell function and the development of peripheral insulin resistance in offspring. "
[Show abstract][Hide abstract] ABSTRACT: Background:
Ethanol consumption during pregnancy can lead to a range of adverse developmental outcomes in children, termed fetal alcohol spectrum disorder (FASD). Central nervous system injury is a debilitating and widely studied manifestation of chronic prenatal ethanol exposure (CPEE). However, CPEE can also cause structural and functional deficits in metabolic pathways in offspring.
Objectives and Methods:
This study tested the hypothesis that CPEE increases whole-body adiposity and disrupts pancreatic structure in guinea pig offspring. Pregnant guinea pigs received ethanol (4 g kg−1 maternal body weight per day) or isocaloric-sucrose/pair-feeding (control) for 5 days per week throughout gestation.
Male and female CPEE offspring demonstrated growth restriction at birth, followed by a rapid period of catch-up growth before weaning (postnatal day (PD) 1–7). Whole-body magnetic resonance imaging (MRI) in young adult offspring (PD100–140) revealed increased visceral and subcutaneous adiposity produced by CPEE. At the time of killing (PD150–200), CPEE offspring also had increased pancreatic adipocyte area and decreased β-cell insulin-like immunopositive area, suggesting reduced insulin production and/or secretion from pancreatic islets.
CPEE causes increased adiposity and pancreatic dysmorphology in offspring, which may signify increased risk for the development of metabolic syndrome and type 2 diabetes mellitus.
[Show abstract][Hide abstract] ABSTRACT: Blood glucose is the primary cellular substrate and in vivo must be tightly maintained. The liver plays a key role in glucose homeostasis increasing or decreasing glucose output and uptake during fasting and feeding. Glucokinase (GCK) is central to this process. Its activity is modulated in a coordinated manner via a complex set of mechanisms: in the postprandial period, the simultaneous rise in glucose and insulin increases GCK activity by enhanced gene expression, changes in cellular location, and interaction with regulatory proteins. Conversely, in the fasting state, the combined decrease in glucose and insulin concentrations and increase in glucagon concentrations, halt GCK activity. Herein we summarize the current knowledge regarding the regulation of hepatic GCK activity.
International Union of Biochemistry and Molecular Biology Life 01/2011; 63(1):1-6. DOI:10.1002/iub.411 · 3.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Although moderate drinking has been shown to lower insulin resistance levels, it is still unclear whether alcoholic beverages could be remedies for insulin resistance. To elucidate this, the correlation between levels of ethanol consumption and insulin resistance were cross-sectionally examined in 371 non-diabetic male Japanese workers. Multiple regression analysis demonstrated that the ethanol consumption level was inversely correlated with the insulin resistance level assessed by homeostatic model assessment (HOMA-IR, p = 0.0014), the serum insulin level (p = 0.0007), and pancreatic β-cell function, also assessed by HOMA (HOMA-β, p = 0.0002), independently from age, body mass index (BMI), and blood pressure, liver function tests, and lipid profiles status, as well as serum adiponectin. The correlations were true in subjects with normal BMIs (up to 25.0 kg/m(2), n = 301) or normal HOMA-IR (up to 2.0 μIU·mg/μL·dL n = 337), whereas all of them were non-significant in those with excessive BMIs (n = 70) or in those with HOMA-IR of more than 2.0 (n = 34). Although it is still unclear whether the reductions of these parameters by ethanol consumption are truly due to the improvement of insulin resistance, at least, these effects are not applicable to subjects with obesity and/or insulin resistance. Thus, alcoholic beverages could not be remedies for insulin resistance or metabolic syndrome.
International Journal of Environmental Research and Public Health 07/2011; 8(7):3019-31. DOI:10.3390/ijerph8073019 · 2.06 Impact Factor
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