Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In epidemiological studies, moderate alcohol consumption has been consistently associated with a reduced risk of myocardial infarction (MI). About half of Japanese show an extremely high sensitivity to alcohol (ethanol), which is due to a missense mutation from glutamic acid (Glu) to lysine (Lys) at codon 487 in an isoenzyme of aldehyde dehydrogenase (ALDH2) with a low Km. We obtained a preliminary result that subjects homozygous for the Lys 487 allele had higher risk for myocardial infarction. The purpose of the present study was to assess this hypothesis by employing a larger cohort of subjects with MI. The experimental group consisted of 342 male subjects with demonstrated MI who were selected randomly from our outpatient clinic. As controls, we employed 1,820 male subjects with no cardiovascular complications who were selected from the Suita Study. All subjects provided their written informed consent to participate in the genetic analyses. Subjects with MI were older and had higher body mass index, higher prevalence of diabetes mellitus, higher prevalence of smoking habit, higher prevalence of the Lys/Lys genotype (homozygous for Lys 487 allele), and lower high density lipoprotein (HDL) cholesterol level (HDL-C). The ALDH2 genotype affected the level of alcohol consumption, and HDL-C. Multiple logistic analyses indicated that the odds ratio of the Lys/Lys genotype to the Lys/Glu+Glu/Glu genotype was 1.56 (p=0.0359). Inclusion of HDL-C as one of the independent variables downplayed the importance of the ALDH2 genotype. This may indicate that the ALDH2 genotype affects MI via its effects on HDL-C. In conclusion, the ALDH2 Lys/Lys genotype is a risk factor for myocardial infarction in Japanese men due to its influence on HDL cholesterol level.
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PMID:Aldehyde dehydrogenase 2 gene is a risk factor for myocardial infarction in Japanese men. 1245 18

We investigated the effect of kaikasaponin III (KS-III) on Phase I and II enzymes and tissue factor (TF) activity to elucidate the pharmacological actions of this immunosuppressive saponin in the diabetic rat. This compound was obtained from the flower of Pueraria thunbergiana (Leguminosae) by chromatographic isolation. This crude drug (Puerariae Flos) has been used as a therapeutic agent for diabetes mellitus in traditional Korean medicine. KS-III prolonged the bleeding time and plasma clotting time in streptozotocin (STZ)-treated rats and increased the TF activity, suggesting that this compound has anti-thrombosis activity in STZ-induced rats. It also inhibited the formation of malondialdehyde (MDA) and hydroxy radicals in serum and liver, but promoted superoxide dismutase (SOD) activity. Low MDA concentrations and low xanthine oxidase and aldehyde oxidase activities were observed in the KS-III-treated rats, suggesting that such Phase I enzyme activities are the major source of lipid peroxidation. However, KS-III increased Phase II enzyme activities such as SOD, glutathione peroxidase, and catalase, suggesting the activation of free radical-scavenging enzymes. These results suggest that KS-III may exhibit its hypoglycemic and hypolipidemic effects by up-regulating or down-regulating antioxidant mechanisms via the changes in Phase I and II enzyme activities.
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PMID:Effect of kaikasaponin III obtained from Pueraria thunbergiana flowers on serum and hepatic lipid peroxides and tissue factor activity in the streptozotocin-induced diabetic rat. 1511 50

In the history of diabetes, chlorpropamide alcohol flushing test (CPAF) was a big topic in the 1970s to 1980s. Alcohol tolerance after chlorpropamide has prognostic significance, with the intolerant group (CPAF-positive group) being less prone to develop vascular complication than the tolerant group (CPAF-negative group). A mechanism of CPAF has been regarded as the inhibition of aldehyde dehydrogenase 2 (ALDH2) by an N-alkyl-substituted derivative of chlorpropamide, and the expression of these mutations of ALDH2 and alcohol dehydrogenase 2 (ADH2) could determine the alcohol tolerance among the Japanese population. Therefore, we hypothesized that expression of different ALDH2 and ADH2 polymorphisms may induce differences in vascular complications in diabetes and conducted two studies. The first study (study 1) was to determine the association of ALDH2/AHD2 polymorphism with diabetic complications. To know the association of ALDH2/AHD2 polymorphism with diabetic vasculopathy and neuropathy, a total of 158 patients with type 2 diabetes were divided into four groups on the basis of ALDH2 "activity" and ADH2 "superactivity." The frequency of proteinuria and the percentage of proliferative retinopathy among the patients with retinopathy was higher in those with active ALDH2 and superactive ADH2. We speculated that protein kinase C isoforms up-regulated by 4-hydroxynonenal that was detoxified by ALDH2 and ADH2 may account for the long-term development of diabetic nephropathy and severe retinopathy. As for neuropathy, the frequency of symptomatic neuropathy was higher in patients with inactive ALDH2 and usual ADH2. We speculate that increased tissue levels of toxic aldehyde could result from inactive ALDH2 and usual ADH2 expression, which results in the increased level of reactive aldehyde in sensory neuron pathway, thereby causing symptomatic polyneuropathy.
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PMID:ALDH2/ADH2 polymorphism associated with vasculopathy and neuropathy in type 2 diabetes. 1531 96

Findings obtained from numerous prospective cohort and case-control studies on alcohol consumption and pancreatic cancer risk have been inconsistent, with many confounding variables present in various investigations. However, heavy alcohol consumption has been known to be a major cause of chronic pancreatitis and a risk factor for type 2 diabetes mellitus, both of which are linked to pancreatic cancer. It has been established that an extensive normal interaction exists between the exocrine and endocrine pancreas, as well as in inflammatory processes and carcinogenesis. Alcohol and its metabolites (acetaldehyde and fatty acid ethyl esters) can alter metabolic pathways involved in the inflammatory response and carcinogenesis, and they are mediated by one or more of the following mechanisms: (1) premature activation of zymogens; (2) induction of the inflammatory response through activation of nuclear transcription factors, including nuclear factor-kappa and activation protein 1; (3) increased production of reactive oxygen species, resulting in oxidative DNA damage and altered effect of dietary antioxidants; (4) activation of pancreatic stellate cells, which leads to fibrosis; (5) gene mutation in enzymes related to cytochrome P450, glutathione S-transferase, aldehyde dehydrogenase, cationic trypsinogen, and pancreatic secretory trypsin inhibitor; (6) synergistic effects of ethanol and tobacco carcinogen on NNK [nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone] metabolism; and (7) dysregulation of proliferation and apoptosis. These various metabolic effects of alcohol can lead to or interact with other risk factors (genetic, dietary, environmental, and lifestyle factors) that result in acute and chronic pancreatitis and diabetes mellitus and, ultimately, affect the multistep process of carcinogenesis toward the development of pancreatic cancer.
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PMID:Alcohol and pancreatic cancer. 1605 82

The objective of the present study was to examine the association between a polymorphism of the aldehyde dehydrogenase 2 (ALDH2) gene and lacunar infarcts of the brain. We conducted a population-based, cross-sectional study on residents from two age groups (61- and 72-year olds). A total of 376 subjects participated in the study, which included brain magnetic resonance image and genetic analysis of the ALDH2 gene. Of the 61- and 72-year-old subjects, 46.4% and 64.3%, respectively, had one or more lacunar infarcts. The average number of infarcts also increased from 2.0 to 2.8 in men and from 2.3 to 3.5 in women. No significant association between the ALDH2 genotype and the presence of lacunar infarction (> or =1) was found. However, in subjects with lacunar infarction, the genotype of ALDH2 *1/*1 was associated with a larger number of the lesion ['single' versus 'multiple' odds ratio (OR) 3.73, 95%CI: 1.43-9.74] in men. The OR was comparable even after adjusting for alcohol consumption, tobacco habits, age, hypertension, hypercholesterolemia, and diabetes mellitus (DM) (OR 3.88; 95% CI: 1.10-13.66). In women, there was no significant association between the ALDH2 genotypes and lacunar infarcts. The present study revealed that the ALDH2 *1/*1 genotype was significantly associated with the prevalence of multiple lacunar infarcts in Japanese men.
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PMID:A polymorphism of the aldehyde dehydrogenase 2 gene is a risk factor for multiple lacunar infarcts in Japanese men: the Takahata Study. 1738 93

Earlier, we have shown the occurrence of oxidative impairments and their progression in the testis of diabetic adult rats. This study investigated the vulnerability of immature testis to oxidative stress and mitochondrial dysfunctions in a prepubertal (PP) diabetic rat model. PP male rats (4/6-week-old) rendered diabetic by an acute dose of streptozotocin were monitored for induction of oxidative stress in testis cytosol/mitochondria. Diabetic rats of both age groups showed severe hyperglycemia, testicular atrophy and marked oxidative damage as evidenced by enhanced generation of reactive oxygen species, hydroperoxide and malondialdehyde levels (4 week > 6 week). Mitochondrial dysfunctions manifested as reduction in the activities of aldehyde dehydrogenase, tricarboxylic acid cycle enzymes, enhanced activities of oxidative phosphorylation enzymes, perturbations in calcium homeostasis and membrane potential. These evidences suggest that an immature testis is vulnerable to oxidative stress under diabetes, which may play a significant role in the development of testicular degeneration, leading to impaired fertility in adulthood.
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PMID:Evidence of oxidative stress and mitochondrial dysfunctions in the testis of prepubertal diabetic rats. 1944 88

Type 2 diabetes is a major global health problem. It is generally accepted that type 2 diabetes is the result of gene-environmental interaction. However, the mechanism underlying the interaction is unclear. Diet change is known to play an important role in type 2 diabetes. The fact that the global high prevalence of type 2 diabetes has occurred following the spread of food fortification worldwide suggests a possible involvement of excess niacin intake. Our recent study found that nicotinamide overload and low nicotinamide detoxification may induce oxidative stress associated with insulin resistance. Based on the relevant facts, this review briefly summarized the relationship between the prevalence of type 2 diabetes and the nicotinamide metabolism changes induced by excess niacin intake, aldehyde oxidase inhibitors, liver diseases and functional defects of skin. We speculate that the gene-environmental interaction in type 2 diabetes may be a reflection of the outcome of the association of chronic nicotinamide overload-induced toxicity and the relatively low detoxification/excretion capacity of the body. Reducing the content of niacin in foods may be a promising strategy for the control of type 2 diabetes.
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PMID:[Chronic nicotinamide overload and type 2 diabetes]. 2017 94

Transplanted murine bone marrow (BM) progenitor cells recruit to the injured pancreas and induce endogenous beta cell proliferation to improve islet function. To enrich for analogous human progenitor cell types that stimulate islet regeneration, we purified human BM based on high-aldehyde dehydrogenase activity (ALDH(hi)), an enzymatic function conserved in hematopoietic, endothelial, and mesenchymal progenitor lineages. We investigated the contributions of ALDH(hi) mixed progenitor cells or culture-expanded, ALDH-purified multipotent stromal cell (MSC) subsets to activate endogenous programs for islet regeneration after transplantation into streptozotocin-treated NOD/SCID mice. Intravenous injection of uncultured BM ALDH(hi) cells improved systemic hyperglycemia and augmented insulin secretion by increasing islet size and vascularization, without increasing total islet number. Augmented proliferation within regenerated endogenous islets and associated vascular endothelium indicated the induction of islet-specific proliferative and pro-angiogenic programs. Although cultured MSC from independent human BM samples showed variable capacity to improve islet function, and prolonged expansion diminished hyperglycemic recovery, transplantation of ALDH-purified regenerative MSC reduced hyperglycemia and augmented total beta cell mass by stimulating the formation of small beta cell clusters associated with the ductal epithelium, without evidence of increased islet vascularization or Ngn3(+) endocrine precursor activation. Thus, endogenous islet recovery after progenitor cell transplantation can occur via distinct regenerative mechanisms modulated by subtypes of progenitor cells administered. Further, understanding of how these islet regenerative and pro-angiogenic programs are activated by specific progenitor subsets may provide new approaches for combination cellular therapies to combat diabetes.
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PMID:Transplanted human bone marrow progenitor subtypes stimulate endogenous islet regeneration and revascularization. 2141 81

The genes encoding the enzymes for metabolising alcohol dehydrogenase 1B (ADH1B) and aldehyde dehydrogenase 2 (ALDH2) - exhibit genetic polymorphism and ethnic variations. Although the ALDH2*2 variant allele has been widely accepted as protecting against the development of alcoholism in Asians, the association of the ADH1B*2 variant allele with drinking behaviour remains inconclusive. The goal of this study was to determine whether the polymorphic ADH1B and ALDH2 genes are associated with stroke in male Han Chinese with high alcohol consumption. Sixty-five stroke patients with a history of heavy drinking (HDS) and 83 stroke patients without such a history (NHDS) were recruited for analysis of the ADH1B and ALDH2 genotypes from the stroke registry in the Tri-Service General Hospital, Taipei, Taiwan, between January 2000 and December 2001. The allelotypes of ADH1B and ALDH2 were determined using the polymerase chain reaction-restriction fragment length polymorphism method. The HDS patients (3 per cent) showed a significantly lower ALDH2*2 allele frequency than NHDS patients (27 per cent) (p < 0.001). After controlling for age, patients with HDS were associated with a significantly higher occurrence of cigarette smoking (p < 0.01) and liver dysfunction (p < 0.01). Multiple logistic regression analyses revealed that the ALDH2*2 variant allele was an independent variable exhibiting strong protection (odds ratio 0.072; 95 per cent confidence interval 0.02-0.26) against HDS after adjustment for hypertension, diabetes mellitus, smoking status and liver dysfunction. By contrast, allelic variations in ADH1B exerted no significant effect on HDS. The present study indicated that, unlike ALDH2*2, ADH1B*2 appears not to be a significant negative risk factor for high alcohol consumption in male Han Chinese with stroke.
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PMID:The role of ALDH2 and ADH1B polymorphism in alcohol consumption and stroke in Han Chinese. 2215 4

Effects of vitamin E and selenium supplementation on aldehyde oxidase (AO) and xanthine oxidase (XO) activities and antioxidant status in liver, kidney, and heart of streptozotocin (STZ)-induced diabetic rats were examined. AO and XO activities increased significantly after induction of diabetes in rats. Following oral vitamin E (300 mg/kg) and sodium selenite (0.5 mg/kg) intake once a day for 4 weeks, XO activity decreased significantly. AO activity decreased significantly in liver, but remained unchanged in kidney and heart of vitamin E- and selenium-treated rats compared to the diabetic rats. Total antioxidants status, paraoxonase-1 (PON1) and erythrocyte superoxide dismutase activities significantly decreased in the diabetic rats compared to the controls, while a higher fasting plasma glucose level was observed in the diabetic animals. The glutathione peroxidase activity remained statistically unchanged. Malondialdehyde and oxidized low-density lipoprotein levels were higher in the diabetic animals; however, these values were significantly reduced following vitamin E and selenium supplementation. In summary, both AO and XO activities increase in STZ-induced diabetic rats, and vitamin E and selenium supplementation can reduce these activities. The results also indicate that administration of vitamin E and selenium has hypolipidemic, hypoglycemic, and antioxidative effects. It decreases tissue damages in diabetic rats, too.
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PMID:Aldehyde and xanthine oxidase activities in tissues of streptozotocin-induced diabetic rats: effects of vitamin E and selenium supplementation. 2223 35


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