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Aldehyde dehydrogenase 2 polymorphism is an important gene for insulin resistance in Japanese patients with type 2 diabetes

ABSTRACT:

Background

Aldehyde dehydrogenase 2 (ALDH2) is an important enzyme involved in alcohol metabolism. ALDH2 polymorphism has been reported as a risk factor for type 2 diabetes mellitus (T2DM) and is associated with liver insulin resistance due to alcohol consumption in non-diabetic individuals. Herein, we investigated the association between ALDH2 polymorphisms and insulin resistance in patients with T2DM.

Methods

We performed a meal tolerance test and the hyperinsulinemic-euglycemic clamp on 71 Japanese participants: 34 patients with T2DM, and 37 non-diabetic participants. We analyzed the ALDH2 polymorphism (ALDH2 rs67); GG type was defined as the T2DM high-risk group, compared with the low-risk AG and AA groups.

Results

Glucose levels were similar in the high- and low-risk T2DM groups. The high-risk group for T2DM showed a significantly higher BMI (p < 0.005), insulin resistance in HOMA-IR (p < 0.05), and Insulin sensitivity index (p < 0.05); however, there were no significant differences in insulin resistance in the clamp test (p = 0.10). Alcohol consumption did not differ significantly between groups (p = 0.66). Non-diabetic participants also showed higher HOMA-IR insulin resistance in the high-risk group (p < 0.05), but insulin resistance levels in the glucose clamp tests (p = 0.56) and insulin secretion were not significant.

Conclusion

The results suggest that ALDH2 is an important gene associated with insulin resistance and obesity in Japanese patients with type 2 diabetes.

SUBMITTER: Okura T

PROVIDER: S-EPMC10130494 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Project description:Mitochondrial aldehyde dehydrogenase 2 (ALDH2) detoxifies reactive aldehydes in the micro- and macrovasculature. These substrates, including methylglyoxal and 4-hydroxynonenal formed from glucose and lipids, cause protein carbonylation and mitochondrial dysfunction, forming advanced glycation end products (AGEs). The present study aimed to confirm the association between the inactive ALDH2*2 allele and diabetic retinopathy (DR).A retrospective longitudinal analysis was conducted, among 234 Japanese patients with type 2 diabetes mellitus (DM) (156 males and 78 females) who had no DR signs at baseline and were treated for more than half a year. The ALDH2*1/*2 alleles were determined using a real-time TaqMan allelic discrimination assay. Multivariate-adjusted hazard ratios (HRs) and 95% confidential intervals (CIs) for the cumulative incidence of the development of DR were examined using a Cox proportional hazard model, taking drinking habits and the serum ?-glutamyltransferase (GGT) level into consideration.The frequency of the ALDH2*2 allele was 22.3%. Fifty-two subjects cumulatively developed DR during the follow-up period of 5.5 ± 2.5 years. The ALDH2*2 allele carriers had a significantly higher incidence of DR than the non-carriers (HR: 1.92; P = 0.02). The incidence of DR was significantly higher in the drinkers with the ALDH2*2 allele than in those with the ALDH2*1/*1 genotype (HR: 2.61; P = 0.03), while the incidence of DR in the non-drinkers did not differ significantly between the ALDH2 genotype groups (P > 0.05). The incidence of DR was significantly higher in the ALDH2*2 allele carriers with a high GGT level than in the non-carriers with a high or low GGT level (HR: 2.45; P = 0.03; and HR: 2.63; P = 0.03, respectively).To the best of our knowledge, this is the first report of a significant association between the ALDH2*2 allele and the incidence of DR. These findings provide additional evidence that ALDH2 protects both microvasculature and macrovasculature against reactive aldehydes generated under conditions of sustained oxidative stress, although further investigations in larger cohorts are needed to verify the results.

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