Deficiency of Mitochondrial Aldehyde Dehydrogenase Increases Type 2 Diabetes Risk in Males via Autophagy Dysregulation
The global diabetes epidemic has emerged as a significant public health concern, with China being particularly affected. In 2014, China had 102.9 million diabetic adults, accounting for 24.4% of the world’s diabetic population, despite representing only 18.7% of the global population. The prevalence of diabetes and prediabetes in China was estimated at 10.9% and 35.7%, respectively, positioning the country among those with the highest diabetes rates worldwide. While sedentary lifestyles and energy-dense diets are major contributors to this epidemic, genetic factors also play a critical role in determining an individual’s susceptibility to environmental challenges.
Aldehyde dehydrogenase 2 (ALDH2) is a key enzyme responsible for detoxifying toxic aldehydes by oxidizing them into non-reactive acids. Emerging evidence suggests that ALDH2 deficiency is associated with an increased risk of cardiovascular and metabolic diseases, alcohol intolerance, nitroglycerin tolerance, and carcinoma. Notably, the ALDH2∗2 allele, a loss-of-function mutation, is present in approximately 50% of East Asians and 8% of the global population. This mutation has been linked to a higher prevalence of diabetes in patients with coronary artery disease (CAD), accompanied by elevated C-reactive protein (CRP) levels. Although ALDH2 mutations are associated with various diabetes risk factors, the direct mechanisms remain unclear. This study explores the pathogenicity and mechanisms of ALDH2 deficiency in the development of type 2 diabetes through laboratory and clinical investigations.
To investigate the metabolic consequences of ALDH2 deficiency, wild-type (WT) and ALDH2-knockout (ALDH2-KO) mice were fed either a normal diet (ND) or a high-fat diet (HFD) for 26 weeks. Intraperitoneal glucose tolerance tests (IPGTTs) were conducted to measure fasting glucose levels and glucose tolerance. At 6 weeks, fasting glucose levels and IPGTT curves were similar between WT and ALDH2-KO mice. However, by 32 weeks, ALDH2-KO mice exhibited elevated fasting glucose levels and impaired glucose tolerance compared to WT mice. These differences were more pronounced in HFD-fed mice, suggesting that ALDH2 deficiency independently contributes to diabetes risk, which is exacerbated by high fat intake.
Skeletal muscle, being the most insulin-sensitive and glucose-consuming organ, was further analyzed to determine the impact of ALDH2 deficiency on insulin sensitivity. Quadriceps muscles from WT and KO mice were isolated after 32 weeks of HFD or ND, and the expression levels of GLUT-1 and GLUT-4, proteins responsible for glucose uptake in skeletal muscle, were evaluated. While GLUT-1 expression remained stable, GLUT-4, the primary regulatory target of insulin, was significantly reduced in KO mice, with further decreases observed in HFD-fed KO mice. This finding underscores the role of ALDH2 deficiency in impairing insulin sensitivity.
Autophagy, a cellular renewal and catabolic process, has been implicated in the exacerbation of insulin resistance in diabetes. ALDH2 is thought to regulate autophagy, and its deficiency may disrupt this process. To explore this, the study evaluated the levels of p62, an autophagic end product, as well as the expression and phosphorylation levels of components in the Akt/AMPK/mTOR signaling pathway. Results showed that p62 levels were decreased in HFD-fed WT mice and further reduced in HFD-fed KO mice, indicating upregulated autophagy. Additionally, phosphorylation levels of Akt and mTOR were reduced in KO mice and further decreased in HFD-fed KO mice. Although AMPK phosphorylation levels were elevated in KO mice, there was no significant difference between HFD-fed WT and KO mice. These findings suggest that ALDH2 deficiency inhibits mTOR phosphorylation, activates autophagy through the suppression of Akt phosphorylation, and potentially contributes to insulin resistance.
The study also examined the correlation between ALDH2 genotypes and diabetes prevalence in humans. A cohort of 850 patients undergoing routine health examinations at Huashan Hospital, Fudan University, was analyzed. Diabetes was defined as either a prior diagnosis or fasting glucose levels ≥7 mmol/L. Among the participants, 70 (8.2%) had diabetes. The diabetic group had a higher proportion of males, older age, and a higher hypertension rate compared to the non-diabetic group. Notably, ALDH2 AA homozygotes, particularly in males, exhibited a higher prevalence of diabetes compared to those with at least one functional ALDH2∗1 allele. The prevalence of diabetes in males with the ALDH2 AA genotype was 22.73%, twice that of males with other genotypes. In contrast, diabetes prevalence was lower and more comparable among females across all ALDH2 genotypes. These findings suggest that ALDH2 mutations contribute to diabetes risk in the Chinese population, particularly in males.
Previous clinical studies on the association between ALDH2 mutations and diabetes have been limited by factors such as biological sex, alcohol consumption, and comorbidities. However, a recent meta-analysis of genome-wide association studies involving 433,540 East Asian individuals identified a 2-Mb single-nucleotide polymorphism (SNP) near ALDH2 (rs12231737) significantly correlated with type 2 diabetes prevalence. This SNP exhibited strong sex-specific differences, with compelling evidence of association in males but not in females. This study highlights ALDH2’s intrinsic capacity to independently trigger type 2 diabetes or interact with environmental factors such as diet and age, potentially through the dysregulation of autophagy in skeletal muscle via the Akt/AMPK/mTOR signaling pathway.
The treatment of diabetes has evolved from simple glycemic control to include cardiovascular protection, as evidenced by the use of sodium-glucose cotransporter-2 (SGLT-2) inhibitors, dipeptidyl peptidase 4 (DPP4) inhibitors, and glucagon-like peptide-1 (GLP-1) analogs. Given ALDH2’s extensive cardioprotective role beyond insulin sensitivity regulation, ALDH2 supplementation or activation represents a promising therapeutic target for diabetes treatment.
In conclusion, ALDH2 deficiency increases the risk of type 2 diabetes, particularly in males, through mechanisms involving autophagy dysregulation and impaired insulin sensitivity. These findings underscore the importance of ALDH2 in metabolic health and highlight its potential as a therapeutic target for diabetes and related cardiovascular conditions.
doi.org/10.1097/CM9.0000000000001408
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