A Causal Relationship between Vitamin C Intake with Hyperglycemia and Metabolic Syndrome Risk: A Two-Sample Mendelian Randomization Study

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Abstract

Excessive oxidative stress can contribute to metabolic syndrome (MetS), and antioxidants can protect against its development. Vitamin C (VC) is a well-known antioxidant, and observational studies have associated a deficiency with an increased MetS risk. This study tested the hypothesis that dietary VC intake caused an inverse relation of MetS and its components risk using a two-sample Mendelian randomization (MR) method in adults ≥40 years in a city hospital-based (n = 58,701) and Ansan/Ansung plus rural (n = 13,598) cohorts. Independent genetic variants associated with dietary VC intake were explored using a genome-wide association study (GWAS) with significance levels of p < 5 × 10−5 and linkage disequilibrium (r2 threshold of 0.001), after adjusting for the covariates related to MetS, in a city hospital-based cohort (n = 52,676) excluding the participants having vitamin supplementation. MR methods, including inverse-variance weighting (IVW), weighted median, MR-Egger, and weighted model, were used to determine the causal relationship between the dietary VC intake and the risk of MetS and its components in Ansan/Ansung plus rural cohorts (n = 11,733). Heterogeneity and leave-one-out sensitivity analyses were conducted. Energy intake, as well as other nutrient intakes, were significantly lower in the low VC intake group than in the high VC intake group, but the incidence of MetS and its components, including hyperglycemia, hypertriglyceridemia, and hypertension, was observationally higher in inadequate low VC intake in the combined cohorts. In MR analysis, insufficient dietary VC intake increased the risk of MetS, hyperglycemia, hypertriglyceridemia, and hypertension in an IVW (p < 0.05). In contrast, only the serum fasting blood glucose concentration was significantly associated with VC intake in weight median analysis (p < 0.05), but there was no significant association of low dietary VC with MetS and its components in MR-Egger. There was no likelihood of heterogeneity and horizontal pleiotropy in MetS and its components. A single genetic variant did not affect their association in the leave-one-out sensitivity analysis. In conclusion, insufficient dietary VC intake potentially increased the MetS and hyperglycemia risk in Asian adults. Low VC intake can contribute to increasing type 2 diabetes incidence in Asians.

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Chronic Adipose Tissue Inflammation Linking Obesity to Insulin Resistance and Type 2 Diabetes

Federica Zatterale, Michele Longo, Jamal Naderi … (2020)

Obesity is one of the major health burdens of the 21st century as it contributes to the growing prevalence of its related comorbidities, including insulin resistance and type 2 diabetes. Growing evidence suggests a critical role for overnutrition in the development of low-grade inflammation. Specifically, chronic inflammation in adipose tissue is considered a crucial risk factor for the development of insulin resistance and type 2 diabetes in obese individuals. The triggers for adipose tissue inflammation are still poorly defined. However, obesity-induced adipose tissue expansion provides a plethora of intrinsic signals (e.g., adipocyte death, hypoxia, and mechanical stress) capable of initiating the inflammatory response. Immune dysregulation in adipose tissue of obese subjects results in a chronic low-grade inflammation characterized by increased infiltration and activation of innate and adaptive immune cells. Macrophages are the most abundant innate immune cells infiltrating and accumulating into adipose tissue of obese individuals; they constitute up to 40% of all adipose tissue cells in obesity. In obesity, adipose tissue macrophages are polarized into pro-inflammatory M1 macrophages and secrete many pro-inflammatory cytokines capable of impairing insulin signaling, therefore promoting the progression of insulin resistance. Besides macrophages, many other immune cells (e.g., dendritic cells, mast cells, neutrophils, B cells, and T cells) reside in adipose tissue during obesity, playing a key role in the development of adipose tissue inflammation and insulin resistance. The association of obesity, adipose tissue inflammation, and metabolic diseases makes inflammatory pathways an appealing target for the treatment of obesity-related metabolic complications. In this review, we summarize the molecular mechanisms responsible for the obesity-induced adipose tissue inflammation and progression toward obesity-associated comorbidities and highlight the current therapeutic strategies.

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Oxidative stress and metabolic disorders: Pathogenesis and therapeutic strategies.

Vibha Rani, Gagan Deep Jhingan, Rakesh K Singh … (2016)

Increased body weight and metabolic disorder including insulin resistance, type 2 diabetes and cardiovascular complications together constitute metabolic syndrome. The pathogenesis of metabolic syndrome involves multitude of factors. A number of studies however indicate, with some conformity, that oxidative stress along with chronic inflammatory condition pave the way for the development of metabolic diseases. Oxidative stress, a state of lost balance between the oxidative and anti-oxidative systems of the cells and tissues, results in the over production of oxidative free radicals and reactive oxygen species (ROS). Excessive ROS generated could attack the cellular proteins, lipids and nucleic acids leading to cellular dysfunction including loss of energy metabolism, altered cell signalling and cell cycle control, genetic mutations, altered cellular transport mechanisms and overall decreased biological activity, immune activation and inflammation. In addition, nutritional stress such as that caused by high fat high carbohydrate diet also promotes oxidative stress as evident by increased lipid peroxidation products, protein carbonylation, and decreased antioxidant system and reduced glutathione (GSH) levels. These changes lead to initiation of pathogenic milieu and development of several chronic diseases. Studies suggest that in obese person oxidative stress and chronic inflammation are the important underlying factors that lead to development of pathologies such as carcinogenesis, obesity, diabetes, and cardiovascular diseases through altered cellular and nuclear mechanisms, including impaired DNA damage repair and cell cycle regulation. Here we discuss the aspects of metabolic disorders-induced oxidative stress in major pathological conditions and strategies for their prevention and therapy.

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Oxidative stress, insulin resistance, dyslipidemia and type 2 diabetes mellitus.

Surapon Tangvarasittichai (2015)

Oxidative stress is increased in metabolic syndrome and type 2 diabetes mellitus (T2DM) and this appears to underlie the development of cardiovascular disease, T2DM and diabetic complications. Increased oxidative stress appears to be a deleterious factor leading to insulin resistance, dyslipidemia, β-cell dysfunction, impaired glucose tolerance and ultimately leading to T2DM. Chronic oxidative stress, hyperglycemia and dyslipidemia are particularly dangerous for β-cells from lowest levels of antioxidant, have high oxidative energy requirements, decrease the gene expression of key β-cell genes and induce cell death. If β-cell functioning is impaired, it results in an under production of insulin, impairs glucose stimulated insulin secretion, fasting hyperglycemia and eventually the development of T2DM.