Hyperhomocysteinemia-related serum metabolome alterations not normalized by short-term folic acid treatment.

INTRODUCTION: Hyperhomocysteinemia (HHCys) is an independent risk factor for various diseases such as cardiovascular diseases, Alzheimer's, and cancers. Folate deficiency is one of the significant reasons for HHCys. However, it is not known whether folate deficiency with HHCys is associated with any serum metabolites. OBJECTIVES: Our objective was to identify the metabolic alterations in people having folate deficiency with HHCys and check whether a short-term folic acid therapy could reverse those metabolic changes. METHODS: The study enrolled 34 participants aged between 18 and 40 years having folate deficiency (< 4.6 ng/mL) with HHCys (> 15 µmol/L) and 21 normal healthy individuals. A short-term intervention of oral folic acid (5 mg/day) was done in the HHCys group for 30 days. Untargeted metabolomics analysis of serum was performed in all study subjects before and after the folic acid treatment. Different univariate methods and the multivariable-adjusted linear regression models were employed to determine an association between homocysteine level and metabolite profile. RESULTS: Metabolomics analysis data showed that many metabolites involved in the biochemical pathways of lipid metabolisms such as polyunsaturated fatty acids, glycerolipids, and phospholipids were downregulated in the HHCys group. Short-term oral folic acid therapy significantly reduced their serum homocysteine level. However, the metabolic pathway alterations observed in folate-deficient HHCys-condition were unaltered even after the folic acid treatment. CONCLUSIONS: Our study revealed that people who have a folic acid deficiency with HHCys have an altered metabolite profile related to lipid metabolism, which cannot be reversed by short-term folic acid therapy.

Plasma leptin level mirrors metabolome alterations in young adults.

INTRODUCTION: Leptin is known to regulate pathways of energy metabolism, reproduction, and control appetite. Whether plasma leptin levels reflect changes in metabolites of these pathways is unknown. OBJECTIVES: We aimed to find whether there is an association between leptin levels and levels of metabolites of energy and hormone metabolism. METHODS: We performed an untargeted metabolomics analysis of plasma from 110 healthy adults (men: women = 1:1; aged 18-40 years), using liquid chromatography-tandem mass spectrometry. Blood samples were collected from all the study subjects in the fasting state. Clinical features and markers of obesity and Type 2 diabetes mellitus (T2DM) were assessed in all. The association between levels of metabolites and clinical and biochemical parameters was identified using the multivariable-adjusted linear regression model and PLS-DA analysis. RESULTS: The leptin level was found to have a significant association with a substantial number of metabolites in women and men. Leptin level was positively associated with glycocholic acid and arachidic acid, metabolites related to energy metabolisms, pregnanediol-3-glucuronide, a metabolite of progesterone metabolism, and quercetin 3'-sulfate, a diet-derived metabolite. Leptin level was negatively associated with ponasteroside A and barringtogenol C levels. Leptin level was positively correlated with adiponectin and negatively with total calorie intake and levels of triglyceride and very-low-density lipoprotein. Leptin levels were associated with lipid and sex hormone metabolism in women, while metabolites involved in amino acid metabolism were correlated to leptin in men. CONCLUSION: Our study indicates that leptin level reflects metabolome alterations and hence could be a useful marker to detect early changes in energy and hormone metabolisms.

Postprandial Metabolism is Impaired in Overweight Normoglycemic Young Adults without Family History of Diabetes.

While the risk factors for Type 2 diabetes (T2DM) are known, early predictive markers of transition from normal to a prediabetes state are unidentified. We studied the basal metabolism and metabolic response to a mixed-meal challenge in 110 healthy subjects in the age group of 18 to 40 years (Male:Female = 1:1); grouped into first degree relatives of patients with T2DM (n = 30), those with a body mass index >23 kg/m2 but <30 kg/m2 (n = 30), those with prediabetes (n = 20) and normal controls (n = 30). We performed an untargeted metabolomics analysis of plasma and related that with clinical and biochemical parameters, markers of inflammation, and insulin sensitivity. Similar to prediabetes subjects, overweight subjects had insulin resistance and significantly elevated levels of C-peptide, adiponectin and glucagon and lower level of ghrelin. Metabolites such as MG(22:2(13Z, 16Z)/0:0/0:0) and LysoPC (15:0) were reduced in overweight and prediabetes subjects. Insulin sensitivity was significantly lower in men. Fasting levels of uric acid, xanthine, and glycochenodeoxycholic-3-glucuronide were elevated in men. However, both lysophospholipids and antioxidant defense metabolites were higher in women. Impaired postprandial metabolism and insulin sensitivity in overweight normoglycemic young adults indicates a risk of developing hyperglycemia. Our results also indicate a higher risk of diabetes in young men.

Incidence of type 2 diabetes mellitus and prediabetes in Kerala, India: results from a 10-year prospective cohort.

BACKGROUND: Kerala, the southern state of India, has experienced sudden rise in the prevalence estimates of diabetes. A cohort study on the incidence of type 2 diabetes mellitus (T2DM) in Kerala state thus aptly bridges the lacuna of incidence estimate of T2DM from a population at risk. METHODS: A 10-year prospective cohort study was carried out in two urban wards of central Kerala. The individuals who participated in the baseline survey in 2007 were again invited for a follow-up study in 2017. The data was analyzed using IBM SPSS Statistics for windows (version 21.0). Logistic regression analysis was used to estimate odds ratios and 95% confidence intervals. Findings are based on the 10-year follow-up data from 869 participants from the cohort. RESULTS: The overall follow-up and response rate of the study was 68.9 and 86.9% respectively. During the follow-up period, 190 people (21.9%) developed T2DM. The incidence rate of T2DM and impaired fasting glucose (IFG) were 24.5 per 1000 person years and 45.01 per 1000 person years respectively. Nearly 60% of participants with baseline IFG were converted to T2DM group in the follow-up period. Age > 45 years, family history of T2DM, BMI ≥ 25 kg/m2 and presence of central obesity emerged as important risk factors for incident T2DM. CONCLUSION: High incidence of prediabetes over diabetes observed in this study shows an epidemic trend of T2DM in Kerala, India. It requires an immediate public health action.

Distinct Predictors and Comorbidities in Early Onset Type 2 Diabetes Mellitus Among Asian Indians.

BACKGROUND: The incidence of type 2 diabetes mellitus (T2DM) is increasing worldwide, and the age of disease onset is falling. Although there is rising prevalence of early onset T2DM in India, little is known about their clinical characteristics and cardiovascular risks profiles. The aim of this study was to address this knowledge gap by comparing the characteristics of early onset T2DM and usual onset T2DM patients from our clinic population in India. METHODS: We studied the clinical and biochemical parameters of 98 consecutive early onset T2DM patients of age <45 and <5 years of disease duration and compared those parameters with 86 consecutive usual onset T2DM patients of age >50 years and similar disease duration. RESULTS: There was a strong component of family history of T2DM in early onset T2DM patients; however, no difference was observed in body mass index or waist circumference between the groups. When compared with usual onset group, the early onset T2DM patients were more hypertriglycedemic, with higher total cholesterol, higher total cholesterol/high-density lipoprotein (HDL) ratio, higher low-density lipoprotein levels, and lower HDL cholesterol. Early onset T2DM patients showed significantly worse glycemic control and rapid decline in insulin secretion compared with usual onset T2DM patients. CONCLUSIONS: Our results demonstrate that early onset T2DM in Asian Indians appears to be a disease phenotype with adverse risk factors having poor glycemic control and longer disease duration demanding strategies for novel clinical management.