• Low maternal vitamin B12 status is associated with lower cord blood HDL cholesterol in white caucasians living in the UK

      Adaikalakoteswari, A; Vatish, M; Lawson, A; Wood, C; Sivakumar, K; McTernan, P; Webster, C; Anderson, N; Yajnik, C; Tripathi, G; et al. (MDPI, 02/04/2015)
      Background and Aims: Studies in South Asian population show that low maternal vitamin B12 associates with insulin resistance and small for gestational age in the offspring. Low vitamin B12 status is attributed to vegetarianism in these populations. It is not known whether low B12 status is associated with metabolic risk of the offspring in whites, where the childhood metabolic disorders are increasing rapidly. Here, we studied whether maternal B12 levels associate with metabolic risk of the offspring at birth. Methods: This is a cross-sectional study of 91 mother-infant pairs (n = 182), of white Caucasian origin living in the UK. Blood samples were collected from white pregnant women at delivery and their newborns (cord blood). Serum vitamin B12, folate, homocysteine as well as the relevant metabolic risk factors were measured. Results: The prevalence of low serum vitamin B12 (<191 ng/L) and folate (<4.6 μg/L) were 40% and 11%, respectively. Maternal B12 was inversely associated with offspring’s Homeostasis Model Assessment 2-Insulin Resistance (HOMA-IR), triglycerides, homocysteine and positively with HDL-cholesterol after adjusting for age and BMI. In regression analysis, after adjusting for likely confounders, maternal B12 is independently associated with neonatal HDL-cholesterol and homocysteine but not triglycerides or HOMA-IR. Conclusions: Our study shows that low B12 status is common in white women and is independently associated with adverse cord blood cholesterol
    • Methyl donor deficiency due to low vitamin b12 impairs insulin signalling in human adipocytes by down regulating AKT pathway via PTEN and TRB3

      Adaikalakoteswari, A; Finer, S; Voyias, P.D; McCarthy, M; Vatish, M; Moore, J; Smart-Halajko, M; Bawazeer, N; Al-Daghri, N.M; McTernan, P.G; et al. (American Diabetes Association, 17/06/2014)
    • Telmisartan reverses antiretroviral-induced adipocyte toxicity and insulin resistance in vitro

      Pushpakom, S.P; Adaikalakoteswari, A; Owen, A; Back, D.J; Tripathi, G; Kumar, S; McTernan, P; Pirmohamed, M; University of Warwick (Sage, 21/02/2018)
      Antiretroviral therapy in HIV-positive patients leads to insulin resistance which is central to the pathogenesis of various metabolic abnormalities and cardiovascular disease seen in this patient group. We have investigated the dose–response relationship of telmisartan, an antihypertensive, on adipocytes in vitro in order to determine whether it may have metabolic beneficial effects. Using in vitro chronic toxicity models (3T3-F442A murine and primary human adipocytes), we evaluated the effects of different concentrations of telmisartan on adipocyte differentiation and adipogenic gene expression using lipid accumulation assays and real-time polymerase chain reaction, respectively. Adipokine secretion and expression of insulin signalling mediators were evaluated using enzyme-linked immunosorbent assays. Telmisartan partially reversed the deleterious effects of antiretrovirals on adipocyte lipid accumulation, expression of adipogenic regulators (peroxisome proliferator receptor-gamma and lipin 1), adipokine secretion and expression of the insulin signalling mediator pAktSer473. The metabolic effects of telmisartan followed a non-monotonic response with the maximal effect observed at 5 µM in the primary human adipocyte model. Telmisartan has beneficial metabolic effects in adipocytes in vitro, but its potential to reduce antiretroviral-induced cardiometabolic disease in HIV-infected individuals needs to be evaluated in a well-designed adequately powered clinical trial.
    • Vitamin B12 deficiency induces cholesterol biosynthesis by limiting S-adenosyl methionine and altering the methylation of Srebf1 and Ldlr genes

      Adaikalakoteswari, A; Finer, S; Voyias, P.D; McCarthy, C; Moore, J; Smart-Halajko, M; Bawazeer, N; Al-Daghri, N.M; McTernan, P.G; University of Westminster
      Maternal vitamin B12 deficiency affecting one-carbonmetabolism influences metabolic status and the degree of insulinresistance of the offspring in adulthood. But its significance andmechanism in the development of adiposity and adipose tissuedysfunction is unknown. To investigate the role of vitamin B12 in the developmentof adipocyte dysfunction. Human pre-adipocytes were differentiatedin customised media with varying concentrations of B12. Adipo-cytes cultured in low B12 (0.15nM) or no B12 conditions hadincreased cholesterol and homocysteine levels and reduced glucoseuptake capacity compared to control (B12 500nM). Global DNAmethylation profiling and bisulphite pyrosequencing showed thatthe promoter regions of sterol regulatory element-binding tran-scription factor 1 (SREBF1) and low density lipoprotein receptor(LDLR) were hypomethylated in B12 deficient conditions, consis-tent with the increased gene expressions. The S-adenosyl methio-nine/S-adenosyl homocysteine ratio was significantly lower in B12deficient conditions. Inhibition of methylation in high B12 condi-tions by 5-aza-2-deoxycytidine led to increased cholesterol accu-mulation but not homocysteine. In two independent clinicalstudies, women at child bearing age (age: 19–39 years) and inearly pregnancy (16–18 weeks), showed that low B12 was asso-ciated with higher total cholesterol, LDL cholesterol and choles-terol to HDL ratio. Regression analysis in the pregnant cohortadjusting for all confounders showed B12 levels to be indepen-dently associated with total cholesterol and triglyceride levels. Vitamin B12 deficiency leads to adipocyte dysfunc-tion by inducing cholesterol biosynthesis and homocysteine.Induction of cholesterol biosynthesis was due to hypomethylationof SREBF1 and LDLR. Clinical observations support that the B12effect is independent and our findings show this link is probably causal.
    • Vitamin B12 deficiency is associated with adverse lipid profile in Europeans and Indians with type 2 diabetes.

      Adaikalakoteswari, A; Jayashri, R; Sukumar, N; Venkataraman, H; Pradeepa, R; Gokulakrishnan, K; Anjana, R.M; McTernan, P.G; Tripathi, G; Patel, V; et al. (BMC, 26/09/2014)
      Metformin, a standard therapy in type 2 diabetes, reduces vitamin B12 levels. Studies linking low vitamin B12 levels and cardiovascular disease are equivocal and suggest improving B12 levels may help in primary prevention. The role of vitamin B12 deficiency on cardiovascular risk factors, especially in type 2 diabetes has not been explored. The aim of this study is to investigate whether vitamin B12 deficiency in type 2 diabetes patients is associated with cardiovascular risk factors in two different ethnic groups in UK and India. Type 2 diabetes patients from two secondary care diabetic centres (Europeans - UK and Indians - India) were studied. Serum vitamin B12, folate and biochemical parameters were measured. The prevalence rates of vitamin B12 deficiency (<191 ng/L) were 27% and 12% in Europeans and Indians, respectively and higher in metformin treated type 2 diabetes patients. In linear regression analysis, after adjusting for all likely confounding factors, vitamin B12 independently associated with triglycerides in both the populations and cholesterol/HDL ratio in Indians. Logistic regression showed type 2 diabetes patients with vitamin B12 deficiency were at significantly higher odds of having coexisting coronary artery disease (CAD) in Europeans with similar but non-significant trend in Indians, after adjusting for all likely confounding factors. The prevalence of vitamin B12 deficiency is common in type 2 diabetes patients and is associated with adverse lipid parameters. Type 2 diabetes management guidelines should include the recommendation for regular testing for B12 levels, especially for those on metformin.
    • Vitamin B12 insufficiency induces cholesterol biosynthesis by limiting s-adenosylmethionine and modulating the methylation of SREBF1 and LDLR genes

      Adaikalakoteswari, A; Finer, S; Voyias, P.D; McCarthy, C.M; Vatish, M; Moore, J; Smart-Halajko, M; Bawazeer, N; Al-Daghri, N.M; McTernan, P.G; et al. (BMC, 27/02/2015)
      The dietary supply of methyl donors such as folate, vitamin B12, betaine, methionine, and choline is essential for normal growth, development, and physiological functions through the life course. Both human and animal studies have shown that vitamin B12 deficiency is associated with altered lipid profile and play an important role in the prediction of metabolic risk, however, as of yet, no direct mechanism has been investigated to confirm this.