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Biomedical subjects

Ashok Balasubramanyam

Publications and source records attributed to Ashok Balasubramanyam.

At least 19 recordsLinked to original sources
PubMed2025

Erythritol, Erythronate, and Cardiovascular Outcomes in Older Adults in the ARIC Study.

BACKGROUND: Circulating erythritol, an endogenously produced metabolite and an artificial sweetener, is associated with cardiovascular outcomes. OBJECTIVES: The authors assessed associations of erythritol and its downstream metabolite, erythronate, with cardiovascular risk factors and events in older adults in the ARIC (Atherosclerosis Risk In Communities) study (visit 5, 2011-2013). METHODS: We included 4,006 participants without prevalent cardiovascular disease and with metabolomic profiling. Erythritol and erythronate were measured by mass spectrometry. We analyzed associations of log-transformed erythritol and erythronate with cardiovascular risk factors and events using Cox proportional hazard models. RESULTS: Participants in the highest tertiles of erythritol or erythronate were older, more likely to have diabetes, hypertension, hyperlipidemia, or microalbuminuria, and had higher body mass index and cardiac biomarkers and lower estimated glomerular filtration rate (P&#xa0;<&#xa0;0.001). Over median follow-up of 8.41 (7.62, 8.93) years, higher erythritol and erythronate concentrations were significantly associated with heart failure (HF) hospitalization, HF with preserved ejection fraction, cardiovascular death, and total mortality after adjustment for demographics and traditional cardiovascular risk factors. Erythronate was additionally significantly associated with coronary heart disease (HR: 1.30 [95% CI: 1.04-1.61], P&#xa0;=&#xa0;0.02), stroke (1.40 [95% CI: 1.08-1.83], P&#xa0;=&#xa0;0.012), and HF with reduced ejection fraction (1.38 [95% CI: 1.09-1.74], P&#xa0;=&#xa0;0.007). Diabetes status did not modify any of these associations (P for interaction >0.20). CONCLUSIONS: Circulating erythritol and erythronate levels are markers of cardiometabolic health and cardiovascular outcomes in an older adult population. In particular, erythronate is associated with all cardiovascular outcomes assessed. Future studies should assess the role of erythronate and its related pathways in cardiovascular disease.

artificial sweetener↗
PubMed2006

Association of amino-terminal-specific antiglutamate decarboxylase (GAD65) autoantibodies with beta-cell functional reserve and a milder clinical phenotype in patients with GAD65 antibodies and ketosis-prone diabetes mellitus.

CONTEXT: We previously characterized patients presenting with diabetic ketoacidosis prospectively into four subgroups of ketosis-prone diabetes mellitus (KPDM), based on the presence or absence of beta-cell autoimmunity (A+ or A-) and beta-cell functional reserve (B+ or B-). The A+B- KPDM subgroup comprises patients with classic, autoimmune type 1 diabetes, whereas the A+B+ KPDM subgroup has only partial beta-cell loss and a distinct clinical phenotype. OBJECTIVE: We hypothesized that epitope specificity of autoantibodies directed against the 65-kDa isoform of glutamate decarboxylase (GAD65) reflects differences in beta-cell destruction. DESIGN: Sera of sequential GAD65Ab-positive KPDM patients admitted for diabetic ketoacidosis (n = 36) were analyzed for their epitope recognition using five GAD65-specific recombinant Fab and their ability to inhibit GAD65 enzymatic activity. All patients were followed longitudinally to assess beta-cell functional reserve and insulin dependence. RESULTS: Binding to an amino-terminal epitope defined by monoclonal antibody DPD correlated positively with fasting serum C-peptide levels at baseline (P = 0.0008) and after 1 yr (P = 0.007). Binding to the DPD-defined epitope also correlated positively with area under the curve for C-peptide after glucagon stimulation (P = 0.007) and with homeostasis model assessment percent B at 1 yr (P = 0.03). Binding to the DPD-defined epitope was significantly stronger in A+B+ than in A+B- patients (P = 0.001). Sera of 16 patients (44%) significantly inhibited GAD65 enzymatic activity, but this did not correlate with beta-cell function. CONCLUSION: DPD-defined epitope specificity is correlated directly with preserved beta-cell functional reserve in GAD65Ab-positive patients and is associated with the milder clinical phenotype of A+B+ KPDM.

Adult↗
PubMed2006

Effects of transgenic expression of HIV-1 Vpr on lipid and energy metabolism in mice.

HIV infection is associated with abnormal lipid metabolism, body fat redistribution, and altered energy expenditure. The pathogenesis of these complex abnormalities is unclear. Viral protein R (Vpr), an HIV-1 accessory protein, can regulate gene transcription mediated by the glucocorticoid receptor and peroxisome proliferator-activated receptor-gamma and affect mitochondrial function in vitro. To test the hypothesis that expression of Vpr in liver and adipocytes can alter lipid metabolism in vivo, we engineered mice to express Vpr under control of the phosphoenolpyruvate carboxykinase promoter in a tissue-specific and inducible manner and investigated the effects of dietary fat, indinavir, and dexamethasone on energy metabolism and body composition. The transgenic mice expressed Vpr mRNA in white and brown adipose tissues and liver and immunoaffinity capillary electrophoresis revealed that they had free Vpr protein in the plasma. Compared with wild-type (WT) animals, Vpr mice had lower plasma triglyceride levels after 6 wk (P < 0.05) but not after 10 wk of a high-fat diet and lower plasma cholesterol levels after 10 wk of high-fat diet (P < 0.05). Treatment with dexamethasone obviated group differences, whereas indinavir had no significant independent effect on lipids. In the fasted state, Vpr mice had a higher respiratory quotient than WT mice (P < 0.05). These data provide the first in vivo evidence that HIV-1 Vpr expressed at low levels in adipose tissues and liver can 1) circulate in the blood, 2) regulate lipid and fatty acid metabolism, and 3) alter fuel selection for oxidation in the fasted state.

Adipose Tissue↗
PubMed2006

Heart positive: design of a randomized controlled clinical trial of intensive lifestyle intervention, niacin and fenofibrate for HIV lipodystrophy/dyslipidemia.

Dyslipidemia and insulin resistance occur in a large proportion of HIV-infected patients treated with highly active antiretroviral therapy (HAART); anthropomorphic changes, such as lipoatrophy and central obesity, occur in a subset of patients. This cluster of clinical features, which is termed HIV lipodystrophy, places patients at increased risk for cardiovascular disease. Currently, there is no consensus on the appropriate therapy for the management of HIV lipodystrophy for which the underlying defects are enhanced lipolysis, impaired fat oxidation, increased hepatic VLDL-triglyceride synthesis and secretion, and impaired disposal of intestinally-derived lipoprotein-triglycerides. We describe the design of a randomized, placebo-controlled trial to compare the effects of usual care to diet, exercise and lipid-lowering drugs on lipid profiles of patients with HIV lipodystrophy. The trial will randomize 200 patients into five groups. Outcomes of usual care, diet and exercise alone or in combination with niacin, fenofibrate or both medications will be compared after six months. Unique aspects of the design include an interactive Internet Diet Management system to increase ATP-III recommended dietary compliance for metabolic syndrome, and a supervised program of aerobic and resistance exercises. The study is powered to detect a 20% decrease in triglycerides with the lifestyle intervention and an additional 20% improvement with the addition of niacin and/or fenofibrate. Secondary outcomes include assessment of lipid profile changes, LDL and HDL particle size, plasma cholesterol ester transport protein activity, visceral and subcutaneous fat distribution, glucose tolerance, insulin resistance, and leptin and adiponectin levels.

Adult↗
PubMed2006

Serum response factor MADS box serine-162 phosphorylation switches proliferation and myogenic gene programs.

Phosphorylation of a cluster of amino acids in the serum response factor (SRF) "MADS box" alphaI coil DNA binding domain regulated the transcription of genes associated with proliferation or terminal muscle differentiation. Mimicking phosphorylation of serine-162, a target of protein kinase C-alpha, with an aspartic acid substitution (SRF-S162D) completely inhibited SRF-DNA binding and blocked alpha-actin gene transcription even in the presence of potent myogenic cofactors, while preserving c-fos promoter activity because of stabilization of the ternary complex via Elk-1. Introduction of SRF-S162D into SRF null ES cells permitted transcription of the c-fos gene but was unable to rescue expression of myogenic contractile genes. Transition of proliferating C2C12 myoblasts to postfusion myocytes after serum withdrawal was associated with a progressive decline in SRF-S162 phosphorylation and an increase in alpha-actin gene expression. Hence, the phosphorylation status of serine-162 in the alphaI coil may constitute a novel switch that directs target gene expression into proliferation or differentiation programs.

Actins↗
PubMed2006

Rise of plasma ghrelin with weight loss is not sustained during weight maintenance.

OBJECTIVE: Ghrelin is postulated to be an orexigenic signal that promotes weight regain after weight loss (WL). However, it is not known whether this putative effect of ghrelin is sustained after weight stabilization. The objective of this study was to investigate the relationship of plasma ghrelin concentrations to active WL and weight maintenance in obese subjects. RESEARCH METHODS AND PROCEDURES: This study was a randomized clinical trial, with a 12-month follow-up period. Obese Mexican-American women matched for age and BMI were randomized to a 12-month WL program (n = 25) or no intervention (controls, n = 23). Interventions included diet, exercise, and orlistat. Body weight and fasting ghrelin, leptin, insulin, and glucose concentrations were measured at baseline and 6 and 12 months. RESULTS: The WL group lost 8.5% of body weight after 6 months and maintained the new weight for the next 6 months. Ghrelin concentrations increased significantly at 6 months but returned to baseline at 12 months. Baseline ghrelin concentrations were directly related to the degree of WL achieved after 12 months. Controls experienced no change in BMI or ghrelin levels. There were no associations between plasma ghrelin and leptin or insulin concentrations. DISCUSSION: Consistent with previous results, ghrelin rises in response to WL, perhaps as a counterregulatory mechanism. However, the present results indicate that ghrelin concentrations return to baseline with sustained weight maintenance, suggesting that its effects are unlikely to regulate long-term energy balance. Baseline ghrelin concentrations are related to the degree of WL that can be achieved by active weight reduction.

Adult↗
PubMed2006

In vivo arginine production and intravascular nitric oxide synthesis in hypotensive sepsis.

BACKGROUND: Arginine is important in the response to infections and is a precursor for the synthesis of the vasodilator nitric oxide (NO). Low plasma arginine is correlated with a worse prognosis in patients with sepsis, and increased NO has been implicated in the hypotension of sepsis. Data on in vivo arginine and NO kinetics are lacking in hypotensive septic adults. OBJECTIVE: We aimed to measure in vivo arginine production and the intravascular NO synthesis rate in hypotensive septic patients. DESIGN: Arginine flux and the fractional and absolute synthesis rates of plasma NO were measured in fasted healthy (n = 10) and hypotensive septic (n = 6) adults by using a 6-h constant infusion of [15N2-guanidino]arginine. Urinary excretion of the NO metabolites nitrite and nitrate (NOx) and plasma concentrations of NOx, arginine, and creatinine were also measured. RESULTS: All patients had hyperdynamic septic shock and impaired renal function. Compared with the control subjects, the patients had slower arginine flux (99 +/- 8 compared with 50 +/- 7 micromol x kg(-1) x h(-1); P < 0.01), lower plasma arginine concentrations (75 +/- 8 compared with 40 +/- 11 micromol/L; P < 0.01), higher plasma NOx concentrations (30 +/- 4 compared with 65 +/- 1.8 micromol/L), and a slower fractional synthesis rate of NOx. There was no significant difference in the absolute synthesis rate of NOx between groups. In patients with sepsis, the plasma NOx concentration correlated with the glomerular filtration rate and plasma creatinine but not with mean arterial pressure. CONCLUSIONS: Patients with septic shock have a shortage in the availability of arginine associated with a slower production. Impaired renal excretion of NOx is a contributor to the high plasma NOx in these patients.

Adult↗
PubMed2006

Physiologic growth hormone replacement improves fasting lipid kinetics in patients with HIV lipodystrophy syndrome.

BACKGROUND: HIV lipodystrophy syndrome (HLS) is characterized by accelerated lipolysis, inadequate fat oxidation, increased hepatic reesterification, and a high frequency of growth hormone deficiency (GHD). The effect of growth hormone (GH) replacement on these lipid kinetic abnormalities is unknown. OBJECTIVE: We aimed to measure the effects of physiologic GH replacement on lipid kinetics in men with HLS and GHD. DESIGN: Seven men with HLS and GHD were studied with the use of infusions of [13C1]palmitate, [2H5]glycerol, and [2H3]leucine to quantify total and net lipolysis, palmitate and free fatty acid (FFA) oxidation, and VLDL apolipoprotein B-100 synthesis before and after 6 mo of GH replacement (maximum: 5 microg x kg(-1) x d(-1)). RESULTS: GH replacement decreased the rates of total lipolysis [FFA(total) rate of appearance (x +/- SE): from 4.80 +/- 1.24 to 3.32 +/- 0.76 mmol FFA x kg fat(-1) x h(-1); P < 0.05] and net lipolysis (FFA(net) rate of appearance: from 1.87 +/- 0.34 to 1.20 +/- 0.25 mmol FFA x kg fat(-1) x h(-1); P < 0.05). Fat oxidation decreased (from 0.28 +/- 0.02 to 0.20 +/- 0.02 mmol FFA x kg lean body mass(-1) x h(-1); P < 0.002), as did the rate of appearance of FFAs available for intrahepatic reesterification (from 0.50 +/- 0.13 to 0.29 +/- 0.09 mmol FFA x kg fat(-1) x h(-1); P < 0.03). Fractional and absolute synthetic rates of VLDL apolipoprotein B-100 were unaltered. These kinetic changes were associated with a decrease in the waist-to-hip ratio but no significant change in fasting plasma lipid concentrations. Fasting plasma glucose concentrations increased after treatment (from 5.2 +/- 0.2 to 5.8 +/- 0.3 mmol/L; P < 0.01). CONCLUSIONS: Physiologic GH replacement has salutary effects on abnormal lipid kinetics in HLS. The effects are mediated by diminished lipolysis and hepatic reesterification rather than by increased fat oxidation.

Adipocytes↗
PubMed2006

Accuracy and predictive value of classification schemes for ketosis-prone diabetes.

OBJECTIVE: Ketosis-prone diabetes (KPD) is an emerging, heterogeneous syndrome. A sound classification scheme for KPD is essential to guide clinical practice and pathophysiologic studies. Four schemes have been used and are based on immunologic criteria, immunologic criteria and insulin requirement, BMI, and immunologic criteria and beta-cell function (Abeta classification). The aim of the present study is to compare the four schemes for accuracy and predictive value in determining whether KPD patients have absent or preserved beta-cell function, which is a strong determinant of long-term insulin dependence and clinical phenotype. RESEARCH DESIGN AND METHODS: Consecutive patients (n = 294) presenting with diabetic ketoacidosis and followed for 12-60 months were classified according to all four schemes. They were evaluated longitudinally for beta-cell autoimmunity, clinical and biochemical features, beta-cell function, and insulin dependence. beta-Cell function was defined by peak plasma C-peptide response to glucagon >or=1.5 ng/ml. The accuracy of each scheme to predict absent or preserved beta-cell function after 12 months of follow-up was tested using multiple statistical analyses. RESULTS: The "Abeta" classification scheme was the most accurate overall, with a sensitivity and specificity of 99.4 and 95.9%, respectively, positive and negative likelihood ratios of 24.55 and 0.01, respectively, and an area under the receiver operator characteristic curve of 0.972. CONCLUSIONS: The Abeta scheme has the highest accuracy and predictive value in classifying KPD patients with regard to clinical outcomes and pathophysiologic subtypes.

Adult↗
PubMed2006

Health outcomes beyond glucose control.

Direct and indirect costs for diabetes mellitus place a large economic burden on the US healthcare system. Diabetes and cardiovascular disease (CVD) are closely interrelated, and it is estimated that much of the burden of CVD too is attributable to diabetes. Insulin resistance may be the common link between diabetes and CVD, often manifested clinically as the metabolic syndrome. The thiazolidinediones (TZDs) reduce insulin resistance and have favorable effects on lipids, blood pressure, and other cardiovascular risk factors. Large clinical trials have shown that early, aggressive intervention with lifestyle changes and pharmacotherapy with TZDs and other agents may slow progression to overt diabetes in high-risk patients and reduce the risk of cardiovascular and other complications; this could reduce healthcare resource utilization and costs.

Cardiovascular Diseases↗
PubMed2006

Case study.

Explore the source record for details and available documents.

Adult↗
PubMed2005

Severely dysregulated disposal of postprandial triacylglycerols exacerbates hypertriacylglycerolemia in HIV lipodystrophy syndrome.

BACKGROUND: The pathogenesis of hypertriacylglycerolemia, a characteristic feature of HIV lipodystrophy syndrome (HLS), is incompletely understood. One mechanism is accelerated lipolysis in the fasted state, but the severity of the hypertriacylglycerolemia suggests that additional underlying abnormalities may exist in the disposal of dietary fat. OBJECTIVE: Our objective was to investigate abnormalities in dietary fat disposal in the pathogenesis of hypertriacylglycerolemia in HLS. DESIGN: We studied 6 nondiabetic men with HLS and 6 men without HIV matched for age and body mass index as control subjects for 8 h after consumption of an isocaloric meal containing 2 g labeled [(13)C(3)]tripalmitin. Chylomicron-triacylglycerol disposal was estimated from labeled [(13)C(1)]palmitate in the plasma chylomicron fraction, and [(13)C(1)]palmitate oxidation was estimated from the (13)CO(2) enrichment in the breath and CO(2) production, over 8 h after the meal. RESULTS: HLS patients had significantly elevated concentrations of fasting plasma triacylglycerols in both chylomicron (x + SE: 100.3 +/- 49.5 compared with 29.2 +/- 2.2 mg/dL; P < 0.01) and VLDL (82.4 +/- 39.0 compared with 10.8 +/- 2.8 mg/dL; P < 0.01) fractions. Chylomicron-triacylglycerol-derived [(13)C(1)]palmitate disposal was markedly lower in the HLS patients (3.09 +/- 0.41 compared with 6.42 +/- 0.18 mmol [(13)C(1)]palmitate/8 h; P < 0.001) in the 8-h postmeal period. Further, HLS patients had lowered storage of chylomicron-triacylglycerols (0.74 +/- 0.38 compared with 5.05 +/- 0.16 mmol; P < 0.0001) and elevated plasma [(13)C(1)]palmitate concentrations (2.01 +/- 0.27 compared with 1.18 +/- 0.16 mmol; P < 0.05) 8 h after the meal. CONCLUSIONS: Patients with HLS have key defects that markedly impair postprandial disposal and storage of chylomicron-triacylglycerols. These defects contribute significantly to hypertriacylglycerolemia in HLS.

Antiretroviral Therapy, Highly Active↗
PubMed2005

Accelerometer feedback to promote physical activity in adults with type 2 diabetes: a pilot study.

This study examined whether giving activity feedback to obese, sedentary adults with Type 2 diabetes would improve their adherence to a home-based walking program. 49 subjects were recruited. Ten failed a treadmill cardiovascular test. Another 9 dropped out before the intervention, and 4 dropped out during the intervention. The remaining 26 adults (14 women, 12 men; age M = 48.1 yr., SD = 7.1) received behavioral counseling monthly for 3 mo. regarding exercise. All subjects wore a triaxial accelerometer during these 3 months. Randomly, half of the subjects were blind to the data from the accelerometers, i.e., no feedback, and had counseling based on their self-report diaries. The other half had access to the accelerometer data, got a computerized graph of their physical activity for the period between counseling sessions, and had counseling based on these objective data, i.e., feedback. The feedback group showed an increase in exercise over the 3 mo. The nonfeedback group showed an increase in activity at 1.5 mo. but reverted to their baseline exercise levels at 3 mo. However, analysis of variance showed there was at least an 8% probability that this effect was due to chance, so the hypothesis that feedback would improve exercise adherence could not be supported. Further studies with larger sample sizes and greater control of experimental conditions are needed to determine the utility of objective activity feedback.

Adult↗
PubMed2004

Cardiovascular implications of HIV-associated dyslipidemic lipodystrophy.

The emergence of a new metabolic syndrome in patients with HIV infection, termed "HIV-associated dyslipidemic lipodystrophy" (HADL), is characterized by central fat redistribution, severe dyslipidemia, and insulin resistance and predisposes to an increased risk of cardiovascular disease. The factors promoting the development of cardiovascular disease in this condition are not well understood and may involve contributions from antiretroviral drugs and components of the HIV virus, as well as inflammatory cytokines, leading to accelerated lipolysis, dyslipidemia, lipotoxic insulin resistance, and vascular inflammation. In this article, we review HADL in terms of metabolic, molecular, and cytokine derangements leading to cardiovascular disease.

Antiretroviral Therapy, Highly Active↗
PubMed2004

Lipid lowering effects of statins and fibrates in the management of HIV dyslipidemias associated with antiretroviral therapy in HIV clinical practice.

OBJECTIVES: Dyslipidemia associated with antiretroviral therapy is a common clinical problem among HIV-infected patients. Considering that the challenge of adherence to drugs (both antiretroviral and lipid lowering) may be substantial in routine HIV care, our objective was to evaluate the lipid-lowering effects of statins and fibrates in the management of HIV dyslipidemias in clinical practice setting. METHODS: Retrospective review of 103 ethnically diverse dyslipidemic HIV patients on antiretroviral therapy treated with lipid-lowering drugs (using National Cholesterol Education and Prevention II [NCEP II] guidelines) who were followed for a median of 70 weeks. RESULTS: An overall mean reduction of 16% in total cholesterol, 20% non-HDL cholesterol, and 18% in triglycerides was noted. There were no significant changes in HDL levels. On evaluation of the different drug classes, the mean (median) change in total cholesterol, were -9 (-7)% with fibrates, -11 (-14)% with statins and -23 (-22)% for dual therapy with fibrates and statins. The triglycerides decreased by -11 (-40)% in those treated with fibrates; -1 (-21)% in those with statins alone, and -32 (-42)% in those with dual therapy. Overall less than a fifth of patients reached the defined NCEP target goal reduction. On logistic regression analysis, only stopping protease inhibitors/ritonavir was independently associated with significant cholesterol reduction (OR: 10.14; 95% CI: 2.1-48.9; p < 0.005). CONCLUSION: In a primary care setting, the use of statins and/or fibrates may add to the complexity of HIV care, with only modest lipid lowering effects.

Adult↗
PubMed2004

Thiazolidinediones: a review of their mechanisms of insulin sensitization, therapeutic potential, clinical efficacy, and tolerability.

The thiazolidinediones (TZDs) rosiglitazone and pioglitazone are newer additions to the antidiabetic armamentarium and are indicated for the treatment of type 2 diabetes mellitus (T2DM) in the United States. The TZDs are peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists that provide clinically effective glycemic control and unique pharmacologic effects on multiple risk factors for T2DM-related morbidity, including improvement of insulin sensitivity and endothelial dysfunction, reduction of blood pressure, and amelioration of dyslipidemia. Weight gain and fluid retention occur with TZD therapy, especially when they are administered in higher doses and in combination with insulin. Although fluid retention associated with the use of TZDs is generally mild and reversible, these agents should not be used in patients with New York Heart Association Class III or IV heart failure symptoms. The findings of ongoing, long-term, prospective studies will clarify the role of the TZDs in the treatment of T2DM, particularly in terms of the durability of improvements in glycemic control, insulin sensitivity, pancreatic beta- cell function, and cardiovascular health.

Blood Glucose↗