Papers by Ashok Balasubramanyam
The Journal of Clinical Endocrinology & Metabolism
Context Some individuals present with forms of diabetes that are “atypical” (AD), which do not co... more Context Some individuals present with forms of diabetes that are “atypical” (AD), which do not conform to typical features of either type 1 diabetes (T1D) or type 2 diabetes (T2D). These forms of AD display a range of phenotypic characteristics that likely reflect different endotypes based on unique etiologies or pathogenic processes. Objective To develop an analytical approach to identify and cluster phenotypes of AD. Methods We developed Discover Atypical Diabetes (DiscoverAD), a data mining framework, to identify and cluster phenotypes of AD. DiscoverAD was trained against characteristics of manually classified patients with AD among 278 adults with diabetes within the Cameron County Hispanic Cohort (CCHC) (Study A). We then tested DiscoverAD in a separate population of 758 multiethnic children with T1D within the Texas Children's Hospital Registry for New-Onset Type 1 Diabetes (TCHRNO-1) (Study B). Results We identified an AD frequency of 11.5% in the CCHC (Study A) and 5.3%...
The Journal of Clinical Endocrinology & Metabolism, 2021
Context Accumulating evidence indicates that type 2 diabetes (T2D) is phenotypically heterogeneou... more Context Accumulating evidence indicates that type 2 diabetes (T2D) is phenotypically heterogeneous. Defining and classifying variant forms of T2D are priorities to better understand its pathophysiology and usher clinical practice into an era of “precision diabetes.” Evidence Acquisition and Methods We reviewed literature related to heterogeneity of T2D over the past 5 decades and identified a range of phenotypic variants of T2D. Their descriptions expose inadequacies in current classification systems. We attempt to link phenotypically diverse forms to pathophysiology, explore investigative methods that have characterized “atypical” forms of T2D on an etiological basis, and review conceptual frameworks for an improved taxonomy. Finally, we propose future directions to achieve the goal of an etiological classification of T2D. Evidence Synthesis Differences among ethnic and racial groups were early observations of phenotypic heterogeneity. Investigations that uncover complex interactio...
The American Journal of Clinical Nutrition, 2006
Background: Arginine is important in the response to infections and is a precursor for the synthe... more 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 [ 15 N 2-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 Ȁ 8 compared with 50 Ȁ 7 mol • kg Ҁ1 • h Ҁ1 ; P 0.01), lower plasma arginine concentrations (75 Ȁ 8 compared with 40 Ȁ 11 mol/L; P 0.01), higher plasma NOx concentrations (30 Ȁ 4 compared with 65 Ȁ 1.8 mol/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.
Alzheimer's & dementia : the journal of the Alzheimer's Association, Jan 17, 2018
Changes in glucose levels may represent a powerful metabolic indicator of dementia in African-Ame... more Changes in glucose levels may represent a powerful metabolic indicator of dementia in African-Americans with diabetes. It is unclear whether these changes also occur in Caucasians. A secondary data analysis using electronic medical records from 5228 African-Americans and Caucasians aged ≥65 years was carried out. Mixed effects models with repeated serum glucose measurements were used to compare changes in glucose levels between African-Americans and Caucasian patients with and without incident dementia. African-Americans and Caucasians with diabetes had significantly different changes in glucose levels by dementia status (P < .0001). African-Americans experienced a significant decline in glucose levels before the dementia diagnosis (estimated glucose decline 1.3421 mg/dL per year, P < .0001) than those who did not develop dementia. Caucasians with and without dementia showed stable glucose levels over time (P = .3071). Significant changes in glucose levels precede dementia in ...
Alzheimer's & dementia : the journal of the Alzheimer's Association, Jan 25, 2016
High blood glucose levels may be responsible for the increased risk for dementia in diabetic pati... more High blood glucose levels may be responsible for the increased risk for dementia in diabetic patients. A secondary data analysis merging electronic medical records (EMRs) with data collected from the Indianapolis-Ibadan Dementia project (IIDP). Of the enrolled 4105 African Americans, 3778 were identified in the EMR. Study endpoints were dementia, mild cognitive impairment (MCI), or normal cognition. Repeated serum glucose measurements were used as the outcome variables. Diabetic participants who developed incident dementia had a significant decrease in serum glucose levels in the years preceding the diagnosis compared to the participants with normal cognition (P = .0002). They also had significantly higher glucose levels up to 9 years before the dementia diagnosis (P = .0367). High glucose levels followed by a decline occurring years before diagnosis in African American participants with diabetes may represent a powerful presymptomatic metabolic indicator of dementia.
Metabolism, 2011
HIV-associated dyslipemic lipodystrophy (HADL) is a heterogeneous syndrome of fat redistribution,... more HIV-associated dyslipemic lipodystrophy (HADL) is a heterogeneous syndrome of fat redistribution, hypertriglyceridemia, and insulin resistance, associated with markedly accelerated rates of lipolysis, intraadipocyte and intrahepatic reesterification, and very low-density lipoprotein-triglyceride synthesis and release. The objective of the study was to determine if rosiglitazone can ameliorate these lipid kinetic defects in patients with HADL. Infusions of [(13)C(1)]palmitate and [(2)H(5)]glycerol were used to measure total and net lipolysis, adipocyte and hepatic reesterification, and plasma free fatty acid (FFA) oxidation in 9 men with HADL, before and after 3 months of treatment with rosiglitazone (8 mg/d). Rosiglitazone treatment significantly increased both total lipolysis (R(a) FFA(total) from 3.37 ± 0.40 to 4.57 ± 0.68 mmol FFA per kilogram fat per hour, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .05) and adipocyte reesterification (1.25 ± 0.35 to 2.43 ± 0.65 mmol FFA per kilogram fat per hour, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .05). However, there was no change in net lipolysis (R(a) FFA(net) 2.47 ± 0.43 to 2.42 ± 0.37 mmol FFA per kilogram fat per hour), plasma FFA oxidation (0.30 ± 0.046 to 0.32 ± 0.04 mmol FFA per kilogram lean body mass per hour), or FFA flux available for hepatic reesterification (0.59 ± 0.07 to 0.56 ± 0.10 mmol FFA per kilogram fat per hour). There were significant decreases in fasting plasma insulin concentrations and insulin resistance, but not in fasting plasma lipid or glucose concentrations. There was a significant decrease in waist to hip ratio (0.98 ± 0.02 to 0.95 ± 0.02, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .05) consistent with a significant increase in hip circumference (0.93 ± 0.02 to 0.95 ± 0.02 m, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .05), without change in waist circumference. Rosiglitazone significantly increased adipocyte reesterification and improved insulin sensitivity, but the potential benefit of these changes was compromised by increase in total lipolysis. Combining rosiglitazone with agents designed to blunt lipolysis could expand depleted peripheral adipose depots in patients with HIV lipodystrophy.
Journal of Infection, 2004
Objectives. Dyslipidemia associated with antiretroviral therapy is a common clinical problem amon... more 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 2 9 (2 7)% with fibrates, 2 11 (2 14)% with statins and 2 23 (2 22)% for dual therapy with fibrates and statins. The triglycerides decreased by 2 11 (2 40)% in those treated with fibrates; 2 1 (221)% in those with statins alone, and 2 32 (2 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.
The Journal of Clinical Endocrinology & Metabolism, 2003
Reduced fat-free mass (FFM) in GH-deficient (GHD) adults is improved by GH replacement, but the p... more Reduced fat-free mass (FFM) in GH-deficient (GHD) adults is improved by GH replacement, but the protein metabolic changes are unclear. Using iv [ 2 H 3 ]leucine and oral l-[ 13 C 1 ]leucine infusions and dual emission x-ray absorptiometry, we compared leucine kinetics and body composition in eight GHD adults and eight healthy controls in the fasted and fed states, before and after 2 wk and 6 months of GH replacement. Leucine kinetics were not different between pretreatment GHD subjects and controls. After 2 wk of GH treatment, leucine oxidation decreased in the GHD subjects compared with baseline values [fasted, 41 ؎ 6 vs. 30 ؎ 5 mol/kg FFM⅐h (P < 0.01); fed, 49 ؎ 3 vs. 41 ؎ 3.6 mol/kg FFM⅐h (P < 0.05)], leucine balance improved [fasted, ؊14 ؎ 4 vs. ؊3.5 ؎ 3 mol/kg FFM⅐h (P < 0.01); fed, 65 ؎ 10 vs. 72 ؎ 7 mol/kg FFM⅐h (P ؍ 0.07)], and protein synthesis increased [fasted, 116 ؎ 5 vs. 131 ؎ 6 mol/kg FFM⅐h (P < 0.05); fed, 103 ؎ 6 vs. 116 ؎ 6 mol/kg FFM⅐h (P < 0.05)]. After 6 months of GH treatment, these changes were not maintained in the fed state. The five GHD subjects with decreased FFM at baseline showed a significant increase after 6 months of GH treatment (P < 0.05). GH replacement in GHD acutely improves protein balance by stimulating synthesis and inhibiting catabolism. After 6 months, protein kinetics reached a new homeostasis to maintain the net gain in FFM.
Expert Opinion on Pharmacotherapy, 2010
Patients infected with HIV are at high risk for dyslipidemia, insulin resistance and cardiovascul... more Patients infected with HIV are at high risk for dyslipidemia, insulin resistance and cardiovascular disease. Therapies to reverse these risks are complex, sometimes controversial, and not uniformly effective. Pathophysiology of the lipid abnormalities in HIV is discussed, including the causes of alterations in triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and insulin resistance. We discuss the therapy of dyslipidemia in HIV using a combination of available clinical evidence and expert opinion based on extensive clinical experience, with discussions of lifestyle intervention and diet, conventional pharmacotherapy with lipid-lowering medications including statins, fibrates, niacin and thiazolidinediones for dyslipidemia, and newer therapeutic approaches including omega fatty acids, acipimox, growth hormone and leptin. A detailed understanding of the pathophysiology and rational or evidence-based approach to therapy of lipid abnormalities in patients infected with HIV. Treatment of dyslipidemia in patients with HIV is challenging and complicated by the risk of drug interactions. Appropriate therapy requires a sound understanding of pathophysiology and the principles of pharmacological and nonpharmacological therapeutic interventions. An evidence-based approach that combines lifestyle changes and drugs that are both safe and effective, singly and in combination, is described.
Clinical Infectious Diseases, 2001
Annals of Internal Medicine, 2005
Endocrine Reviews
Over the past four decades, the clinical care of people living with HIV (PLWH) evolved from treat... more Over the past four decades, the clinical care of people living with HIV (PLWH) evolved from treatment of acute opportunistic infections to the management of chronic, non-communicable comorbidities. Concurrently, our understanding of adipose tissue function matured to acknowledge its important endocrine contributions to energy balance. PLWH experience changes in the mass and composition of adipose tissue depots before and after initiating antiretroviral therapy (ART), including regional loss (lipoatrophy), gain (lipohypertrophy), or mixed lipodystrophy. These conditions may coexist with generalized obesity in PLWH and reflect disturbances of energy balance regulation caused by HIV persistence and ART drugs. Adipocyte hypertrophy characterizes visceral (VAT) and subcutaneous adipose tissue depot (SAT) expansion, as well as ectopic lipid deposition that occurs diffusely in the liver, skeletal muscle, and heart. PLWH with excess VAT exhibit adipokine dysregulation coupled with increased...
Biomolecules, 2022
Ghrelin receptor, a growth hormone secretagogue receptor (GHS-R), is expressed in the pancreas. E... more Ghrelin receptor, a growth hormone secretagogue receptor (GHS-R), is expressed in the pancreas. Emerging evidence indicates that GHS-R is involved in the regulation of glucose-stimulated insulin secretion (GSIS), but the mechanism by which GHS-R regulates GSIS in the pancreas is unclear. In this study, we investigated the role of GHS-R on GSIS in detail using global Ghsr−/− mice (in vivo) and Ghsr-ablated pancreatic islets (ex vivo). GSIS was attenuated in both Ghsr−/− mice and Ghsr-ablated islets, while the islet morphology was similar between WT and Ghsr−/− mice. To elucidate the mechanism underpinning Ghsr-mediated GSIS, we investigated the key steps of the GSIS signaling cascade. The gene expression of glucose transporter 2 (Glut2) and the glucose-metabolic intermediate—glucose-6-phosphate (G6P) were reduced in Ghsr-ablated islets, supporting decreased glucose uptake. There was no difference in mitochondrial DNA content in the islets of WT and Ghsr−/− mice, but the ATP/ADP ratio...
Islet autoimmunity may contribute to β-cell dysfunction in type 2 diabetes (T2D). Its prevalence ... more Islet autoimmunity may contribute to β-cell dysfunction in type 2 diabetes (T2D). Its prevalence and clinical significance have not been rigorously determined. In this ancillary study to the Glycemia Reduction Approaches in Diabetes-A Comparative Effectiveness (GRADE) Study, we investigated the prevalence of cellular and humoral islet autoimmunity in patients with T2D duration 4·0±3·0 y, HbA1c 7·5±0·5% on metformin alone. We measured T cell autoreactivity against islet proteins, islet autoantibodies against GAD65, IA2, ZnT8, and β-cell function. Cellular islet autoimmunity was present in 41·3%, humoral islet autoimmunity in 13·5%, and both in 5·3%. β-cell function calculated as iAUC-CG and ∆C-peptide(0– 30)/∆glucose(0–30) from an oral glucose tolerance test was lower among T cell-positives (T+) than T cell-negatives (T-) using two different adjustments for insulin sensitivity (iAUC-CG: 13·2% [95% CI 0·3, 24·4%] or 11·4% [95% CI 0·4, 21·2%] lower; ∆C-peptide(0–30)/∆glucose(0–30)) 19%...
A-β- KPD: not a predominantly monogenic syndrome The “A-β- ” subtype of Ketosis-Prone Diabetes (K... more A-β- KPD: not a predominantly monogenic syndrome The “A-β- ” subtype of Ketosis-Prone Diabetes (KPD) is not predominantly a monogenic diabetic syndrome
OBJECTIVEdKetosis-prone diabetes (KPD) is characterized by diabetic ketoacidosis (DKA) in patient... more OBJECTIVEdKetosis-prone diabetes (KPD) is characterized by diabetic ketoacidosis (DKA) in patients lacking typical features of type 1 diabetes. A validated classification scheme for KPD includes two autoantibody-negative (“A2”) phenotypic forms: “A2b2” (lean, early onset, lacking b-cell functional reserve), and “A2b+” (obese, late onset, with substantial b-cell functional reserve after the index episode of DKA). Recent longitudinal analysis of a large KPD cohort revealed that the A2b+ phenotype includes two distinct subtypes distinguished by the index DKA episode having a defined precipitant (“provoked,”with progressive b-cell function loss over time) or no precipitant (“unprovoked,” with sustained b-cell functional reserve). These three A2 KPD subtypes are characterized by absence of humoral islet autoimmune markers, but a role for cellular islet autoimmunity is unknown.
Diabetes, 2021
Persons living with HIV (PLWH) manifest chronic disorders of brown and white adipose tissues that... more Persons living with HIV (PLWH) manifest chronic disorders of brown and white adipose tissues that lead to diabetes and metabolic syndrome. The mechanisms that link viral factors to defective adipose tissue function and abnormal energy balance in PLWH remain incompletely understood. Here, we explored how the HIV accessory protein viral protein R (Vpr) contributes to adaptive thermogenesis in two mouse models and human adipose tissues. Uncoupling protein 1 (UCP1) gene expression was strongly increased in subcutaneous white adipose tissue (WAT) biopsy specimens from PLWH and in subcutaneous WAT of the Vpr mice, with nearly equivalent mRNA copy number. Histology and functional studies confirmed beige transformation in subcutaneous but not visceral WAT in the Vpr mice. Measurements of energy balance indicated Vpr mice displayed metabolic inflexibility and could not shift efficiently from carbohydrate to fat metabolism during day-night cycles. Furthermore, Vpr mice showed a marked inabili...
We appreciate the reviewers' careful reading of our manuscript, and their constructive critiques.... more We appreciate the reviewers' careful reading of our manuscript, and their constructive critiques. We have responded to all of their queries and suggestions, and believe that the manuscript is much improved as a result. Below are our specific responses to each of the reviewers' comments. REVIEWER 1 Major 1. The title of this paper and the goal according to the introduction is to assess the effect of ethnicity... This study design only allows for assessment of the relationship between or association of, and as a cross sectional study is not designed to formally test the effect of any variable on another. I strongly suggest amending the title and stated goal of the study to reflect this. RESPONSE: The reviewer's comment is very well taken. This is a cross-sectional study, hence it is not possible in a longitudinal manner to assess the "effect" of ethnicity. We have amended the title and stated goal to indicate that this study was designed to assess the relationship of ethnicity and CD4 count on glycemic regulation in HIV patients on stable HAART.
American Journal of Physiology-Endocrinology and Metabolism, 1999
We investigated the effect of nutrient intake on glucose metabolism in normal Mexican-Americans (... more We investigated the effect of nutrient intake on glucose metabolism in normal Mexican-Americans ( n = 6) and European-Americans ( n = 6). Subjects were studied after an 18-h fast and after 5–6 h of ingestion of hourly meals that supplied 6.35 or 12.75 μmol glucose ⋅ kg−1⋅ min−1. Endogenous glucose production (EGP), gluconeogenesis (GNG), and glycogenolysis (GLY) were estimated by mass isotopomer analysis with [U-13C]glucose infusions. Fasting EGP, GNG, and GLY did not differ between the groups. Food ingestion lowered the molar rate of GNG by only 31%. However, while consuming the lower quantity of nutrients, Mexican-Americans had higher plasma glucose ( P < 0.05), a 39% higher rate of EGP ( P< 0.05), and a 68% ( P < 0.025) higher rate of GLY than the European-Americans. At the higher intake, EGP and GLY were suppressed completely in both groups. There was a linear relationship between insulin concentrations, EGP, and GLY in both groups, but the slope of the line was signifi...
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Papers by Ashok Balasubramanyam