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1.  Comparison of DXA and MRI-measured adipose tissue depots in HIV-infected and control subjects 
Studies in persons without HIV infection have compared dual energy X-ray absorptiometry (DXA) and magnetic resonance imaging (MRI) measured adipose tissue (AT), but no such study has been conducted in HIV+ subjects, who have a high prevalence of regional fat loss.
We compared DXA with MRI-measured trunk, leg, arm, and total fat in HIV+ and control subjects.
Cross-sectional analysis in 877 HIV+ and 260 controls in FRAM (Fat Redistribution and Metabolic Change in HIV Infection), stratified by sex and HIV status.
Univariate associations of DXA with MRI were strongest for total and trunk fat (r≥0.92), and slightly weaker in leg (r≥0.87) and arm (r≥0.71). Estimated limb fat averaged substantially higher for DXA than MRI for HIV+ and control, men and women (all p<0.0001). Trunk showed much less difference between DXA and MRI, but was still statistically significant (p<0.0001). Bland-Altman plots showed increasing differences and variability; higher average limb fat in controls and HIV+ (both p<0.0001) was associated with greater DXA vs. MRI difference. As controls have more limb fat than HIV+, the bias leads to even higher fat measured by DXA than by MRI when controls are compared to HIV+; more HIV+ subjects had leg fat in the bottom decile of controls by DXA than by MRI (p<0.0001).
Although DXA and MRI-measured AT depots correlate strongly in HIV+ subjects and controls, differences increase as average fat increases, particularly for limb fat. DXA may estimate a higher peripheral lipoatrophy prevalence than MRI in HIV+ subjects.
PMCID: PMC3156610  PMID: 18842798
DXA; MRI; adipose tissue depots; lipoatrophy; HIV infection
2.  Association of Upper Trunk and Visceral Adipose Tissue Volume With Insulin Resistance in Control and HIV-Infected Subjects in the FRAM Study 
Visceral obesity is associated with insulin resistance, but the association of other regional adipose depots with insulin resistance is not understood. In HIV infection, buffalo hump (upper trunk fat) is associated, but the association of upper trunk fat with insulin resistance has not been examined in controls. To determine the independent association of adipose depots other than visceral with insulin resistance, we performed a cross-sectional analysis of controls and HIV-infected subjects in the Fat Redistribution and Metabolic Change in HIV Infection (FRAM) study, who had measurements of glucose, insulin, and adipose tissue volumes by whole-body magnetic resonance imaging. We studied 926 HIV-positive persons from 16 academic medical center clinics and trials units with demographic characteristics representative of US patients with HIV infection and 258 FRAM controls from the population-based Coronary Artery Risk Development in Young Adults study. We measured visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) volume in the legs, arms, lower trunk (back and abdomen), and upper trunk (back and chest) and assessed their association with the homeostasis model of assessment (HOMA) and HOMA >4 by stepwise multivariable analysis. The prevalence of HOMA >4 as a marker of insulin resistance was 28% among controls compared with 37% among HIV-infected subjects (P = 0.005). Among controls, those in the highest tertile of upper trunk SAT volume had an odds ratio (OR) of 9.0 (95% confidence interval [CI]: 2.4 to 34; P = 0.001) for having HOMA >4 compared with the lowest tertile, whereas in HIV-positive subjects, the OR was lower (OR = 2.09, 95% CI: 1.36 to 3.19; P = 0.001). Among controls, the highest tertile of VAT volume had an OR of 12.1 (95% CI: 3.2 to 46; P = 0.0002) of having HOMA >4 compared with the lowest tertile, whereas in HIV-positive subjects, the OR was 3.12 (95% CI: 2.0 to 4.8; P < 0.0001). After adjusting for VAT and upper trunk SAT, the association of other SAT depots with HOMA >4 did not reach statistical significance. Thus, VAT and upper trunk SAT are independently associated with insulin resistance in controls and in HIV-infected persons.
PMCID: PMC3164883  PMID: 18167644
buffalo hump; fat distribution; insulin resistance; lipodystrophy; visceral obesity
3.  Whole body proteolysis rate is elevated in HIV-associated insulin resistance 
Diabetes  2006;55(10):2849-2855.
Type 2 diabetes (T2DM) is characterized by impaired glucose tolerance (IGT) and insulin resistance with respect to glucose metabolism, but not amino acid metabolism. We examined whether whole body leucine and protein metabolism are dysregulated in HIV-infected people with IGT. Glucose and leucine kinetics were measured under fasting insulin conditions and during euglycemic-hyperinsulinemia using primed constant infusions of 2H2-glucose and 13C-leucine in 10 HIV-seronegative control subjects, 16 HIV+ with normal glucose tolerance, and 21 HIV+IGT. Glucose disposal rate during hyperinsulinemia was lower in HIV+IGT than the other two groups. Absolute plasma leucine levels and rate of appearance (whole body proteolysis) were higher in HIV+IGT at all insulin levels, but declined in response to hyperinsulinemia in parallel to those in the other two groups. HIV+IGT had greater visceral adiposity, fasting serum IL-8 and FFA levels, and higher lipid oxidation rates during the clamp than the other two groups. The findings implicate several factors in the insulin-signaling pathway that may be further dysregulated in HIV+IGT, and support the notion that insulin-signaling pathways for glucose and leucine metabolism may be disrupted by increased proinflammatory adipocytokines (IL-8) and increased lipid oxidation. Increased proteolysis may provide amino acids for gluconeogenesis; exacerbating hyperglycemia in HIV.
PMCID: PMC1764855  PMID: 17003352
muscle amino acid metabolism; insulin signaling; adipocytokine; lipotoxicity; substrate partitioning; mass spectrometry; stable isotope tracer methods; HIV=human immunodeficiency virus; AIDS=acquired immunodeficiency syndrome; HAART=highly active antiretroviral therapy; FFM=fat-free mass; T2DM=type 2 diabetes mellitus; BCAA=branched chain amino acids; Rd=rate of disposal; Ra=rate of appearance; IGT=impaired glucose tolerance; FFA=serum free fatty acids; VAT=visceral adipose tissue content; SAT=subcutaneous adipose tissue content; TAT=total adipose tissue content; HOMA=homeostasis model assessment of insulin resistance; RIA=radioimmunoassay; NRTI= nucleoside analog reverse transcriptase inhibitors; NNRTI= non-nucleoside analog reverse transcriptase inhibitor; PI= protease inhibitor
4.  The Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM): Methods, Design, and Sample Characteristics 
American journal of epidemiology  2006;163(9):860-869.
The Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM), initiated in 2000, investigates the prevalence and correlates of changes in fat distribution, insulin resistance, and dyslipidemia among human immunodeficiency virus (HIV)-infected men and women compared with a population-based group of control men and women. Between June 2000 and September 2002, 1,480 participants (1,183 HIV-infected persons and 297 controls) were enrolled in FRAM. Measurements taken included whole-body magnetic resonance imaging for quantification of regional fat, anthropometric measurements, central laboratory analysis of metabolites, and assessment of symptoms, sociodemographic factors, and lifestyle. Similar measurements were repeated among FRAM participants 4 years later (FRAM 2) for investigation of the progression of fat distribution changes, insulin resistance, and hyperlipidemia. In FRAM 2, which is ongoing, investigators are also determining the associations of subclinical cardiovascular disease, as measured by carotid intimal-medial wall thickness, with HIV infection, fat distribution changes, insulin resistance, and other proatherogenic changes in serum lipid levels. The demographic characteristics of HIV-infected FRAM men and women were comparable to those reported from a national random sampling of HIV-infected men and women receiving medical care in the United States. The representativeness of the FRAM sample increases its value as a resource for studies on fat distribution, metabolic changes, and atherosclerosis in HIV infection.
PMCID: PMC3170407  PMID: 16524955
body fat distribution; dyslipidemias; HIV infections; insulin resistance; lipodystrophy; metabolism
5.  Postchallenge Hyperglycemia Is Positively Associated With Diabetic Polyneuropathy 
Diabetes Care  2012;35(9):1891-1893.
To assess the prevalence of distal sensorimotor polyneuropathy (DSPN) in an older population and to examine its relationship with prediabetes.
Glucose tolerance status was determined in 61- to 82-year-old participants (n = 1,100) of the population-based Cooperative Health Research in the Region of Augsburg (KORA) F4 Survey (2006–2008). Clinical DSPN was defined as bilaterally impaired foot-vibration perception and/or foot-pressure sensation.
Prevalence of clinical DSPN was similar in subjects with known diabetes (22.0%) and subjects with combined impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) (23.9%). Among prediabetic subgroups, IFG-IGT, but not isolated-IFG and -IGT, was associated with a higher risk of clinical DSPN, compared with normal glucose tolerance. A J-shaped association was observed between clinical DSPN and quartiles of 2-h postchallenge glucose, but not with fasting glucose and HbA1c levels.
Subjects with IFG-IGT and known diabetes had a similar prevalence of clinical DSPN. Elevated 2-h postload glucose levels appeared important for disease risk.
PMCID: PMC3424984  PMID: 22751964
6.  Association of HIV Infection and HIV/HCV Coinfection With C-Reactive Protein Levels 
Inflammation is a potential mechanism to explain the accelerated atherosclerosis observed in HIV- and hepatitis C virus (HCV)–infected persons. We evaluated C-reactive protein (CRP) in HIV-infected and HIV/HCV-coinfected individuals in the era of effective antiretroviral (ARV) therapy.
Cross-sectional study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) cohort and controls from the Coronary Artery Risk Development in Young Adults (CARDIA) study.
CRP levels were measured in 1135 HIV-infected participants from the FRAM cohort and 281 controls from the CARDIA study. The associations of HIV and HIV/HCV infection with CRP levels were estimated by multivariable linear regression.
Compared with controls, HIV monoinfection was associated with an 88% higher CRP level in men (P < 0.0001) but with no difference in women (5%; P = 0.80) in multivariate analysis. CRP levels were not associated with ARV therapy, HIV RNA level, or CD4 cell count. Compared with controls, HIV/HCV coinfection was associated with a 41% lower CRP level in women (P = 0.012) but with no difference in men (+4%; P = 0.90). Among HIV-infected participants, HCV coinfection was associated with 50% lower CRP levels after multivariable analysis (P < 0.0001) in men and women. Greater visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were strongly associated with CRP levels. Among HIV- infected participants, CRP levels were 17% (P < 0.001) and 21% (P = 0.002) higher per doubling of VAT and SAT; among controls, CRP levels were 34% (P < 0.001) and 61% (P = 0.009) higher, respectively.
In the absence of HCV coinfection, HIV infection is associated with higher CRP levels in men. HCV coinfection is associated with lower CRP levels in men and women.
PMCID: PMC2561207  PMID: 18344877
cardiovascular disease; C-reactive protein; hepatitis C virus; HIV; inflammation
7.  Prevalence and factors associated with dry skin in HIV infection: the FRAM study 
AIDS (London, England)  2007;21(15):2051-2057.
Complaints of dry skin in HIV-infected individuals were reported after the advent of HAART. The objective of the study was to evaluate the prevalence of dry skin and associated factors in HIV-infected and control subjects.
A total of 1026 HIV-infected subjects and 274 controls [from the Coronary Artery Risk Development in Young Adults (CARDIA) study, a population-based study of cardiovascular risk assessment] in the Study of Fat Redistribution and Metabolic Change in HIV infection (FRAM) had skin assessed by self-report and examination. Multivariable logistic regression identified factors associated with dry skin.
Self-reported dry skin was more prevalent in HIV-infected subjects than controls. In multivariable analysis, HIV infection was associated with self-reported dry skin. In HIV-infected men, current indinavir use, CD4 cell count less than 200 cells/μl and recent opportunistic infections were associated with dry skin. Indinavir use had an elevated risk in men with CD4 cell counts of 200 cells/μl or greater but not with CD4 cell counts less than 200 cells/μl. In HIV-infected women, a CD4 cell count less than 200 cells/μl was associated with dry skin; indinavir use did not reach statistical significance but, as in men, indinavir use had an elevated risk in those with higher CD4 cell counts than in those with CD4 cell counts less than 200 cells/μl.
Dry skin is more common in HIV-infected individuals than controls. In HIV-infected individuals, low CD4 cell counts and indinavir use in those with higher CD4 cell counts are associated with dry skin.
PMCID: PMC3166536  PMID: 17885295
complication; dermatology; opportunistic infection; protease inhibitors; retinoid
8.  Association Between Hepatitis C Virus Coinfection and Regional Adipose Tissue Volume in HIV-Infected Men and Women 
Coinfection with hepatitis C virus (HCV) is reported to be associated with a higher prevalence of lipodystrophy than HIV infection alone. We examine the association between HCV and adipose tissue volume in HIV-infected men and women.
Cross-sectional analysis of HIV-infected subjects from the study of Fat Redistribution and Metabolic Change in HIV Infection. MRI measured regional adipose tissue volume. Detectable HCV RNA defined HCV infection.
Twenty percent of 792 men and 26% of 329 women were HIV/HCV-coinfected. HIV/HCV-coinfected and HIV-monoinfected women had similar amounts of subcutaneous adipose tissue (SAT) in the leg, lower trunk, upper trunk, and arm and similar amounts of visceral adipose tissue (VAT). Similar findings were seen in men, except in the leg and VAT. After adjustment, HCV infection remained associated with more leg fat in men (12.2%, 95% confidence interval [CI]: 0.3 to 25.3; P = 0.043). Among those on stavudine, HIV-monoinfected men had less leg fat (−7% effect per year of stavudine use, 95% CI: −9 to −5; P < 0.001); a weaker association was seen in HIV/HCV-coinfected men (−2% effect, 95% CI: −7 to 3; P = 0.45). Indinavir was associated with less leg fat (−4% in HIV-monoinfected men, 95% CI: −6 to −1; P = 0.002; −5% in HIV/HCV-coinfected men, 95% CI: −11 to 2; P = 0.14).
Our findings suggest that HIV/HCV coinfection is not associated with less SAT in men and women. HCV infection seems to mitigate the loss of leg fat seen in HIV-infected men on stavudine.
PMCID: PMC3164885  PMID: 17356466
adipose tissue volume; fat distribution; hepatitis C virus; HIV; lipodystrophy
9.  Pre-Clinical Atherosclerosis due to HIV Infection: Carotid Intima-Medial Thickness Measurements from the FRAM Study 
AIDS (London, England)  2009;23(14):1841-1849.
Cardiovascular disease (CVD) is an increasing cause of morbidity and mortality in HIV-infected patients. However, it is controversial whether HIV infection contributes to accelerated atherosclerosis independent of traditional CVD risk factors.
Cross-sectional study of HIV-infected and control subjects without pre-existing CVD from the study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) and the Multi-Ethnic Study of Atherosclerosis (MESA). Pre-clinical atherosclerosis was assessed by carotid intima-medial thickness (IMT) measurements in the internal/bulb and common regions in HIV-infected and control subjects after adjusting for traditional CVD risk factors.
For internal carotid, mean IMT was 1.17±0.50mm for HIV-infected participants and 1.06±0.58mm for controls (p<0.0001). After multivariable adjustment for demographic characteristics, the mean difference of HIV-infected vs. controls was +0.188mm (95%CI 0.113-0.263, p<0.0001). Further adjustment for traditional CVD risk factors modestly attenuated the HIV association (+0.148mm, 95%CI 0.072-0.224, p=0.0001). For the common carotid, HIV infection was independently associated with greater IMT (+0.033mm, 95%CI 0.010, 0.056, p=0.005). The association of HIV infection with IMT was similar to that of smoking which was also associated with greater IMT (internal +0.173mm, common +0.020mm).
Even after adjustment for traditional CVD risk factors, HIV infection was accompanied by more extensive atherosclerosis measured by IMT. The stronger association of HIV infection with IMT in the internal/bulb region compared to the common carotid may explain previous discrepancies in the literature. The association of HIV infection with IMT was similar to that of traditional CVD risk factors, such as smoking.
PMCID: PMC3156613  PMID: 19455012
HIV; carotid IMT; smoking; cholesterol; diabetes; atherosclerosis
10.  Fat Distribution in Women With HIV Infection 
Both peripheral fat loss and central fat gain have been reported in women with HIV infection. We determined the fat changes that are specific to HIV infection in women.
HIV-infected and control women from the study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) were compared. Lipoatrophy or lipohypertrophy was defined as concordance between participant report of fat change and clinical examination. Whole-body magnetic resonance imaging measured regional adipose tissue volumes. The relationship among different adipose tissue depots was assessed. Factors associated with individual depots were analyzed using multivariate linear regression.
HIV-infected women reported more fat loss than controls in all peripheral and most central depots. Peripheral lipoatrophy was more frequent in HIV-infected women than controls (28% vs. 4%, P < 0.001), whereas central lipohypertrophy was similar (62% vs. 63%). Among HIV-infected women, those with central lipohypertrophy were less likely to have peripheral lipoatrophy (odds ratio, 0.39; 95% confidence interval, 0.20 to 0.75, P = 0.006) than those without central lipohypertrophy. On magnetic resonance imaging, HIV-infected women with clinical peripheral lipoatrophy had less subcutaneous adipose tissue (SAT) in peripheral and central sites and less visceral adipose tissue (VAT) than HIV-infected women without peripheral lipoatrophy. Compared with controls, HIV-infected women had less SAT in the legs, regardless of the presence or absence of lipoatrophy. However, those without lipoatrophy had more VAT and upper trunk SAT than controls. Use of the antiretroviral drug stavudine was associated with less leg SAT but was not associated with VAT. The use of highly active antiretroviral therapy, however, was associated with more VAT.
Peripheral lipoatrophy occurs commonly in HIV-infected women but is not associated with reciprocally increased VAT or trunk fat.
PMCID: PMC3166343  PMID: 16837863
HIV; lipodystrophy; lipoatrophy; lipohypertrophy; visceral obesity; fat redistribution; body composition
11.  Cystatin C Level as a Marker of Kidney Function in Human Immunodeficiency Virus Infection 
Archives of internal medicine  2007;167(20):2213-2219.
Although studies have reported a high prevalence of end-stage renal disease in human immunodeficiency virus (HIV)-infected individuals, little is known about moderate impairments in kidney function. Cystatin C measurement may be more sensitive than creatinine for detecting impaired kidney function in persons with HIV.
We evaluated kidney function in the Fat Redistribution and Metabolic Change in HIV Infection (FRAM) cohort, a representative sample of 1008 HIV-infected persons and 290 controls from the Coronary Artery Risk Development in Young Adults (CARDIA) study in the United States.
Cystatin C level was elevated in HIV-infected individuals; the mean±SD cystatin C level was 0.92±0.22 mg/L in those infected with HIV and 0.76±0.15 mg/L in controls (P<.001). In contrast, both mean creatinine levels and estimated glomerular filtration rates appeared similar in HIV-infected individuals and controls (0.87±0.21 vs 0.85±0.19 mg/dL [to convert to micromoles per liter, multiply by 88.4] [P=.35] and 110±26 vs 106±23 mL/min/1.73 m2 [P=.06], respectively). Persons with HIV infection were more likely to have a cystatin C level greater than 1.0 mg/L (OR, 9.8; 95% confidence interval, 4.4-22.0 [P<.001]), a threshold demonstrated to be associated with increased risk for death and cardiovascular and kidney disease. Among participants with HIV, potentially modifiable risk factors for kidney disease, hypertension, and low high-density lipoprotein concentration were associated with a higher cystatin C level, as were lower CD4 lymphocyte count and coinfection with hepatitis C virus (all P<.001).
Individuals infected with HIV had substantially worse kidney function when measured by cystatin Clevel compared with HIV-negative controls, whereas mean creatinine levels and estimated glomerular filtration rates were similar. Cystatin C measurement could be a useful clinical tool to identify HIV-infected persons at increased risk for kidney and cardiovascular disease.
PMCID: PMC3189482  PMID: 17998494
12.  Impaired Fasting Glucose in Cystic Fibrosis 
Diabetes Care  2010;33(12):2660-2664.
While glucose tolerance abnormalities are common in cystic fibrosis (CF), impaired fasting glucose (IFG) has scarcely been explored. No studies have examined the relation between IFG and clinical status.
Data were retrieved from the University of Minnesota CF database on oral glucose tolerance tests (OGTTs) performed in 1996–2005. Subjects were identified as normal glucose tolerance (NGT), impaired glucose tolerance (IGT), or CF–related diabetes without fasting hyperglycemia (CFRD FH−). Patients with fasting hyperglycemia were excluded. The presence of IFG was assessed within each category. In a separate case-control cohort study, subjects with IFG were matched to CF control subjects by age, sex, and OGTT class to explore outcomes.
For the total population (n = 310), the prevalence of IFG was 22%, and by OGTT class was NGT 14%, IGT 31%, CFRD FH− 53%. Within the cohort study, mortality was significantly reduced in IFG (two vs. nine deaths, odds ratio [OR] = 0.2 [95% CI 0.04–0.9]). IFG did not confer increased risk of progression to diabetes (OR 0.66 [0.29–1.48]). Lung function was better in pediatric IFG subjects with IGT and not significantly worse in adults with IGT or adults and children with NGT and CFRD FH−. BMI was not significantly different in IFG subjects versus control subjects.
Contrary to expectations in patients with CF, IFG appeared to be associated with improved survival and was not associated with worse nutritional or pulmonary status or increased progression to fasting hyperglycemia.
PMCID: PMC2992208  PMID: 21115768
13.  Correlation Between Prediabetes Conditions and Microalbuminuria 
Nephro-urology Monthly  2013;5(2):741-744.
Impaired fasting glucose (IFG), and impaired glucose tolerance (IGT) are two prediabetes conditions which have some correlation with macrovascular disorders. The risk of microvascular complications in these groups is not clear.
The prevalence of albuminuria in subjects with IFG and IGT was evaluated in the present study.
Patients and Methods
In this study three groups of subjects were entered (45 subjects in each group): IFG, IGT, and normal glucose tolerance as control. The urine albumin-creatinine ratio was studied in morning spot urine samples to detect microalbuminuria. The subjects were followed up for two years, and blood sugar and urine albumin and glycosylated hemoglobin (HbA1C) were measured every 6 months.
The prevalence rate of microalbuminuria was 15.5% in the prediabetic groups, while no one had microalbuminuria in the control group (P = 0.005). The prevalence of microalbuminuria in patients with IFG or IGT was not significantly different (17.8% vs. 13.3%) (P = 0.4). Fourteen subjects (4 in IFG group and 10 in IGT group) developed diabetes mellitus within a 2-year follow-up period (P = 0.1). Thirty six percent of subjects with albuminuria, and twelve percent of subjects without albuminuria progressed to diabetes mellitus during a 2-year follow-up (P = 0.02, odd ratio = 4.1; CI95%, 1.13-15.1).
The risk of microalbuminuria in prediabetic subjects is high, and probably prediabetic subjects are at higher risk of progression to diabetes mellitus. We suggest periodically evaluation of albuminuria in prediabetic patients after the diagnosis.
PMCID: PMC3703132  PMID: 23841037
Glucose Tolerance; Diabetic Nephropathies; Diabetes Mellitus, Type 2
14.  Prevalence of Pre-Diabetes and Its Association With Clustering of Cardiometabolic Risk Factors and Hyperinsulinemia Among U.S. Adolescents 
Diabetes Care  2009;32(2):342-347.
OBJECTIVE—Impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) are considered to constitute “pre-diabetes.” We estimated the prevalence of IFG, IGT, and pre-diabetes among U.S. adolescents using data from a nationally representative sample.
RESEARCH DESIGN AND METHODS—We analyzed data from participants aged 12–19 years in the National Health and Nutrition Examination Survey 2005–2006. We used fasting plasma glucose and 2-h glucose during an oral glucose tolerance test to assess the prevalence of IFG, IGT, and pre-diabetes and used the log-binomial model to estimate the prevalence ratios (PRs) and 95% CIs.
RESULTS—The unadjusted prevalences of IFG, IGT, and pre-diabetes were 13.1, 3.4, and 16.1%, respectively. Boys had a 2.4-fold higher prevalence of pre-diabetes than girls (95% CI 1.3–4.3). Non-Hispanic blacks had a lower rate than non-Hispanic whites (PR 0.6, 95% CI 0.4–0.9). Adolescents aged 16–19 years had a lower rate than those aged 12–15 years (0.6, 0.4–0.9). Overweight adolescents had a 2.6-fold higher rate than those with normal weight (1.3–5.1). Adolescents with two or more cardiometabolic risk factors had a 2.7-fold higher rate than those with none (1.5–4.8). Adolescents with hyperinsulinemia had a fourfold higher prevalence (2.2–7.4) than those without. Neither overweight nor number of cardiometabolic risk factors was significantly associated with pre-diabetes after adjustment for hyperinsulinemia.
CONCLUSIONS—Pre-diabetes was highly prevalent among adolescents. Hyperinsulinemia was independently associated with pre-diabetes and may account for the association of overweight and clustering of cardiometabolic risk factors with pre-diabetes.
PMCID: PMC2628705  PMID: 18957533
15.  High prevalence of undiagnosed diabetes and abnormal glucose tolerance in the Iranian urban population: Tehran Lipid and Glucose Study 
BMC Public Health  2008;8:176.
To estimate the prevalence of diagnosed and undiagnosed diabetes mellitus, impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and combined IFG/IGT in a large urban Iranian population aged ≥ 20 years.
The study population included 9,489 participants of the Tehran Lipid and Glucose Study with full relevant clinical data. Age-standardized prevalence of diabetes and glucose intolerance categories were reported according to the 2003 American Diabetes Association definitions. Age-adjusted logistic regression models were used to estimate the numbers needed to screen (NNTS) to find one person with undiagnosed diabetes.
The prevalence of diagnosed and undiagnosed diabetes, isolated IFG, isolated IGT, and combined IFG/IGT were 8.1%, 5.1%, 8.7%, 5.4% and 4.0% in men and 10%, 4.7%, 6.3%, 7.6%, and 4.5% in women respectively. Participants with undiagnosed diabetes had higher age, body mass index (BMI), waist circumference, systolic and diastolic blood pressures, triglycerides (all p values <0.001) and lower HDL-cholesterol (only in women, p < 0.01) compared to normoglycemic subjects. Undiagnosed diabetes was associated with family history of diabetes, increased BMI (≥ 25 kg/m2), abdominal obesity, hypertriglyceridemia, hypertension and low HDL-cholesterol levels. Among men, a combination of increased BMI, hypertension, and family history of diabetes led to a NNTS of 1.6 (95% CI: 1.57–1.71) and among women a combination of family history of diabetes and abdominal obesity, yielded a NNTS of 2.2 (95% CI: 2.1–2.4).
In conclusion, about one third of Tehranian adults had disturbed glucose tolerance or diabetes. One- third of total cases with diabetes were undiagnosed. Screening individuals with BMI ≥ 25 kg/m2 (men), hypertension (men), abdominal obesity (women) and family history of diabetes may be more efficient.
PMCID: PMC2413226  PMID: 18501007
16.  Cystatin C, Albuminuria, and 5-Year All-Cause Mortality in HIV-Infected Persons 
Compared with controls, HIV-infected persons have a greater prevalence of kidney disease as assessed by high levels of cystatin C and albuminuria, but not as assessed by creatinine level. However, the clinical importance of elevated cystatin C and albuminuria in the HIV-infected population has not been studied.
Study Design
We conducted an observational cohort study to determine the association of kidney disease (measured by albuminuria, cystatin C, and serum creatinine) with mortality.
Setting & Participants
922 HIV-infected persons enrolled in the FRAM (Fat Redistribution and Metabolic Change in HIV infection) study.
Serum cystatin C and serum creatinine were used to estimate glomerular filtration rate (eGFR). Albuminuria was defined as a positive urine dipstick (≥1+) or a urine albumin-creatinine ratio > 30 mg/g.
5-year mortality
At baseline, reduced kidney function (eGFRSCysC <60 mL/min/1.73m2) or albuminuria was present in 28% of participants. After five years of follow-up, mortality was 48% among those with both eGFRSCysC <60 mL/min/1.73m2 and albuminuria, 23% in those with eGFRSCysC <60 mL/min/1.73m2 alone, 20% in those with albuminuria alone, and 9% in those with neither condition. After multivariable adjustment for demographics, cardiovascular risk factors, HIV-related factors, and inflammatory markers, eGFRSCysC <60 mL/min/1.73m2 and albuminuria were associated with nearly a twofold increase in mortality, whereas eGFRSCr <60 mL/min/1.73m2 did not appear to have any substantial association with mortality. Together, eGFRSCysC <60 mL/min/1.73m2 and albuminuria accounted for 17% of the population-level attributable risk for mortality.
Vital status was unknown in 261 participants from the original cohort.
Kidney disease marked by albuminuria or increased cystatin C levels appears to be an important risk factor for mortality in HIV-infected individuals. A substantial proportion of this risk may be unrecognized because of the current reliance on serum creatinine to estimate kidney function in clinical practice.
PMCID: PMC3164880  PMID: 20709438
kidney disease; mortality; HIV infection
17.  Diabetes and Other Disorders of Glycemia in a Rural South African Community 
Diabetes Care  2008;31(9):1783-1788.
OBJECTIVE—The purpose of this study was to determine the prevalence of diabetes, impaired glucose tolerance (IGT), impaired fasting glycemia (IFG), and associated risk factors in a rural South African black community.
RESEARCH DESIGN AND METHODS—This was a cross-sectional survey conducted by random cluster sampling of adults aged >15 years. Participants had a 75-g oral glucose tolerance test using the 1998 World Health Organization criteria for disorders of glycemia.
RESULTS—Of 1,300 subjects selected, 1,025 subjects (815 women) participated (response rate 78.9%). The overall age-adjusted prevalence of diabetes was 3.9%, IGT 4.8%, and IFG 1.5%. The prevalence was similar in men and women for diabetes (men 3.5%; women 3.9%) and IGT (men 4.6%; women 4.7%) but higher in men for IFG (men 4.0%; women 0.8%). The prevalence of diabetes and IGT increased with age both in men and women, with peak prevalence in the 55- to 64-year age-group for diabetes and in the ≥65-year age-group for IGT. Of the cases of diabetes, 84.8% were discovered during the survey. In multivariate analysis, the significant independent risk factors associated with diabetes included family history (odds ratio 3.5), alcohol ingestion (2.8), waist circumference (1.1), systolic blood pressure (1.0), serum triglycerides (2.3), and total cholesterol (1.8); hip circumference was protective (0.9).
CONCLUSIONS—There is a moderate prevalence of diabetes and a high prevalence of total disorders of glycemia, which suggests that this community, unlike other rural communities in Africa, is well into an epidemic of glucose intolerance. There is a low proportion of known diabetes and a significant association with potentially modifiable risk factors.
PMCID: PMC2518345  PMID: 18523142
18.  Simple anthropometric measures correlate with metabolic risk indicators as strongly as magnetic resonance imaging–measured adipose tissue depots in both HIV-infected and control subjects2 
Studies in persons without HIV infection have compared percentage body fat (%BF) and waist circumference as markers of risk for the complications of excess adiposity, but only limited study has been conducted in HIV-infected subjects.
We compared anthropometric and magnetic resonance imaging (MRI)–based adiposity measures as correlates of metabolic complications of adiposity in HIV-infected and control subjects.
The study was a cross-sectional analysis of 666 HIV-positive and 242 control subjects in the Fat Redistribution and Metabolic Change in HIV Infection (FRAM) study assessing body mass index (BMI), waist (WC) and hip (HC) circumferences, waist-to-hip ratio (WHR), %BF, and MRI-measured regional adipose tissue. Study outcomes were 3 metabolic risk variables [homeostatic model assessment (HOMA), triglycerides, and HDL cholesterol]. Analyses were stratified by sex and HIV status and adjusted for demographic, lifestyle, and HIV-related factors.
In HIV-infected and control subjects, univariate associations with HOMA, triglycerides, and HDL were strongest for WC, MRI-measured visceral adipose tissue, and WHR; in all cases, differences in correlation between the strongest measures for each outcome were small (r ≤ 0.07). Multivariate adjustment found no significant difference for optimally fitting models between the use of anthropometric and MRI measures, and the magnitudes of differences were small (adjusted R2 ≤ 0.06). For HOMA and HDL, WC appeared to be the best anthropometric correlate of metabolic complications, whereas, for triglycerides, the best was WHR.
Relations of simple anthropometric measures with HOMA, triglycerides, and HDL cholesterol are approximately as strong as MRI-measured whole-body adipose tissue depots in both HIV-infected and control subjects.
PMCID: PMC2587301  PMID: 18541572
19.  Associations of antiretroviral drug use and HIV-specific risk factors with carotid intima–media thickness 
AIDS (London, England)  2010;24(14):2201-2209.
Previous research has demonstrated an increase in carotid intima–media thickness (cIMT) in HIV-infected individuals compared to controls. However, the reason for this increased level of subclinical vascular disease is unknown.
To identify HIV-related risk factors for increased cIMT.
We evaluated the relationship between HIV-related characteristics (including markers of HIV disease severity and use of antiretroviral therapy) and cIMT measurements in the internal/bulb and common carotid regions among 538 HIV-infected participants from the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM). We used Bayesian model averaging to estimate the posterior probability of candidate HIV and non-HIV-related risk factors being true predictors of increased cIMT. Variables with a posterior probability of more than 50% were used to develop a selected regression model for each of the anatomic regions.
For common cIMT, the Bayesian model selection process identified age, African-American race, and systolic and diastolic blood pressure with probability more than 95%, HDL cholesterol with probability 85% and Hispanic ethnicity with probability 51%. Among the HIV-related factors included in the analysis, only tenofovir use was selected (51% probability). In the selected model, duration of tenofovir use was associated with lower common cIMT (−0.0094 mm/year of use; 95% confidence interval: −0.0177 to −0.0010). For internal cIMT, no HIV-related risk factors were above the 50% posterior probability threshold.
We observed an inverse association between duration of tenofovir use and common carotid cIMT. Whether this association is causal or due to confounding by indication needs further investigation.
PMCID: PMC3224487  PMID: 20671544
atherosclerosis; carotid intima–media thickness; HIV; tenofovir
20.  Illicit drug use and HIV treatment outcomes in a US cohort 
AIDS (London, England)  2008;22(3):357-365.
To determine the prevalence of illicit drug use and the impact on HIV treatment.
Multivariable regression of cross-sectional data from 1163 HIV-infected and 294 controls from the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM).
An analysis of (1) prevalence of specific illicit drug use (ever, current), (2) being on HAART among those with an indication and (3) current HIV RNA and CD4 cell count among HAART users.
Median age was 42 years, approximately 50% were non-Caucasian and 33% were women. Eighty-six percent of HIV-infected and 67% of controls reported ever using illicit drugs (P <0.0001); 28% of HIV-infected and 16% of controls reported current use (P = 0.0001). In adjusted models, current cocaine use and past heroin use were associated with not currently being on HAART. Among HAART users, those reporting past heroin use were as likely to have an undetectable HIV viral load as those who had never used heroin. Current and past cocaine use and current heroin use was associated with lower odds of undetectable HIV RNA. Past amphetamine use was associated with having an undetectable HIV. Similar results were seen for CD4 lymphocyte counts.
Illicit drug use in the US is common, although far fewer report current use than past use. Among HIV-infected patients, understanding of the type of illicit drugs used and whether drug use was in the past or ongoing is important, because of their differential effects on HIV treatment outcomes.
PMCID: PMC3189479  PMID: 18195562
amphetamines; cocaine; heroin; HIV; street drugs; viral load
21.  Evaluation of Cardiac Functions with Tissue Doppler Imaging in Prediabetic Subjects 
Korean Circulation Journal  2013;43(2):82-86.
Background and Objectives
The aim of the present study was to evaluate left ventricle systolic and diastolic function, using tissue Doppler echocardiography (TDE), in relation to blood glucose status in prediabetic patients who had no evidence of heart disease by conventional echocardiography (CE).
Subjects and Methods
We included 60 patients (30 female, 30 male) and 20 healthy controls (10 male, 10 female). All participants were randomised into four groups according to their oral glucose tolerance test. Group-I consisted of those patients who had only impaired fasting glucose (IFG). group-II consisted of patients who had only impaired glucose tolerance (IGT) and group-III consisted of patients who had both IFG and IGT, that is so-called combined glucose intolerance. Group-IV included the healthy controls. All subjects underwent both CE and TDE.
No significant differences were found among the four groups in terms of CE. There was no significant difference between group-IV and group-I with respect to the early peak diastolic velocity (Ea) of medial mitral annulus (11.65±0.66 vs. 9.72±1.58, p>0.05), whereas a statistically significant difference was found between group-IV and group-II (11.65±0.66 vs. 9.06±1.07, p<0.001) and between group-IV and group-III (11.65±0.66 vs. 9.74±1.09, p<0.05).
Diastolic myocardial dysfunction in prediabetic patients may be identified by quantitative TDE before the appearance of CE indices of myocardial dysfunction.
PMCID: PMC3596668  PMID: 23508684
Type 2 diabetes mellitus; Diabetic cardiomyopathies; Tissue Doppler imaging; Glucose intolerance
22.  Prevalence of Type 2 Diabetes and Impaired Glucose Regulation with Associated Cardiometabolic Risk Factors and Depression in an Urbanizing Rural Community in Bangladesh: A Population-Based Cross-Sectional Study 
Diabetes & Metabolism Journal  2012;36(6):422-432.
To determine the prevalence of type 2 diabetes (T2DM) and impaired glucose regulation (impaired fasting glucose [IFG] and impaired glucose tolerance [IGT]) in an urbanizing rural population of Bangladesh and associated cardiometabolic risk indicators and depression.
A total of 2,293 subjects aged ≥20 years in an urbanizing rural Bangladeshi community were investigated. Socio-demographic and anthropometric details, blood pressure, fasting plasma glucose (FPG), 2 hours after 75 g plasma glucose (2hPG), glycosylated hemoglobin, fasting serum insulin and lipid profiles were studied. Presence of depressive symptoms using Montogomery-Asberg Depression Rating Scale was also assessed.
The prevalence of IFG, IGT, IFG+IGT, and T2DM were 3.4%, 4.0%, 1.2%, and 7.9%, respectively. The prevalence of T2DM and impaired glucose regulation differed between males and females, but, both increased with age in both sexes. FPG and 2hPG had positive correlation. Employing logistic regression, it was found that increased age, waist to hip ratio, systolic blood pressure, total cholesterol, triglycerides, and depression were independent risk indicators for diabetes. Both insulin resistance and β-cell deficiency were significantly related for causation of diabetes. Among the study population, 26.2% had general obesity, 39.8% central obesity, 15.5% hypertension, 28.7% dyslipidemia, 17.6% family history of diabetes, and 15.3% had depression. Physical inactivity and smoking habits were significantly higher in male.
Rising prevalence of diabetes and impaired glucose regulation in this urbanizing rural population exist as a significant but hidden public health problem. Depression and other cardiometabolic risk indicators including obesity, hypertension, and dyslipdemia were also prevalent in this population.
PMCID: PMC3530713  PMID: 23275936
Bangladesh; Diabetes mellitus; Impaired glucose regulation; Prevalence
23.  Genes Linked to Energy Metabolism and Immunoregulatory Mechanisms are Associated with Subcutaneous Adipose Tissue Distribution in HIV-infected Men 
Pharmacogenetics and genomics  2011;21(12):798-807.
Genetic studies may help explain abnormalities of fat distribution in HIV-infected patients treated with antiretroviral therapy (ARV).
Subcutaneous adipose tissue (SAT) volume measured by magnetic resonance imaging (MRI) in leg, lower trunk, upper trunk, and arm was examined in 192 HIV-infected Caucasian men, ARV-treated from the Fat Redistribution and Metabolic Change in HIV infection (FRAM) study. Single nucleotide polymorphisms (SNPs) were assayed using the Illumina HumanCNV370-quad beadchip. Multivariate and univariate genome wide association analyses of the four SAT depots were implemented in PLINK software adjusted for age and ARV duration. Functional annotation analysis (FAA) using Ingenuity Systems Pathway Analysis tool (IPA) was carried out for markers with P<10-3 near known genes identified by multivariate analysis.
Loci (rs10504906, rs13267998, rs921231) in or near the anion exchanger solute carrier family 26, member 7 isoform a (SLC26A7) were strongly associated with upper trunk and arm SAT (9.8*10-7≤P<7.8*10-6). Loci (rs193139, rs7523050, rs1761621) in and near a gene rich region including G-protein-signaling modulator 2 (GPSM2) and syntaxin binding protein 3 (STXBP3) were significantly associated with lower body SAT depots (9.9*10-7≤P<9.5*10-6). GPSM2 is associated with cell division and cancer while STXBP3 is associated with glucose metabolism in adipoctyes. IPA identified atherosclerosis, mitochondrial function and T-Cell mediated apoptosis as processes related to SAT volume in HIV-infected individuals (P<5*10-3).
Our results are limited by the small sample size and replication is needed, however this genomic scan uncovered new genes associated with metabolism and inflammatory pathways that may affect SAT volume in ARV-treated HIV-infected patients.
PMCID: PMC3210910  PMID: 21897333
HIV; HAART; GWAS; Subcutaneous Fat; SAT
24.  Cardiovascular Characteristics in Subjects With Increasing Levels of Abnormal Glucose Regulation 
Diabetes Care  2013;36(4):992-997.
To evaluate whether impaired fasting glucose (IFG) or the combination of IFG and impaired glucose tolerance (IGT) is associated with progressive abnormalities of cardiac geometry and function.
We studied 562 nondiabetic (311 women), nonhypertensive participants of the second Strong Heart Study exam, without prevalent cardiovascular (CV) disease and with estimated glomerular filtration rate ≥60 mL/min/1.73 m2 (age 46–65 years, 198 with isolated IFG [35%], and 132 with combined IFG and IGT [23%]). Anthropometric parameters, insulin resistance, fibrinogen, C-reactive protein (CRP), lipid profile, blood pressure (BP), and echocardiographic parameters were compared with 232 participants with normal glucose tolerance (NGT).
BMI, prevalence of central obesity, homeostatic model assessment index of insulin resistance, plasma triglycerides, fibrinogen, and CRP increased progressively across categories of glucose intolerance (P < 0.0001), with the IFG+IGT group having higher values than those with isolated IFG (0.05 < P < 0.0001). Compared with NGT, both IFG and IFG+IGT exhibited greater left ventricular (LV) mass (P < 0.0001) and lower Doppler early peak rapid filling velocity to peak atrial filling velocity ratio (P < 0.005), without differences in LV systolic function. The odds of LV hypertrophy (LV mass index >46.7 in women or >49.2 g/m2.7 in men) was 3.5 in IFG participants (95% CI 0.68–17.76; P = NS) and 9.76 (2.03–46.79; P = 0.004) in IFG+IGT, compared with NGT, after adjustment for age, sex, heart rate, systolic BP, and waist circumference (WC). In the overall sample, LV mass index was associated with WC (P = 0.033), CRP (P = 0.027), and 2-h oral glucose tolerance test (P = 0.001) independently of confounders.
Cardiometabolic profile and markers of inflammation are more severely altered in men and women with both IFG and IGT compared with those with IFG alone. These individuals, in the absence of hypertension, have a 10-fold greater probability of preclinical CV disease (LV hypertrophy).
PMCID: PMC3609517  PMID: 23223343
25.  Intermuscular Adipose Tissue and Metabolic Associations in HIV Infection 
Obesity (Silver Spring, Md.)  2010;19(2):283-291.
Intermuscular adipose tissue (IMAT) is associated with metabolic abnormalities similar to those associated with visceral adipose tissue (VAT). Increased IMAT has been found in obese human immunodeficiency virus (HIV)-infected women. We hypothesized that IMAT, like VAT, would be similar or increased in HIV-infected persons compared with healthy controls, despite decreases in subcutaneous adipose tissue (SAT) found in HIV infection. In the second FRAM (Study of Fat Redistribution and Metabolic Change in HIV infection) exam, we studied 425 HIV-infected subjects and 211 controls (from the Coronary Artery Risk Development in Young Adults study) who had regional AT and skeletal muscle (SM) measured by magnetic resonance imaging (MRI). Multivariable linear regression identified factors associated with IMAT and its association with metabolites. Total IMAT was 51% lower in HIV-infected participants compared with controls (P = 0.003). The HIV effect was attenuated after multivariable adjustment (to −28%, P < 0.0001 in men and −3.6%, P = 0.70 in women). Higher quantities of leg SAT, upper-trunk SAT, and VAT were associated with higher IMAT in HIV-infected participants, with weaker associations in controls. Stavudine use was associated with lower IMAT and SAT, but showed little relationship with VAT. In multivariable analyses, regional IMAT was associated with insulin resistance and triglycerides (TGs). Contrary to expectation, IMAT is not increased in HIV infection; after controlling for demographics, lifestyle, VAT, SAT, and SM, HIV+ men have lower IMAT compared with controls, whereas values for women are similar. Stavudine exposure is associated with both decreased IMAT and SAT, suggesting that IMAT shares cellular origins with SAT.
PMCID: PMC3731045  PMID: 20539305

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