Preethi Srikanthan

Relative Muscle Mass Is Inversely Associated with Insulin Resistance and Prediabetes. Findings from The Third National Health and Nutrition Examination Survey

CONTEXT Insulin resistance, the basis of type 2 diabetes, is rapidly increasing in prevalence; very low muscle mass is a risk factor for insulin resistance. OBJECTIVE The aim was to determine whether increases in muscle mass at average and above average levels are associated with improved glucose regulation. DESIGN We conducted a cross-sectional analysis of National Health and Nutrition Examination Survey III data. PARTICIPANTS Data from 13,644 subjects in a national study were evaluated. OUTCOME MEASUREMENTS We measured homeostasis model assessment of insulin resistance (HOMA-IR), blood glycosylated hemoglobin level, prevalence of transitional/pre- or overt diabetes (PDM), and prevalence of overt diabetes mellitus. RESULTS All four outcomes decreased from the lowest quartile to the highest quartile of skeletal muscle index (SMI), the ratio of total skeletal muscle mass (estimated by bioelectrical impedance) to total body weight. After adjusting for age, ethnicity, sex, and generalized and central obesity, each 10% increase in SMI was associated with 11% relative reduction in HOMA-IR (95% confidence interval, 6-15%) and 12% relative reduction in PDM prevalence (95% CI, 1-21%). In nondiabetics, SMI associations with HOMA-IR and PDM prevalence were stronger. CONCLUSIONS Across the full range, higher muscle mass (relative to body size) is associated with better insulin sensitivity and lower risk of PDM. Further research is needed to examine the effect of appropriate exercise interventions designed to increase muscle mass on incidence of diabetes.

Sarcopenia Exacerbates Obesity-Associated Insulin Resistance and Dysglycemia: Findings from the National Health and Nutrition Examination Survey III

Background Sarcopenia often co-exists with obesity, and may have additive effects on insulin resistance. Sarcopenic obese individuals could be at increased risk for type 2 diabetes. We performed a study to determine whether sarcopenia is associated with impairment in insulin sensitivity and glucose homeostasis in obese and non-obese individuals. Methodology We performed a cross-sectional analysis of National Health and Nutrition Examination Survey III data utilizing subjects of 20 years or older, non-pregnant (N = 14,528). Sarcopenia was identified from bioelectrical impedance measurement of muscle mass. Obesity was identified from body mass index. Outcomes were homeostasis model assessment of insulin resistance (HOMA IR), glycosylated hemoglobin level (HbA1C), and prevalence of pre-diabetes (6.0≤ HbA1C<6.5 and not on medication) and type 2 diabetes. Covariates in multiple regression were age, educational level, ethnicity and sex. Principal Findings Sarcopenia was associated with insulin resistance in non-obese (HOMA IR ratio 1.39, 95% confidence interval (CI) 1.26 to 1.52) and obese individuals (HOMA-IR ratio 1.16, 95% CI 1.12 to 1.18). Sarcopenia was associated with dysglycemia in obese individuals (HbA1C ratio 1.021, 95% CI 1.011 to 1.043) but not in non-obese individuals. Associations were stronger in those under 60 years of age. We acknowledge that the cross-sectional study design limits our ability to draw causal inferences. Conclusions Sarcopenia, independent of obesity, is associated with adverse glucose metabolism, and the association is strongest in individuals under 60 years of age, which suggests that low muscle mass may be an early predictor of diabetes susceptibility. Given the increasing prevalence of obesity, further research is urgently needed to develop interventions to prevent sarcopenic obesity and its metabolic consequences.

Diabetes and Femoral Neck Strength: Findings from The Hip Strength Across the Menopausal Transition Study

CONTEXT Diabetes mellitus is associated with increased hip fracture risk, despite being associated with higher bone mineral density in the femoral neck. OBJECTIVE The objective of the study was to test the hypothesis that composite indices of femoral neck strength, which integrate dual-energy x-ray absorptiometry derived femoral neck size, femoral neck areal bone mineral density, and body size and are inversely associated with hip fracture risk, would be lower in diabetics than in nondiabetics and be inversely related to insulin resistance, the primary pathology in type 2 diabetes. DESIGN This was a cross-sectional analysis. SETTING AND PARTICIPANTS The study consisted of a multisite, multiethnic, community-dwelling sample of 1887 women in pre- or early perimenopause. OUTCOME MEASUREMENTS Composite indices for femoral neck strength in different failure modes (axial compression, bending, and impact) were measured. RESULTS Adjusted for age, race/ethnicity, menopausal stage, body mass index, smoking, physical activity, calcium and vitamin D supplementation, and study site, diabetic women had higher femoral neck areal bone mineral density [+0.25 sd, 95% confidence interval (CI) (+0.06, +0.44) sd] but lower composite strength indices [-0.20 sd, 95% CI (-0.38, -0.03) sd for compression, -0.19 sd, 95% CI (-0.38, -0.003) sd for bending, -0.19 sd, 95% CI (-0.37, -0.02) sd for impact] than nondiabetic women. There were graded inverse relationships between homeostasis model-assessed insulin resistance and all three strength indices, adjusted for the same covariates. CONCLUSIONS Despite having higher bone density, diabetic women have lower indices of femoral neck strength relative to load, consistent with their documented higher fracture risk. Insulin resistance appears to play an important role in bone strength reduction in diabetes.

Waist-Hip-Ratio as a Predictor of All-Cause Mortality in High-Functioning Older Adults

PURPOSE The relationship between obesity and mortality in older adults is debated, with concern that body mass index (BMI) may be an imperfect measure of obesity in this age group. We assessed the relationship between three measures of obesity and all-cause mortality in a group of healthy older adults. METHODS We analyzed data from the MacArthur Successful Aging Study, a longitudinal study of high-functioning men and women, ages 70-79 years at baseline. We examined 12-year, all-cause mortality risk by BMI, waist circumference, and waist-to-hip circumference ratio (WHR). Proportional hazards regression was used to adjust for gender, race, baseline age, and smoking status. We tested for obesity interactions with gender, race, and smoking status and conducted stratified analyses based on the results of interaction testing. RESULTS There was no association between all-cause mortality and BMI or waist circumference in either unadjusted or adjusted analyses. In contrast, all-cause mortality increased with WHR. There was an interaction with sex, so that there was a graded relationship between WHR and mortality in women (relative hazard, 1.28 per 0.1 increase in WHR; 95% confidence interval, 1.05-1.55) and a threshold relationship in men (relative hazard 1.75 for WHR>1.0 compared to WHR< or =1.0; 95% confidence interval, 1.06-2.91). CONCLUSION WHR rather than BMI appears to be the more appropriate yardstick for risk stratification of high-functioning older adults.

Insulin resistance and bone strength: findings from the study of midlife in the United States.

Although several studies have noted increased fracture risk in individuals with type 2 diabetes mellitus (T2DM), the pathophysiologic mechanisms underlying this association are not known. We hypothesize that insulin resistance (the key pathology in T2DM) negatively influences bone remodeling and leads to reduced bone strength. Data for this study came from 717 participants in the Biomarker Project of the Midlife in the United States Study (MIDUS II). The homeostasis model assessment of insulin resistance (HOMA‐IR) was calculated from fasting morning blood glucose and insulin levels. Projected 2D (areal) bone mineral density (BMD) was measured in the lumbar spine and left hip using dual‐energy X‐ray absorptiometry (DXA). Femoral neck axis length and width were measured from the hip DXA scans, and combined with BMD and body weight and height to create composite indices of femoral neck strength relative to load in three different failure modes: compression, bending, and impact. We used multiple linear regressions to examine the relationship between HOMA‐IR and bone strength, adjusted for age, gender, race/ethnicity, menopausal transition stage (in women), and study site. Greater HOMA‐IR was associated with lower values of all three composite indices of femoral neck strength relative to load, but was not associated with BMD in the femoral neck. Every doubling of HOMA‐IR was associated with a 0.34 to 0.40 SD decrement in the strength indices (p < 0.001). On their own, higher levels of fasting insulin (but not of glucose) were independently associated with lower bone strength. Our study confirms that greater insulin resistance is related to lower femoral neck strength relative to load. Further, we note that hyperinsulinemia, rather than hyperglycemia, underlies this relationship. Although cross‐sectional associations do not prove causality, our findings do suggest that insulin resistance and in particular, hyperinsulinemia, may negatively affect bone strength relative to load.

Abdominal Aortic Calcium, Coronary Artery Calcium, and Cardiovascular Morbidity and Mortality in the Multi-Ethnic Study of Atherosclerosis

Objective—To evaluate the predictive value of abdominal aortic calcium (AAC) for incident cardiovascular disease (CVD) independent of coronary artery calcium (CAC). Approach and Results—We evaluated the association of AAC with CVD in 1974 men and women aged 45 to 84 years randomly selected from the Multi-Ethnic Study of Atherosclerosis participants who had complete AAC and CAC data from computed tomographic scans. AAC and CAC were each divided into following 3 percentile categories: 0 to 50th, 51st to 75th, and 76th to 100th. During a mean of 5.5 years of follow-up, there were 50 hard coronary heart disease events, 83 hard CVD events, 30 fatal CVD events, and 105 total deaths. In multivariable-adjusted Cox models including both AAC and CAC, comparing the fourth quartile with the ⩽50th percentile, AAC and CAC were each significantly and independently predictive of hard coronary heart disease and hard CVD, with hazard ratios ranging from 2.4 to 4.4. For CVD mortality, the hazard ratio was highly significant for the fourth quartile of AAC, 5.9 (P=0.01), whereas the association for the fourth quartile of CAC (hazard ratio, 2.1) was not significant. For total mortality, the fourth quartile hazard ratio for AAC was 2.7 (P=0.001), and for CAC, it was 1.9, P=0.04. Area under the receiver operating characteristic curve analyses showed improvement for both AAC and CAC separately, although improvement was greater with CAC for hard coronary heart disease and hard CVD, and greater with AAC for CVD mortality and total mortality. Sensitivity analyses defining AAC and CAC as continuous variables mirrored these results. Conclusions—AAC and CAC predicted hard coronary heart disease and hard CVD events independent of one another. Only AAC was independently related to CVD mortality, and AAC showed a stronger association than CAC with total mortality.

Age at menopause and incident heart failure: the Multi-Ethnic Study of Atherosclerosis.

ObjectiveThis study aims to evaluate the associations of early menopause (menopause occurring before age 45 years) and age at menopause with incident heart failure (HF) in postmenopausal women. We also explored the associations of early menopause and age at menopause with left ventricular (LV) measures of structure and function in postmenopausal women. MethodsWe included 2,947 postmenopausal women, aged 45 to 84 years without known cardiovascular disease (2000-2002), from the Multi-Ethnic Study of Atherosclerosis. Cox proportional hazards models were used to examine the associations of early menopause and age at menopause with incident HF. In 2,123 postmenopausal women in whom cardiac magnetic resonance imaging was obtained at baseline, we explored the associations of early menopause and age at menopause with LV measures using multivariable linear regression. ResultsAcross a median follow-up of 8.5 years, we observed 71 HF events. There were no significant interactions with ethnicity for incident HF (Pinteraction > 0.05). In adjusted analysis, early menopause was associated with an increased risk of incident HF (hazard ratio, 1.66; 95% CI, 1.01-2.73), whereas every 1-year increase in age at menopause was associated with a decreased risk of incident HF (hazard ratio, 0.96; 95% CI, 0.94-0.99). We observed significant interactions between early menopause and ethnicity for LV mass-to-volume ratio (LVMVR; Pinteraction = 0.02). In Chinese-American women, early menopause was associated with a higher LVMVR (+0.11; P = 0.0002), whereas every 1-year increase in age at menopause was associated with a lower LVMVR (−0.004; P = 0.04) at baseline. ConclusionsOlder age at menopause is independently associated with a decreased risk of incident HF. Concentric LV remodeling, indicated by a higher LVMVR, is present in Chinese-American women who experienced early menopause at baseline.

Relation of Muscle Mass and Fat Mass to Cardiovascular Disease Mortality

We evaluated the relation between components of body composition and mortality in patients with cardiovascular disease (CVD). Dual x-ray absorptiometry body composition data from the National Health and Nutrition Examination Survey 1999 to 2004 was linked to total and CVD mortality data 1999 to 2006 in 6,451 patients with CVD. Kaplan-Meier survival analysis for the end points of total and CVD mortality was plotted by quartiles of muscle mass, fat mass, and categories of body mass index (BMI). Subjects were stratified into 4 groups (low muscle/low fat mass, low muscle/high fat mass, high muscle/low fat mass, and high muscle/high fat mass). Adjusted Cox proportional hazards regression determined hazard ratios for total and CVD mortality. Rates of cardiovascular/total mortality were lower in higher quartiles of muscle mass, fat mass, and higher categories of BMI (p <0.001). The high muscle/low fat mass group had a lower risk of CVD and total mortality (risk-adjusted hazard ratios of 0.32, 95% confidence interval 0.14 to 0.73 and 0.38, 95% confidence interval 0.22 to 0.68, for CVD and total mortality, respectively). Thus, increasing fat mass, muscle mass, and BMI were all correlated with improved survival. The specific subgroup of high muscle and low fat mass had the lowest mortality risk compared with other body composition subtypes. This suggests the importance of body composition assessment in the prediction of cardiovascular and total mortality in patients with CVD.

Characterization of Intra-myocellular Lipids using 2D Localized Correlated Spectroscopy and Abdominal Fat using MRI in Type 2 Diabetes

A major goal of this pilot study was to quantify intramyocellular lipids (IMCL), extramyocellular lipids (EMCL), unsaturation index (UI) and metabolites such as creatine (Cr), choline (Ch) and carnosine (Car), in the soleus muscle using two-dimensional (2D) localized correlated spectroscopy (L-COSY). Ten subjects with type 2 diabetes (T2D), controlled by lifestyle management alone, and 9 healthy control subjects, were studied. In T2D patients only, the following measurements were obtained: body mass index (BMI); waist circumference (WC); abdominal visceral and subcutaneous fat quantified using breath-held magnetic resonance imaging (MRI); a fasting blood draw for assessment of glucose, insulin, and estimation of homeostasis model assessment of insulin resistance (HOMA-IR), HbA1c, and high-sensitivity c-reactive protein (hs-CRP). Analysis of the soleus muscle 2D L-COSY spectral data showed significantly elevated IMCL ratios with respect to Cr and decreased IMCL UI in T2D when compared to healthy subjects (P < 0.05). In T2D subjects, Pearson correlation analysis showed a positive correlation of IMCL/Cr with EMCL/Cr (0.679, P < 0.05) and HOMA-IR (0.633, P < 0.05), and a non-significant correlation of visceral and subcutaneous fat with magnetic resonance spectroscopy (MRS) and other metrics. Characterization of muscle IMCL and EMCL ratios, UI, and abdominal fat, may be useful for the noninvasive assessment of the role of altered lipid metabolism in the pathophysiology of T2D, and for assessment of the effects of future therapeutic interventions designed to alter metabolic dysfunction in T2D.

La paradoja de la obesidad: es hora de adoptar una perspectiva nueva sobre un paradigma antiguo

Since the first description of the relationship between increased body mass index (BMI) and heart failure (HF) in 2001, BMI has been used in numerous studies as a definition of obesity and has emerged with a reputation of being a good prognosticator of outcomes in patients with HF. Approximately two-thirds of HF patients are overweight or obese (BMI 25 kg/m). In that first study, of 1203 patients with severe HF, Horwich et al. reported that overweight and obese (BMI>27.8 kg/m) HF patients had reduced risk-adjusted hazard ratio for mortality at 5 years. Curtis et al., in 7767 individuals with stable HF, noted that individuals with BMI<18.5 kg/m had the worst survival, while those with BMI>30 kg/m had the best survival. Gustafsson et al., in 4700 patients with both systolic and diastolic HF, noted that increasing BMI across the 4 study groups (underweight, BMI<18.5 kg/m; normal weight, BMI 18.5 to 24.9 kg/m; overweight, BMI 25 to 29.9 kg/m; and obese, BMI>30 kg/m) was associated with increased chance of survival. A meta-analysis of 9 observational studies including over 28 000 HF subjects demonstrated overweight BMI (25-29.9 kg/m) and obese BMI ( 30 kg/m) to be associated with 16% and 12% decreased risk (risk-adjusted) for mortality, respectively, compared to normal BMI (20-24.9 kg/m). Conversely, in a study of 1929 HF patients enrolled in a clinical trial, Anker et al. defined cachexia as individuals having more than 6% loss of total body weight from baseline, and by this definition found cachexia to be the strongest independent risk factor for mortality. By evaluating mortality in individuals with HF and a diagnosis of either obesity or malnutrition in the largest clinical study of its kind in Spain, Zapatero et al. assessed the mortality impact for individuals presumably at either extreme of body mass; however, they did not use BMI or weight as a part of this definition. Using the coding system established by the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM), 5th edition, Zapatero et al. were able to confirm the higher mortality associated with those defined as being malnourished, while a diagnosis of obesity reduces mortality and risk of hospital readmission. Such a move away from use of BMI is novel and