Plasma fatty acid-binding protein 4, nonesterified fatty acids, and incident diabetes in older adults

OBJECTIVE

To examine the relation of fatty acid–binding protein (FABP)4 and nonesterified fatty acids (NEFAs) to diabetes in older adults.

RESEARCH DESIGN AND METHODS

We ascertained incident diabetes among 3,740 Cardiovascular Health Study participants (1992–2007) based on the use of hypoglycemic medications, fasting glucose ≥126 mg/dL, or nonfasting glucose ≥200 mg/dL. FABP4 and NEFA were measured on specimens collected between 1992 and 1993.

RESULTS

Mean age of the 3,740 subjects studied was 74.8 years. For each SD increase in log FABP4, hazard ratios (HRs) for diabetes were 1.35 (95% CI 1.10–1.65) for women and 1.45 (1.13–1.85) for men controlling for age, race, education, physical activity, cystatin C, alcohol intake, smoking, self-reported health status, and estrogen use for women (P for sex-FABP4 interaction 0.10). BMI modified the FABP4-diabetes relation (P = 0.009 overall; 0.02 for women and 0.135 for men), in that statistically significant higher risk of diabetes was mainly seen in men with BMI <25 kg/m² (HR per SD: 1.78 [95% CI 1.13–2.81]). There was a modest and nonsignificant association of NEFA with diabetes (P_trend = 0.21). However, when restricted to the first 5 years of follow-up, multivariable-adjusted HRs for diabetes were 1.0 (ref.), 1.68 (95% CI 1.12–2.53), and 1.63 (1.07–2.50) across consecutive tertiles of NEFA (P_trend = 0.03).

CONCLUSIONS

Plasma FABP4 was positively associated with incident diabetes in older adults, and such association was statistically significant in lean men only. A significant positive association between plasma NEFA and incident diabetes was observed during the first 5 years of follow-up.Type 2 diabetes is associated with high costs and societal burden, with current estimated total cost in the U.S. of $174 billion (1,2). The growing epidemic of obesity threatens to expand this burden substantially, highlighting the crucial importance of better understanding the link between adiposity and type 2 diabetes. Indeed, we have previously demonstrated that various measures of adiposity including BMI and waist circumference are individually associated with an increased risk of diabetes in older U.S. adults (3). Adipose tissues produce multiple adipokines with diverse functions including modulation of inflammation, thrombogenicity, insulin resistance, and other metabolic effects (4,5). As one of these adipokines, fatty acid–binding protein (FABP)4 (or adipocyte FABP or adipocyte protein 2 [aP2]) serves as a carrier protein for fatty acids and other lipophilic substances between extra- and intracellular membranes (6,7). FABP4 is expressed by adipocytes, where it makes up ~8% of the total protein of mature adipocytes, and by macrophages (8,9). FABP4-deficient mice remain insulin sensitive even when challenged by high-fat diets that induce obesity (10). Conversely, in animal models, expression of FABP4 in adipocytes has been associated with overall insulin resistance (11–13).While FABP4 has been associated with a higher risk of stroke (14), mortality (14), and metabolic syndrome (8,15), only a single human study among 544 middle-aged Chinese adults has reported a prospective association between plasma FABP4 and incident type 2 diabetes (16). Earlier studies have reported that FABP4 may inhibit stearoyl-CoA enzyme in the de novo lipogenesis as well as enhance the activity of hepatic sensitive lipase (17): two pathways that influence plasma concentrations of nonesterified fatty acids (NEFAs). It is unclear whether FABP4 influences the relationship of NEFA with diabetes.While some studies have reported a positive association between NEFA and type 2 diabetes in middle-aged and younger adults (18,19), other investigators have shown an inverse association between NEFA and type 2 diabetes (20). Elevated NEFA may increase peripheral insulin resistance (21,22) and impair insulin secretion via their toxic effects on pancreatic β-cells (23,24) or increased endogenous glucose production (25). However, no previous study has evaluated whether plasma NEFA and FABP4 individually or jointly influence the risk of type 2 diabetes in older individuals. The current project sought to prospectively examine the relation of plasma FABP4 and NEFA with incident type 2 diabetes in a geographic and racially diverse cohort of older adults in the U.S.     

Alcohol consumption, interleukin-6 and apolipoprotein E genotypes, and concentrations of interleukin-6 and serum amyloid P in older adults

BACKGROUND: Whether alcohol intake is associated with concentrations of interleukin-6 (IL-6) and serum amyloid P (SAP) is uncertain. OBJECTIVE: We determined how alcohol intake and apolipoprotein E (apo E) and IL-6 promoter (IL-6 -174G-->C) polymorphisms interact for concentrations of IL-6 and SAP. DESIGN: In the Cardiovascular Health Study, 2454 older adults reported their intake of beer, wine, and liquor and underwent measurements of circulating IL-6 and SAP. RESULTS: Alcohol intake was not associated with IL-6 concentrations among apo E4-negative or IL-6C-positive participants but was positively associated among both apo E4-positive and IL-6C-negative participants (P for trend = 0.02 for both). The corresponding interactions on SAP were not significant for alcohol overall but were similar for liquor intake. CONCLUSIONS: Among older adults free of clinical cardiovascular disease, specific IL-6 promoter and apo E alleles appeared to confer positive associations of alcohol consumption with IL-6 concentrations. Genetic heterogeneity should be considered in understanding the cardiovascular effects of alcohol intake.     

Prospective study of alcohol consumption and risk of dementia in older adults

Context  Alcohol consumption has been associated with complex changes in cerebral vasculature and structure in older adults. How alcohol consumption affects the incidence of dementia is less clear. Objective  To determine the prospective relationship of alcohol consumption and risk of dementia among older adults. Design, Setting, and Participants  Nested case-control study of 373 cases with incident dementia and 373 controls who were among 5888 adults aged 65 years and older who participated in the Cardiovascular Health Study, a prospective, population-based cohort study in 4 US communities. The controls were frequency-matched on age, death before 1999, and their attendance of a 1998-1999 clinic. Participants in this study underwent magnetic resonance imaging (MRI) of the brain and cognitive testing between 1992 and 1994 and were followed up until 1999. Main Outcome Measures  Odds of incident dementia, ascertained by detailed neurological and neuropsychological examinations according to average alcohol consumption, assessed by self-reported intake of beer, wine, and liquor at 2 visits prior to the date of the MRI. Results  Compared with abstention, the adjusted odds for dementia among those whose weekly alcohol consumption was less than 1 drink were 0.65 (95% confidence interval [CI], 0.41-1.02); 1 to 6 drinks, 0.46 (95% CI, 0.27-0.77); 7 to 13 drinks, 0.69 (95% CI, 0.37-1.31); and 14 or more drinks, 1.22 (95% CI, 0.60-2.49; P for quadratic term = .001). A trend toward greater odds of dementia associated with heavier alcohol consumption was most apparent among men and participants with an apolipoprotein E 4 allele. We found generally similar relationships of alcohol use with Alzheimer disease and vascular dementia. Conclusions  Compared with abstention, consumption of 1 to 6 drinks weekly is associated with a lower risk of incident dementia among older adults.      

Circulating Levels of Carboxy‐Methyl‐Lysine (CML) Are Associated With Hip Fracture Risk: The Cardiovascular Health Study

Advanced glycation end products (AGE) in bone tissue are associated with impaired biomechanical properties and increased fracture risk. Here we examine whether serum levels of the AGE carboxy‐methyl‐lysine (CML) are associated with risk of hip fracture. We followed 3373 participants from the Cardiovascular Health Study (age 78 years; range, 68–102 years; 39.8% male) for a median of 9.22 years (range, 0.01–12.07 years). Rates of incident hip fracture were calculated by quartiles of baseline CML levels, and hazard ratios were adjusted for covariates associated with hip fracture risk. A subcohort of 1315 participants had bone mineral density (BMD) measurement. There were 348 hip fractures during follow‐up, with incidence rates of hip fracture by CML quartiles of 0.94, 1.34, 1.18, and 1.69 per 100 participant‐years. The unadjusted hazard ratio of hip fracture increased with each 1 SD increase (189 ng/mL) of CML level (hazard ratio, 1.27; 95% confidence interval [CI], 1.16–1.40]; p < 0.001). Sequential adjustment for age, gender, race/ethnicity, body mass index (BMI), smoking, alcohol consumption, prevalent coronary heart disease (CHD), energy expenditure, and estimated glomerular filtration rate (based on cystatin C), moderately attenuated the hazard ratio for fracture (1.17; 95% CI, 1.05–1.31; p = 0.006). In the cohort with BMD testing, total hip BMD was not significantly associated with CML levels. We conclude that increasing levels of CML are associated with hip fracture risk in older adults, independent of hip BMD. These results implicate AGE in the pathogenesis of hip fractures. © 2014 American Society for Bone and Mineral Research.