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.