Fasting Plasma Free Fatty Acids and Risk of Type 2 Diabetes

Abstract

OBJECTIVE -To evaluate whether plasma levels of free fatty acids (FFAs) are independently associated with incidence of type 2 diabetes. RESEARCH DESIGN AND METHODS-A case-cohort design was used to randomly select 580 incident cases of diabetes and 566 noncases from 10,275 African-American and white men and women in the Atherosclerosis Risk in Communities study, aged 45-64 years and without prevalent diabetes at the baseline exam. Incident diabetes was ascertained at three exams over 9 years of follow-up. FFA levels were measured in plasma samples collected at the baseline exam.RESULTS -At baseline, FFA level was inversely associated with height and positively associated with female sex, BMI, waist circumference, waist-to-hip ratio, heart rate, plasma triglycerides, and an inflammation score quantifying levels of six systemic inflammation markers. Relative risks for incident diabetes (fourth vs. first quartile of FFAs) were increased in a basic model adjusted for age, sex, race, and center (hazard ratio 1.68, 95% CI 1.20 -2.34) and in a model further adjusted for baseline fasting glucose, insulin, BMI, waist circumference, triglycerides, and the inflammation score (1.63, 1.04 -2.57). Relative risks associated with a greater FFA level were lowest among those of normal weight and highest among the obese, but a formal test of interaction between FFAs and BMI was not statistically significant.CONCLUSIONS -Individuals with higher fasting levels of plasma FFAs were at modestly higher risk of type 2 diabetes in this cohort of middle-aged adults. Diabetes Care 27:77-82, 2004S everal decades of basic science and animal research provide considerable support for a causal role of free fatty acids (FFAs) in the etiology of type 2 diabetes, possibly through detrimental effects on insulin and glucose metabolism (1). Higher FFAs may cause peripheral insulin resistance by interfering with the access of insulin to skeletal muscle or interfering with insulin signaling resulting in reduced glucose transport into muscle (2,3). Chronically elevated FFAs may also impair insulin secretory function through toxic effects on pancreatic ␤-cells as predicted by the "lipotoxicity hypothesis" (4). Finally, increased flux of FFAs into the liver, particularly from lipolysis of visceral adipose depots, may lead to excessive endogenous glucose production (5).FFAs may mediate the effects of established and novel factors on risk of diabetes. For example, elevated FFAs in obesity (6,7), possibly associated with increased FFA flux from adipose to nonadipose tissues, may provide a mechanistic link between increased fat mass and the development of insulin resistance, glucose intolerance, and ␤-cell dysfunction that promote the onset of diabetes. Individuals with autonomic nervous system dysfunction may be at increased risk of diabetes because of higher circulating catecholamine levels, which in turn have major effects on rates of lipolysis in adipose tissue and FFA release (8). Finally, elevations in FFAs may accompany chronic, low-grade systemic inflam...

The in vivo effects of the Pro12Ala PPARγ2 polymorphism on adipose tissue NEFA metabolism: the first use of the Oxford Biobank

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Metabolomics in diabetes research

“…Many studies have demonstrated that obese subjects often exhibit elevated fatty acid levels due to the enlarged volume of adipose tissue (Opie & Walfish 1963, Jensen et al 1989). Furthermore, higher levels of fatty acids are related to a greater risk for diabetes (Paolisso et al 1995, Charles et al 1997, Pankow et al 2004, although the underlying mechanisms are not completely understood. However, elevated levels of free fatty acids induce insulin resistance in muscle and liver tissue by decreasing insulinstimulated glucose uptake and glycogenesis (Griffin et al 1999, Boden 2003, Wilding 2007.…”

Obesity and metabolic disease: is adipose tissue the culprit?

“…To these effects could be added a long-term effect of elevated NEFA concentrations to impair glucosestimulated insulin secretion (Zhou & Grill, 1995;Carpentier et al 1999). These effects together may well explain why elevated NEFA concentrations are a predictor of future development of type 2 diabetes (Paolisso et al 1995;Charles et al 1997;Pankow et al 2004). The adverse effects of elevated NEFA concentrations also extend into other areas.…”