CONTEXT AND OBJECTIVE: Soluble CD36 (sCD36) may be an early marker of insulin resistance and atherosclerosis. The objective of this prospective study was to evaluate sCD36 as a predictor of type 2 diabetes and to study its relationship with components of the metabolic syndrome (MetSy). DESIGN, SETTING, PARTICIPANTS, AND OUTCOME MEASURES: We conducted a case-referent study nested within a population-based health survey. Baseline variables included sCD36, body mass index, blood pressure, blood lipids, adipokines, inflammatory markers, and beta-cell function. A total of 173 initially nondiabetic cohort members who developed type 2 diabetes during 10 yr of follow-up were matched (1:2) with referents. Exploratory factor analysis was applied to hypothesize affiliation of sCD36 to the MetSy components. RESULTS: Doubling of baseline sCD36 increases the odds ratio for diabetes development by 1.24 in the general study population and by 1.45 in the female population (P < 0.025). Comparing upper sCD36 quartiles with lower, odds ratio for diabetes was 4.6 in women (P = 0.001), 3.15 in men (P = 0.011), and 2.6 in obese individuals (P < 0.025). Multivariate analysis shows that sCD36 does not predict diabetes independent of fasting plasma glucose and insulin. Factor analysis of 15 variables generates a six-factor model explaining 66-69% of total variance, where sCD36, body mass index, insulin, proinsulin, and leptin were assigned to the obesity/insulin resistance cluster. CONCLUSIONS: Upper quartile sCD36 is associated with elevated diabetes risk independent of age, gender, and obesity. Baseline sCD36 does not, however, predict diabetes independent of fasting glucose and insulin. sCD36 clusters with important markers of insulin resistance and MetSy that are key predictors of type 2 diabetes.

AIMS/HYPOTHESIS: Intramyocellular lipids (IMCL) accumulation is a classical feature of metabolic diseases. We hypothesised that IMCL accumulate mainly as a consequence of increased adiposity and independently of type 2 diabetes. To test this, we examined IMCL accumulation in two different models and four different populations of participants: muscle biopsies and primary human muscle cells derived from non-obese and obese participants with or without type 2 diabetes. The mechanism regulating IMCL accumulation was also studied. METHODS: Muscle biopsies were obtained from ten non-obese and seven obese participants without type 2 diabetes, and from eight non-obese and eight obese type 2 diabetic patients. Mitochondrial respiration, citrate synthase activity and both AMP-activated protein kinase and acetyl-CoA carboxylase phosphorylation were measured in muscle tissue. Lipid accumulation in muscle and primary myotubes was estimated by Oil Red O staining and fatty acid translocase (FAT)/CD36 localisation by immunofluorescence. RESULTS: Obesity and type 2 diabetes are independently characterised by skeletal muscle IMCL accumulation and permanent FAT/CD36 relocation. Mitochondrial function is not reduced in type 2 diabetes. IMCL accumulation was independent of type 2 diabetes in cultured myotubes and was correlated with obesity markers of the donor. In obese participants, membrane relocation of FAT/CD36 is a determinant of IMCL accumulation. CONCLUSIONS/INTERPRETATION: In skeletal muscle, mitochondrial function is normal in type 2 diabetes, while IMCL accumulation is dependent upon obesity or type 2 diabetes and is related to sarcolemmal FAT/CD36 relocation. In cultured myotubes, IMCL content and FAT/CD36 relocation are independent of type 2 diabetes, suggesting that distinct factors in obesity and type 2 diabetes contribute to permanent FAT/CD36 relocation ex vivo.

Platelet hyper-reactivity and a systemic prothrombotic state are associated with atherosclerosis and other inflammatory conditions. CD36, a member of the Type 2 scavenger receptor family, is a multiligand pattern recognition receptor that recognizes specific oxidized phospholipids, molecules expressed on microbial pathogens, apoptotic cells, and cell-derived microparticles. Recent studies have demonstrated that CD36 binding to oxidized LDL or microparticles activates a specific signaling pathway that induces platelet activation. This pathway is activated in vivo in the setting of hyperlipidemia and oxidant stress. Genetic deletion of CD36 protects mice from pathological thrombosis associated with hyperlipidemia without any apparent effect on normal hemostasis. Targeting CD36 or its signaling pathway could potentially lead to the development of novel antithrombotic therapies for patients with atheroinflammatory disorders.

Silverstein RL. Clin Lipidol. 2009 Dec;4(6):767.