Plasma Acylcarnitine Profiles Suggest Incomplete Long-Chain Fatty Acid β-Oxidation and Altered Tricarboxylic Acid Cycle Activity in Type 2 Diabetic African-American Women

Abstract

Inefficient muscle long-chain fatty acid (LCFA) combustion is associated with insulin resistance, but molecular links between mitochondrial fat catabolism and insulin action remain controversial. We hypothesized that plasma acylcarnitine profiling would identify distinct metabolite patterns reflective of muscle fat catabolism when comparing individuals bearing a missense G304A uncoupling protein 3 (UCP3 g/a) polymorphism to controls, because UCP3 is predominantly expressed in skeletal muscle and g/a individuals have reduced whole-body fat oxidation. MS analyses of 42 carnitine moieties in plasma samples from fasting type 2 diabetics (n = 44) and nondiabetics (n = 12) with or without the UCP3 g/a polymorphism (n = 28/genotype: 22 diabetic, 6 nondiabetic/genotype) were conducted. Contrary to our hypothesis, genotype had a negligible impact on plasma metabolite patterns. However, a comparison of nondiabetics vs. type 2 diabetics revealed a striking increase in the concentrations of fatty acylcarnitines reflective of incomplete LCFA beta-oxidation in the latter (i.e. summed C10- to C14-carnitine concentrations were approximately 300% of controls; P = 0.004). Across all volunteers (n = 56), acetylcarnitine rose and propionylcarnitine decreased with increasing hemoglobin A1c (r = 0.544, P < 0.0001; and r = -0.308, P < 0.05, respectively) and with increasing total plasma acylcarnitine concentration. In proof-of-concept studies, we made the novel observation that C12-C14 acylcarnitines significantly stimulated nuclear factor kappa-B activity (up to 200% of controls) in RAW264.7 cells. These results are consistent with the working hypothesis that inefficient tissue LCFA beta-oxidation, due in part to a relatively low tricarboxylic acid cycle capacity, increases tissue accumulation of acetyl-CoA and generates chain-shortened acylcarnitine molecules that activate proinflammatory pathways implicated in insulin resistance.

Metabolic signatures and risk of type 2 diabetes in a Chinese population: an untargeted metabolomics study using both LC-MS and GC-MS

“…Carnitine also facilitates the removal of short-and mediumchain fatty acids that accumulate during normal metabolic processes from the mitochondria. Previous studies have demonstrated significantly increased free carnitine and acylcarnitine levels in patients with type 2 diabetes compared with healthy controls, which may be linked to insulin resistance [3,8,41,42]. In this study, we observed that free carnitine was accumulated in cases; however, a medium-chain acylcarnitine (C10) was associated with a lower risk of type 2 diabetes.…”

Coordinated balancing of muscle oxidative metabolism through PGC-1α increases metabolic flexibility and preserves insulin sensitivity

“…The exact connection between acylcarnitines and insulin sensitivity is a future issue that needs to be addressed. A possible mechanism might involve the induction of NFκB through acycarnitines as previously demonstrated in vitro [23]. Finally, while an effect of PGC-1α on ROS detoxification and mitochondrial uncoupling has been shown in previous studies in vitro [24; 25], we now for the first time demonstrate unchanged levels of ROS in muscle of PGC-1α transgenic mice compared to wild-type controls.…”

Early Prediction of Developing Type 2 Diabetes by Plasma Acylcarnitines: A Population-Based Study

“…Recent studies in obese and diabetic animal models showed that acylcarnitines might reflect mild FAO dysregulation and "mitochondrial stress" (4). Moreover, different profiles of acylcarnitines were detected comparing cases of obesity, insulin resistance, metabolic syndrome, or diabetes with relevant controls (7)(8)(9)(10). However, it remains to be evaluated whether acylcarnitines are able to identify high-risk individuals for future development of type 2 diabetes.…”