Abstract
Patients with type 2 diabetes (T2D) are known to have mitochondrial dysfunction and increased insulin resistance (IR), but the underlying mechanisms are not well understood. We reported previously that (a) adequacy of the antioxidant glutathione (GSH) is necessary for optimal mitochondrial fatty-acid oxidation (MFO); (b) supplementing the GSH precursors glycine and N-acetylcysteine (GlyNAC) in mice corrected GSH deficiency, reversed impaired MFO, and lowered oxidative stress (OxS) and IR; and (c) supplementing GlyNAC in patients with T2D improved GSH synthesis and concentrations, and lowered OxS. However, the effect of GlyNAC on MFO, MGO (mitochondrial glucose oxidation), IR and plasma FFA (free-fatty acid) concentrations in humans with T2D remains unknown. This manuscript reports the effect of supplementing GlyNAC for 14-days on MFO, MGO, IR and FFA in 10 adults with T2D and 10 unsupplemented non-diabetic controls. Fasted T2D participants had 36% lower MFO (p < 0.001), 106% higher MGO (p < 0.01), 425% higher IR (p < 0.001) and 76% higher plasma FFA (p < 0.05). GlyNAC supplementation significantly improved fasted MFO by 30% (p < 0.001), lowered MGO by 47% (p < 0.01), decreased IR by 22% (p < 0.01) and lowered FFA by 25% (p < 0.01). These results provide proof-of-concept that GlyNAC supplementation could improve mitochondrial dysfunction and IR in patients with T2D, and warrant additional research.
Highlights
Type 2 diabetes (T2D) is associated with mitochondrial dysfunction [1,2] which involves the impaired oxidation of fatty-acids (FA) [3,4,5,6,7,8,9,10,11,12,13]
glycine and Nacetylcysteine (GlyNAC) supplementation was associated with a 30% increase in mitochondrial fatty-acid oxidation (MFO) (p = 0.0009), and a 47% decrease in mitochondrial glucose oxidation (MGO) (p = 0.001)
Because GlyNAC supplementation improves fuel metabolism, it will be important to study its effects on body composition including liver fat content in future studies. These results suggest that GlyNAC supplementation could improve mitochondrial health in patients with T2D, and support the need for future clinical trials to investigate the impact of GlyNAC supplementation on improving the health of diabetic patients
Summary
Type 2 diabetes (T2D) is associated with mitochondrial dysfunction [1,2] which involves the impaired oxidation of fatty-acids (FA) [3,4,5,6,7,8,9,10,11,12,13]. We reported that supplementing these patients with T2D with glycine and cysteine (provided as N-acetylcysteine, NAC) for a short duration of 2 weeks corrected the impaired GSH synthesis, improved intracellular GSH concentrations, and lowered OxS, without a decrease in fasting blood glucose concentrations [39]. This combination of glycine and NAC is abbreviated as GlyNAC. MFO and lowered IR [40] The results of these rodent studies suggest that GSH adequacy is critically important for optimal and efficient mitochondrial function, and that GlyNAC supplementation could be important for improving mitochondrial dysfunction and lowering IR. This manuscript reports unpublished data on mitochondrial fuel oxidation, insulin resistance and free-fatty acid (FFA) concentrations from a previous study investigating the effect of supplementing GlyNAC in patients with T2D [39]
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