Mitochondria play critical role in energy metabolism. However, the alteration of mitochondrial function in diabetes is still controversial. To address this issue, we measured the liver and muscle mitochondrial function in animal models characterizing different stages of type 1 and 2 diabetes. Streptozotocin-induced diabetic mice, db/db mice and high-fat diet-induced obese mice were used in this study. Both in early stage (3 weeks after STZ injection) and late stage (3 months after STZ injection) of type 1 diabetic mice, liver mitochondrial oxidative phosphorylation (OXPHOS) increased significantly, among which the complex IV-dependent oxygen consumption rate (OCR) was the most prominent, indicating that complex IV may play an important role in the pathophysiology of type 1 diabetes. The liver mitochondrial complex I and II-dependent OXPHOS increased greatly in prediabetes and early stage (12-week-old db/db mice) of type 2 diabetes. At the late stage (42-week-old db/db mice) of type 2 diabetes, the OXPHOS declined to almost normal, and alteration of complex I-dependent OCR was the most significant. In contrast, no change of mitochondrial OXPHOS was observed in the muscle of all disease models. Besides, no alteration of ATP, ADP and AMP contents in the tissues was observed. Our in vitro experiments showed that among specific chemical inhibitors to complex I, II, III or IV in mitochondrial respiratory chain, rotenone (complex I inhibitor) and myxothiazol (complex III inhibitor) enhanced glucose consumption and lactate release. But only rotenone decreased glucose output in primary hepatocytes in the absence of cytotoxicity.
In summary, the mitochondrial OXPHOS of liver rather than muscle increases in diabetes. And inhibition of complex I may ameliorate hyperglycemia by reducing hepatic glucose production and inducing glycolysis. Our results provide evidences for using complex I inhibitors (e.g., metformin and berberine) as oral antidiabetic agents.
M. Alimujiang: None. M. Yu: None. J. Yin: None.
National Natural Science Foundation of China (81670790, 31171128)