Abstract
Skeletal muscles play an essential role in whole-body glucose homeostasis. They are a key organ system engaged in the development of insulin resistance, and also a crucial tissue mediating the beneficial metabolic effects of physical activity. However, molecular mechanisms underlying both these processes in skeletal muscle remain unclear. The aim of our study was to compare metabolomic profiles in skeletal muscle of patients at different stages of dysglycemia, from normoglycemia through prediabetes to T2D, and its changes under a mixed-mode (strength and endurance) exercise intervention. We performed targeted metabolomics comprising several major metabolite classes, including amino acids, biogenic amines and lipid subgroups in skeletal muscles of male patients. Dysglycemic groups differed significantly at baseline in lysophosphatidylcholines, phosphatidylcholines, sphingomyelins, glutamine, ornithine, and carnosine. Following the exercise intervention, we detected significant changes in lipids and metabolites related to lipid metabolism, including in ceramides and acylcarnitines. With their larger and more significant change over the intervention and among dysglycemic groups, these findings suggest that lipid species may play a predominant role in both the pathogenesis of type 2 diabetes and its protection by exercise. Simultaneously, we demonstrated that amino acid metabolism, especially glutamate dysregulation, is correlated to the development of insulin resistance and parallels disturbances in lipid metabolites.
Highlights
Type 2 diabetes (T2D) is one of the most common metabolic disorder
We found significant differences in most of the studied metabolic and anthropometric parameters, including Haemoglobin A1c (HbA1c), both fasting and 2-hour glucose, HOMA-b, HOMA-IR, total and visceral fat mass, as well as exercise capacity (VO2max)
For parameters of insulin sensitivity (HOMA-IR and Matsuda index), the most advanced insulin resistance appeared not in T2D but in prediabetic patients. This is likely because all diabetic patients were metformin-only treated with well controlled diabetes (
Summary
Type 2 diabetes (T2D) is one of the most common metabolic disorder. With the prognostics that by 2045 globally there will be 400 million people with diabetes, with vast majority being type 2, makes the disease one of the most emerging challenges of the healthcare systems worldwide [1]. It was shown that T2D development is associated with decreased muscle mass, altered fiber composition, mitochondrial dysfunction and ectopic accumulation of lipids in the tissue, combined with altered concentration of different lipid species, including diacylglycerol (DAG), ceramides or sphingolipids [4,5,6,7,8,9]. It is still debated whether these changes in skeletal muscles precede the development of T2D and contribute to the etiology of the disease, or whether it is a consequence of the disease [10]
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