Type 2 diabetes alters metabolic and transcriptional signatures of glucose and amino acid metabolism during exercise and recovery

Abstract

Aims/hypothesis The therapeutic benefit of physical activity to prevent and treat type 2 diabetes is commonly accepted. However, the impact of the disease on the acute metabolic response is less clear. To this end, we investigated the effect of type 2 diabetes on exercise-induced plasma metabolite changes and the muscular transcriptional response using a complementary metabolomics/transcriptomics approach. Methods We analysed 139 plasma metabolites and hormones at nine time points, and whole genome expression in skeletal muscle at three time points, during a 60 min bicycle ergometer exercise and a 180 min recovery phase in type 2 diabetic patients and healthy controls matched for age, percentage body fat and maximal oxygen consumption (VResults Pathway analysis of differentially regulated genes upon exercise revealed upregulation of regulators of GLUT4 (SLC2A4RG, FLOT1, EXOC7, RAB13, RABGAP1 and CBLB), glycolysis (HK2, PFKFB1, PFKFB3, PFKM, FBP2 and LDHA) and insulin signal mediators in diabetic participants compared with controls. Notably, diabetic participants had normalised rates of lactate and insulin levels, and of glucose appearance and disappearance, after exercise. They also showed an exercise-induced compensatory regulation of genes involved in biosynthesis and metabolism of amino acids (PSPH, GATM, NOS1 and GLDC), which responded to differences in the amino acid profile (consistently lower plasma levels of glycine, cysteine and arginine). Markers of fat oxidation (acylcarnitines) and lipolysis (glycerol) did not indicate

Intact Regulation of the AMPK Signaling Network in Response to Exercise and Insulin in Skeletal Muscle of Male Patients With Type 2 Diabetes: Illumination of AMPK Activation in Recovery From Exercise

“…These observations question previous hypotheses indicating exercise intolerance at the level of AMPK and downstream target PGC-1a in patients with T2D (8,36). Normal metabolic signaling during exercise is also implied by other observations in patients with T2D; for example, normal glucose uptake across the working limb (28,30), similar changes in metabolic flexibility and transcriptional profile (29,37), and similar changes in skeletal muscle protein adaptations to exercise (20). In the study by Sriwijitkamol relative to ACC and TBC1D1 protein levels in skeletal muscle biopsy specimens obtained from overweight/obese subjects with (■) or without (□) T2D on the baseline day and the exercise day (see Fig.…”

“…This further questions the concept of impaired exercise-mediated AMPK signaling in male patients with T2D. In support of this, the metabolic and transcriptional profile in response to exercise revealed no impairments in subjects with T2D compared with healthy control subjects (29).…”

“…Previous studies have shown that the increment in muscle glucose uptake and whole-body glucose disposal during exercise is normal in patients with T2D (28)(29)(30). Hence, we hypothesized that exercise-mediated regulation of TBC1D1 phosphorylation is also intact in patients with T2D.…”

A Glycine-Insulin Autocrine Feedback Loop Enhances Insulin Secretion From Human β-Cells and Is Impaired in Type 2 Diabetes

“…Proper neurotransmitter signaling is critical for coordinating insulin secretion from all the islets in the pancreas, and dysfunction in this signaling may be involved with the pathogenesis of diabetes. A multitude of recent metabolic studies investigating biomarkers for type 2 diabetes (T2D) have identified glycine as a potential candidate (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). A strong correlation exists between plasma glycine concentrations and insulin sensitivity (7,13), glucose disposal (8), and obesity (9,17).…”

Genome-scale transcriptional analysis reveals key genes associated with the development of type II diabetes in mice

“…In the present study, activation of the compensatory mechanisms to increase serine, glycine and the levels of creatine may be induced by the differential expression of phosphoserine phosphatase, GATM and GLDC in the skeletal muscle of individuals with diabetes (40). Additionally, a recent study demonstrated that reduced GATM expression may diminish the capacity for phosphocreatine storage, and modify cellular energy storage and adenosine monophosphate-activated protein kinase (AMPK) signaling pathway conduction (41).…”