Low level activity thresholds for changes in NMR biomarkers and genes in high risk subjects for Type 2 Diabetes

Abstract

Our objectives were to determine if there are quantitative associations between amounts and intensities of physical activities (PA) on NMR biomarkers and changes in skeletal muscle gene expressions in subjects with high risk for type 2 diabetes (T2D) performing a 3-month PA intervention. We found that PA was associated with beneficial biomarker changes in a factor containing several VLDL and HDL subclasses and lipids in principal component analysis (P = <0.01). Division of PA into quartiles demonstrated significant changes in NMR biomarkers in the 2nd - 4th quartiles compared to the 1st quartile representing PA of less than 2850 daily steps (P = 0.0036). Mediation analysis of PA-related reductions in lipoproteins showed that the effects of PA was 4-15 times greater than those of body weight or fat mass reductions. In a subset study in highly active subjects' gene expressions of oxidative fiber markers, Apo D, and G0/G1 Switch Gene 2, controlling insulin signaling and glucose metabolism were significantly increased. Slow walking at speeds of 2-3 km/h exceeding 2895 steps/day attenuated several circulating lipoprotein lipids. The effects were mediated rather by PA than body weight or fat loss. Thus, lower thresholds for PA may exist for long term prevention of cardio-metabolic diseases in sedentary overweight subjects.

Figure 1

Flow chart of the study participants. OGTT – oral glucose tolerance test; IGM – impaired glucose tolerance.

Figure 2

Percentage changes in lipoprotein lipids, triglycerides, fatty acids and glycoprotein in the physical activity quartiles (number of daily steps) and SDs (vertical bars). Horizontal lines with asterisks above the quartiles 2nd–4th indicate significant reductions (p < 0.0036) between the 1st and other quartiles. Data were log transformed and adjusted to baseline, sex and age. Numbers of observations were 17 in each quartile. For abbreviations P present particles, L VLDL – large VLDL, XL – Extra Large; XXL - Extremely Large, TG- triglycerides, D - diameter, Faw79S - ω7 and ω 9 fatty acids (FA), MU - monounsaturated, GP - glycoprotein acetyl, Tot - total, C - cholesterol and PG - phosphoglycerides.

Figure 3

(A) Hierarchical clustering analysis of differentially regulated probes between highly active subjects (HIGH IMPACT (IMP)) and low active subjects (LOW IMP). 318 probes that were differentially regulated (p-value < 0.001) were clustered using Ward’s minimum variance method of clustering implemented in hclust library in R. (B) Individual qPCR measurements alongside with microarrays values for selected genes of particular interest. Mean Fold change ± SEM are represented for each group. Asterisks mean p value < 0.05.

Figure 4

Summary of the results of physical activity intervention on circulating biomarkers and skeletal muscle gene expressions. The intervention included increased physical activity and weight loss leading to reduction of several circulating VLDL and LDL subclasses and fatty acids via decreased hepatic delivery and increased oxidation. Fatty acids were also released from adipose tissues reducing visceral fat mass⁸ and utilized by skeletal muscle for energy production leading up-regulation of fast muscle fiber genes and down-regulation of slow muscle fiber genes. Expression of PPK3 was up-regulated and expressions of TFG3 and RRAD were down-regulated improving insulin sensitivity by decreasing plasma insulin and HOMA. Up-regulation of the APO D expression might be related to decreased circulating lipoprotein lipids and fatty acids and up-regulation of the PPP1R3 and G0S2 to improved formation of muscle cell glycogen from glucose. Downward arrows indicate decrease and upward arrows stimulation; Ø no change.