Abstract
Lifestyle interventions with weight loss can improve insulin sensitivity in type 2 diabetes (T2D), but mechanisms are unclear. We explored circulating and skeletal muscle metabolite signatures of altered peripheral (pIS) and hepatic insulin sensitivity (hIS) in overweight and obese T2D individuals that were randomly assigned a 12-week Paleolithic-type diet with (diet-ex, n = 13) or without (diet, n = 13) supervised exercise. Baseline and post-intervention measures included: mass spectrometry-based metabolomics and lipidomics of skeletal muscle and plasma; pIS and hIS; ectopic lipid deposits in the liver and skeletal muscle; and skeletal muscle fat oxidation rate. Both groups lowered BMI and total % fat mass and increased their pIS. Only the diet-group improved hIS and reduced ectopic lipids in the liver and muscle. The combined improvement in pIS and hIS in the diet-group were associated with decreases in muscle and circulating branched-chain amino acid (BCAA) metabolites, specifically valine. Improved pIS with diet-ex was instead linked to increased diacylglycerol (34:2) and triacylglycerol (56:0) and decreased phosphatidylcholine (34:3) in muscle coupled with improved muscle fat oxidation rate. This suggests a tissue crosstalk involving BCAA-metabolites after diet intervention with improved pIS and hIS, reflecting reduced lipid influx. Increased skeletal muscle lipid utilization with exercise may prevent specific lipid accumulation at sites that perturb insulin signaling.
Highlights
The global burden of type 2 diabetes (T2D) continues to rise in conjunction with obesity, sedentary lifestyle, and energy-dense diets [1]
There were no significant differences between treatment groups regarding anthropometry, insulin sensitivity, 1HMRS-measured ectopic fat, or DXA-derived body composition
We observed no significant difference between the groups after intervention in regard to hepatic insulin sensitivity (hIS) and peripheral insulin sensitivity (pIS), the HMRS-measured ectopic fat, or DXA-derived body composition
Summary
The global burden of type 2 diabetes (T2D) continues to rise in conjunction with obesity, sedentary lifestyle, and energy-dense diets [1]. In obesity, when the buffering capacity of adipose tissue to store excess fats is impaired, non-adipose tissues, such as muscle, liver, and pancreas, tend to accumulate lipids (ectopic lipids). This may induce a state of “cellular toxicity” and contribute to insulin resistance (IR) and β-cell dysfunction in T2D. Endurance-trained athletes have elevated muscle lipids despite being highly insulin sensitive [6] This phenomenon can be explained in part by differences in lipid utilization and sub-cellular compartmentalization of metabolic by-products in the muscle [5] and the buffering capacity and insulin sensitivity in other tissues, such as the liver [7]. The increased BCAA influx may compete with lipid oxidation and lead to the accumulation of incompletely oxidized lipids, i.e., toxic lipid intermediates [10]
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