Determinants of increased muscle insulin sensitivity of exercise-trained versus sedentary normal weight and overweight individuals
Dominik Pesta, Evrim Anadol, Theresia Sarabhai, Yvo Op den Kamp, Sofiya Gancheva, Nina Trinks, Oana‐Patricia Zaharia, Lucia Mastrototaro, Kun Lyu, Ivo Habets, Yvonne M. H. Bruls, Bedair Dewidar, Jürgen Weiß, Vera B. Schrauwen‐Hinderling, Dongyan Zhang, Rafael Calais Gaspar, Klaus Straßburger, Yuliya Kupriyanova, Hadi Al‐Hasani, Julia Szendroedi, Patrick Schrauwen, Esther Phielix, Gerald I. Shulman, Michael Roden
Abstract
The athlete’s paradox states that intramyocellular triglyceride accumulation associates with insulin resistance in sedentary but not in endurance-trained humans. Underlying mechanisms and the role of muscle lipid distribution and composition on glucose metabolism remain unclear. We compared highly trained athletes (ATHL) with sedentary normal weight (LEAN) and overweight-to-obese (OVWE) male and female individuals. This observational study found that ATHL show higher insulin sensitivity, muscle mitochondrial content, and capacity, but lower activation of novel protein kinase C (nPKC) isoforms, despite higher diacylglycerol concentrations. Notably, sedentary but insulin sensitive OVWE feature lower plasma membrane-to-mitochondria sn -1,2-diacylglycerol ratios. In ATHL, calpain-2, which cleaves nPKC, negatively associates with PKCε activation and positively with insulin sensitivity along with higher GLUT4 and hexokinase II content. These findings contribute to explaining the athletes’ paradox by demonstrating lower nPKC activation, increased calpain, and mitochondrial partitioning of bioactive diacylglycerols, the latter further identifying an obesity subtype with increased insulin sensitivity (NCT03314714).