Comparison of intramyocellular lipid metabolism in patients with diabetes and male athletes

Abstract

Despite opposing insulin sensitivity and cardiometabolic risk, both athletes and patients with type 2 diabetes have increased skeletal myocyte fat storage: the so-called "athlete's paradox". In a parallel non-randomised, non-blinded trial (NCT03065140), we characterised and compared the skeletal myocyte lipid signature of 29 male endurance athletes and 30 patients with diabetes after undergoing deconditioning or endurance training respectively. The primary outcomes were to assess intramyocellular lipid storage of the vastus lateralis in both cohorts and the secondary outcomes were to examine saturated and unsaturated intramyocellular lipid pool turnover. We show that athletes have higher intramyocellular fat saturation with very high palmitate kinetics, which is attenuated by deconditioning. In contrast, type 2 diabetes patients have higher unsaturated intramyocellular fat and blunted palmitate and linoleate kinetics but after endurance training, all were realigned with those of deconditioned athletes. Improved basal insulin sensitivity was further associated with better serum cholesterol/triglycerides, glycaemic control, physical performance, enhanced post insulin receptor pathway signalling and metabolic sensing. We conclude that insulin-resistant, maladapted intramyocellular lipid storage and turnover in patients with type 2 diabetes show reversibility after endurance training through increased contributions of the saturated intramyocellular fatty acid pools. Clinical Trial Registration: NCT03065140: Muscle Fat Compartments and Turnover as Determinant of Insulin Sensitivity (MISTY).

Fig. 1. Study consort and flow diagram, showing selection of the two study populations after screening, baseline study investigations (V1), exercise interventions and post-intervention study investigations (V2).

HbA1C—haemoglobin A1C; HDL—high-density lipoprotein; LDL—low-density lipoprotein; VO₂—oxygen consumption; CPET—cardiopulmonary exercise test.

Fig. 2. ¹H-Magnetic resonance spectroscopy of total, saturated and unsaturated intramyocellular lipid bonds.

2A: Top: Representative localisation of the spectroscopy voxel for ¹H-magnetic resonance of the right vastus lateralis. Middle: Colour-coded schematic showing protons connected to carbon nuclei in single (saturated) covalent bonds in blue and red and protons connected to double/triple (unsaturated) carbon bonds or adjacent to double/triple bonds, which are shown in green and purple, respectively. Bottom: The same colour-coding shows how the different proton species process at different frequencies in the magnetic field, generating different spectral peaks as shown by the different chemical shifts (parts per million, ppm) of saturated (0.9 ppm, 1.3 ppm) and unsaturated (2.1 ppm, 5.2 to 5.3 ppm) intramyocellular lipid peaks. Main extramyocellular lipid (EMCL) peak is separated at 1.5 ppm (yellow). 2B: Intramyocellular total lipids and fractions of saturated and unsaturated carbon bonds within intramyocellular lipid (n = 25 athletes and n = 22 patients with type 2 diabetes), Arb U = arbitrary units. Data is shown as individual data points with means and error bars for standard deviation. Baseline and post-interventions comparisons between groups were performed using t-tests. Top: Intra-myocellular fractional lipid mass in athletes and type 2 diabetes patients before and after exercise intervention Middle: Intra-myocellular fraction of saturated lipids in athletes and type 2 diabetes patients before and after exercise intervention. Bottom: Intra-myocellular fraction of unsaturated lipids in athletes and type 2 diabetes patients before and after exercise intervention.

Fig. 3. Skeletal muscle saturated and unsaturated lipid turnover and insulin receptor pathway/metabolic sensing.

Data are shown as individual data points with means and error bars for standard deviation. Arb U arbitrary units. 3A: Top: Fractional incorporation rate for [U⁻¹³C] Palmitate (16:0) before and after exercise intervention in athletes and patients with type 2 diabetes (n = 11 athletes and n = 12 patients with type 2 diabetes) Baseline and post-interventions comparisons between groups were performed using t tests. Bottom: Fractional incorporation rate for [U⁻¹³C] Linoleate (18.2 n-6) before and after exercise intervention in athletes and patients with type 2 diabetes (n = 11 athletes and n = 12 patients with type 2 diabetes). 3B: Top: Ratio of phosphorylated protein kinase B (AKT) to total of AKT (p/t AKT) protein levels before and after exercise intervention in athletes and patients with type 2 diabetes (n = 8 in each group). Baseline and post-interventions comparisons between groups were performed using t tests. Bottom: Ratio of phosphorylated 5’ adenosine monophosphate-activated protein kinase (AMPK) to total of AMPK (p/t AMPK) protein levels before and after exercise intervention in athletes and patients with type 2 diabetes (n = 8 in each group). Below are representative western blot examples from n = 4 in each group.