Type 2 diabetes (T2D) is associated with β-cell dysfunction. Although exercise is considered beneficial in T2D, the effects of moderate intensity endurance exercise training on β-cell function in humans with T2D are not known. GWAS uncovered Ras-Responsive Element Binding Protein 1 (RREB1) as a risk factor for T2D and in vitro studies suggest RREB1 impairs β-cell function; no studies have investigated exercise effects on RREB1. Here, we determined the effects of moderate intensity exercise training on β-cell function, RREB1, insulin, glucagon, and amylin in humans with T2D (7F/3M, 49±5y, BMI 30±3kg/m2) . Subjects completed 10-weeks of supervised exercise (Wks 1-3: 20-30min/day; 3X/wk; ∼50% VO2peak and Wks 4-10: 45-60min/day; 4X/wk; ∼70% VO2peak) . Fasting blood samples for OGTT, HbA1c, and hormones were obtained pre- and post-training (48hr) . Serum RREB1 was measured pre- and post-training and also in response to a single bout of maximal exercise. Training decreased HbA1c (7.7% to 7.2%, P=0.01) , pro-insulin (-18%, P=0.03) , pro-insulin/c-peptide ratio (-8%, P=0.03) , and glucose (OGTT: 90min, -18%, P=0.01; 120min, -15%, P<0.001) . Both β-cell function (late-phase disposition index, +38%, P=0.01) and insulin sensitivity (Stumvoll Index, +25%, P=0.01) improved. Body weight and composition, VO2peak, glucagon, amylin, c-peptide, and insulin were unchanged. Baseline RREB1 negatively correlated with the exercise-induced increase in late-phase disposition index (R= -0.71, P=0.03) , consistent with an inhibitory role of RREB1. Training did not alter serum RREB1, but interestingly, acute exercise decreased RREB1 both before (-51%, P<0.01) and after training (-11%, P=0.04) . Thus, RREB1 is an exercise-regulated serum factor whose decrease may function to improve β-cell function with exercise.
In conclusion, moderate intensity exercise training, in the absence of increased VO2peak, improves late phase β-cell function and glucose control in humans with T2D.
H.Zhang: None. R.Middelbeek: Research Support; Novo Nordisk. L.Simpson: None. N.P.Carbone: None. L.J.Goodyear: None.
National Institutes of Health (K23-DK114550, R01-DK112283, 5P30DK36836, 5P30DK057521-20)