30-LB: Effect of Intense Lifestyle Therapy in People with Obesity and Type 2 Diabetes

Weight loss and exercise are the cornerstones of therapy for patients with obesity and type 2 diabetes (T2D). However, successful compliance with therapy is difficult to achieve. We conducted an 8-month randomized, controlled trial in persons with obesity and T2D to determine the effect of intensive lifestyle therapy (ILT), delivered at a worksite setting, on body weight, cardiometabolic function, and cellular metabolic pathways. Subjects were assigned to Standard Care (SC; n=8, BMI:38±5, fasting blood glucose [FBG]:161±19 mg/dl, HbA1c:7.6±1.1%) or ILT (n=10, BMI:37±6, FBG:150±32 mg/dl, HbA1c:7.0±1.1%), which involved weekly diet-behavior therapy sessions and 4 d/wk of supervised resistance and endurance exercise training. Weight loss was greater in the ILT than SC group (17±7% vs. 1±2%, P<0.05). All cardiometabolic outcomes improved more in the ILT than SC group: i) insulin sensitivity (glucose disposal rate during a hyperinsulinemic-euglycemic clamp increased by 116±78% vs. 15±9%, P<0.05); ii) β-cell function (insulin secretion in response to an oral glucose load relative to insulin sensitivity increased by 194±205% vs. 12±20%, P<0.05); and iii) cardiorespiratory fitness (VO_{2 peak} during cycle ergometer exercise increased by 28±22% vs. -2±15%, P<0.05). The most upregulated biological pathways enriched in differentially expressed genes (DEGs) in skeletal muscle, assessed by RNA-seq, after ILT involved mitochondrial function and sirtuin signaling pathways. Upstream regulators of these DEGs included NAD dependent deacetylase sirtuin-3 (SIRT3) and NAMPT (FDR<0.05). In addition, ILT increased muscle NAD content by 51±46% (P<0.05). FBG and HbA1c decreased to 108±31 mg/dl and to 6.1±0.9%, despite a 60% decrease in the use of diabetes medications after ILT, but did not change with SC. We conclude that marked diet-induced weight loss and exercise training can be achieved in a structured worksite setting and has profound therapeutic cardiometabolic effects in people with obesity and T2D.