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Context: Roux-en-Y gastric bypass surgery (RYGB) markedly improves glycemia in patients with type 2 diabetes (T2D), but underlying mechanisms and changes over time are incompletely understood.

Objective: Integrated assessment of neuroendocrine and metabolic changes over time inT2D patients undergoing RYGB.

Design and Setting: Follow-up of single-center randomized study.

Patients: Thirteen patients with obesity andT2D compared to 22 healthy subjects.

Interventions: Blood chemistry, adipose biopsies, and heart rate variability were obtained before and 4, 24, and 104 weeks post-RYGB.

Results: After RYGB, glucose-lowering drugs were discontinued and hemoglobin A1c fell from mean 55 to 41 mmol/mol by 104 weeks (P < 0.001). At 4 weeks, morning cortisol (P < 0.05) and adrenocorticotropin (P = 0.09) were reduced by 20%. Parasympathetic nerve activity (heart rate variability derived) increased at 4 weeks (P < 0.05) and peaked at 24 weeks (P < 0.01). C-reactive protein (CRP) and white blood cells were rapidly reduced (P < 0.01). At 104 weeks, basal and insulin-stimulated adipocyte glucose uptake increased by 3-fold vs baseline and expression of genes involved in glucose transport, fatty acid oxidation, and adipogenesis was upregulated (P < 0.01). Adipocyte volume was reduced by 4 weeks and more markedly at 104 weeks, by about 40% vs baseline (P < 0.01).

Conclusions: We propose this order of events: (1) rapid glucose lowering (days); (2) attenuated cortisol axis activity and inflammation and increased parasympathetic tone (weeks); and (3) body fat and weight loss, increased adipose glucose uptake, and whole-body insulin sensitivity (months-years; similar to healthy controls).Thus, neuroendocrine pathways can partly mediate early glycemic improvement after RYGB, and adipose factors may promote long-term insulin sensitivity and normoglycemia.