Time Course of Metabolic, Neuroendocrine, and Adipose Effects During 2 Years of Follow-up After Gastric Bypass in Patients With Type 2 Diabetes

Abstract

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 in T2D patients undergoing RYGB.

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

Patients: Thirteen patients with obesity and T2D 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.

Trial registration: ClinicalTrials.gov NCT02729246.

Keywords: RYGB; T2D; adipose effects; neuroendocrine changes.

© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.

Figures

Figure 1.

Inflammatory, hormonal and lipolysis measures. Fasting morning levels of (A) insulin, (B) IGF-1, (C) ACTH, (D) cortisol, (E) CRP, (F) WBC, (G) FFAs, and (H) glycerol at baseline and at 4, 24, and 104 weeks after RYGB. Data are expressed as means ± SD. P-values from pairwise comparison with baseline, after using mixed effects model, corrected for false detection rate. *P < 0.05, ***P < 0.01, ***P < 0.001.

Figure 2.

Adipocyte morphology after RYGB. (A) Average adipocyte volumes shown in picoliters (pL; means ± SEM, horizontal lines) for baseline, post-LCD, 4 weeks, 24 weeks, 104 weeks and controls, respectively (n = 12, 12, 10, 12, 11, and 22, respectively). *P < 0.05, ***P < 0.001 vs baseline; ##P < 0.01 for controls vs 104 weeks. (B) Representative images of adipocyte size from 1 subject at different study visits. All images and measurements were obtained using a light microscope with a magnification of ×100.

Figure 3.

Adipocyte glucose uptake after RYGB. Basal and insulin-stimulated glucose uptake in isolated adipocytes. (A) Adjusted for number of cells; (B) adjusted for cell surface area. Data are shown as means ± SEM. **P < 0.01; ***P < 0.001 vs baseline. Abbreviation: NS, nonsignificant for controls vs 104 weeks.

Figure 4.

Adipocyte lipolysis after RYGB. (A) Isolated adipocytes were incubated without hormones or (B) with isoproterenol 0.5 µM together with different concentrations of insulin (0-100 µU/mL), and glycerol release was measured. Data are means ± SEM, and there were no significant differences (baseline vs post-LCD, 4 weeks, 24 weeks, and 104 weeks postsurgery; n = 12, 7, 10, 12, and 8, respectively, due to limited tissue amounts).

Figure 5.

Schematic and hypothetical overview of changes after RYGB as they occur over time. Grey arrows, clinical effects; white arrows, effects on endocrine, autonomic nerve, and adipose functions, which may contribute to the favorable clinical effects.