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 HbA1c fell from mean 55 to 41 mmol/mol by 104 weeks (p<0.001). At 4 weeks, morning cortisol (p<0.05) and ACTH (p=0.09) were reduced by 20%. Parasympathetic nerve activity (HRV-derived) increased at 4 weeks (p<0.05) and peaked at 24 weeks (p<0.01). 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, increased parasympathetic tone (weeks). 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.

Response of multiple hormones to glucose and arginine challenge in T2DM after gastric bypass

“…The subjects were randomly assigned 2:1 to RYGB or standard-of-care medical treatment without any other weight-lowering treatment. Further characteristics of this cohort are presented in Supplementary Table 1 and have been reported previously ( 8 , 9 , 20 ). Data on other neuroendocrine responses from this cohort in a shorter follow-up have been previously reported, together with fasting data ( 8 , 9 ).…”

“…This exploratory post hoc analysis is part of a previously described randomized controlled trial ( 8 , 9 , 20 ) carried out in 19 patients (18–65 years, BMI: 30–45 kg/m 2 ) with T2DM, diagnosed less than 10 years before the study entry and treated with oral antidiabetic medication (Supplementary Table 2, see section on supplementary materials given at the end of this article). The subjects were randomly assigned 2:1 to RYGB or standard-of-care medical treatment without any other weight-lowering treatment.…”

“…Individuals randomized to surgery followed a low-calorie diet (LCD, 3350–4600 kJ/day) for 4 weeks after the pre-surgery visit before undergoing surgical intervention, according to clinical routine. After RYGB, antidiabetic medications were reduced or withdrawn, and other medication changes were made as clinically appropriate ( 9 ).…”

“…This is related to the rearranged gastrointestinal anatomy resulting in rapid transport of ingested nutrients to the small intestine ( 3 ). However, CNS and neuroendocrine pathways have been suggested to play a role in mediating the effects of RYGB on glucose homeostasis ( 9 , 10 ).…”

“…We have recently reported rapid effects on neuroendocrine regulation following RYGB ( 8 ) as well as early and late adipose tissue effects in patients with obesity and T2DM ( 9 , 20 ). We have now performed additional exploratory analyses in the same cohort, and the current work aimed to explore the changes in the dynamic endocrine response induced by RYGB in patients with T2DM using two different nutrient challenges, namely intravenous arginine challenge and OGTT.…”