Improved acylated ghrelin suppression at 2 years in obese patients with type 2 diabetes: effects of bariatric surgery vs standard medical therapy

Abstract

OBJECTIVE Roux-en-Y gastric bypass (RYGB) produces more durable glycemic control than sleeve gastrectomy (SG) or intensive medical therapy (IMT). However, the contribution of acylated ghrelin (AG), a gluco-regulatory/appetite hormone, to improve glucose metabolism and body composition in patients with type 2 diabetes (T2D) following RYGB is unknown. DESIGN STAMPEDE (Surgical Treatment and Medication Potentially Eradicate Diabetes Efficiently) was a prospective, randomized controlled trial. SUBJECTS Fifty-three (body mass index: 36 ± 3 kg m−2, age: 49 ± 9 years) poorly controlled patients with T2D (HbA1c (glycated hemoglobin): 9.7 ± 2%) were randomized to IMT, IMT + RYGB or IMT + SG and underwent a mixed-meal tolerance test at baseline, 12, and 24 months for evaluation of AG suppression (postprandial minus fasting) and beta-cell function (oral disposition index; glucose-stimulated insulin secretion × Matsuda index). Total/android body fat (dual-energy X-ray absorptiometry) was also assessed. RESULTS RYGB and SG reduced body fat comparably (15–23 kg) at 12 and 24 months, whereas IMT had no effect. Beta-cell function increased 5.8-fold in RYGB and was greater than IMT at 24 months (P < 0.001). However, there was no difference in insulin secretion between SG vs IMT at 24 months (P = 0.32). Fasting AG was reduced fourfold following SG (P < 0.01) and did not change with RYGB or IMT at 24 months. AG suppression improved more following RYGB than SG or IMT at 24 months (P = 0.01 vs SG, P = 0.07 vs IMT). At 24 months, AG suppression was associated with increased postprandial glucagon-like peptide-1 (r = −0.32, P < 0.02) and decreased android fat (r = 0.38; P < 0.006). CONCLUSIONS Enhanced AG suppression persists for up to 2 years after RYGB, and this effect is associated with decreased android obesity and improved insulin secretion. Together, these findings suggest that AG suppression is partly responsible for the improved glucose control after RYGB surgery.

Acylated and desacyl ghrelin are associated with hepatic lipogenesis, β-oxidation and autophagy: role in NAFLD amelioration after sleeve gastrectomy in obese rats

“…As expected, sleeve gastrectomy reduced desacyl ghrelin levels, due to the resection of the gastric fundus, the major production site of the hormone15. By contrast, plasma acylated ghrelin remained unchanged after bariatric surgery, which is in accordance with other authors2641, and the acylated/desacyl ghrelin ratio increased, suggesting an enhanced post-transcriptional modification in order to maintain the circulating levels of the acylated hormone. In a previous work of our group, we found that both acylated and desacyl ghrelin stimulated intracellular lipid accumulation in human differentiated omental adipocytes through the upregulation of PPARγ and SREBP-1c and other fat-storage related molecules20.…”

“…Circulating ghrelin concentrations decrease after sleeve gastrectomy due to the resection of the gastric fundus15 with RYGB additionally suppressing post-prandial ghrelin levels26. The aim of the present study was to analyze in diet-induced obese rats the implication of ghrelin isoforms in the improvement of hepatosteatosis after sleeve gastrectomy, a restrictive bariatric surgery procedure.…”

Effect of Laparoscopic Sleeve Gastrectomy on Fasting Gastrointestinal, Pancreatic, and Adipose-Derived Hormones and on Non-Esterified Fatty Acids

“…It has been hypothesized that LSG results in acute alterations to the regulation of appetite and mechanical function of the gut, both directly via excision of the greater curvature of the stomach, and indirectly through downstream endocrine and nutrient processing changes, all of which act to promote prolonged weight reduction [5]. Prior studies have demonstrated decreased levels of leptin and ghrelin [10, 11] and increased GLP-1 [12] following LSG, but much less is known about other molecular factors implicated in the regulation of blood-glucose homeostasis, gastric function, and emerging markers of adiposity. Additionally, many studies have sought to measure these hormones as surrogate markers of efficacy to evaluate LSG compared to other bariatric techniques [13], rather than to ascertain the mechanism of action of LSG.…”

Sleeve gastrectomy, but not duodenojejunostomy, preserves total beta-cell mass in Goto-Kakizaki rats evaluated by three-dimensional optical projection tomography

“…In general, the anti-diabetic effect of surgery is present prior to significant weight loss, indicating that the anatomical circumvention or manipulation per se is the underlying contributor to T2DM remission [13][14][15]. Altered secretion of gastrointestinal hormones such as glucagon-like peptide 1 (GLP-1), ghrelin and gastrin has been attributed to the rapid postoperative improvement in glycemic control [16][17][18]. All these hormones regulate pancreatic BCM in preclinical studies [19][20][21].…”