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.

Roux-en-Y gastric bypass (RYGB) surgery reverses diabetes (T2DM) in ~80% of patients. Ghrelin regulates glucose homeostasis, but its role in T2DM remission after RYGB surgery is unclear. Nine obese T2DM subjects underwent a mixed meal tolerance test before and at 1 and 12 months after RYGB. Changes in ghrelin, body weight, GLP-1, glucose tolerance, and insulin sensitivity were measured. At 1 month, body weight, glycemia and insulin sensitivity were improved, while ghrelin concentrations were reduced (p<0.05). After 12 months, body weight and fasting glucose were reduced (30% and 16% respectively; p<0.05) and insulin sensitivity was enhanced (3-fold; p<0.05). Ghrelin suppression improved by 32% at 12 months (p<0.05), and this was associated with weight loss (R=0.72, p=0.03), enhanced insulin sensitivity (R=-0.78, p=0.01) and peak post-prandial GLP-1 (R=-0.73, p=0.03). These data suggest that post-prandial ghrelin suppression may be part of the mechanism that contributes to diabetes remission after RYGB surgery.

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Diabetes Mellitus (DM) is a chronic disease, with a rapidly increasing worldwide incidence and prevalence. Diabetes accounts for 8% of the US population, according to the United States Centers for Disease Control and Prevention. In terms of individuals, this number comes to a staggering 24 million. 1 In 2007, the total direct medical cost of treating diabetes and its associated complications was $116 billion. More than half of this is spent in treating its complications, both micro and macrovasular. Indirect costs in terms of disability, loss of work or premature mortality amounted to an additional $58 billion. 2 Several trials have shown the benefits of improved glycemic control on microvasular complications 3 – 7 and a propensity to reduce macrovasular disease. Furthermore tight glycemic control early in the disease, so called the legacy effect, has shown to reduce mortality. 5 However, these and several other trials have shown the progressive and unrelenting nature of the disease. Reduced efficacies of existing medications over prolonged periods, and continued beta cell dysfunction have lead to unmet glycemic targets. In addition, current antidiabetic medications have significant side effects most of which include hypoglycemia and weight gain. All the above points are rasion d'être that new additional therapies are needed. Recently, new classes of agents targeting the incretin system have become available. These can be divided into two broad categories; glucagon like peptide-1 (GLP-1) agonists/analogs (exenatide, liraglutide), and dipeptidyl peptidase-4 (DPP-4) inhibitors (sitagliptin, vildagliptin, and Saxagliptin (undergoing phase 3 trials)). Exenatide, a 39-amino acid peptide produced in the salivary gland of the Gila monster lizard, is a GLP-1 agonist. It is the first of its class approved for use as adjunctive therapy, in patients with Type 2 diabetes mellitus (T2DM). Current data suggests that exenatide, in combination with metformin, glyburide, or a glitazone, results in significant reductions in fasting and postprandial plasma glucose and hemoglobin A1c (HbA1c). Apart form gastrointestinal side effects, exenatide is relatively well tolerated and does not cause hypoglycemia when used alone. Additionally, the drug serves to promote moderate weight loss. The authors aim to provide a comprehensive overview of exenatide, detail its mechanism of action, and discuss its role in the present day treatment of patients with T2DM.