Hindgut hypothesis for improvement in diabetes secondary to bariatric surgery

• diabetes remission results from improvements in both insulin resistance and beta-cell dysfunction, but the degree of their improvement also depends on the type of surgery performed (1,2,3,4,5)
  
  
• restrictive procedure (LAGB) is thought to achieve glycemic control purely through weight loss without an entero-hormonal effect
  • therefore, the remission of diabetes is slow and occurs in parallel with gradual weight loss
    
    
• the most investigated metabolic procedure is roux-en-Y gastric bypass (RYGB), which exhibits significant hormonal changes after surgery; the glycemic control is acute and immediate via an anti-diabetic weight-independent mechanism, even without significant weight loss after surgery
  • the magnitude of metabolic control is much greater than the expected degree of weight loss, which might be a clue that the altered hormonal milieu of gut-hormone release explains the metabolic disease control

Proposed mechanisms for improved glycaemic control secondary to bariatric surgery (apart from secondary to weight loss):

Foregut effect

• 'foregut hypothesis' proposes that the exclusion of the duodenum and proximal jejunum from the transit of nutrients may prevent the secretion of a putative signal that promotes insulin resistance and T2DM, suggesting that a yet unidentified inhibitory product from the proximal bowel causes metabolic changes (anti-incretin)
  • hypothesis was based on an animal study by Rubino et al, which supported the foregut hypothesis as a dominant mechanism in improving glucose homeostasis after RYGB (1)

Hindgut effect

• 'hindgut hypothesis' proposes that diabetes control results from the expedited delivery of nutrients to the distal bowel, thus producing a physiologic signal that improves glucose homeostasis
  • potential mediators of this effect are glucagon-like peptide-1 (GLP-1), GIP (incretin effect) and peptide YY (non-incretin)
  • rapid delivery of nutrients has been demonstrated to stimulate the 'L' cells in the distal intestine to secrete incretin, thus enhancing insulin secretion and insulin sensitivity
  • peptide YY is an anorexic hormone co-secreted with GLP-1 from intestinal L cells in response to nutrients
    • acts to decrease food intake due to faster satiation and may reduce insulin resistance
    • studies have shown the elevation of peptide YY together with GLP-1 in response to nutrients after RYGB, which is not observed after LAGB

Ghrelin effect

• Ghrelin is an orexigenic gut hormone and has stimulatory effects on growth hormone release
  • mainly secreted from the gastric fundus and displays an ultradian rhythm with an increase before meals and a decrease after meals
    • ghrelin levels decrease dramatically in patients who have undergone RYGB
    • ghrelin is undoubtedly decreased after sleeve gastrectomy
    • ghrelin has also been shown to have diabetogenic effects because ghrelin administration in humans suppresses insulin secretion, even in the setting of ghrelin-induced hyperglycemia

Role of bile acid

• bile acids are a key stimulus for the farnesoid X receptor in the liver, affecting hepatic metabolism and G-protein-coupled bile acid-activated receptors (TGR5) of the enteroendocrine L-cells and promoting the release of incretin
  • thus, bile acids play an important role in glucose homoeostasis
    • post-operative increases in circulating bile acids have been suggested to contribute to the metabolic benefits of bariatric surgery; however, their mechanisms remain undefined
    • clinical trials with the bile acid sequestrant colesevelam have shown its effectiveness in improving glycemic control in patients with T2DM
    • the re-route of nutrients due to altered physio-anatomy after gastric bypass may also affect the enterohepatic recirculation of bile acids and contribute to improved glycemic control

Reference:

• Rubino F, Forgione A, Cummings DE, Vix M, Gnuli D, Mingrone G, Castagneto M, Marescaux J. The mechanism of diabetes control after gastrointestinal bypass surgery reveals a role of the proximal small intestine in the pathophysiology of type 2 diabetes. Ann Surg. 2006;244:741-749.
• Rubino F, Gagner M. Potential of surgery for curing type 2 diabetes mellitus. Ann Surg. 2002;236:554-559.
• Lee WJ, Chong K, Chen CY, Chen SC, Lee YC, Ser KH, Chuang LM. Diabetes remission and insulin secretion after gastric bypass in patients with body mass index > 35 kg/m2. Obes Surg. 2011;21:889-895.
• Arterburn DE, Courcoulas AP. Bariatric surgery for obesity and metabolic conditions in adults .BMJ. 2014 Aug 27;349