Diabetes Mellitus is a form of metabolic disease with loss or dysfunction in glycemic control. Type II Diabetes Mellitus (T2DM) is characterized by the loss of glycemic control due to developed insulin resistance. T2DM is the most common form of diabetes and a growing epidemic that is affecting 9.4% Americans and 8.5% of the population worldwide. Associated with obesity, genetic predisposition, and environmental factors such as sedentary lifestyle, uncontrolled T2DM causes hyperglycemia, eventually leading to other potential complications including hyperlipidemia, increased risk for cardiovascular diseases, nerve damage and sleep apnea. Additionally, T2DM poses a high financial burden on the USA, costing $372 billion in direct medical costs and reduced productivity.
Because obesity is the main driver of insulin insensitivity of T2DM, the current standard of care for T2DM focuses on managing the weight of patients. The initial approach of weight control entails lifestyle interventions, including exercise routine and diet change, with additional glycemic control medication prescribed if the first line of intervention is not effective. T2DM management is particularly challenging in obese patients, and many anti-hyperglycemic medications currently in the market lead to weight gain, which may further add to metabolic control problems. For such a challenge, bariatric surgeries are considered as a T2DM treatment option.
Roux-en-Y gastric bypass (RYGB) is the most commonly practiced bariatric surgery in the United States. RYGB is shown to be the most effective treatment for prolonged weight loss leading to metabolic and hormonal changes that ultimately improve glucose metabolism and other complications of diabetes such as hypertension. Interestingly, these beneficial effects against T2DM are observed within days after the operation, before any significant weight loss takes place. T2DM patients after undergoing RYGB showed significant improvement in insulin sensitivity and increased insulin secretion. Additionally, up to 85% of patients showed complete T2DM remission through reporting significantly lowered fasting and post prandial blood glucose levels as well as lowered HbA1c value without the use of anti-hyperglycemic medication. In addition to T2DM remissions, T2DM-related complications were improved after RYGB. Improvement in hyperlipidemia, hypertension, and sleep apnea are reported after the operation.
The immediate, weight-loss independent anti-diabetic effects are resulting from the intestinal anatomic alteration from RYGB. This intestinal anatomical change leads to metabolic hormonal profile, bile acid metabolism, and gut microbiota composition.
Glucagon-like peptide-1 (GLP-1) is an incretin, or a hormonal factor secreted post prandially in the small intestine, that is known to promote insulin secretion and facilitate blood glucose level regulation. A significant increase in GLP-1 level is observed after RYGB. This change is hypothesized through hindgut theory and foregut theory.
Protein Tyrosine Tyrosine (PYY) is another gut hormone secreted by L-cells in the ileum-colon. PYY was appreciated as an anorexigenic appetite regulator, and recently, the hormone is recognized to play a direct role in glycemic control. Increased PYY serum level in patients after RYGB surgery is consistently reported, and this change in serum PYY explained through hindgut theory and foregut theory as PYY is co-secreted with GLP-1. The increased level of PYY is shown to improve glycemic control in T2DM through the restoration of pancreatic islet morphology and function.
RYGB not only affects the gut hormonal profile, but the operation also raises total circulating bile acid concentration. Bile acids have recently been appreciated as endocrine factors that stimulate the release of GLP-1 and PYY. Changes in gastrointestinal anatomy resulting from RYGB may affect enterohepatic recirculation of bile acid, leading to the observed increase in total bile acid. An increase in total bile acids is correlated with several markers indicating normalized glycemic control and changes in the gut microbiota of the patients.
The microbiota profile for T2DM patients is not fully established due to the inconsistent data reporting structures and discrepancies in reported results. Generally, decreased biodiversity in gut microbiota has been associated with increased obesity, and an increase in lipopolysaccharide-producing microbe drive the low-grade inflammation that leads to insulin resistance of the host. Reconfiguration of the gastrointestinal tract from RYGB leads to increased diversity in gut microbiota composition and markers showing improved metabolic state. Changes in gut microbiota after RYGB led to an increase in GLP-1 release through signaling pathways involving GPCRs activation and to increase in bile acids.
Roux-en-Y gastric bypass deems to be a safe, effective therapeutic option for T2DM treatment for obese to severely obese patients. The exact physiological mechanism of the effects of RYGB on T2DM patients still remains elusive, but the current understanding of the effects of RYGB had led to the discovery of many potential therapeutic targets for T2DM.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/41282 |
| Date | 10 July 2020 |
| Creators | Kim, Hanna |
| Contributors | Franzblau, Carl |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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