Effect of Bariatric Surgery on Mechanisms of Type 2 Diabetes

Obesity and type 2 diabetes mellitus (T2DM) are two of the greatest public health problems of the 21st century. Lifestyle changes and pharmacotherapy, which are mainstay treatments for T2DM have had limited success. More intensive lifestyle weight management such as in the Look AHEAD trial reported an 8.6% weight loss after 1 year, while the Diabetes Prevention Program reported a 7% weight loss after 2 years, and a 58% decrease in the risk of developing T2DM. In contrast,we have observed a 31% weight loss together with 83% remission of T2DM in severely obese patients after Roux-en-Y gastric bypass (RYGB) surgery. However, direct evidence of the glycemic benefits of bariatric surgery from randomized control trials is lacking; there is no clear consensus that RYGB surgery is a good treatment option for moderately obese T2DM patients; and the mechanisms responsible for reversing T2DM after surgery remain unclear but may involve pancreatic insulin secretion and skeletal muscle and hepatic insulin resistance.

The objective of this application is to evaluate the effects of RYGB surgery on glycemic control and underlying mechanisms that contribute to T2DM in obese subjects (BMI: 30-40 kg/m2). Our central hypothesis is that RYGB surgery will reduce hyperglycemia via reversal of beta-cell dysfunction and decrease hepatic and peripheral insulin resistance. The approach requires a 12-month randomized controlled trial. The rationale is based on data showing that RYGB lowers fasting and postprandial glucose, and increases the GLP-1 response to a meal. However, the therapeutic efficacy of RYGB surgery in obesity-related T2DM needs to be demonstrated in a randomized trial.

Inclusion criteria

• candidate for general surgery
• 18 to 60 years old
• BMI 27-43
• type 2 diabetes
• willing to participate in either study arm
• understand and comply with requirements of each arm
• not pregnant
• willing to use reliable birth control for duration of study

Exclusion criteria

• prior bariatric surgery of any type
• prior complex abdominal surgery
• abdominal, thoracic, pelvic, obstetrical surgery within last 6 months
• significant cardiovascular disease
• kidney disease with a creatinine greater than or equal to 1.8 mg/dl
• chronic liver disease except for NAFLD/NASH
• celiac, malabsorptive, inflammatory bowel disorders
• psychiatric disorders requiring 3 or more medications
• pregnancy
• cancer except squamous or basal cell skin cancer or cancer in remission
• anticoagulation therapy that can't be stopped for surgery
• clotting disorders
• severe pulmonary disease