Bariatric Surgery And Adipose Inflammation Dysfunction and Type 2 Diabetes Mellitus

Bariatric surgery quickly improves tissue specific insulin sensitivity. Changes in glucose
metabolism are seen within days after surgery, prior to any significant weight loss--raising
the question of a difference between dietary restriction and early food intake after surgery.
A major factor in the development of insulin resistance is obesity. It has been noted that by
3 months following Roux-en Y gastric bypass surgery in obese patients with (T2DM), fasting
glucose and insulin levels are improved independent of weight loss, insulin resistance in
muscle is lowered, and that the pro-inflammatory profile of resident microphages is lowered
improving insulin sensitivity.

The focus of this proposal is to define the mechanism by which bariatric surgery improves
impacts insulin sensitivity. Our long-term goal is to correlate these changes with direct
measures of adipose tissue insulin resistance to develop novel immunotherapies towards
reducing insulin resistance without surgery.

Our central hypothesis is that gastrointestinal rearrangement by various mechanisms impacts
adipose tissue and improves the pro-inflammatory profile of macrophages improving insulin
sensitivity and glucose homeostasis. To test this hypothesis we propose the following aims:

Specific Aim 1. Recruit a patient population and measure insulin sensitivity using
homeostatic model assessment (HOMA) to measure insulin resistance (IR), cytokines, incretins,
and serum adipokines in morbidly obese patients • prior to and 7-10 days following bariatric
surgery while on a hypocaloric diet (surgery group) and •prior to and 7-10 days while
following hypocaloric diet similar to bariatric surgery (diet group). Subjects will be
assigned to the two arms; subjects assigned to the hypocaloric diet may be offered bariatric
surgery after completion of the diet.

Specific Aim 2.

- Profile inflammatory macrophages, T cells and secreted factors in subcutaneous and
visceral adipose tissue of patients prior to and following RYGB and hypocaloric diet
treatments. • prior to and 7-10 days following surgery

- prior to and 7-10 days following hypocaloric diet similar to bariatric surgery

Specific Aim 3.

Assess the effects of bariatric surgery on ROS (reactive oxygen species) production,
expression of transcription factors and enzymes of mitochondrial biogenesis, tissue FABP4,
and biomarkers of oxidative stress and protein carbonylation in patients prior to and
following surgery and in control diet subjects maintained on hypocaloric diet.

Specific Aim 4.

Determine the impact of bariatric surgery on lipolysis and the role of TLQP-21 (a genetically
derived peptide that increases energy expenditure and prevents the early phase of
diet-induced obesity).

Inclusion Criteria::

1. Candidate for RYGB gastric bypass with insurance approval.

2. Willing to accept randomization to either immediate surgery, or delayed surgery after
diet study.

3. Willing to undergo two sessions of testing before, and ten days after surgery (or
initiation of dietary intervention).

4. BMI 35-45kg/m2

5. Pre-diabetes (ADA criteria) or T2DM with HbA1c< 8%.

Exclusion criteria:

1. T1DM.

2. Serious illness such as cancer, active chronic infection, cardiovascular disease
greater that New York Heart Association class 2, chronic renal failure, chronic lung
disease.

3. Inflammatory or celiac intestinal disease.

4. Untreated thyroid disease.

5. Serious psychiatric disease.

6. Excessive alcohol use.

7. Illicit drug use. -