Effect of Liraglutide (Victoza) on Inflammation in Human Adipose Tissue and Blood

It has now been established that the high risk of cardiovascular disease that is associated
with obesity and type 2 diabetes is related to the systemic inflammation that underlies these
conditions. Previous studies have shown that there are numerous types of immune cells in
human adipose tissue, some of these are the macrophages. These cells can exist in two states:
M2, which can inhibit classical inflammatory response, and M1 which secrete proinflammatory
cytokines. The investigators have data to suggest that the role of inflammatory cells in
adipose tissue is a strong contributor to systemic inflammation. A recent study showed that a
GLP-1 analog (liraglutide, also known as Victoza) may help decrease inflammation via
promoting M2 differentiation of macrophages. The purpose of this study is to quantify
macrophage phenotype (M1 vs M2) in subcutaneous adipose tissue in moderately-obese diet
controlled diabetics at baseline, after four weeks of weight-maintenance using liraglutide,
and after 12 weeks of liraglutide treatment as compared to placebo.

Aim 1: Quantify M1 and M2 (surface and intracellular markers) polarization via flow cytometry
in subcutaneous abdominal adipose tissue and peripheral blood mononuclear cells at baseline
and after 4 weeks administration of liraglutide versus placebo to weight-stable, obese, type
2 diabetic patients. Weight loss will be prevented in order to ascertain the effect of
liraglutide alone.

Aim 2: Quantify M1 and M2 (surface and intracellular markers) polarization via flow cytometry
in subcutaneous adipose tissue and peripheral blood mononuclear cells after 12 weeks of
liraglutide treatment, during which dietary restrictions are lifted and spontaneous weight
loss, as would occur in the clinical setting, is allowed. To eliminate confounding by weight
loss, a placebo-treated group will undergo matched dietary weight loss for comparison to the
liraglutide group to ascertain whether changes in macrophage polarization at 12 weeks are
greater in the liraglutide group.

Aim 3: Quantify macrophage-mediated localized and systemic inflammation by measuring
M1/M2-related inflammatory cytokines in adipose tissue and peripheral blood after 4 and 12
weeks administration of liraglutide versus placebo to obese, type 2 diabetic patients.

Inclusion Criteria:

- BMI between 25 and 42 kg/m2

- Diet-controlled diabetics, or diabetics on Metformin that have permission from Primacy
Care Physician to wash-out of the drug for 6 weeks prior to the study and for the
duration of the study

- HbA1C between 6.0 - 7.9 (those on Metformin must have a HbA1c level below 7.5 prior to
wash-out period)

- Fasting Blood Glucose < 150 mg/dl

- Women must be post-menopausal or surgically sterile within age range

- Subjects must live in vicinity of Stanford University

Exclusion Criteria:

- Prior Bariatric surgery

- Personal or family history of medullary thyroid cancer

- MEN2 Syndrome

- Thyroid Nodules (not evaluated by PCP)

- Pancreatitis (acute or chronic)

- Gallstones

- Fasting plasma triglycerides > 400 mg/dl

- Cardiovascular disease

- Major organ disease

- Unstable hypertension (BP >160/100 mm Hg)

- Heavy alcohol use

- Self-reported weight change of >2kg over past 6 weeks

- Medication known to affect blood glucose, insulin sensitivity, or inflammation

- NSAIDs (must cease use 4 weeks prior to study enrollment)

- Previous use of liraglutide, Januvia, Byetta, or Lira.