Liraglutide Actions on the Liver: Effects on Glucose Phosphorylation

It is known that liraglutide impacts favorably glucose homeostasis in type 2 diabetic
patients, but not the exact mechanism of this effect. In particular, liraglutide's acute and
chronic effects on the liver are not well understood. The aim of our study is to determine
whether liraglutide acutely and/or chronically changes hepatic GCK activity in vivo in type 2
diabetic patients, and to quantify this effect. We hypothesize that liraglutide increases GCK
activity and that this results in increased hepatic glucose uptake, contributing to a
lowering of glycemia.

Our specific aims are:

1. to measure liraglutide's acute effect on GCK activity changes in vivo in type 2 diabetic
patients;

2. to assess whether chronic treatment with liraglutide determines a change in liver GCK
activity in type 2 diabetic patients, as assessed during an IVGTT.

We expect that liraglutide acutely and/or chronically increases GCK activity, thus
contributing to higher liver glucose uptake and lower glycemia.

Primary endpoints

1. GCK activity (acute effect) during IVGTTs with and without liraglutide administration.
GCK activity will be calculated based on lactate and glucose measurements during the
IVGTT

2. GCK activity during IVGTTs before and after 6 weeks of liraglutide treatment (IVGTT3).

Secondary endpoints

1. SI-IVGTT (insulin sensitivity during an intravenous glucose tolerance test) as
quantified by the MINMOD analysis of the IVGTT

2. Acute insulin response to glucose (AIRg) and the disposition index (DI-MINMOD), the
ability of beta cell to compensate for changes in insulin sensitivity.

This is a study designed to investigate the effect of liraglutide in type 2 diabetes
therefore subjects are selected from type 2 diabetes population of the Los Angeles basin
area. The study population is represented by type 2 diabetics (age 18-65 y old, T2DM
diagnosed by current American Diabetes Association diagnostic criteria ( HbA1c ≥ 6.5 % or
fasting plasma glucose ≥ 126 mg/dl or 2h plasma glucose ≥ 200 mg/dL during an OGTT or in a
patient with classic symptoms of hyperglycemia or hyperglycemic crisis a random plasma
glucose ≥ 200 mg/dl).

Inclusion Criteria:

- 18- 65 years of age (inclusive)

- Ability to provide informed consent before any trial-related activities

- Ability to communicate effectively with research staff

- Ability to return for follow up visit

- Adequate IV access

- If a female of childbearing potential, non-pregnant and taking reliable contraception

- Documented T2DM (per most recent American Diabetes Association criteria);

- Drug naïve or treated with metformin only;

- Diabetes should be well controlled (as defined by HbA1 ≤ 7.5%, FPG <180 mg/dl).

Exclusion Criteria:

- Pregnant, breast-feeding or the intention of becoming pregnant or not using adequate
contraceptive measures

- Presence of cancer or any clinically significant cardiac, respiratory, renal, hepatic,
gastrointestinal, endocrinological, haematological, neurological, or psychiatric
diseases or disorders (inclusion will be discussed with attending physician)

- Liver disease; history of alcoholism.

- Known or suspected allergy to liraglutide

- Contraindications to liraglutide: patients with a personal or family history of
medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome
type 2

- Patients with a history of pancreatitits

- Patients that have been treated with drugs that promote weight loss (e.g., Xenical®
[orlistat], Meridia® [sibutramine], Acomplia® [rimonabant], Acutrim®
[phenylpropanolamine], or similar over-the-counter medications) within 3 months of
study start

- Patients that have been treated with diabetes drugs: injectables, (e.g GLP-1R agonists
(Byetta® [exenatide], Victoza® [liraglutide]) amylin analogues; insulin and insulin
analogues) or oral agents other than metformin (e.g.DPP-IV- inhibitors (Januvia®
[sitagliptin], Onglyza® [saxagliptin] or Janumet® [sitagliptin and metformin]),insulin
sensitizers (thiazolidindiones: pioglitazone [Actos®]); or sulfonylureas) within 3
months of study start.

- The receipt of any investigational drug within 3 months prior to study start.

- Type 1 diabetes