Role of Growth Hormone Antagonism in Modulating Insulin Sensitivity in Subjects With Pre-diabetes (PEGIR)

Role of Growth Hormone Antagonism in Modulating Insulin Sensitivity in Subjects With Insulin Resistance But Without Diabetes

Growth hormone is well known to cause changes in glucose regulation. People with Laron syndrome are born without the growth hormone receptor and are protected from diabetes. Mice who are engineered without the growth hormone receptor are similarly protected from diabetes. Conversely, people who have excessive amounts of growth hormone, such as patients with acromegaly, have an increased risk for type 2 diabetes. In acromegaly patients, treatment with pegvisomant, a medication that reduces insulin like growth factor-1 by blocking the growth hormone receptor, significantly improves insulin resistance. Pegvisomant has not been explored as a possibility for the treatment of type 2 diabetes or insulin resistance in people without acromegaly. In this study, the investigators hope to study the metabolic effects of pegvisomant on people who have insulin resistance but not diabetes. Pegivosmant is expected to improve insulin resistance in the liver, fat and muscle as well as decrease serum free fatty acids.

Pegvisomant 20 mg subcutaneously Qday will be administered by the study subject for 28 days during this study.

Investigators will measure insulin sensitivity via hyperinsulinemic euglycemic clamp prior to the initiation of the study medication and then again at the end of the 28 days to evaluate the effect of pegvisomant on insulin sensitivity and reported as HOMA-IR. HOMA-IR was derived from fasting insulin and fasting glucose by the calculation: fasting insulin (microU/L) x fasting glucose (nmol/L)/22.5

Treatment with pegvisomant is expected to alter lipolysis. To assess this investigators will do fasting and steady state stable isotope measurements prior to treatment with pegvisomant and at day 28 after treatment with pegvisomant.

Inclusion Criteria: BMI between 18-35 Homeostatic model assessment - insulin resistance (HOMA-IR) >2.77 Able to administer daily subcutaneous injections of pegvisomant Exclusion Criteria: Pregnancy Breastfeeding in the last 6 months Liver function tests greater than 3x the upper limits of normal unstable diet over the last 3 months unstable weight over the last 6 months unstable lipid lowering regimen diabetes - type 1 or type 2 History of major gastrointestinal surgery History of pancreatic, liver, biliary, or intestinal disease Fasting blood glucose >126 Fasting triglycerides>500 A1c>6.5