Clinical trial NCT01956929: Metformin's Effect on Glucagon-induced Glucose Production and Protein Metabolism.
Official title: Metformin's Effect on Glucagon-induced Endogenous Glucose Production, Protein Metabolism and Resting Energy Expenditure in Insulin Resistant Individuals.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Insulin Resistance
Prediabetic State
Keywords: Insulin Resistance
Prediabetic State
Metformin
Lead sponsor: Mayo Clinic
Sponsor class: OTHER
First posted: 2013-10-08
Enrollment: 12
Sex: ALL
Minimum age (years): 35
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: This study is being done to understand metformin's mechanisms of action regarding glucose production, protein metabolism, and mitochondrial function.

Detailed description: It is believed that Metformin antagonizes the action of glucagon through different pathways. In mice, Metformin leads to inhibition of adenylate cyclase, reduction of levels of cyclic AMP and protein kinase A (PKA) activity, therefore blocking glucagon-dependent glucose output form hepatocytes. Glucagon plays an important role in the increased catabolic state seen in insulin deficiency. Hyperglucagonaemia states have been shown to accelerate proteolysis and leucine oxidation in insulin-deficient humans. Patients with insulin resistance and increased levels of glucagon have an increased in energy expenditure which may contribute to the catabolic state associated with this condition. We hypothesized that treatment with Metformin for 2 weeks will significantly inhibit glucagon-induced endogenous glucose production in insulin resistant individuals. We also hypothesized that glucagon-induced alterations in whole body protein metabolism and the increases in O2 consumption associated with hyperglucagonaemia states will be significantly inhibited by Metformin in these individuals. This would open the door for the development of other antidiabetic drugs with antagonism of glucagon as their principal mechanism of action.

Eligibility criteria: Inclusion Criteria:

* 35-65 years of age
* Fasting blood glucose \>100 mg/dl
* BMI 27-36 kg/m2
* Waist Circumference: Men ≥ 104 cm; women ≥ 88 cm
* If previously on anti-diabetic medication, should be off for at least 1 month

Exclusion Criteria:

* Active use of hypoglycemic agents (\< 1 month)
* Renal failure, creatinine ≥ 1.5 mg/dL in men or ≥ 1.4 mg/dL in women
* Alanine aminotransferase levels exceed 135 IU/L or aspartate aminotransferase levels exceed 129 IU/L (3 x the upper limit of normal)
* Congestive Heart Failure (EF \< 40 %)
* Active coronary artery disease
* Recent (less than 6 weeks) or planned imaging study requiring IV contrast
* Participation in structured exercise (\> 2 hr per week)
* Recent change in dietary habits or weight
* Tobacco use
* Use of systemic glucocorticoids
* Anti-coagulant therapy (warfarin/heparin)
* Pregnancy or breastfeeding
* Alcohol consumption greater than 2 drinks/day
* Uncontrolled Hypothyroidism, abnormal thyroid stimulating hormone levels
* Metformin Allergy

Primary outcomes:
measure: Change in Glucagon-induced endogenous glucose production.
timeFrame: Measured at week 0, 2, 4, 6 and 8
Secondary outcomes:
measure: Change in glucagon-induced alterations in whole body protein metabolism and resting energy expenditure.
timeFrame: Measured at week 0, 2, 4, 6 and 8
Other outcomes:
Locations:
city: Rochester
country: United States
facility: Mayo Clinic in Rochester
state: Minnesota
Study officials:
affiliation: Mayo Clinic
name: K Nair, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: