Metformin's Effect on Glucagon-induced Glucose Production and Protein Metabolism.

NCT ID: NCT01956929

Last Updated: 2017-09-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 12 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-10-31
• Study Completion Date: 2016-03-31

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.

Conditions

Insulin Resistance; Prediabetic State

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: DOUBLE

Study Groups

Metformin

2 weeks of Metformin use. First week 1000mg/day, Second week Max dose of 2000 mg/day.

Group Type: EXPERIMENTAL

Metformin

Intervention Type: DRUG

Metformin 1000mg daily for one week, then 2000 mg daily for the second week. 4 week washout period, then crossover to placebo.

Placebo

2 weeks of Placebo (lactulose pills)

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo tablets for 2 weeks, then 4 weeks of washout period, then crossover to metformin.

Interventions

Metformin

Metformin 1000mg daily for one week, then 2000 mg daily for the second week. 4 week washout period, then crossover to placebo.

Intervention Type: DRUG

Placebo

Placebo tablets for 2 weeks, then 4 weeks of washout period, then crossover to metformin.

Intervention Type: DRUG

Other Intervention Names

Glucophage; Lactulose

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

• Minimum Eligible Age: 35 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Mayo Clinic

OTHER

Sponsor Role: lead

Responsible Party

K. Sreekumaran Nair

Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

K Nair, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Mayo Clinic

Locations

Mayo Clinic in Rochester

Rochester, Minnesota, United States

Countries

United States

Other Identifiers

13-004966

Identifier Type: -

Identifier Source: org_study_id