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

Sponsor

Mayo Clinic (Other)

Overall Status

Completed

CT.gov ID

NCT01956929

Collaborator

(none)

Enrollment

Location

Arms

Duration (Months)

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Insulin Resistance Prediabetic State	Drug: Metformin Drug: Placebo	Phase 1

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

12 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Basic Science

Official Title:

Metformin's Effect on Glucagon-induced Endogenous Glucose Production, Protein Metabolism and Resting Energy Expenditure in Insulin Resistant Individuals.

Study Start Date :

Oct 1, 2013

Actual Primary Completion Date :

Mar 1, 2016

Actual Study Completion Date :

Mar 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Metformin 2 weeks of Metformin use. First week 1000mg/day, Second week Max dose of 2000 mg/day.	Drug: Metformin Metformin 1000mg daily for one week, then 2000 mg daily for the second week. 4 week washout period, then crossover to placebo. Other Names: Glucophage
Placebo Comparator: Placebo 2 weeks of Placebo (lactulose pills)	Drug: Placebo Placebo tablets for 2 weeks, then 4 weeks of washout period, then crossover to metformin. Other Names: Lactulose

Arm

Intervention/Treatment

Experimental: Metformin

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

Drug: Metformin

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

Other Names:

Glucophage

Placebo Comparator: Placebo

2 weeks of Placebo (lactulose pills)

Drug: Placebo

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

Other Names:

Lactulose

Outcome Measures

Primary Outcome Measures

Change in Glucagon-induced endogenous glucose production. [Measured at week 0, 2, 4, 6 and 8]
To assess the effect of Metformin on glucose metabolism, at baseline and during a period of hyperglucagonemia, endogenous glucose production will be measured using a stable isotope tracer during the application of a somatostatin-based pancreatic clamp. Participants will be assessed before and following two weeks of consuming either metformin or placebo.

Secondary Outcome Measures

Change in glucagon-induced alterations in whole body protein metabolism and resting energy expenditure. [Measured at week 0, 2, 4, 6 and 8]
Alterations in whole body protein metabolism will be measured by using leucine as a tracer that measures leucine flux, and leucine transamination and oxidation as measures of leucine catabolism. Whole body oxygen consumption will be assessed by open circuit indirect calorimetry with a ventilated hood system. Skeletal muscle biopsies will be obtained at baseline and four hours after a high fat, high glycemic meal. Mitochondria will be isolated from the muscle samples to assess mitochondrial oxygen consumption and hydrogen peroxide emissions using high-resolution respirometry and spectrofluorometry, respectively. In addition, we will measure skeletal muscle intracellular AMP-activated protein kinase activity.

Eligibility Criteria

Criteria

Ages Eligible for Study:

35 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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