Insulin ResistancePhase 1NCT01956929
Metformin's Effect on Glucagon-induced Glucose Production and Protein Metabolism.
A Phase 1 study testing Metformin in people with Insulin Resistance and Prediabetic State, run by Mayo Clinic at 1 site in United States.
Trial summary
This study is being done to understand metformin's mechanisms of action regarding glucose production, protein metabolism, and mitochondrial function. Read more about this study
- Who is it for?
- Ages 35 to 65 yearsHealthy volunteers can take part
- Conditions the study is for
- Insulin Resistance, Prediabetic State
- What is being tested?
- Metformin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 12 participants
- Where
- 1 siteUnited States
- Study dates
- Oct 2013to Mar 2016
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 35 to 65 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 15Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
Mayo Clinic in Rochester
Rochester, Minnesota, 55905
About this study
Official title: Metformin's Effect on Glucagon-induced Endogenous Glucose Production, Protein Metabolism and Resting Energy Expenditure in Insulin Resistant Individuals.
This study is being done to understand metformin's mechanisms of action regarding glucose production, protein metabolism, and mitochondrial function.
Read the 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
- Being tested
- Metformin, Placebo
- Keywords
- Insulin Resistance, Prediabetic State, Metformin
- Medical subject headings
- Insulin Resistance, Prediabetic State
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MetforminDrug
Also called Glucophage
Metformin 1000mg daily for one week, then 2000 mg daily for the second week. 4 week washout period, then crossover to placebo.
PlaceboDrug
Also called Lactulose
Placebo tablets for 2 weeks, then 4 weeks of washout period, then crossover to metformin.
| Study group | Role | What they receive |
|---|---|---|
| Metformin | Experimental | 2 weeks of Metformin use. First week 1000mg/day, Second week Max dose of 2000 mg/day. Receives: Drug: Metformin |
| Placebo | Placebo comparator | 2 weeks of Placebo (lactulose pills) Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Glucagon-induced endogenous glucose production.
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.
Measured: Measured at week 0, 2, 4, 6 and 8
Secondary outcomes (1)
Change in glucagon-induced alterations in whole body protein metabolism and resting energy expenditure.
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.
Measured: Measured at week 0, 2, 4, 6 and 8
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Oct 2013 (estimated)
- Study startOct 2013
- Primary completionMar 2016
- Study completionMar 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Insulin ResistanceStudies of the same condition, open and under way.
- More trials run by Mayo ClinicThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 12 participants (actual)
Sponsor and investigators
- Lead sponsor
- Mayo Clinic
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, K. Sreekumaran Nair, Mayo Clinic
- Investigators
- K Nair, MD, PhD, Principal investigator, Mayo Clinic
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01956929
- Sponsor's protocol ID
- 13-004966
- Status last verified
- Aug 2017
- First submitted
- 23 Sep 2013
- Last updated
- 1 Sep 2017
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 1 Sep 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Metformin's Effect on Glucagon-induced Endogenous Glucose Production, Protein Metabolism and Resting Energy Expenditure in Insulin Resistant Individuals.
- ClinicalTrials.gov ID
- NCT01956929
- Acronym / sponsor ID
- 13-004966
- Conditions
- Insulin Resistance, Prediabetic State
- Keywords
- Insulin Resistance, Prediabetic State, Metformin
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 12 participants (actual)
- Lead sponsor
- Mayo ClinicUniversity, hospital or other
- Study start
- Oct 2013
- Primary completion
- Mar 2016 (actual)
- Study completion
- Mar 2016 (actual)
- First posted
- 8 Oct 2013 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Metformin | Experimental | Drug: Metformin2 weeks of Metformin use. First week 1000mg/day, Second week Max dose of 2000 mg/day. |
| Placebo | Placebo comparator | Drug: Placebo2 weeks of Placebo (lactulose pills) |
Who may qualify
- Ages
- 35 to 65 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 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
Key exclusion criteria (15 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MetforminAlso: GlucophageMetformin 1000mg daily for one week, then 2000 mg daily for the second week. 4 week washout period, then crossover to placebo. | Drug | Metformin |
| PlaceboAlso: LactulosePlacebo tablets for 2 weeks, then 4 weeks of washout period, then crossover to metformin. | Drug | Placebo |
Primary outcome
Change in Glucagon-induced endogenous glucose production.
Time frame: 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.
1 secondary outcome
Change in glucagon-induced alterations in whole body protein metabolism and resting energy expenditure.
Time frame: Measured at week 0, 2, 4, 6 and 8
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Sep 2017.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
K Nair, MD, PhD principal investigator
Mayo Clinic
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Metformin in people with Insulin Resistance and Prediabetic State, run by Mayo Clinic at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 1 Sep 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Glucagon-induced endogenous glucose production. (time frame: Measured at week 0, 2, 4, 6 and 8). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Sep 2017.