Metformin and Longevity Genes in Prediabetes

Overview[ - collapse ][ - ]

Purpose Pre-diabetes, a condition characterized by hyperglycaemia, is associated with increased cardiovascular risk and reduced life expectancy, as compared to the general population. AMP-activated protein kinase (AMPK) is an enzyme that plays a key role in cellular energy homeostasis and metabolism, and recently it has been demonstrated that AMPK regulates aging pathways, as well. AMPK is susceptible to modulation through pharmacologic (e.g. metformin) and non-pharmacologic (e.g. physical exercise) interventions. This clinical trial aims to describe the effects of the AMPK pathway on longevity genes and inflammation in the setting of pre-diabetes in vivo and in vitro. To this end, the investigators will compare treatment with metformin (500 mg t.i.d) for 2 months, versus placebo in pre-diabetic subjects. The investigators will assess expression of longevity genes SIRT1, p66Shc, p53 and mTOR in peripheral blood mononuclear cells (PBMCs) ex vivo. The investigators will evaluate monocyte polarization by flow cytometry, according to the expression of surface antigens (CD68, CCR2, CD163, CD206, CX3CR1) to determine the prevalence of pro- or anti-inflammatory cells. Inflammatory cytokines (TNF-alpha, MCP-1, IL-1, IL-6, IL-10, CCL12) will also be determined. In the in vitro study the investigators will evaluate the effects of AMPK activation or inhibition on longevity gene and protein expression.
ConditionInsulin Resistance
Prediabetes
Aging
Inflammation
InterventionDrug: Metformin
Drug: placebo
PhasePhase 4
SponsorUniversity of Padova
Responsible PartyUniversity of Padova
ClinicalTrials.gov IdentifierNCT01765946
First ReceivedJanuary 8, 2013
Last UpdatedMarch 12, 2013
Last verifiedMarch 2013

Tracking Information[ + expand ][ + ]

First Received DateJanuary 8, 2013
Last Updated DateMarch 12, 2013
Start DateJune 2010
Estimated Primary Completion DateMarch 2013
Current Primary Outcome MeasuresLongevity gene expression [Time Frame: 2 month after treatment] [Designated as safety issue: No]Change in the expression of longevity genes Sirtuin-1, p66Shc, mTor, p53 in peripheral blood mononuclear cells (PBMC)
Current Secondary Outcome Measures
  • Insulin sensitivity [Time Frame: 2 months after treatment] [Designated as safety issue: No]A dynamic measure of insulin sensitivity (Si) from the frequently sampled OGTT
  • Monocyte polarization status [Time Frame: 2 months after treatment] [Designated as safety issue: No]Polarization of circulating monocytes in M1 (CD68+CCR2+) and M2 (CX3CR1+CD163+/CD206+)

Descriptive Information[ + expand ][ + ]

Brief TitleMetformin and Longevity Genes in Prediabetes
Official TitleEffects of Metformin on Longevity Gene Expression and Inflammation and Prediabetic Individuals. A Placebo-controlled Trial
Brief Summary
Pre-diabetes, a condition characterized by hyperglycaemia, is associated with increased
cardiovascular risk and reduced life expectancy, as compared to the general population.
AMP-activated protein kinase (AMPK) is an enzyme that plays a key role in cellular energy
homeostasis and metabolism, and recently it has been demonstrated that AMPK regulates aging
pathways, as well. AMPK is susceptible to modulation through pharmacologic (e.g. metformin)
and non-pharmacologic (e.g. physical exercise) interventions. This clinical trial aims to
describe the effects of the AMPK pathway on longevity genes and inflammation in the setting
of pre-diabetes in vivo and in vitro. To this end, the investigators will compare treatment
with metformin (500 mg t.i.d) for 2 months, versus placebo in pre-diabetic subjects. The
investigators will assess expression of longevity genes SIRT1, p66Shc, p53 and mTOR in
peripheral blood mononuclear cells (PBMCs) ex vivo. The investigators will evaluate monocyte
polarization by flow cytometry, according to the expression of surface antigens (CD68, CCR2,
CD163, CD206, CX3CR1) to determine the prevalence of pro- or anti-inflammatory cells.
Inflammatory cytokines (TNF-alpha, MCP-1, IL-1, IL-6, IL-10, CCL12) will also be determined.
In the in vitro study the investigators will evaluate the effects of AMPK activation or
inhibition on longevity gene and protein expression.
Detailed DescriptionNot Provided
Study TypeInterventional
Study PhasePhase 4
Study DesignAllocation: Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Subject), Primary Purpose: Treatment
Condition
  • Insulin Resistance
  • Prediabetes
  • Aging
  • Inflammation
InterventionDrug: Metformin
Metformin tablets 500 mg tris in die (tid)
Other Names:
GlucophageDrug: placebo
Study Arm (s)
  • Experimental: Metformin
    Metformin tablets 500 mg tid for 2 months
  • Placebo Comparator: Placebo
    Placebo tables tid for 2 months

Recruitment Information[ + expand ][ + ]

Recruitment StatusCompleted
Estimated Enrollment38
Estimated Completion DateMarch 2013
Estimated Primary Completion DateMarch 2013
Eligibility Criteria
Inclusion Criteria:

- Pre-diabetes, defined as IFG (fasting glucose between 100 and 125 mg/dl) or IGT (2h
post-oral glucose load (75g) between 140 and 199 mg/dl);

- Age 40-75 years;

- Both genders.

Exclusion Criteria:

- Type 1 or 2 diabetes mellitus;

- Pregnancy, lactation;

- Acute, chronic or inflammatory diseases;

- Neoplasms;

- Immunological diseases, organ transplantation, steroid therapy;

- Uncontrolled arterial hypertension (systolic pressure > 180 mmHg or diastolic > 120
mmHg);

- Recent(within 3 months) surgical intervention or cardiovascular accidents;

- Known allergy to metformin.
GenderBoth
Ages40 Years
Accepts Healthy VolunteersNo
ContactsNot Provided
Location CountriesItaly

Administrative Information[ + expand ][ + ]

NCT Number NCT01765946
Other Study ID NumbersMetAge
Has Data Monitoring CommitteeNo
Information Provided ByUniversity of Padova
Study SponsorUniversity of Padova
CollaboratorsNot Provided
Investigators Principal Investigator: Angelo Avogaro, M.D. Ph.D. University of Padova
Verification DateMarch 2013

Locations[ + expand ][ + ]

University Hospital Diabetes Outpatient Clinic
Padova, Italy, 35128