Metformin and Longevity Genes in Prediabetes

Study Overview
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Brief Summary
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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.

Official Title
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Effects of Metformin on Longevity Gene Expression and Inflammation and Prediabetic Individuals. A Placebo-controlled Trial

Conditions
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Insulin Resistance, Prediabetes, Aging, Inflammation

Intervention / Treatment
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* Drug: Metformin
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metformin<br>Metformin tablets 500 mg tid for 2 months | Drug: Metformin<br>* Metformin tablets 500 mg tris in die (tid)<br>* Other names: Glucophage;|
| Placebo Comparator: Placebo<br>Placebo tables tid for 2 months | Drug: placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Longevity gene expression | Change in the expression of longevity genes Sirtuin-1, p66Shc, mTor, p53 in peripheral blood mononuclear cells (PBMC) | 2 month after treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin sensitivity | A dynamic measure of insulin sensitivity (Si) from the frequently sampled OGTT | 2 months after treatment | 
| Monocyte polarization status | Polarization of circulating monocytes in M1 (CD68+CCR2+) and M2 (CX3CR1+CD163+/CD206+) | 2 months after treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Longevity genes, Inflammation, Metformin, Insulin resistance, Prediabetes