Aging, Inflammation, Insulin Resistance, Prediabetes
Conditions
Keywords
Insulin resistance, Prediabetes, Longevity genes, Inflammation, Metformin
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.
Interventions
DRUGMetformin
Metformin tablets 500 mg tris in die (tid)
DRUGplacebo
Sponsors
University of Padova
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
40 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Longevity gene expression | 2 month after treatment | Change in the expression of longevity genes Sirtuin-1, p66Shc, mTor, p53 in peripheral blood mononuclear cells (PBMC) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Insulin sensitivity | 2 months after treatment | A dynamic measure of insulin sensitivity (Si) from the frequently sampled OGTT |
| Monocyte polarization status | 2 months after treatment | Polarization of circulating monocytes in M1 (CD68+CCR2+) and M2 (CX3CR1+CD163+/CD206+) |
Countries
Italy
Outcome results
None listed