Metformin and Longevity Genes in Prediabetes

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

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.

Study Overview

• Status: Completed
• Conditions: Inflammation; Insulin Resistance; Aging; Prediabetes
• Intervention / Treatment: Drug: placebo; Drug: Metformin

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Phase 4

Contacts and Locations

Study Locations

• Italy
  • Padova, Italy, 35128
    • University Hospital Diabetes Outpatient Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Metformin; Metformin tablets 500 mg tid for 2 months	Drug: Metformin; Metformin tablets 500 mg tris in die (tid); Other Names: Glucophage
Placebo Comparator: Placebo; Placebo tables tid for 2 months	Drug: placebo

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Padova
• Investigators: Principal Investigator: Angelo Avogaro, M.D. Ph.D., University of Padova

Publications and helpful links

General Publications

• de Kreutzenberg SV, Ceolotto G, Cattelan A, Pagnin E, Mazzucato M, Garagnani P, Borelli V, Bacalini MG, Franceschi C, Fadini GP, Avogaro A. Metformin improves putative longevity effectors in peripheral mononuclear cells from subjects with prediabetes. A randomized controlled trial. Nutr Metab Cardiovasc Dis. 2015 Jul;25(7):686-93. doi: 10.1016/j.numecd.2015.03.007. Epub 2015 Mar 24.

Study record dates

Study Major Dates

• Study Start: June 1, 2010
• Primary Completion (Actual): March 1, 2013
• Study Completion (Actual): March 1, 2013

Study Registration Dates

• First Submitted: January 8, 2013
• First Submitted That Met QC Criteria: January 10, 2013
• First Posted (Estimate): January 11, 2013

Study Record Updates

• Last Update Posted (Estimate): March 13, 2013
• Last Update Submitted That Met QC Criteria: March 12, 2013
• Last Verified: March 1, 2013

More Information

Terms related to this study

• Keywords: Inflammation; Insulin resistance; Prediabetes; Metformin; Longevity genes
• Additional Relevant MeSH Terms: Pathologic Processes; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Hyperinsulinism; Hyperglycemia; Inflammation; Prediabetic State; Glucose Intolerance; Insulin Resistance; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: MetAge