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Metformin improves circulating endothelial cells and endothelial progenitor cells in type 1 diabetes: MERIT study
Fahad W Ahmed1,2, Rachel Rider1, Michael Glanville2
1Department of Diabetes, Queen Elizabeth Hospital, Gateshead, UK.
Insights
Metformin improves endothelial progenitor cells (EPCs) and reduces circulating endothelial cells (cECs) in type 1 diabetes patients, potentially offering cardiovascular protection. These benefits occur without altering glycemic control, suggesting a non-glycemic mechanism of action.
Area of Science:
- Cardiovascular Medicine
- Endocrinology
- Pharmacology
Background:
- Type 1 diabetes (T1D) is linked to increased cardiovascular disease (CVD) risk.
- Reduced endothelial progenitor cells (EPCs) contribute to impaired vascular repair and CVD development in T1D.
- Metformin's cardioprotective effects in T1D may involve modulation of endothelial cell populations.
Purpose of the Study:
- To investigate if metformin's cardioprotective effects in T1D are mediated by increasing circulating EPCs (cEPCs) and pro-angiogenic cells (PACs).
- To assess if metformin decreases circulating endothelial cells (cECs) in T1D patients.
- To determine if these vascular effects occur independently of changes in glycemic control.
Main Methods:
- Open-label, parallel study involving 23 T1D patients treated with metformin (TG), 9 T1D patients on standard treatment (SG), and 23 healthy controls (HC).
- Insulin doses were adjusted to maintain stable glycemic control throughout the 8-week study.
- Flow cytometry was used to quantify cEPCs and cECs; PACs and colony-forming units (CFU-Hill's) were assessed via cell culture.
Main Results:
- Metformin treatment significantly increased cEPCs, PACs, and CFU-Hill's colonies, while decreasing cECs in T1D patients.
- These improvements in vascular cell populations reached levels comparable to healthy controls.
- Glycemic control (HbA1c, glucose variability) remained unchanged in the metformin group, with no significant changes observed in the standard treatment group.
Conclusions:
- Metformin demonstrates potential cardioprotective effects in T1D by enhancing EPCs, PACs, and CFU-Hill's colonies, and reducing cECs.
- These vascular improvements appear to be independent of metformin's hypoglycemic effects.
- Further long-term studies are warranted to confirm metformin's cardiovascular outcomes in T1D.
Background:
Type 1 diabetes is associated with increased cardiovascular disease (CVD). Decreased endothelial progenitor cells (EPCs) number plays a pivotal role in reduced endothelial repair and development of CVD. We aimed to determine if cardioprotective effect of metformin is mediated by increasing circulating endothelial progenitor cells (cEPCs), pro-angiogenic cells (PACs) and decreasing circulating endothelial cells (cECs) count whilst maintaining unchanged glycemic control.
Methods:
This study was an open label and parallel standard treatment study. Twenty-three type 1 diabetes patients without overt CVD were treated with metformin for 8 weeks (treatment group-TG). They were matched with nine type 1 diabetes patients on standard treatment (SG) and 23 age- and sex-matched healthy volunteers (HC). Insulin dose was adjusted to keep unchanged glycaemic control. cEPCs and cECs counts were determined by flow cytometry using surface markers CD45(dim)CD34(+)VEGFR-2(+) and CD45(dim)CD133(-)CD34(+)CD144(+) respectively. Peripheral blood mononuclear cells were cultured to assess changes in PACs number, function and colony forming units (CFU-Hill's colonies).
Results:
At baseline TG had lower cEPCs, PACs, CFU-Hills' colonies and PACs adhesion versus HC (p < 0.001-all variables) and higher cECs versus HC (p = 0.03). Metformin improved cEPCs, PACs, CFU-Hill's colonies number, cECs and PACs adhesion (p < 0.05-all variables) to levels seen in HC whilst HbA1c (one-way ANOVA p = 0.78) and glucose variability (average glucose, blood glucose standard deviation, mean amplitude of glycaemic excursion, continuous overall net glycaemic action and area under curve) remained unchanged. No changes were seen in any variables in SG. There was an inverse correlation between CFU-Hill's colonies with cECs.
Conclusions:
Metformin has potential cardio-protective effect through improving cEPCs, CFU-Hill's colonies, cECs, PACs count and function independently of hypoglycaemic effect. This finding needs to be confirmed by long term cardiovascular outcome studies in type 1 diabetes. Trial registration ISRCTN26092132.
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