Abstract
Micro- and macro-vascular events are directly associated with hyperglycemia in patients with type 2 diabetes mellitus (T2DM), but whether intensive glucose control decreases the risk of diabetic cardiovascular complications remains uncertain. Many studies have confirmed that impaired quality and quantity of mesenchymal stem cells (MSCs) plays a pathogenic role in diabetes. Our previous study found that the abundance of circulating MSCs was significantly decreased in patients with T2DM, which was correlated with the progression of diabetic complications. In addition, metformin-induced MSC apoptosis is one of the reasons for the decreased quantity of endogenous or exogenous MSCs during intensive glucose control. However, the role of glucose in metformin-induced MSC apoptosis during intensive glucose control in T2DM remains unknown. In this study, we found that metformin induces MSC apoptosis during intensive glucose control, while high glucose (standard glucose control) could significantly reverse its adverse effect in an AMPK-mTOR pathway dependent manner. Thus, our results indicate that the poorer clinical benefit of the intensive glucose control strategy may be related to an adverse effect due to metformin-induced MSC apoptosis during intensive glucose control therapy in patients with T2DM.
Highlights
Hyperglycemia is a hallmark of diabetes mellitus
In support of this result, the Real-Time Cellular Analysis (RTCA) showed increased apoptosis in the hUC-mesenchymal stem cells (MSCs) at the lower glucose concentrations in the metformin group (5.5 mM glucose) and normal fasting blood glucose group (6.1 mM glucose), while high glucose showed a protective effect on metformin-induced apoptosis (Fig. 1E)
These results indicate that different glucose levels affect metformin-induced MSC apoptosis in a dose-dependent manner
Summary
Hyperglycemia is a hallmark of diabetes mellitus. Epidemiologic studies indicate that cardiovascular disease is a major cause of death in patients with type II diabetes mellitus (T2DM); the incidence of diabetic cardiovascular complications is directly associated with the degree of hyperglycemia as measured by the plasma glucose or glycated hemoglobin level. We found the unexpected adverse effect that metformin, as a first-line agent used to treat T2DM and a basic glucose-lowering drug used during intensive glucose control, significantly induced MSC apoptosis and damped their therapeutic efficacy in infarcted myocardium[20]. In support of this result, the Real-Time Cellular Analysis (RTCA) showed increased apoptosis in the hUC-MSCs at the lower glucose concentrations in the metformin group (5.5 mM glucose) and normal fasting blood glucose group (6.1 mM glucose), while high glucose showed a protective effect on metformin-induced apoptosis (Fig. 1E). These results indicate that different glucose levels affect metformin-induced MSC apoptosis in a dose-dependent manner.
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