Effects of Metformin on Metabolite Profiles and LDL Cholesterol in Patients With Type 2 Diabetes

Abstract

OBJECTIVEMetformin is used as a first-line oral treatment for type 2 diabetes (T2D). However, the underlying mechanism is not fully understood. Here, we aimed to comprehensively investigate the pleiotropic effects of metformin. RESEARCH DESIGN AND METHODSWe analyzed both metabolomic and genomic data of the population-based KORA cohort. To evaluate the effect of metformin treatment on metabolite concentrations, we quantified 131 metabolites in fasting serum samples and used multivariable linear regression models in three independent cross-sectional studies (n = 151 patients with T2D treated with metformin [mt-T2D]). Additionally, we used linear mixed-effect models to study the longitudinal KORA samples (n = 912) and performed mediation analyses to investigate the effects of metformin intake on blood lipid profiles. We combined genotyping data with the identified metforminassociated metabolites in KORA individuals (n = 1,809) and explored the underlying pathways. RESULTSWe found significantly lower (P < 5.0E-06) concentrations of three metabolites (acyl-alkyl phosphatidylcholines [PCs]) when comparing mt-T2D with four control groups who were not using glucose-lowering oral medication. These findings were controlled for conventional risk factors of T2D and replicated in two independent studies. Furthermore, we observed that the levels of these metabolites decreased significantly in patients after they started metformin treatment during 7 years' follow-up. The reduction of these metabolites was also associated with a lowered blood level of LDL cholesterol (LDL-C). Variations of these three metabolites were significantly associated with 17 genes (including FADS1 and FADS2) and controlled by AMPK, a metformin target. CONCLUSIONSOur results indicate that metformin intake activates AMPK and consequently suppresses FADS, which leads to reduced levels of the three acyl-alkyl PCs and LDL-C. Our findings suggest potential beneficial effects of metformin in the prevention of cardiovascular disease.Type 2 diabetes (T2D) is a chronic disease with diminished response to insulin and relative insulin deficiency (1). Patients with T2D mostly take metformin as first-line oral treatment to lower their glucose levels and to improve insulin sensitivity (2). Despite metformin's use as an antihyperglycemic agent for more than 50 years, its

Response to Comment on Xu et al. Effects of Metformin on Metabolite Profiles and LDL Cholesterol in Patients With Type 2 Diabetes. Diabetes Care 2015;38:1858–1867

“…In fact, our analysis indicated that approximately 29% of the decrease in LDL-C can be explained by repressed FADS activity (2). Still, about 70% of the contribution to the reduction of LDL-C is unclear.…”

“…We thus wonder if the link between the studies can be drawn in such a straightforward manner. Additionally, the study by Giugliano et al (3) is based on the investigation of 12 obese hypertensive women without diabetes; therefore, the underlying design is different from ours (2).…”

Comment on Xu et al. Effects of Metformin on Metabolite Profiles and LDL Cholesterol in Patients With Type 2 Diabetes. Diabetes Care 2015;38:1858–1867

“…In the task of alluding to the mode of action of metformin, Xu et al (1) examined 131 fasting serum metabolites in three independent cross-sectional cohort studies. The authors found decreased concentrations of three metabolites (acyl-alkyl phosphatidylcholines [PCs]) in patients with type 2 diabetes treated with metformin compared with control groups not using glucose-lowering oral medication.…”

“…Xu et al (1) are to be congratulated for their comprehensive study that brings substantial new knowledge to the enigmatic topic of metformin and its pleiotropic mode of action. However, in terms of LDL cholesterol reduction, we wish to draw attention to one mode of action that was not addressed in the study.…”

Statins Plus Metformin: a Promising Combination for Prevention and Treatment of Atherosclerosis

“…[3][4][5] Recent research has shown that metformin significantly lowered blood levels of LDL-C by 11.83 mg/dL (P = 0.02) in patients with T2D. 6 Glueck et al 7 reported that in nondiabetic, morbidly obese subjects with body mass index greater than 30 kg/m2, metformin treatment for 29 weeks lowered LDL-C levels from 126 ± 34 mg/dL to 112 ± 43 mg/dL (P = 0.001), with a linear trend toward decreasing levels throughout (P = 0.036). It was believed that the effect of metformin was associated with adenosine 5-monophosphateactivated protein kinase (AMPK), AMPK activated by metformin can suppress fatty acid desaturases (FADS) synthesis in liver 6.…”