Metabolic Effects of Metformin in the Failing Heart

Abstract

Accumulating evidence shows that metformin is an insulin-sensitizing antidiabetic drug widely used in the treatment of type 2 diabetes mellitus (T2DM), which can exert favorable effects on cardiovascular risk and may be safely used in patients with heart failure (HF), and even able to reduce the incidence of HF and to reduce HF mortality. In failing hearts, metformin improves myocardial energy metabolic status through the activation of AMP (adenosine monophosphate)-activated protein kinase (AMPK) and the regulation of lipid and glucose metabolism. By increasing nitric oxide (NO) bioavailability, limiting interstitial fibrosis, reducing the deposition of advanced glycation end-products (AGEs), and inhibiting myocardial cell apoptosis metformin reduces cardiac remodeling and hypertrophy, and thereby preserves left ventricular systolic and diastolic functions. While a lot of preclinical and clinical studies showed the cardiovascular safety of metformin therapy in diabetic patients and HF, to confirm observed benefits, the specific large-scale trials configured for HF development in diabetic patients as a primary endpoints are necessary.

Keywords: Metformin; diabetes; glucotoxicity; heart failure; lipotoxicity.

Figure 1

The impact of metformin on gluconeogenesis. ADP, adenosine diphosphate; ATP, adenosine triphosphate; NADH, nicotinamide adenine dinucleotide phosphate; PEP, phosphoenolpyruvate. Circles with “−” inside indicate inhibitory effect on the enzyme. Continuous and dotted arrows represent one- and multiple-step reactions, respectively.

Figure 2

The impact of FFA overload on metabolism of the heart. Acetyl-CoA, acetyl coenzyme A; acyl-CoA, acyl coenzyme A; ADP, adenosine diphosphate; ATP, adenosine triphosphate; DAG, diacylglycerol; eNOS, endothelial nitric oxide synthase; FFA, free fatty acids; PDH, pyruvate dehydrogenase; PFK-1, phosphofructokinase 1; PKC, protein kinase C; and TCA, tricarboxylic acid cycle. Continuous and dotted arrows represent one- and multiple-step reactions, respectively. Arrows with circles containing “+” or “−” represent stimulatory and inhibitory effects, respectively.

Figure 3

Regulation of PFK activity in heart failure. ADP, adenosine diphosphate; AMP, adenosine monophosphate; AMPK, AMP activated protein kinase; ATP, adenosine triphosphate; PFK-1, phosphofructokinase 1; PFK-2, phosphofructokinase 2; and Pi, inorganic phosphate. Circles with “+” and “−” represent stimulatory and inhibitory effects, respectively. ↑ and ↓ represent increase and decrease in the concentration of specific compound, respectively.

Figure 4

The effect of metformin on apoptosis. Acetyl-CoA, acetyl coenzyme A; acyl-CoA, acyl coenzyme A; AMPK, AMP-activated protein kinase; LDH, lactate dehydrogenase; PDH, pyruvate dehydrogenase; and SPT, serine palmitoyltransferase. ↑ and ↓ represent increase and decrease in the concentration of specific compound, respectively. Circles with “−” represent inhibitory effect.

Figure 5

Maillard reaction. Carbonyl groups of glucose react with amino groups of proteins (both in dotted frames) to form Schiff bases (yellow) which then are spontaneously converted to Amadori products (yellow). Both of them contribute to formation of low molecular weight reactive dicarbonyls (intermediate products, green) which bind to proteins forming advacned glycation end products (AGEs, red). Continuous and dotted arrows represent one- and multiple-step reactions, respectively.

Figure 6

Different mechanisms of AGE formation. MGO—methylglyoxal, GO—glyoxal, 3-DG—3-deoxyglucosome. Initial, intermediary and terminal steps are shown in yellow, green and orange, respectively. Dotted arrows and lines represent multiple-step reactions.