Diabetes Mellitus and Cardiovascular Diseases: Nutraceutical Interventions Related to Caloric Restriction

Abstract

Type 2 diabetes (T2DM) and cardiovascular disease (CVD) are closely associated and represent a key public health problem worldwide. An excess of adipose tissue, NAFLD, and gut dysbiosis establish a vicious circle that leads to chronic inflammation and oxidative stress. Caloric restriction (CR) is the most promising nutritional approach capable of improving cardiometabolic health. However, adherence to CR represents a barrier to patients and is the primary cause of therapeutic failure. To overcome this problem, many different nutraceutical strategies have been designed. Based on several data that have shown that CR action is mediated by AMPK/SIRT1 activation, several nutraceutical compounds capable of activating AMPK/SIRT1 signaling have been identified. In this review, we summarize recent data on the possible role of berberine, resveratrol, quercetin, and L-carnitine as CR-related nutrients. Additionally, we discuss the limitations related to the use of these nutrients in the management of T2DM and CVD.

Keywords: L-carnitine; berberine; caloric restriction; cardiovascular diseases; diabetes; quercetin; resveratrol.

Figure 1

Schematic representation of the strong interconnection between T2DM and CVD. Excessive adipose depots, gut dysbiosis, and NAFLD are key risk factors that promote T2DM and CVD. At the molecular level, oxidative stress and inflammatory condition are the primary mediators of metabolic and cardiac damages. These processes are orchestrated by AMPK impaired signaling (modified by Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License).

Figure 2

T2DM and CVD: AMPK–SIRT1 signaling cascade. AMPK, the main mediator of CR action, synergically acts with SIRT1. AMPK actives SIRT1, increasing NAD⁽⁺⁾levels, while SIRT1 promotes AMPK activity by Liver Kinase B1 (LKB1). AMPK/SIRT1 regulating the eNOS/NOX ratio increases NO bioavailability and mitigates endothelial dysfunction. Moreover, AMPK and SIRT1 activated PGC-1α, which is the primary factor involved in mitochondrial biogenesis. Then, AMPK/SIRT1/PGC-1α activation counteracts oxidative condition. PPARs are other common targets of SIRT1/AMPK: PPARα activation is related to inflammation, PPARγ, interacting with PGC-1α, improves adipose tissue plasticity and adipose browning tissue. Finally, PPARδ upregulation improves glucose metabolism in skeletal muscle.

Figure 3

CR-related nutrients. Calorie restriction through AMPK/SIRT activation reduces the risk of developing T2DM and CVD. Berberin, resveratrol, quercetin and L-carnitine are also capable of activating AMPK/SIRT1 and therefore could be used as CR mimetics to preserve a healthy cardiometabolic state.