The ABA/LANCL Hormone/Receptor System in the Control of Glycemia, of Cardiomyocyte Energy Metabolism, and in Neuroprotection: A New Ally in the Treatment of Diabetes Mellitus?

Abstract

Abscisic acid (ABA), long known as a plant stress hormone, is present and functionally active in organisms other than those pertaining to the land plant kingdom, including cyanobacteria, fungi, algae, protozoan parasites, lower Metazoa, and mammals. The ancient, cross-kingdom role of this stress hormone allows ABA and its signaling pathway to control cell responses to environmental stimuli in diverse organisms such as marine sponges, higher plants, and humans. Recent advances in our knowledge about the physiological role of ABA and of its mammalian receptors in the control of energy metabolism and mitochondrial function in myocytes, adipocytes, and neuronal cells allow us to foresee therapeutic applications for ABA in the fields of pre-diabetes, diabetes, and cardio- and neuro-protection. Vegetal extracts titrated in their ABA content have shown both efficacy and tolerability in preliminary clinical studies. As the prevalence of glucose intolerance, diabetes, and cardiovascular and neurodegenerative diseases is steadily increasing in both industrialized and rapidly developing countries, new and cost-efficient therapeutics to combat these ailments are much needed to ensure disease-free aging for the current and future working generations.

Keywords: AMPK; LANCL1/2; NO; PGC-1α; Sirt1/3; cardioprotection; hypoxia; mitochondrial proton gradient; neurodegeneration; oxidative stress.

Figure 1

Structure of abscisic acid. Abscisic acid exists in two enantiomers: S-(+)-ABA, which is the predominant form in plants, and R-(−)-ABA. Most studies in mammals employed a racemic mixture. When individually tested on innate immune cells, both ABA enantiomers were similarly effective in the induction of an intracellular Ca²⁺ increase and in stimulating chemotaxis [1].

Figure 2

Non-overlapping functions of ABA and insulin in muscle and adipose tissue. ABA and insulin both stimulate glucose uptake by muscle and adipose tissue. Insulin, via Akt, stimulates the conversion of metabolic energy into storage forms, such as muscle glycogen and fatty acids and white adipocyte triglycerides. Activated Akt inhibits AMPK (blunted red line). Instead, ABA stimulates energy production via increased mitochondrial activity and biogenesis in muscle and adipose cells and thermogenesis. BAT, brown adipose tissue; WAT, white adipose tissue; FA, fatty acids; TG, triglycerides.

Figure 3

The ABA/LANCL system activates the AMPK/PGC-1α/Sirt1-3 axis. By activating the AMPK/PGC-1α/Sirt1-3 axis in myocytes and neuronal cells, the ABA/LANCL system impacts the fundamental physiological functions related to cell glucose uptake and metabolism, mitochondrial biogenesis and function, and protection from oxidative stress. These functions are all called upon to reduce the systemic effects of diabetes. Red arrows indicate increase (right and left panel) or decrease (central panel) of the indicated effects.