How lactic acid regulates insulin/glucagon secretion: hypoxia, obesity, and diabetes
Posted May 04 2009 12:43am
How lactic acid regulates insulin/glucagon secretion and How hypoxia causes elevated blood pressure, obesity, and diabetes mellitus
Transmembrane movement of lactate has two pathways, simple diffusion and H + -lactate facilitated diffusion through monocarbohydrate transporter(MCT), both electrogenic but in opposing direction. Since facilitated efflux of lactate-H + generates outward current, for it to occur, meaningful concentration of lactic acid is needed to overcome the pullback force by membrane potential. Efflux of H + -lactate by facilitated diffusion alkalizes near by granule docking site, which is able to trigger exocytosis by disrupting granule Ca 2+ store.
Islet β cell produces tiny amount of lactic acid, presumed to be short in materializing facilitated diffusion. The only option is by simple diffusion, generating inward electric current, which eventually progresses to action potential with help of elevated glucose level and closure of ATP sensitive K + channel.
On the contrary, metabolism in α cell is reported to be predominated by anaerobic glycolysis. Lactate production rate in α cell is presumed to be high enough to employ hybrid of simple diffusion, generating inward current; and facilitated diffusion generating outward current. The competence between these two different diffusion pathways dictates the electrical behavior of α cell. At high level of glucose, membrane can be hyperpolarized due to growing amount of H + -lactate facilitated diffusion which in turn boosts granule exocytosis by alkalizing nearby docking site.
Hypoxia can be far more prevalent than commonly perceived. Each of such health risking factors as hyperlipidimia, hyperglycemia, and overproduction of free radicals can cause hypoxia by decreasing deformability of erythrocyte, resulting in lower filterability.As compensation to decreased deformability of erythrocyte, elevated blood pressure is required to meet the oxygen demand by brain.
Hypoxia influences secretion of insulin and glucagon by upregulating production of lactic acid, which causes hyperinsulinemia and either upregulates or downregulates secretion of glucagon depending on degree of hypoxia and glucose level. Adipocyte is highly expressed of insulin receptor, at the same magnitude as hepatocyte. Therefore growing plasma insulin by hypoxia is in favor for building-up of fat at adipocyte.
Hypoxia imposes constant oxidative stress to islet β cell which is by design in favor of oxidative phosphorylation. Long term exposure to hypoxia may play a role in failure of β cell, which leads to diabetes mellitus.
Lastly, adrenaline is discussed for its possible role in genesis of distinct type of diabetes mellitus.