Effects on Plasma Glucose and Lactate

Abstract

Injection of amylin or amylin agonists, including human and rat amylin, pramlintide, salmon calcitonin, and calcitonin gene-related peptide (CGRP), increases the plasma levels of lactate and glucose in non-diabetic fasting rats and mice. This response can be useful in identifying and defining amylin agonists (amylinomimetic agents) (Cooper et al.) and has been investigated in several studies. Increases in plasma glucose and lactate are not present in all species. In humans, for example, increases in lactate are observed at high pramlintide doses but not at doses that would be used to therapeutically regulate plasma glucose. In species where it occurs, the increase in plasma lactate with amylin is comparable to that observed with exercise or adrenergic agents, and it is distinguishable from the very high levels observed during lactic acidosis (as may occur with biguanides). In contrast to lactic acidosis, the plasma lactate with amylin is derived from skeletal muscle rather than liver. Increases in plasma lactate and glucose in some species may initially appear inconsistent with a glucose-lowering effect of amylin agonists. But glycemic effects are due to actions in skeletal muscle and are present only in some species, whereas glucose-lowering actions are attributable to effects in gastrointestinal systems and are present in all species studied to date. And while glycemic effects are most pronounced in the fasted state, glucose-lowering effects are most pronounced in the postprandial state. Since they were discovered first, effects of higher doses of amylin on plasma glucose, especially in the fasted state, are described first and are related to concomitant changes in plasma lactate. These effects are prominent in rodents but are barely discernible in humans. Effects of lower doses of pramlintide to suppress plasma glucose profiles in the postprandial period are also observable in normal and diabetic rats, however, and are covered here as well. The relationship between plasma lactate and glucose concentrations can be confusing. Via some mechanisms, changes in plasma glucose can drive changes in lactate, while via different mechanisms, changes in lactate can drive changes in glucose concentration. The recursive loop created by these separate links, and for which its discoverers received the Nobel prize, is the Cori cycle (Cori, 1931). This cycle of substrate fluxes, simplified as plasma glucose --> muscle glycogen --> plasma lactate --> liver glycogen --> plasma glucose, is important in the redistribution of carbohydrate fuels in some species (Cori and Cori, 1929) and is discussed here in relation to the role of amylin.