338-LB: ACh Esterase Is a Novel Regulator of Insulin Secretion in Human Islets

Abstract

The neurotransmitter acetylcholine (ACh) plays a major role in regulating insulin secretion. While in several species parasympathetic innervation provides cholinergic input to beta cells, it is the glucagon secreting alpha cell the major source of ACh in human islets. It is still unclear, however, what is the contribution of cholinergic signaling to beta cell function in humans. Here we analyzed how ACh impacts human beta cell function and insulin secretion, using a combination of in vitro and in vivo approaches. To determine the effect of endogenous ACh in insulin secretion, we manipulated ACh esterase activity using different inhibitors such as pyridostigmine and galantamine. Inhibition of ACh esterase led to a significant increase in insulin secretion in isolated human islets in perifusion experiments. To assess the effect of endogenous ACh on human beta cell function in vivo, we transplanted human islets into the anterior chamber of immunocompromised Nude mice. ACh esterase activity was inhibited by local administration of the ACh esterase inhibitor pyridostigmine as eye drops. To control that the inhibitor was entering the anterior chamber of the eye and reaching the islets, we measured the effect it had on pupil size. 30 microM pyridostigmine induced approximately a 20-30% reduction in pupil size. Importantly, mice treated with 30 microM pyridostigmine showed decreased glucose excursion curves and slightly increased insulin levels 15 min after glucose injection. These results indicate that endogenously released ACh from human alpha cells increases insulin secretion from beta cells in vitro and in vivo. ACh esterase is potential novel target for the treatment of diabetes in humans. Disclosure A.M. Tamayo: None. A. Caicedo: None. Funding American Diabetes Association (1-17-ICTS-052 to A.C.)