Influence of a HTR2B Stop Codon on Glucagon Homeostasis and Glucose Excursion in Non-Diabetic Men

Abstract

Limited data are available about the role of the serotonin 2B (5-HT2B) receptor in the function of human islets. This study aimed to test whether the 5-HT2B receptor contributes to glucose, insulin, and glucagon homeostasis in humans, utilizing a hereditary loss-of-function gene mutation in the receptor, which causes a 50% reduction in the production of the receptor protein in heterozygotes. This clinical study enrolled participants recruited by newspaper advertisements and from mental status examinations. A cohort of participants from a young Finnish founder population composed of 68 non-diabetic males with a mean age of 30 was divided into groups for comparison based on being a 5-HT2B receptor loss-of-function gene mutation ( Q20*) heterozygote carrier (=11) or not (=57). Serum levels of glucose, insulin, and glucagon were measured in a 5 h oral glucose tolerance test using a 75 g glucose challenge. Insulin resistance, insulin sensitivity, and beta cell activity were calculated using the homeostasis model assessment (HOMA2) and whole body insulin sensitivity index (WBISI), as well as the ratio of glucagon to insulin was noted. The areas under the curves (AUCs) were also determined. Concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) were measured in cerebrospinal fluid (CSF). Covariate adjusted mean score comparisons were applied. Lower glucagon secretion and decreased glucose excursion were observed among Q20* carriers as compared with individuals who were homozygotes for the wild-type Q20 allele (controls). No differences in insulin secretion, beta cell activity, insulin resistance, or insulin sensitivity were observed. The glucagon to insulin ratio differed between the Q20* carriers and controls. CSF levels of 5-HIAA were similar between groups. Our findings indicate that the 5-HT2B receptor may contribute to the regulation of human glucagon and glucose homeostasis and the interplay between glucagon and insulin secretion.

The effects of a HTR2B stop codon and testosterone on energy metabolism and beta cell function among antisocial Finnish males

“…The regression lines crossed approximately at the testosterone level 27 nmol/L in our sample, which left 10% of the total sample above this pivotal point. Although our results are preliminary and correlative, the results suggest that the effect of testosterone on energy metabolism may partly be dependent of serotonergic mechanisms similar to the relationship between serotonin and insulin-related metabolism (Bennet et al, 2016;Tikkanen et al, 2016). Our results may describe a biochemical physiologic mechanism as the sample was homogeneous and likely exhibited only small variance in behavior.…”

“…Indeed, preliminary evidence that was mostly obtained from animal study settings suggest that serotonin (5-HT) is involved in the control of islet function and links to insulin resistance (IR) (Bennet et al, 2015;Saunders et al, 2014). Moreover, some studies imply that functional silencing of the serotonin 2B (5-HT2B) receptor may have protective effects on risk for IR and type 2 diabetes (T2D) because the function of the receptor seems to alter islet function and glucose homeostasis (Bennet et al, 2016;Kim et al, 2010Kim et al, , 2015Tikkanen et al, 2016;Yamada et al, 1998). However, the role of the G q -coupled serotonin 5-HT2B receptor in human somatic health is poorly characterized, but in psychiatric research studies the 5-HT2B receptor has been recently shown to exert the following tangible effects on human behavior and psychiatric symptoms: increased impulsive behavior, alcoholrelated problem-behavior, emotional dysregulation, mood disorders, and anxiety (Bevilacqua et al, 2010;Tikkanen et al, 2015).…”