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

Abstract

Herein, we examined insulin resistance (IR), insulin sensitivity (IS), beta cell activity, and glucose metabolism in subjects with antisocial personality disorder (ASPD), and whether the serotonin 2B (5-HT2B) receptor and testosterone have a role in energy metabolism. A cohort of subjects belonging to a founder population that included 98 ASPD males, aged 25-30, was divided into groups based on the presence of a heterozygous 5-HT2B receptor loss-of-function gene mutation (HTR2B Q20*; n = 9) or not (n = 89). Serum glucose and insulin levels were measured in a 5 h oral glucose tolerance test (75 g) and indices describing IR, IS, and beta cell activity were calculated. Body mass index (BMI) was also determined. Concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid were measured in cerebrospinal fluid, and testosterone levels from serum. An IR-like state comprising high IR, low IS, and high beta cell activity indices was observed among ASPD subjects without the HTR2B Q20* allele. By contrast, being an ASPD HTR2B Q20* carrier appeared to be preventive of these pathophysiologies. The HTR2B Q20* allele and testosterone predicted lower BMI independently, but an interaction between HTR2B Q20* and testosterone lead to increased insulin sensitivity among HTR2B Q20* carriers with low testosterone levels. The HTR2B Q20* allele also predicted reduced beta cell activity and enhanced glucose metabolism. Reduced 5-HT2B receptor function at low or normal testosterone levels may be protective of obesity. Results were observed among Finnish males having an antisocial personality disorder, which limits the generality.

Serotonergic regulation of insulin secretion

“…In vitro results regarding the Htr2 family are more in line with the anticipated mechanism of action; as these receptors couple to Gα q protein following intracellular activation of the phospholipase C pathway, with a subsequent increase in intracellular Ca 2+ , an increase in insulin secretion would hence be anticipated following activation of the Htr2 family, and antagonist treatment would inhibit insulin release. Corroborating in vitro results, it was recently shown that humans carrying a loss‐of‐function mutation in the HTR2B gene (HTR2B Q20*) secrete less insulin compared with non‐carriers after an oral glucose load . This suggests that loss of Htr2b influences insulin secretion in vivo in humans.…”