The effects of a HTR2B stop codon and testosterone on energy metabolism and beta cell function among antisocial Finnish males
Introduction
Comorbidities of psychiatric and metabolic disorders are frequent. For example, more than 25% of individuals diagnosed with diabetes also suffer from depression (Lustman and Clouse, 2005). The combined impact of metabolic and psychiatric disorders decreases daily executive performance and quality of life, causes severe organ complications, and increases mortality, which support a rationale to further examine metabolic pathophysiologies associated with distinct psychiatric disorders. ASPD is a psychiatric disorder, with a prevalence of 1% (Lenzenweger et al., 2007), which is linked to an inherently impulsive lifestyle that puts ASPD patients at risk for metabolic disorders because of challenges in maintaining a healthy diet and physical exercise. A Finnish violent offender population saturated with ASPD individuals has been shown to exhibit elevated basal insulin levels (Ojala et al., 2015).
In addition to the clinical hypothesis that patients with ASPD are at an increased risk for insulin-related pathophysiologies, we also hypothesized that the serotonergic pathway could alter insulin secretion and glucose homeostasis. 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., 2010, Kim et al., 2015, Tikkanen et al., 2016, Yamada et al., 1998). However, the role of the Gq-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, alcohol-related problem-behavior, emotional dysregulation, mood disorders, and anxiety (Bevilacqua et al., 2010, Tikkanen et al., 2015).
To examine the effects of the serotonergic pathway, we studied heterozygous carriers of a 5-HT2B receptor gene mutation (HTR2B Q20*) detected in a Finnish young founder population (Bevilacqua et al., 2010). HTR2B Q20* is a point-mutation of the 5-HT2B receptor gene, which is located at 2q36-q37. The mutation results in interrupted expression of the 5-HT2B receptor in lymphoblastoid cells, which results in a 50% reduction of the expression of the receptor protein in heterozygous individuals (Bevilacqua et al., 2010). The prevalence of the hereditary HTR2B Q20* is relatively high (2.2%) in the Finnish general population. Testosterone was included in analyzes because testosterone levels has been suggested to be elevated in HTR2B knockout mice and heterozygous HTR2B Q20* carriers in comparison to carriers of the wild type allele (Bevilacqua et al., 2010). Also, reduced testosterone levels have been associated with IR, T2D and obesity (Haffner et al., 1994, Jones, 2010).
Section snippets
Subjects and subgroups
Subjects were obtained from a genotyped cohort that included Finnish alcoholic violent offenders, their relatives, along with healthy controls who were recruited by newspaper advertisements; the cohort included a total of 875 subjects. This cohort was collected to detect biological risk factors for psychiatric disorders and impulsive behaviors. All subjects diagnosed with ASPD that had participated in an oral glucose tolerance test (OGTT) were included without pre-selection, resulting in a
Measurements of glucose, insulin, IR, IS, beta cell activity, AUCs, and testosterone
No subjects exhibited pathological fasting or OGTT glucose values (i.e., impaired fasting glucose, IGT, or diabetes). However, ASPD subjects without HTR2B Q20* had increased IR, decreased IS, and high beta cell activity values; a significant difference in AUCs was observed between the groups. Table 1 and Fig. 1 display the most notable differences between groups. Testosterone levels were equal between groups.
Effects of metabolic predictors and age on BMI, IR, IS and beta cell activity
The multiple regression analyses were adjusted for age, BMI (not in the model where BMI
Discussion
Our main finding in the larger cohort of ASPD subjects without HTR2B Q20* was that they exhibited an IR-like state characterized by high IR, low IS, and high beta cell activity indices, even though they were non-obese and normoglycemic. IGT was not observed during the OGTT. Thus, it is notable that the glucose levels at the 2 h measurements in the OGTT among ASPD subjects without HTR2B Q20* were not sufficiently aberrant to claim clinically diagnostic IR or T2D. However, the combination of an
Authors’ contributions
M.V contributed to the design of the study. R.T and M.V contributed to the structuring of the data and planning the focus of analysis. R.T had full access to all data and takes responsibility for data analysis. R.T, M.V, and T.S contributed to the disposition of the manuscript. M.K contributed with sampling and laboratory analyses. All authors contributed i) to the drafting of the manuscript, ii) intellectual assessment of the work, and iii) read the manuscript and approved the contributions.
Role of funding source
This work was supported by the Orion Research Foundation, Swedish Research Council (project number: 2012-1552 to M.F), and Waldemar von Frenckell Foundation. Excellence in diabetes research (EXODIAB), Krapperup foundation, Åke Wiberg foundation, Royal Physiographic Society, Albert Påhlsson foundation, Crafoord foundation, Childhood Diabetes Foundation, and the Foundation of Sigurd and Elsa Golijes Minne.
Conflicts of interest
All authors claim no conflict of interest.
Acknowledgements
We would like to thank the peer reviewers for providing scientific guidance. We greatly appreciate the epidemiologic perspectives provided by Profs. Leif Groop and Jaakko Kaprio. We also thank the benevolent activity of the several institutions mentioned as funding sources.
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2020, Handbook of Behavioral NeuroscienceCitation Excerpt :The mechanism of 5-HT2B receptor modulation of insulin release involves downstream changes in cellular calcium flux that enhance mitochondrial metabolism (Bennet et al., 2016). Humans with a loss-of-function mutation in the 5-HT2B receptor gene show lower GSIS compared to noncarriers (Tikkanen et al., 2016), and polymorphisms of 5-HT2A and 2C receptor genes are associated with plasma glucose concentrations and the acute insulin response to a glucose load (Kring et al., 2009). However, the effect of 5-HT2B receptor activation might be context specific because prolonged activation results in impaired GSIS (Cataldo et al., 2017) and the selective serotonin reuptake inhibitor (SSRI) fluoxetine inhibits insulin secretion in association with oxidative damage and an increased risk for type 2 diabetes (Almaca et al., 2016; Brown, Majumdar, & Johnson, 2008; De Long, Hyslop, Raha, Hardy, & Holloway, 2014).
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