Investigation of Naturally Occurring Single-Nucleotide Variants in Human TAAR1

Abstract

Activation of trace amine-associated receptor 1 (TAAR1) in endocrine pancreas is involved in weight regulation and glucose homeostasis. The purpose of this study was the identification and characterization of potential TAAR1 variants in patients with overweight/obesity and disturbed glucose homeostasis. Screening for TAAR1 variants was performed in 314 obese or overweight patients with impaired insulin secretion. The detected variants were functionally characterized concerning TAAR1 cell surface expression and signaling properties and their allele frequencies were determined in the population-based Study of Health in Pomerania (SHIP). Three heterozygous carriers of the single nucleotide missense variants p.Arg23Cys (R23C, rs8192618), p.Ser49Leu (S49L, rs140960896), and p.Ille171Leu (I171L, rs200795344) were detected in the patient cohort. While p.Ser49Leu and p.Ille171Leu were found in obese/overweight patients with slightly impaired glucose homeostasis, p.Arg23Cys was identified in a patient with a complete loss of insulin production. Functional in vitro characterization revealed a like wild-type function for I171L, partial loss of function for S49L and a complete loss of function for R23C. The frequency of the R23C variant in 2018 non-diabetic control individuals aged 60 years and older in the general population-based SHIP cohort was lower than in the analyzed patient sample. Both variants are rare in the general population indicating a recent origin in the general gene pool and/or the consequence of pronounced purifying selection, in line with the obvious detrimental effect of the mutations. In conclusion, our study provides hints for the existence of naturally occurring TAAR1 variants with potential relevance for weight regulation and glucose homeostasis.

3-Iodothyronamine and Derivatives: New Allies Against Metabolic Syndrome?

“…The carrier of R23C showed complete loss of insulin production, while the other two carriers were obese/overweight patients with a slight impairment of glucose homeostasis. Accordingly, the functional in vitro characterization of the 3 variants revealed a complete loss of function for R23C, while S49L only partially impaired receptor signaling, and I171L had no effect [96]. Albeit needing confirmation, these findings seem to agree with the hypothesis that there is a balance between T1AM inhibitory and stimulatory effects on glucose-induced insulin secretion in pancreatic β-cells.…”

Trace Amines and Their Receptors

“…Importantly, the effect on insulin secretion was only seen at elevated glucose concentrations, thereby reducing the risk for induction of hypoglycemia. Very recently, signal transduction-altering single nucleotide polymorphisms of TAAR1 were reported in some patients with impaired insulin secretion and were suggested to be a possible predisposing factor for dysfunctional glucose homeostasis (Mühlhaus et al, 2017). The potential utility of TAAR1 agonists was further supported by studies in rodent models of type 2 diabetes mellitus (Table 6).…”

Identification of a subset of trace amine-associated receptors and ligands as potential modulators of insulin secretion

“…Importantly TAAR1 agonists maintain efficacy in vivo, where improved glucose tolerance has been observed, along with increased insulin secretion in response to a glucose challenge [21]. Furthermore, single nucleotide polymorphisms of TAAR1 that result in altered signal transduction were recently reported in a sub-set of patients exhibiting impaired insulin secretion [22]. These studies therefore suggest that TAAR1 may be a novel therapeutic target to treat type 2 diabetes.…”

“…This is an area for future systematic study. In addition, studies on the status of TAAR gene expression in human diabetic patients are also needed, although as noted earlier signal-modifying TAAR1 polymorphisms have recently been linked to impaired insulin secretion in certain patients [22].…”