Genetics of Feline Diabetes Mellitus

Diabetes mellitus (DM) is a common feline endocrinopathy that resembles human type 2 DM. In both species, genetic and environmental factors likely play a role in disease susceptibility.

 

This project was divided into two parts: a clinical study investigating exenatide extended-release (EER), a GLP-1 analogue, as a potential therapeutic for feline DM, and a genetics study to identify genetic risk factors for DM in domestic shorthair (DSH) and Burmese cats (a highly susceptible breed).

 

Twenty-four cats (EER n=11; placebo n=13) were enrolled onto a randomised, double-blinded, placebo-controlled clinical trial examining the effect of monthly injections of EER on β-cell function (BCF) and glycaemic control. EER treatment did not have an effect, but both glycaemic control (assessed by serum fructosamine) and BCF (assessed by glucagon stimulation testing) improved over the 6-month trial period.

 

In the first part of the genetics study, results from a recent genome-wide association study (GWAS) were used to identify potential candidate DM susceptibility genes. Based on their location near GWAS ‘hits’, the coding sequences and predicted regulatory regions of TMEM18, ACP1 and DPP9 were sequenced in diabetic and control cats. DM-associated SNPs were identified in the promoter region of ACP1, which encodes an enzyme involved in insulin signalling, and their functional impact was confirmed using a luciferase reporter assay in a myoblast cell line.  Further combined GWAS data analysis, using genotypes of both DSH and Burmese cats was performed using various statistical models. Here, candidate diabetes susceptibility genes located near the GWAS SNPs showing the strongest association with DM or Burmese breed were DPP9, ACP1, CDK6 (associated with DM in both breeds), DPP10, KLF13 (associated with DM in DSH)and AGBL4 (associated with Burmese breed).

 

Finally, whole genome sequencing (WGS) was performed in four diabetic and four non-diabetic Burmese and two DSH cats to identify novel diabetes-associated variants. Data were analysed using a bespoke GATK-based pipeline, and prioritized by various criteria including potential impact, gene function and allele frequency in diabetic or Burmese cats. Allele frequencies of variants in the 99Lives database of 282 cats were also used to assist with prioritization. In a follow up study, 130 candidate diabetes susceptibility variants were genotyped in 100 diabetic and non-diabetic Burmese and DSH cats. This revealed several novel diabetes-associated variants, some of which were exclusive to Burmese cats. Identification of novel genetic associations in feline diabetes has the potential to reveal novel therapeutic targets in this common condition.