Screening for prediabetes in senior cats and metabolomic characteristics of obesity and Burmese cats

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Type 2 diabetes is the most common form of diabetes in humans and cats, and senior age and obesity are major risk factors. Diabetes is typically diagnosed in cats once clinical signs are evident. In humans, prediabetes is a metabolic state between normal glucose homeostasis and diabetes, and is diagnosed by demonstrating impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG). However, prediabetes has not yet been defined in cats, and reference values for these variables have not been reported for senior cats.In this thesis, the first experiment investigated if the current practice of dosing glucose by bodyweight results in spurious effects on measures of glucose tolerance in obese cats. Glucose data from glucose tolerance and insulin sensitivity tests were analysed before and after 16 cats were fed ad libitum for 9 - 12 months to promote weight gain. Bodyweight and body condition score (BCS) were positively correlated with 2-min, 2-h glucose concentrations and glucose half-life following a glucose tolerance test (GTT) when glucose dosing was by bodyweight. To avoid obese cats being incorrectly classified as having impaired glucose tolerance when glucose was dosed on a bodyweight basis, equations were developed to adjust either glucose dose or 2-h glucose to compensate for obesity. This has important implications for clinical studies assessing the effects of interventions on glucose tolerance when lean and obese cats are compared.The second experiment established methodology and cutpoints for fasting and 2-h glucose during a GTT in healthy, client-owned senior cats (> 8yrs, n=78), by using ear/ paw samples and a portable glucose meter calibrated for feline blood. Fasting blood glucose was measured from ear/paw samples and glucose (0.5 g/kg bodyweight) administered IV, followed by blood glucose measurements at 2 min and 2 h. Cutpoints for fasting and 2-h glucose con were established as the upper limits of 95% reference intervals using cats with BCS 4 or 5 on a 9-point scale and were 6.5 mmol/L for fasting glucose and 9.8 mmol/L for 2-h glucose.The third experiment established a methodology and reference interval for screening blood glucose in senior cats. Blood glucose was measured at the beginning of the consultation in clinically healthy cats (≥8 years, n=120) from an ear/ paw sample using a portable glucose meter, and again after physical examination from a jugular sample. The cutpoint for screening blood glucose was 10.5 mmol/L. Mean screening blood glucose was greater than mean fasting glucose. Based on these results, it is recommended that cats with screening blood glucose from 6.5 mmol/L to 10.5 mmol/L be retested several hours later, and cats with screening values >10.5 mmol/L or a second test > 6.5 mmol/L should have fasting and 2-h blood glucose measured after overnight hospitalization.Metabolomic markers of obesity and prediabetes have been investigated in humans, but there is limited data available in cats. Additionally, there is limited research on metabolomics in Burmese cats, which are reported to have dyslipidaemia and are 3- 4 times more likely to develop diabetes than domestic cats. The last two experiments in the thesis address the effect of obesity and the Burmese breed on the metabolome.A study was performed to identify metabolomic changes associated with obesity in senior cats, and to determine if such metabolites are associated with biochemical measures of abnormal glucose metabolism. Biochemical and GC-MS analyses were performed on blood samples from 21 lean and 18 obese non-Burmese cats. In obese cats, metabolomic analysis identified increased fatty acids (palmitoleic and myristoleic), glycerol, glycolic acid, and phenylanine, whilst only the amino acid alanine was decreased. Palmitoleic acid was positively, and alanine negatively correlated (p<0.05) with leptin concentrations, and glycolic acid and glycerol were positively associated (p<0.05) with insulin. This study is the first to report on metabolomic changes of obesity in senior cats.The final study examined metabolomic differences between Burmese (n=19) and non-Burmese cats (n=30) by GC-MS analysis. In Burmese cats many glucogenic amino acids, together with hydroxyproline and aminobutyric acids were increased, whilst beta-alanine was decreased. Fructose and glucose, cholesterol and some fatty acids, glycerol-3- hosphate and various acids were all decreased in Burmese cats. Urea was also increased in Burmese. Burmese cats had increased insulin, triglyceride, and MCP-1 concentrations which had moderate positive associations with amino acids. Numerous relationships were identified between GC-MS metabolites and measures of glucose metabolism. This study is the first to report metabolite differences between healthy senior non-Burmese and Burmese cats. The findings in this thesis have established the test methodology and reference intervals for fasting and screening blood glucose and glucose tolerance in senior cats. These results have direct application to clinical practice to facilitate earlier diagnosis of prediabetes in cats. Additionally, the identification of metabolite differences in cats associated with obesity or Burmese breed represents potential new biomarkers of metabolic dysfunction in cats at high risk of developing diabetes.