Investigation of the metabolic phenotype and metformin response of ATM heterozygous mice

Abstract

Metformin, as an anti-hyperglycaemic drug, is commonly prescribed for type 2 diabetes (T2D) treatment. However, 35% of patients experience adverse reactions to metformin and some patients that tolerate metformin do not respond with glucose lowering. The identification of biomarkers that inform of metformin response in patients is important as it may ensure metformin is prescribed when most effective.
A pharmacogenetic study by Zhou et al. (2011) studied metformin treatment in T2D patients and determined an association between metformin response and single nucleotide polymorphism (SNP) rs11212617 (minor allele: C). This SNP was linked with the gene Ataxia Telangiectasia Mutated (ATM) as mutations in the ATM gene cause Ataxia Telangiectasia (A-T) and patients have been reported to develop insulin resistance and hyperglycaemia.
Metformin response was studied in C57BL/6J (WT) male mice fed high fat diet (HFD) and B6.129S6-ATMtm1Awb/J heterozygous (ATM+/-) male mice fed HFD through the use of metabolic phenotyping techniques such as body composition analysis, glucose tolerance test, insulin tolerance test and calorimetric monitoring. This study design also allows assessment of the metabolic phenotype of the ATM+/- genotype mice.
ATM+/- mice gained more weight than WT mice over 22 weeks of HFD feeding (F(1,24) = 14.540, p0.001 (WT HFD: n=8 ATM+/- HFD: n=8)) as a result of increased fat accumulation (WT HFD: 12.24g ± 1.874 (n=8); ATM+/- HFD: 19.19g ± 1.249 (n=8) p0.0081). ATM+/- mice fed HFD also exhibited worse glucose tolerance than WT mice fed HFD (F(62.207,10.347) = 6.012, p0.001 (WT HFD: n=8; ATM+/- HFD: n=8), worse insulin sensitivity (F(1,14) = 6.826, p0.020 (ATM+/- HFD: n=8; WT HFD: n=8)) and an increased respiratory exchange ratio (F(1,28) = 5.196, p0.030 (ATM+/- HFD: n=8; WT HFD: n=8)). This indicates that ATM deficiency causes metabolic disruption.
Investigation of metformin response in WT and ATM+/- genotypes suggests an overall effect of metformin on glucose tolerance after 6 weeks of metformin treatment (delivered through diet (114mg/kg)) (F(1,28) = 5.919, p0.022 (WT Vehicle: n=8; WT Metformin: n=8; ATM+/- Vehicle: n=8; ATM+/- Metformin: n=8)) and that metformin improved glucose tolerance in the ATM+/- mice to a greater extent than WT mice (F(1,28) = 4.359, p0.046 (WT Vehicle: n=8; WT Metformin: n=8; ATM+/- Vehicle: n=8; ATM+/- Metformin: n=8)). However, an overall effect of metformin response was not observed in any other parameters; the metformin dose was lower than the metformin dose used by studies in the literature which described metformin response in a number of parameters measured in this study. Furthermore, plasma metformin concentration in the mice 1548ng/mL ± 271.4 (n=6) was lower compared to plasma metformin concentration measured in T2D patients (2700ng/mL); this suggests that the metformin dose delivered in this study was not at an effective magnitude. Consequently, while ATM+/- mice appear more sensitive to metformin the lack of response in the WT mice in parameters where metformin response may be expected suggests this is not conclusive.

Date of Award	2017
Original language	English
Supervisor	Rory McCrimmon (Supervisor) & Calum Sutherland (Supervisor)