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Development and characterisation of a rat model that exhibits both metabolic dysfunction and neurodegeneration seen in type 2 diabetes

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Southam, K ORCID: 0000-0003-3171-6928, de Sousa, C, Daniel, A, Taylor, BVM and Foa, L ORCID: 0000-0003-4131-8341 2022 , 'Development and characterisation of a rat model that exhibits both metabolic dysfunction and neurodegeneration seen in type 2 diabetes' , Journal of Physiology , pp. 1-20 , doi: 10.1113/JP282454.

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Abstract

Accurate modelling type 2 diabetes and diabetic complications in rodents has proven a challenge, largely as a result of the long-time course of disease development in humans. In the present study, we aimed to develop and comprehensively characterise a new rodent model of type 2 diabetes. To do this, we fed Sprague-Dawley rats a high fat/high sugar diet (HFD) to induce obesity and dyslipidaemia. After 3 weeks, we s.c. implanted osmotic mini pumps to enable a 14 day, slow infusion of streptozotocin (STZ; lower dose = 100 mg kg−1; higher dose = 120 mg kg−1) to dose-dependently reduce pancreatic beta cell mass. After removing the mini pumps, we monitored animals for 4 months using a battery of tests to assess both metabolic and neurodegenerative changes across time. Our data demonstrate the combination of the HFD and lower dose STZ leads to induction of early-stage type 2 diabetes defined by moderate hyperglycaemia, hyperinsulinaemia and impaired glucose tolerance, at the same time as the retention of an obese phenotype. By contrast, combining the HFD and higher dose STZ leads to induction of later-stage type 2 diabetes defined by frank hyperglycaemia, hypoinsulinaemia (but not insulin depletion) and severely impaired glucose tolerance, at the same time as retaining an obese phenotype. Regardless of dose of STZ (and level of hyperglycaemia), all diabetic rats exhibited signs of peripheral neurodegeneration in the skin and muscle. Thus, this model recapitulates many of the complex metabolic disturbances seen in type 2 diabetes and provides an excellent platform for investigating the pathophysiological mechanisms that lead to diabetic complications such as peripheral neuropathy.

Item Type: Article
Authors/Creators:Southam, K and de Sousa, C and Daniel, A and Taylor, BVM and Foa, L
Keywords: Type 2 diabetes, obesity, animal model, neurodegeneration
Journal or Publication Title: Journal of Physiology
Publisher: Wiley-Blackwell Publishing Ltd
ISSN: 0022-3751
DOI / ID Number: 10.1113/JP282454
Copyright Information:

2022 The Authors. This is an open access article under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) License, (https://creativecommons.org/licenses/by/4.0/) which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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