Development and characterisation of a rat model that exhibits both metabolic dysfunction and neurodegeneration seen in type 2 diabetes. (2nd March 2022)

• Record Type: Journal Article
• Authors: Southam, Katherine; de Sousa, Chantal; Daniel, Abraham; Taylor, Bruce V.; Foa, Lisa; Premilovac, Dino
• Is Part Of: Journal of physiology. Volume 600:Number 7(2022)
• Page Start: 1611
• Page End: 1630
• Publication Date: 2022-03-02
• Subjects: high fat diet -- insulin resistance -- obesity -- peripheral neuropathy -- streptozotocin -- type 2 diabetes; Physiology -- Periodicals; 612.005
• DOI: 10.1113/JP282454
• Languages: English
• ISSNs: 0022-3751

Abstract

Abstract : 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. Key points: Type 2 diabetes is a major health concern and markedly increases risk cardiovascular and neurodegenerative diseases. Accurate modelling of type 2 diabetes is a major challenge and has impeded our ability to understand the mechanisms that contribute to complications of type 2 diabetes. We have developed a method of inducing different stages of type 2 diabetes using a high fat/high sugar diet and 14 day infusion of streptozotocin to dose‐dependently destroy pancreatic beta cell mass. Over 4 months, we comprehensively characterised these animals and confirmed that they develop sustained metabolic dysfunction and progressive peripheral neurodegeneration as seen in type 2 diabetes. This new model will improve our ability to investigate the pathophysiological mechanisms that link type 2 diabetes with complications such as neurodegeneration. Abstract : Abstract figure legend The combination of a long‐term high fat diet and 2 week osmotic mini pump infusion of streptozotocin (STZ) enables induction of different stages of type 2 diabetes in rats. This method leads to sustained obesity, dyspidaemia and moderate hyperglycaemia, as well as either hyperinsulinaemia (100 gm kg −1 STZ) or hypoinsulinaemia (120 mg kg −1 STZ), depending on the dose of STZ utilised. Over the course of ∼4 months, these animals develop signs of peripheral nerve degeneration in skin and muscle as seen in type 2 diabetes.