Abstract
ABSTRACTThe persistent rise in global incidence of type 2 diabetes (T2D) continues to have significant public health and economic implications. The availability of relevant animal models of T2D is critical to elucidating the complexity of the pathogenic mechanisms underlying this disease and the implications this has on susceptibility to T2D complications. Whilst many high-fat diet-induced rodent models of obesity and diabetes exist, growing appreciation of the contribution of high glycaemic index diets on the development of hyperglycaemia and insulin resistance highlight the requirement for animal models that more closely represent global dietary patterns reflective of modern society. To that end, we sought to develop and validate a murine model of T2D based on consumption of an energy-dense diet containing moderate levels of fat and a high glycaemic index to better reflect the aetiopathogenesis of T2D. Male C57BL/6 mice were fed an energy-dense (ED) diet and the development of pathological features used in the clinical diagnosis of T2D was assessed over a 30-week period. Compared with control mice, 87% of mice fed an ED diet developed pathognomonic signs of T2D including glucose intolerance, hyperglycaemia, glycosylated haemoglobin (HbA1c) and glycosuria within 30 weeks. Furthermore, dyslipidaemia, chronic inflammation, alterations in circulating leucocytes and renal impairment were also evident in ED diet-fed mice compared with mice receiving standard rodent chow. Longitudinal profiling of metabolic and biochemical parameters provide support of an aetiologically and clinically relevant model of T2D that will serve as a valuable tool for mechanistic and therapeutic studies investigating the pathogenic complications of T2D.
Highlights
Type 2 diabetes (T2D) continues to be a global health priority with a significant proportion of health care budgets directed to management of T2D and its complications
After 30 weeks of feeding, ED diet mice demonstrated greater visceral (∼sixfold, epididymal and retroperitoneal) and subcutaneous (∼ninefold, inguinal) fat pad mass when compared with control mice fed SD diet (Table 1).Wet tissue weights of liver, spleen and pancreas were significantly greater in mice fed an ED diet for 30 weeks compared with control mice that received a SD diet (Table 1)
ED diet feeding results in increased fasting blood glucose, glycosylated haemoglobin (HbA1c) and glucose intolerance Prior to dietary intervention, fasting blood glucose levels were comparable between groups (SD, 9.6±1.7 mmol l−1 and ED, 10.8± 3.1 mmol l−1; P=0.10)
Summary
Type 2 diabetes (T2D) continues to be a global health priority with a significant proportion of health care budgets directed to management of T2D and its complications. T2D is a multifarious, progressive disease involving a Australian Institute of Tropical Health and Medicine, Division of Tropical Health and Medicine, James Cook University, Townsville, Queensland 4811, Australia. The transition from pre-diabetic states to T2D involves the progressive failure of pancreatic beta (β)cells, involving reduced β-cell mass and increased apoptosis. There is growing appreciation of the convergence of T2D and communicable diseases such as tuberculosis, which account for a significant proportion of global morbidity and mortality (Bridson et al, 2014; Hodgson et al, 2015)
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