Combination of high-fat/high-fructose diet and low-dose streptozotocin to model long-term type-2 diabetes complications

David André Barrière,Geneviève Roussy,Christophe Noll,Philippe Sarret,Jean-Michel Longpré,Anissa Kessai,Nicolas Beaudet,Karyn Kirby,André C Carpentier,Pedro Geraldes,Farah Lizotte,Karine Belleville

doi:10.1038/s41598-017-18896-5

David André Barrière, Geneviève Roussy + Show 10 more

Open Access

https://doi.org/10.1038/s41598-017-18896-5

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Journal: Scientific Reports	Publication Date: Jan 11, 2018
Citations: 112	License type: open-access

Affiliation: Université de Sherbrooke

Abstract

The epidemic of type 2 diabetes mellitus (T2DM) is fueled by added fructose consumption. Here, we thus combined high-fat/high-fructose diet, with multiple low-dose injections of streptozotocin (HF/HF/Stz) to emulate the long-term complications of T2DM. HF/HF/Stz rats, monitored over 56 weeks, exhibited metabolic dysfunctions associated with the different stages of the T2DM disease progression in humans: an early prediabetic phase characterized by an hyperinsulinemic period with modest dysglycemia, followed by a late stage of T2DM with frank hyperglycemia, normalization of insulinemia, marked dyslipidemia, hepatic fibrosis and pancreatic β-cell failure. Histopathological analyses combined to [18F]-FDG PET imaging further demonstrated the presence of several end-organ long-term complications, including reduction in myocardial glucose utilization, renal dysfunction as well as microvascular neuropathy and retinopathy. We also provide for the first time a comprehensive µ-PET whole brain imaging of the changes in glucose metabolic activity within discrete cerebral regions in HF/HF/Stz diabetic rats. Altogether, we developed and characterized a unique non-genetic preclinical model of T2DM adapted to the current diet and lifestyle that recapitulates the major metabolic features of the disease progression, from insulin resistance to pancreatic β-cell dysfunction, and closely mimicking the target-organ damage occurring in type 2 diabetic patients at advanced stages.

Highlights

Type 2 diabetes is a long-term metabolic disorder that represents a global public health challenge, affecting industrialized countries, and increasing drastically in developing nations[1]
This second phase was characterized by a frank fasting and post-intraperitoneal glucose tolerance test (IPGTT) hyperglycemia (Fig. 1A,B, P < 0.001), high triglyceride concentrations (Fig. 1E, P < 0.001), higher levels of plasma fructosamine (Fig. 2A, P < 0.001) and glycated hemoglobin (HbA1c) (Fig. 2B, P < 0.01), as well as pancreatic beta-cell dysfunction leading to insulinopenia and decrease in C-peptide levels (Fig. 1C,D, P < 0.05)
Data gathered in clinical trials present compelling evidence to suggest that added sugar and especially added fructose provided from high-fructose corn syrup are posing a serious and growing public health problem, worsening the epidemic of type 2 diabetes[1,8,9]

Summary

Introduction

Type 2 diabetes is a long-term metabolic disorder that represents a global public health challenge, affecting industrialized countries, and increasing drastically in developing nations[1]. We propose to combine the main diet stressors encountered in the human population, namely high fat/ high fructose diet, with multiple low-dose injections of Stz to study the long-term complications associated with the development of T2DM. To determine if this new animal model is advantageous to closely mimic the human condition, we monitored during 56 weeks the effects of this HF/HF/Stz regimen on the time-course metabolic changes as well as on the end-organ damage

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Results

Conclusion