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

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.

Shorea roxburghii Leaf Extract Ameliorates Hyperglycemia Induced Abnormalities in High Fat/Fructose and Streptozotocin Induced Diabetic Rats

“…The combination of high fat diet/high sugar with STZ has been extensively used for establishing T2DM animal models. This model has been reported to represent the pathogenesis of T2DM in humans . Typical symptoms experienced in T2DM animal models including increase in FGB, polyphagia, polydipsia and body weight reduction were evidently observed in all the diabetic rat groups.…”

“…The animals were fed with the HFD/HF for four weeks. After four weeks of dietary manipulation with HFD/HF solution, rats were fasted overnight and injected with freshly prepared solution of STZ (35 mg/kg) dissolved in 0.1 m of citrate buffer (pH 4.5) via intraperitoneal route . Three days after the administration of STZ, blood was obtained from the tail veins of the rats in other to measure the fasting blood glucose levels (FBG) with the aid of a glucose meter (Accu Check Performa, Roche Diagnostics, Germany).…”

Effects of Anchomanes difformis on Inflammation, Apoptosis, and Organ Toxicity in STZ-Induced Diabetic Cardiomyopathy

“…High dosage of STZ has been reported to result in complete destruction of the beta cells, a model of type I diabetes. Recent studies report the effective use of low doses of STZ to induce insulin resistance, a model of type II diabetes (T2D) [25][26][27]. Administration of 10% fructose for two weeks followed by 40 mg/kg BW of STZ was demonstrated by Wilson and Islam to cause partial destruction of the beta cells and insulin resistance in rats, which are typical of T2D [28].…”

Effects of allyl isothiocyanate on insulin resistance, oxidative stress status, and transcription factors in high‐fat diet/streptozotocin‐induced type 2 diabetes mellitus in rats

“…Therefore, the current work was carried out to examine the beneficial properties of AITC on insulin resistance, oxidative stress, and transcription factors in T2DM induced by high‐fat diet (HFD)/streptozotocin (STZ) in rats. We used the HFD/STZ model as it is more efficient in establishing a T2DM rat model similar to human nonhemotoxic diabetes …”