Streptozotocin (STZ) high fat diet (HFD) model of diabetes

We have developed a robust and reproducible model of diabetes that combines exposure to a high-fat diet (HFD) with several sequential low doses of streptozotocin (STZ).

HFD induce insulin resistance and STZ specifically targets and destroys the insulin-producing β-cells of the pancreas, resulting in markedly impaired insulin secretion and concomitant hyperglycaemia. This model, established in mice and rats, displays several diabetic complications such as kidney injury similar to that observed in diabetic patients (diabetic nephropathy).

An example of how empagliflozin (an SGLT2 inhibitor) and exenatide (a GLP-1 receptor agonist) influence the diabetic status of the HFD/STZ rat is shown below.

Empagliflozin and, to a lesser extent, exenatide improve glucose tolerance in the HFD/STZ rat model

Empagliflozin, but not exenatide, lower plasma glucose and insulin and blood HbA1c in the HFD/STZ rat model

The STZ/HFD mouse model shows impaired renal function.

Structural changes in kidneys of STZ/HFD rat model indicate initiation of tissue remodelling.

Diabetic Nephropathy

Our model can be used to assess potential treatments of diabetic nephropathy. We can determine the degree of renal impairment with a range of biomarkers including:

• Urinary Biomarkers (Albumin, Creatinine, Protein, TIM-1 and Cystatin-C)
• Plasma Biomarkers (Creatinine and Urea)
• Glomerular Filtration Rate (FITC Insulin Clearance Test)
• Kidney Hypertrophy (Kidney Weight)
• Histopathological Changes e.g. Glomerulosclerosis, tubulo interstitial changes and interstitial and glomerular fibrosis.

Alongside our HFD STZ model, we can also assess kidney function in other models of nephropathy, for example, the ZDF rat.

Diabetic Neuropathy

Diabetic neuropathy can be assessed in animal models of diabetes by measuring:

• Thermal Pain Sensitivity (Hargreaves test). This test measures the latency of an animal to withdraw a hind paw from a radiant heat source
• Mechanical Allodynia (von Frey test). This test determines the threshold at which an animal will withdraw a hind paw from mechanical pressure applied from calibrated von Frey filaments.

We have shown the development of thermal hypoalgesia and mechanical allodynia in STZ-treated rodents maintained on a high-fat diet and db/db mice.

The HFD/STZ mouse exhibits a sustained mechanical allodynia

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