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. 2016 Jun 2;11(6):e0156346.
doi: 10.1371/journal.pone.0156346. eCollection 2016.

Short- and Longterm Glycemic Control of Streptozotocin-Induced Diabetic Rats Using Different Insulin Preparations

Gerd Luippold  1 , Jessica Bedenik  1 , Anke Voigt  1 , Rolf Grempler  2
Affiliations

Short- and Longterm Glycemic Control of Streptozotocin-Induced Diabetic Rats Using Different Insulin Preparations

Gerd Luippold et al. PLoS One. .

Abstract

The chemical induction of diabetes with STZ has gained popularity because of the relative ease of rendering normal animals diabetic. Insulin substitution is required in STZ-rats in long-term studies to avoid ketoacidosis and consequently loss of animals. Aim of the present studies was to test different insulin preparations and different ways of administration in their ability to reduce blood glucose in STZ-induced diabetic rats. Single dosing of the long-acting insulin analogue glargine was able to dose-dependently reduce blood glucose over 4 h towards normoglycemia in STZ-treated rats. However, this effect was not sustained until 8 h post injection. A more sustained glucose-lowering effect was achieved using insulin-releasing implants. In STZ-rats, 1 insulin implant moderately lowered blood glucose levels 10 days after implantation, while 2 implants induced normoglycemia over the whole day. According to the glucose-lowering effect 1 as well as 2 insulin implants significantly reduced HbA1c measured after 26 days of implantation. In line with the improved glucose homeostasis due to the implants, urinary glucose excretion was also blunted in STZ-treated rats with 2 implants. Since diabetic nephropathy is one of the complications of longterm diabetes, renal function was characterized in the STZ-rat model. Increases in creatinine clearance and urinary albumin excretion resemble early signs of diabetic nephropathy. These functional abnormalities of the kidney could clearly be corrected with insulin-releasing implants 27 days after implantation. The data show that diabetic STZ-rats respond to exogenous insulin with regard to glucose levels as well as kidney parameters and a suitable dose of insulin implants for glucose control was established. This animal model together with the insulin dosing regimen is suitable to address diabetes-induced early diabetic nephropathy and also to study combination therapies with insulin for the treatment of type 1 diabetes.

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Conflict of interest statement

Competing Interests: This work was supported by Boehringer Ingelheim Pharma GmbH & Co. KG. There are no patents, products in development or marketed products to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Dose-response curve of insulin glargine (1.5, 3, 4.5, 6 IU/animal) in STZ-diabetic rats over 8 h; normoglycemia is indicated by the dotted line.
* p<0.05, ** p<0.01, *** p<0.001 vs. control.
Fig 2
Fig 2. The calculated 8 h-blood glucose AUC (AUC0-8h) of STZ-rats (n = 5 per group).
*** p<0.001 vs. control.
Fig 3
Fig 3. Blood glucose profile in STZ-diabetic rats 10 days after implantation of insulin implants (0.5, 1, 1.5, 2 implants/animal); normoglycemia is indicated by the dotted line.
* p<0.05, ** p<0.01, *** p<0.001 vs. control.
Fig 4
Fig 4. The calculated 12 h-blood glucose AUC (AUC0-12h) of STZ-rats (n = 5 per group).
* p<0.05, ** p<0.01, *** p<0.001 vs. control.
Fig 5
Fig 5. Blood glucose profile in STZ-diabetic rats 26 days after implantation of insulin implants (1 or 2 implants/animal; n = 7 per group); normoglycemia is indicated by the dotted line.
* p<0.05, ** p<0.01, *** p<0.001 vs. control.
Fig 6
Fig 6. Blood HbA1c in STZ-diabetic rats on day 0 and 26 days after implantation of insulin implants (1 or 2 implants/animal; n = 7 per group).
* p<0.05, *** p<0.001 vs. control; + p<0.05, +++ p<0.001 vs. day 0.
Fig 7
Fig 7. Blood ketone profile in STZ-diabetic rats 26 days after implantation of insulin implants (1 or 2 implants/animal; n = 7 per group).
* p<0.05, ** p<0.01, *** p<0.001 vs. control.
See this image and copyright information in PMC

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