Glycemic control promotes pancreatic beta-cell regeneration in streptozotocin-induced diabetic mice

Abstract

Background: Pancreatic beta-cells proliferate following administration of the beta-cell toxin streptozotocin. Defining the conditions that promote beta-cell proliferation could benefit patients with diabetes. We have investigated the effect of insulin treatment on pancreatic beta-cell regeneration in streptozotocin-induced diabetic mice, and, in addition, report on a new approach to quantify beta-cell regeneration in vivo.

Methodology/principal findings: Streptozotocin-induced diabetic were treated with either syngeneic islets transplanted under the kidney capsule or subcutaneous insulin implants. After either 60 or 120 days of insulin treatment, the islet transplant or insulin implant were removed and blood glucose levels monitored for 30 days. The results showed that both islet transplants and insulin implants restored normoglycemia in the 60 and 120 day treated animals. However, only the 120-day islet and insulin implant groups maintained euglycemia (<200 mg/dl) following discontinuation of insulin treatment. The beta-cell was significantly increased in all the 120 day insulin-treated groups (insulin implant, 0.69+/-0.23 mg; and islet transplant, 0.91+/-0.23 mg) compared non-diabetic control mice (1.54+/-0.25 mg). We also show that we can use bioluminescent imaging to monitor beta-cell regeneration in living MIP-luc transgenic mice.

Conclusions/significance: The results show that insulin treatment can promote beta-cell regeneration. Moreover, the extent of restoration of beta-cell function and mass depend on the length of treatment period and overall level of glycemic control with better control being associated with improved recovery. Finally, real-time bioluminescent imaging can be used to monitor beta-cell recovery in living MIP-luc transgenic mice.

Figure 1. Glycemic Control in Streptozotocin-induced Diabetic Mice.

A. Non-fasted (random) blood glucose throughout the treatment and monitoring phases. B. IPGTT comparing glucose tolerance in 120-day insulin-treated STZ-diabetic mice and non-diabetic controls. Txp – transplant.

Figure 2. Representative pancreatic islets showing insulin staining (brown) in untreated STZ-diabetic mice, non-diabetic control and STZ-diabetic mice treated with insulin implants or islet transplant (txp) under the kidney capsule for 60 or 120 days (40x).

Figure 3. Bioluminescence and Glycemic Control in Streptozotocin-induced Diabetic MIP-luc Mice.

A. Representative bioluminescent images of five MIP-luc transgenic mice made diabetic with STZ and insulin treated by islet transplant under the kidney capsule. B. Bioluminescent signal (photons/sec) during the treatment phase. C. Blood glucose levels during the treatment (120 days) phase.