To many people, diabetes connotes problems with the pancreas, insulin and sugar balance. Few associate the disease with difficulty healing wounds. Yet, chronic wounds and tissue death are life-threatening problems faced by many people with diabetes. Because the wound-healing phenotypes of diabetes mouse models have been poorly characterized, choosing appropriate models for wound-healing research has been difficult. To address this problem, a research group led by Thomas Mustoe, M.D., from the Laboratory for Wound Repair and Regenerative Medicine, Northwestern University, analyzed and compared the wound-healing phenotypes of four diabetes mouse models (Fang et al. 2010).
The pathophysiology of diabetes-related wound-healing problems is complex and poorly understood. Most of the research has been conducted using type 1 or monogenic type 2 diabetes models, like the db/db mouse strain BKS.Cg-Dock7m +/+ Leprdb/J . However, type 1 diabetes accounts for only 5-10% of all diabetes cases in the U.S., and the extreme obesity, insulin resistance and hyperglycemia, along with the defective leptin/leptin receptor axis of the db/db model, are not representative of the most common diabetes phenotypes in the general population. Emerging polygenic models, such as NONcNZO10/LtJ, exhibit more moderate diabetes phenotypes and have an intact leptin/leptin receptor axis. Thus, the Mustoe team assessed and compared the wound healing phenotypes of the NONcNZO mouse and three other commonly used diabetes mouse models:
- The "Akita" mouse, strain C57BL/6-Ins2Akita/J – a model of type 1 diabetes
- The streptozotocin (STZ)-induced C57BL/6J mouse – a model of type 1 diabetes
- The db/db mouse – a monogenic model of type 2 diabetes
To account for the different responses to various wound types among mouse models of diabetes, Mustoe and his team assessed how these models respond to three major wound types.
- Cuts. An "incision model" was used to assess collagen deposition in, and the breaking strength of, a healed wound.
- Open wounds. A "splinted excisional model" was used to assess re-epithelialization and granulation tissue deposition in an open wound.
- Ischemia/reperfusion (I/R) injury. A "compression model" was used to assess the repetitive conditions that lead to I/R skin injury.
To avoid the confounding influence of aging, Mustoe and his team conducted all experiments using young adult mice. To ensure that the wound-healing phenotypes of each model were assessed at comparable stages of diabetes progression, each model was kept in a chronic diabetic state for at least eight weeks before experiments began. The research team's results are shown in the table below (adapted from Fang et al. 2010, Table 2).
Wound |
Impaired Wound Healing in Four Diabetes Models |
|||
Akita | STZ-induced | db/db | NONcNZO/LtJ | |
---|---|---|---|---|
Cuts |
No |
Yes |
Yes |
Yes |
Open Wounds |
No |
No |
Yes |
Yes |
I/R Injury |
No |
No |
No |
Yes |
*Control for the Akita mouse: B6J
Control for the STZ-induced mouse: B6J
Control for the db/db mouse: C57BLKS/J
Control for the NONcNZO10/LtJ mouse: NON/ShiLtJ
All three wound types heal normally in the Akita strain. Whereas only cuts heal poorly in the STZ-induced diabetes model, and only cuts and open wounds heal poorly in the db/db model, all three types of wounds heal poorly in the NONcNZO10/LtJ model. Conclusions about these results must be drawn cautiously. Just as a single model does not sufficiently replicate diabetes, a single model does not replicate diabetes-associated wound-healing impairment. However, the monogenic nature and extreme phenotypes of the db/db strain may reduce its effectiveness as a wound-healing model. In contrast, the polygenic nature and multiple wound healing deficits of the NONcNZO10/LtJ strain might make it a more clinically relevant model.
Reference
Fang RC, Kryger ZB, Buck II DW, De La Garza M, Galiano RD, Mustoe TA. 2010. Limitations of the db/db mouse in translational wound healing research: Is the NONcNZO10 polygenic mouse model
superior? Wound Repair Regen Oct 18. doi: 10.1111/j.1524-475X.2010.00634.