The Skin Remodeling in Type 1 Diabetes and Insulin Resistance Animal Models

Abstract

The skin matrix metalloproteinase 3, tissue inhibitors of matrix metalloproteinase 2 and collagen III content changes in type 1 diabetes and insulin resistance treated with insulin and metformin were studied. Healthy adult male Wistar rats were obtained from experimental animal house, Department of Experimental Pharmacology, Medical University in Bialystok. The rats were divided randomly into five groups of 8 rats each. Control rats were injected intraperitoneally by NaCl. Type IDDM was induced by a single injection of Streptozocin. Insulin resistance was induced by a high-fat diet. The chosen groups of rats were also treated with insulin or metformin. ELISA Kits (USCN Life Science, China) were used to measure content of matrix metallo-proteinase 3 (ELISA Kit for Matrix Metalloproteinase 3 – MMP3), tissue inhibitor of matrix metalloproteinase 2 (ELISA Kit for Tissue Inhibitors of Metalloproteinase 2 – TIMP2) and content of collagen type 3 (ELISA Kit for Collagen Type III – COL3). The results were reported as a median. The statistical significance was defined as p<0.05. Type 1 diabetes and insulin resistance have significantly reduced the quality of the skin, shown by the increase in content of matrix metalloproteinase 3 and the decrease in content of tissue inhibitors of matrix metalloproteinase 2. Type 1 diabetes and insulin resistance have reduced the quality of the skin expressed by type III collagen content decrease but for future studies it is recommend to determine rat interstitial collagenase, MMP-13, as well. Insulin and metformin treatment improved the quality of the diabetic skin, demonstrated by the type III collagen content increase.

Redox Signaling in Diabetic Wound Healing Regulates Extracellular Matrix Deposition

“…Diabetes may also impact collagen fibril diameter, but it remains unclear whether fibril thickness is increased or decreased (123,192). Similar decreases in collagen I and collagen III levels have been reported in diabetic rodent models, and histological analysis reveals degeneration of collagen fibers and disorganized epithelial structure as shown in human skin (39,92,93,146). Real-time PCR analysis has shown increased Col1a2, Col3a1, and Col5a1 gene expression in patients with low skin collagen levels, which suggests post-transcriptional regulation of collagen in diabetes, but most studies report only protein or hydroxyproline content (22,123,192).…”

“…Skin biopsy samples from diabetes patients exhibit increased expression of active MMP-1, MMP-2, and MMP-9, as determined by ELISA and gelatin zymography (95,192). Similarly, MMP-2 and MMP-3 are elevated in the skin in rat models of diabetes (92,93). Wound tissue homogenates from diabetes patients have significantly elevated levels of MMP-2, MMP-3, MMP-8, and MMP-9 compared with nondiabetic controls, and analysis of diabetic wound exudate also demonstrates elevated MMP-2 and MMP-9 (102,177).…”

“…Elevated MMP activity in diabetes is compounded by decreased expression of TIMPs, which bind to and inhibit activated MMPs. TIMP-1 and TIMP-2 levels are decreased at baseline in skin biopsy samples from diabetes patients and rodent models (92,93,192). TIMP-2 is also reduced in diabetic wound homogenates (102).…”

Assessment of the concentration of selected metalloproteinases (MMP-2, MMP-3, MMP-9 and MMP-13) in patients with ulcers as a complication of type 2 diabetes

“…Knaœ et al . detected higher MMP-3 activity in the skin of rats with insulin resistance in type 1 diabetes compared to the control group [ 38 ]. Available literature data indicate the involvement of MMP-3 in the pathogenesis of nephropathy complications in the course of type 1 diabetes.…”

“…The sparsity of data from the literature and promising results of our own research encourage continuation of studies on a larger number of subjects. Research can then be extended to substrates and MMP-3 inhibitors to better understand the role of this metalloproteinase in the development of complications of type 2 diabetes in the form of ulceration – especially since, as mentioned earlier, MMP-3 is involved in the activation of MMP-1, which in turn is involved in wound healing and ulceration in the course of diabetes [ 38 ]. In addition, our own study showed a positive correlation between MMP-2 and MMP-3 in the study group with ulcers in the course of type 2 diabetes, which may indicate the simultaneous secretion of both metalloproteinases in complications of type 2 diabetes, leading to the formation of difficult to heal wounds and ulcers ( Figure 3 ).…”