Perspective on Hyperglycemic Diabetic Tissue Breakdown

  This research explored the response to a pressure insult in flank tissue of 15 normal control Wistar and 22 DK non-obese diabetic mice with hyperglycemia and without hyperlipidemia. Tissue was harvested 1, 3, 5, 7, and 14 days after applying a pressure of 8 kg over a 3 cm2 area of abdominal flank skin and from contralateral unwounded skin on about 3 mice at each time interval. Less mature, less cross-linked collagen was reported in the hyperglycemic mice intact skin than in control mice and increased depth of tissue damage in response to pressure compared to controls. It was concluded that the tissue of the hyperglycemic diabetic mice was more susceptible to damage than tissue of normal mice.

Clinical Implications

  The authors suggest that if the findings generalize to humans, diabetic individuals with poorly controlled hyperglycemia may be in double jeopardy: risk of delayed healing plus increased susceptibility of hyperglycemic tissue to damage from an insult, which causes limited or partial-thickness damage in normal individuals. Increased susceptibility to damage of hyperglycemic human diabetic skin has been suggested elsewhere¹ and taurine supplements have been shown to alleviate similar effects on collagen in Wistar rats fed a high-fructose diet.² This work adds to an emerging pattern of findings linking hyperglycemic metabolism to skin and collagen abnormalities.   The observation that hyperglycemic mice had less mature, less-cross-linked cutaneous collagen than normal mice and responded to the same pressure density with deeper skin damage may help explain why diabetic tissue breaks down so readily. It opens promising areas of exploration of current or future replacement tissue or ingrowth matrix interventions laced with cross-linked collagen and/or other stronger matrix molecules that refill wounds in diabetic individuals with tissue less susceptible to damage to prevent recurrence. Available literature on skin replacement materials and cytokines that attract healing cells to populate these matrices may offer fruitful areas of synergy for developing tissue replacement options for filling diabetic foot ulcers with more resilient tissue than was there originally.   This research also underscores the vital importance of glycemic control in maintaining health of not only bones, nerves, and blood vessels, but also skin strength.

Limitations

  Clinical challenges remain for the patient with loss of protective sensation (LOPS) as the large and small nerve fibers³ lose function in hyperglycemic environments. These mice were not walking on their wounds, as diabetic individuals with LOPS do. As a result the mouse model used may bear little resemblance to the healing challenges faced by those with diabetic neuropathy and LOPS. Despite this, the impact of hyperglycemia on skin susceptibility to damage is an important finding that can alert patients and clinicians that it is crucial to control blood sugar and protect the skin of those with diabetes—even before neuropathy deprives it of sensation.   This research does not explain the clinical finding that most non-ischemic, non-infected Wagner Grade 1 or 2 (full-thickness) diabetic foot ulcers heal in 12 weeks or less with good consistent total contact cast or “instant” total contact cast off-loading,⁴ yet even shallow Wagner Grade 1 ulcers fail to do so unless offloaded with a non-removable off-loading device.⁵ Healing capacity in diabetic individuals may often be underestimated as it is obscured by inconsistent ulcer off-loading and skin protection. The importance of off-loading cannot be overstated for diabetic individuals with neuropathy.   It seems that at least one more study is needed to prove that hyperglycemia “induced” the effect. There may be several genetically associated differences between the DK and normal group besides hyperglycemia. To prove it is induced by hyperglycemia, one might compare two genetically identical DK groups: one group hyperglycemic, the other kept in good glycemic control (as naturally as possible, eg, with diet and access to activity wheels) from birth through study end. If the result is replicated, then hyperglycemia is the sole variable that could cause the increase in tissue susceptibility to damage.   As scientists, we see what we look for. This tendency may keep us from appreciating the breadth of a discovery. Extracellular matrix (ECM) is made of many multi-functional molecules of varying strength, resilience and capacity to interact with local cells. Is collagen the sole source of the tissue weakness or are there interactions with other ECM molecules? What cell types, if any, populating the ECM are involved in reducing tissue protection? It is tempting to focus on fibroblasts as they synthesize and extrude collagen, but nature is rarely so simple. Could endothelial cells or their partners (smooth muscle cells) be involved in the increased susceptibility in addition to local inflammatory cells the authors discuss? This study opens many avenues of exploration before we may understand the source(s) of this effect.

Conclusion

  Despite these limitations, the research confirms an important dimension to our understanding of hyperglycemic diabetic tissue breakdown and highlights the importance of glycemic control in preserving skin strength for diabetic individuals.

References

1. Solini A, Santini E, Madec S, Cuccato S, Ferrannini E. Effects of endothelin-1 on fibroblasts from type 2 diabetic patients: possible role in wound healing and tissue repair. Growth Factors. 2007;25(6):392–399. 2. Nandhini TA, Thirunavukkarasu V, Ravichandran MK, Anuradha CV. Taurine prevents fructose-diet induced collagen abnormalities in rat skin. J Diabetes Complications. 2005;19(5):305–311. 3. Casellini CM, Vinik AI. Clinical manifestations and current treatment options for diabetic neuropathies. Endocr Pract. 2007;13(5):550–566. 4. Katz IA, Harlan A, Miranda-Palma B, et al. A randomized trial of two irremovable off-loading devices in the management of plantar neuropathic diabetic foot ulcers. Diabetes Care. 2005;28(3):555–559.