Chronic wounds are a common complication in patients with diabetes that often lead to amputation. These non-healing wounds are described as being stuck in a persistent inflammatory state characterized by accumulation of pro-inflammatory macrophages, cytokines and proteases. Some medications approved for management of type 2 diabetes have demonstrated anti-inflammatory properties independent of their marketed insulinotropic effects and thus have underappreciated potential to promote wound healing. In this review, the potential for insulin, metformin, specific sulfonylureas, thiazolidinediones, and dipeptidyl peptidase-4 inhibitors to promote healing is evaluated by reviewing human and animal studies on inflammation and wound healing. The available evidence indicates that diabetic medications have potential to prevent wounds from becoming arrested in the inflammatory stage of healing and to promote wound healing by downregulating pro-inflammatory cytokines, upregulating growth factors, lowering matrix metalloproteinases, stimulating angiogenesis, and increasing epithelization. However, no clinical recommendations currently exist on the potential for specific diabetic medications to impact healing of chronic wounds. Thus, we encourage further research that may guide physicians on providing personalized diabetes treatments that achieve glycemic goals while promoting healing in patients with chronic wounds.
Unloading skeletal muscle results in atrophy and weakness. Inhibition of calpain activity during unloading reduced atrophy, but the impact on force generation has not been determined. Our hypothesis was that inhibition of calpain, through muscle-specific overexpression of calpastatin, would prevent the disruption of sarcomere structure and decreased specific force (kN/m(2)) observed during unloading. Calpastatin-overexpressing (cp) and wild-type (wt) mice were subjected to 3, 9, or 14 days of hindlimb suspension (HS). Compared with soleus muscles of non-suspended control mice, soleus muscles of wt mice showed a 25% decline in mass after 14 days of HS while maximum isometric force (P(o)) decreased by 40%, resulting in a specific P(o) that was 35% lower than control values. Over the same time period, muscles of cp mice demonstrated 25% declines in both mass and P(o) but no change in specific P(o). Consistent with the preservation of specific force during HS, soleus muscles of cp mice also maintained a high degree of order in sarcomere structure, in contrast to wt muscles that demonstrated misalignment of z-lines and decreased uniformity of thick filament lengths. Susceptibility to lengthening contraction-induced injury increased with the duration of HS and was not different for muscles of cp and wt mice. We conclude that inhibition of calpain activity during unloading preserves sarcomere structure such that the isometric force-generating capability is not diminished, while the effects of unloading on lengthening contraction-induced injury likely occur through calpain-independent mechanisms.
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