Dimitrios Baltzis

Pathogenesis and Treatment of Impaired Wound Healing in Diabetes Mellitus: New Insights

Diabetic foot ulcers (DFUs) are one of the most common and serious complications of diabetes mellitus, as wound healing is impaired in the diabetic foot. Wound healing is a dynamic and complex biological process that can be divided into four partly overlapping phases: hemostasis, inflammation, proliferative and remodeling. These phases involve a large number of cell types, extracellular components, growth factors and cytokines. Diabetes mellitus causes impaired wound healing by affecting one or more biological mechanisms of these processes. Most often, it is triggered by hyperglycemia, chronic inflammation, micro- and macro-circulatory dysfunction, hypoxia, autonomic and sensory neuropathy, and impaired neuropeptide signaling. Research focused on thoroughly understanding these mechanisms would allow for specifically targeted treatment of diabetic foot ulcers. The main principles for DFU treatment are wound debridement, pressure off-loading, revascularization and infection management. New treatment options such as bioengineered skin substitutes, extracellular matrix proteins, growth factors, and negative pressure wound therapy, have emerged as adjunctive therapies for ulcers. Future treatment strategies include stem cell-based therapies, delivery of gene encoding growth factors, application of angiotensin receptors analogs and neuropeptides like substance P, as well as inhibition of inflammatory cytokines. This review provides an outlook of the pathophysiology in diabetic wound healing and summarizes the established and adjunctive treatment strategies, as well as the future therapeutic options for the treatment of DFUs.

Mast Cells Regulate Wound Healing in Diabetes

Diabetic foot ulceration is a severe complication of diabetes that lacks effective treatment. Mast cells (MCs) contribute to wound healing, but their role in diabetes skin complications is poorly understood. Here we show that the number of degranulated MCs is increased in unwounded forearm and foot skin of patients with diabetes and in unwounded dorsal skin of diabetic mice (P < 0.05). Conversely, postwounding MC degranulation increases in nondiabetic mice, but not in diabetic mice. Pretreatment with the MC degranulation inhibitor disodium cromoglycate rescues diabetes-associated wound-healing impairment in mice and shifts macrophages to the regenerative M2 phenotype (P < 0.05). Nevertheless, nondiabetic and diabetic mice deficient in MCs have delayed wound healing compared with their wild-type (WT) controls, implying that some MC mediator is needed for proper healing. MCs are a major source of vascular endothelial growth factor (VEGF) in mouse skin, but the level of VEGF is reduced in diabetic mouse skin, and its release from human MCs is reduced in hyperglycemic conditions. Topical treatment with the MC trigger substance P does not affect wound healing in MC-deficient mice, but improves it in WT mice. In conclusion, the presence of nondegranulated MCs in unwounded skin is required for proper wound healing, and therapies inhibiting MC degranulation could improve wound healing in diabetes.

Endothelial Dysfunction as a Link Between Cardiovascular Risk Factors and Peripheral Neuropathy in Diabetes.

CONTEXT Cardiovascular risk factors are well-known predictors of the development of diabetic peripheral neuropathy (DPN), which has traditionally been considered as a manifestation of diabetes-associated microangiopathy. Because endothelial dysfunction is strongly associated with all cardiovascular risk factors, we hypothesized that it may be a link between cardiovascular risk factors and DPN. OBJECTIVE The primary objective of this study was to test whether endothelial dysfunction is a predictor of DPN. DESIGN AND SETTING This is a cross-sectional analysis of a cohort composed of patients followed at the Microcirculatory Laboratory, Beth Israel Deaconess Medical Center. PATIENTS Participants with diabetes without DPN (n = 192) and with DPN (n = 166), subjects with prediabetes (n = 75), and nondiabetic controls (n = 59) were included. INTERVENTIONS Endothelial function was assessed with flow-mediated dilation (FMD) of the brachial artery. Inflammatory cytokines and biomarkers of endothelial function (soluble intercellular and vascular cell adhesion molecules) were quantified using a multiplex bead-based immunoassay. Neurological assessment included the neuropathy disability score (NDS). MAIN OUTCOME MEASURE The relationship between FMD and NDS assessed using multiple linear regression. RESULTS In addition to already known risk factors of DPN, FMD was strongly associated with NDS (β = -0.24; P < .001). Sensitivity analysis that removed FMD from the model provided similar results for soluble intercellular cell adhesion molecule-1, another biomarker of endothelial function. Confirmatory factor analysis further showed that endothelial dysfunction is a significant mediator between glycosylated hemoglobin and diabetes duration and diabetic complications. CONCLUSIONS This study shows that endothelial dysfunction occurs early in the pathophysiology of diabetes and is a link between cardiovascular risk factors and DPN.

Obstructive Sleep Apnea and Vascular Diseases.

Obstructive sleep apnea (OSA) affects a large proportion of adults, and is as an independent risk factor for cerebrovascular and cardiovascular disease. The repetitive airway obstruction that characterizes OSA results in intermittent hypoxia, intrathoracic pressure swings, and sleep fragmentation, which in turn lead to sympathetic activation, oxidative stress, inflammation, and endothelial dysfunction. This review outlines the associations between OSA and vascular diseases and describes basic mechanisms that may be responsible for this association, in both the micro- and macrocirculation. It also reports on interventional studies that aim to ameliorate OSA and thereby reduce vascular disease burden.

MRI assessment of regional differences in phosphorus-31 metabolism and morphological abnormalities of the foot muscles in diabetes.

To assess differences in the phosphorus‐31 (31P) metabolism and morphology in multiple muscle regions in the forefoot of diabetic patients and normal subjects.

Vascular Dysfunction, Inflammation, and Exercise in Diabetes

Normal vascular function is characterized by a continuous interaction between the endothelium and vascular smooth muscle that maintains optimal vascular tone and organ perfusion via balanced vasodilatory and vasoconstrictive mechanisms. In an environment of chronic hyperglycemia, such as that occurring in diabetes mellitus, normal vascular function is disrupted most likely due to elevations in reactive oxygen species and the compounding effects of vascular inflammation. Such vascular dysfunctions represent key mechanisms for atherosclerotic changes and primary events in the pathogenesis of cardiovascular disease, which remains the single leading cause of mortality for those with type 1 or type 2 diabetes. Exercise has been described as a cornerstone in the management and treatment of diabetes due to its prominent role in improving both metabolic and cardiovascular health. Evidence suggests that habitual physical activity disrupts chronic hyperglycemic by improving glycemic control via enhanced GLUT protein activation and increased insulin sensitivity. Furthermore, exercise-mediated shear stress may enhance vasodilatory capacity by improving expression of endothelial nitric oxide synthase proteins and enhancing nitric oxide bioavailability. Although some specific precautions must be adhered to when prescribing exercise to diabetic populations, the benefits significantly outweigh the consequences of continuing a sedentary lifestyle. This chapter will present a non-exhaustive review focusing on changes in vascular function and inflammatory status from healthy to diabetic states, techniques that are often implemented to quantify such changes in vascular function, and the role of exercise in improving underlying mechanisms critical to maintaining normal vascular function and disrupting the pathogenesis of cardiovascular disease.

Assessment of telomerase activity in leukocytes of type 2 diabetes mellitus patients having or not foot ulcer: Possible correlation with other clinical parameters

Telomerase is the enzyme that maintains telomere length by adding telomeric repeats after each cell division. Numerous metabolic factors such as obesity, insulin resistance or physical inactivity have been associated with shortened telomeres. In the present study, we assessed telomerase activity in diabetic patients having or not foot ulcer. A total of 90 adult patients with type 2 diabetes mellitus (T2DM) were studied. Patients were allocated into two groups according to the absence or presence of active foot ulcers as follows: Νon-ulcer group (N=58) and ulcer group (N=32). Our data revealed that the patients with diabetic ulcers had significantly greater waist circumference and neuropathy disability score, while exhibiting lower telomerase activity, indicating the possible existence of a common clinical profile among ulcer-bearing diabetic patients. Validation of our findings by extending the study in larger patient groups may contribute to the understanding of T2DM pathophysiology and its main clinical implications.