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.
Lower extremity ulcerations represent a major complication in diabetes mellitus and involve multiple physiological factors that lead to impairment of wound healing. Neuropeptides are neuromodulators ...implicated in various processes including diabetic wound healing. Diabetes causes autonomic and small sensory nerve fibers neuropathy as well as inflammatory dysregulation, which manifest with decreased neuropeptide expression and a disproportion in pro- and anti- inflammatory cytokine response. Therefore to fully understand the contribution of autonomic nerve dysfunction in diabetic wound healing it is crucial to explore the implication of neuropeptides. Here, we will discuss recent studies elucidating the role of specific neuropeptides in wound healing.
Diabetic foot ulceration (DFU) is a devastating complication of diabetes whose pathogenesis remains incompletely understood. Here, we profile 174,962 single cells from the foot, forearm, and ...peripheral blood mononuclear cells using single-cell RNA sequencing. Our analysis shows enrichment of a unique population of fibroblasts overexpressing MMP1, MMP3, MMP11, HIF1A, CHI3L1, and TNFAIP6 and increased M1 macrophage polarization in the DFU patients with healing wounds. Further, analysis of spatially separated samples from the same patient and spatial transcriptomics reveal preferential localization of these healing associated fibroblasts toward the wound bed as compared to the wound edge or unwounded skin. Spatial transcriptomics also validates our findings of higher abundance of M1 macrophages in healers and M2 macrophages in non-healers. Our analysis provides deep insights into the wound healing microenvironment, identifying cell types that could be critical in promoting DFU healing, and may inform novel therapeutic approaches for DFU treatment.
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.
Decreased arterial flow-mediated dilation, a marker of endothelial dysfunction, occurs early in the pathophysiology of diabetes and is a link between cardiovascular risk factors and DPN.
Objectives In this study, we have investigated the effects of cannabidiol (CBD) on myocardial dysfunction, inflammation, oxidative/nitrative stress, cell death, and interrelated signaling pathways, ...using a mouse model of type I diabetic cardiomyopathy and primary human cardiomyocytes exposed to high glucose. Background Cannabidiol, the most abundant nonpsychoactive constituent of Cannabis sativa (marijuana) plant, exerts anti-inflammatory effects in various disease models and alleviates pain and spasticity associated with multiple sclerosis in humans. Methods Left ventricular function was measured by the pressure-volume system. Oxidative stress, cell death, and fibrosis markers were evaluated by molecular biology/biochemical techniques, electron spin resonance spectroscopy, and flow cytometry. Results Diabetic cardiomyopathy was characterized by declined diastolic and systolic myocardial performance associated with increased oxidative-nitrative stress, nuclear factor-κB and mitogen-activated protein kinase (c-Jun N-terminal kinase, p-38, p38α) activation, enhanced expression of adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1), tumor necrosis factor-α, markers of fibrosis (transforming growth factor-β, connective tissue growth factor, fibronectin, collagen-1, matrix metalloproteinase-2 and -9), enhanced cell death (caspase 3/7 and polyadenosine diphosphate-ribose polymerase activity, chromatin fragmentation, and terminal deoxynucleotidyl transferase dUTP nick end labeling), and diminished Akt phosphorylation. Remarkably, CBD attenuated myocardial dysfunction, cardiac fibrosis, oxidative/nitrative stress, inflammation, cell death, and interrelated signaling pathways. Furthermore, CBD also attenuated the high glucose-induced increased reactive oxygen species generation, nuclear factor-κB activation, and cell death in primary human cardiomyocytes. Conclusions Collectively, these results coupled with the excellent safety and tolerability profile of CBD in humans, strongly suggest that it may have great therapeutic potential in the treatment of diabetic complications, and perhaps other cardiovascular disorders, by attenuating oxidative/nitrative stress, inflammation, cell death and fibrosis.
We examined the role of vascular function and inflammation in the development and failure to heal diabetic foot ulcers (DFUs). We followed 104 diabetic patients for a period of 18.4 ± 10.8 months. At ...the beginning of the study, we evaluated vascular reactivity and serum inflammatory cytokines and growth factors. DFUs developed in 30 (29%) patients. DFU patients had more severe neuropathy, higher white blood cell count, and lower endothelium-dependent and -independent vasodilation in the macrocirculation. Complete ulcer healing was achieved in 16 (53%) patients, whereas 13 (47%) patients did not heal. There were no differences in the above parameters between the two groups, but patients whose ulcers failed to heal had higher tumor necrosis factor-α, monocyte chemoattractant protein-1, matrix metallopeptidase 9 (MMP-9), and fibroblast growth factor 2 serum levels when compared with those who healed. Skin biopsy analysis showed that compared with control subjects, diabetic patients had increased immune cell infiltration, expression of MMP-9, and protein tyrosine phosphatase-1B (PTP1B), which negatively regulates the signaling of insulin, leptin, and growth factors. We conclude that increased inflammation, expression of MMP-9, PTP1B, and aberrant growth factor levels are the main factors associated with failure to heal DFUs. Targeting these factors may prove helpful in the management of DFUs.
Diabetic foot ulceration is a major complication of diabetes. Substance P (SP) is involved in wound healing, but its effect in diabetic skin wounds is unclear. We examined the effect of exogenous SP ...delivery on diabetic mouse and rabbit wounds. We also studied the impact of deficiency in SP or its receptor, neurokinin-1 receptor, on wound healing in mouse models. SP treatment improved wound healing in mice and rabbits, whereas the absence of SP or its receptor impaired wound progression in mice. Moreover, SP bioavailability in diabetic skin was reduced as SP gene expression was decreased, whereas the gene expression and protein levels of the enzyme that degrades SP, neutral endopeptidase, were increased. Diabetes and SP deficiency were associated with absence of an acute inflammatory response important for wound healing progression and instead revealed a persistent inflammation throughout the healing process. SP treatment induced an acute inflammatory response, which enabled the progression to the proliferative phase and modulated macrophage activation toward the M2 phenotype that promotes wound healing. In conclusion, SP treatment reverses the chronic proinflammatory state in diabetic skin and promotes healing of diabetic wounds.
ABSTRACT
Objective. To facilitate the clinician’s understanding of the basis and treatment of painful diabetic neuropathy (PDN).
Background. PDN is one of several clinical syndromes in patients ...with diabetic peripheral neuropathy (DPN) and presents a major challenge for optimal management.
Methods. A systematic review of the literature was undertaken for articles specific to PDN, using Medline databases between 1966 and 2007.
Results. The epidemiology of PDN has not been well established and on the basis of available data the prevalence of pain is 10% to 20% in patients with diabetes and from 40% to 50% in those with diabetic neuropathy. It has a significant impact on the quality of life and health care costs. Pathophysiologic mechanisms underlying PDN are similar to other neuropathic pain disorders and are broadly characterized as peripheral and central sensitization. The natural course of PDN is variable, with many patients experiencing spontaneous improvement and resolution of pain. Hyperglycemia‐induced pathways result in nerve dysfunction and damage, which lead to hyperexcitable peripheral and central pathways of pain. Glycemic control may prevent or partially reverse DPN and modulate PDN. Quantifying neuropathic pain is difficult, especially for clinical trials, although this has improved recently with the development of neuropathic pain‐specific tools, such as the Neuropathic Pain Questionnaire and the Neuropathic Pain Symptom Inventory. Current therapeutic options are limited to symptomatic treatment and are similar to other types of neuropathic pain.
Conclusions. A better understanding of the peripheral and central mechanisms resulting in PDN is likely to promote the development of more targeted and effective treatment.
Context:
The dipeptidyl peptidase-4 inhibitor, linagliptin, possesses pleiotropic vasodilatory, antioxidant, and anti-inflammatory properties in animals, independent of its glucose-lowering ...properties. Although large, randomized clinical trials are being conducted to better evaluate the efficacy and safety of linagliptin on cardiovascular outcomes, little is known about its effects on vascular function in humans.
Objective:
This study sought to evaluate the effect of linagliptin on surrogates of vascular and mitochondrial function.
Design and Setting:
This was a randomized, double-blind, placebo-controlled trial at a tertiary care center with a large type 2 diabetes referral base.
Patients and Intervention:
Forty participants with type 2 diabetes were included in a 12-wk treatment of either linagliptin 5mg/d or placebo.
Main Outcome Measures:
Micro- and macrovascular functions were assessed using laser Doppler coupled with iontophoresis and with brachial flow-mediated dilation, respectively. Mitochondrial function was assessed by phosphorus-31 metabolites changes in the calf muscle measured by magnetic resonance spectroscopy. Circulating endothelial progenitor cells, as well as inflammatory cytokines, growth factors, and biomarkers of endothelial function were also quantified.
Results:
Linagliptin was associated with an increase in axon reflex-dependent vasodilation, a marker of neurovascular function (P = .05). A trend indicating increased endothelium-dependent microvascular reactivity was observed (P = .07). These were associated with decreases in concentrations of IFNγ (P < .05), IL-6 (P = .03), IL-12 (P < .03), and MIP-1 (P < .04) following linagliptin treatment when compared with placebo.
Conclusions:
This study demonstrates that linagliptin tends to improve endothelial and neurovascular microvascular function and is associated with decreased markers of inflammation in patients with type 2 diabetes. There was no significant effect of linagliptin on mitochondrial function, macrovascular function, or endothelial progenitor cells.
This randomized, placebo-controlled trial shows that linagliptin decreases inflammation and improves microvascular function in patients with type 2 diabetes.
Percent Change in Wound Area of Diabetic Foot Ulcers Over a 4-Week Period Is a Robust Predictor of Complete Healing in a 12-Week
Prospective Trial
Peter Sheehan , MD 1 ,
Peter Jones , MSC 2 ,
...Antonella Caselli , MD 3 ,
John M. Giurini , DPM 3 and
Aristidis Veves , MD 3
1 Diabetes Foot and Ankle Center, Hospital for Joint Diseases Orthopaedic Institute, New York University School of Medicine,
New York, New York
2 With Confidence Ltd., Surrey, U.K.
3 Joslin-Beth Israel Deaconess Foot Center and Microcirculation Laboratory, Department of Surgery, Beth Israel-Deaconess Medical
Center, Harvard Medical School, Boston, Massachusetts
Abstract
OBJECTIVE —To assess the ability of the 4-week healing rate to predict complete healing over a 12-week period in a large prospective
multicenter trial of diabetic patients with foot ulceration.
RESEARCH DESIGN AND METHODS —We examined the change in ulcer area over a 4-week period as a predictor of wound healing within 12 weeks in patients who
were seen weekly in a prospective, randomized controlled trial.
RESULTS —Wound area measurements at baseline and after 4 weeks were performed in 203 patients. The midpoint between the percentage
area reduction from baseline at 4 weeks in patients healed versus those not healed at 12 weeks was found to be 53%. Subjects
with a reduction in ulcer area greater than the 4-week median had a 12-week healing rate of 58%, whereas those with reduction
in ulcer area less than the 4-week median had a healing rate of only 9% ( P < 0.01). The absolute change in ulcer area at 4 weeks was significantly greater in healers versus nonhealers (1.5 vs. 0.8
cm 2 , P < 0.02). The percent change in wound area at 4 weeks in those who healed was 82% (95% CI 70–94), whereas in those who failed
to heal, the percent change in wound area was 25% (15–35; P < 0.001).
CONCLUSIONS —The percent change in foot ulcer area after 4 weeks of observation is a robust predictor of healing at 12 weeks. This simple
tool may serve as a pivotal clinical decision point in the care of diabetic foot ulcers for early identification of patients
who may not respond to standard care and may need additional treatment.
Footnotes
Address correspondence and reprint requests to Aristidis Veves, MD, Joslin Beth Israel Deaconess Foot Center, One Deaconess
Rd., Boston, MA 02215. E-mail: aveves{at}caregroup.harvard.edu .
Received for publication 4 December 2002 and accepted in revised form 25 February 2003.
P.J. is a paid statistical consultant for Ethicon Ltd. P.S. and A.V. have been members of advisory panels for and have received
honoraria and research grants from Johnson & Johnson Wound Management/Ethicon.
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.
DIABETES CARE
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