Deficient Autophagy Contributes to the Development of Diabetic Retinopathy

Autophagy is a self-degradation process essential to maintain intracellular homeostasis and cell survival, controlling elimination of pathogens, damage to organelles, and nutrient recycling to generate energy. Alterations in autophagic flux have been reported in the mechanisms of several diseases such as neurodegenerative diseases, cancer, diabetes mellitus, and its associated complications. Diabetic retinopathy (DR) is a microvascular complication of diabetes, affecting nearly 30% of diabetic patients. Several pathways are triggered and repressed in the development of DR, and autophagy showed to be relevant in the pathogenesis of this devastating complication. In this chapter, autophagy’s involvement in the development and progression of DR will be discussed, mainly in retinal pigmented epithelial cells and retinal microvascular endothelial cells, as well as in Müller cells—the more prominent retinal glial cell.

Advanced Glycation End Products: Formation, Role in Diabetic Complications, and Potential in Clinical Applications

Hyperglycemic conditions and disruptions to glucose-regulating pathways lead to increased formation of highly reactive aldehydes, methylglyoxal and glyoxal, which react with certain arginine and lysine residues in proteins to form advanced glycation end products (AGEs). These AGEs damage the integrity of the retinal vasculature predominantly through two mechanisms: non-receptor-mediated damage, which pertains to the interaction with extracellular matrix and its functional properties, and receptor-mediated damage through AGE interactions with their receptors (RAGE) on pericytes and Muller cells. Damage occurring between AGE and RAGE potentially generates reactive oxygen species, inflammatory cytokines, and growth factors. Both mechanisms result in increased permeability of endothelial tight junctions, and this increased permeability can lead to leaking and eventually ischemia. Once this ischemia becomes significant, neovascularization can occur, the hallmark of proliferative diabetic retinopathy. Current pharmaceutical studies have shown the potential of AGE inhibitors, such as aminoguanidine, in decreasing AGE production, thus minimizing its effects in hyperglycemic conditions. Other pharmaceutical interventions, such as Tanshinone IIA, aim to protect cells from the impacts of AGEs. Future research will not only continue to understand the properties of AGEs and their effects on diabetes and diabetic complications like diabetic retinopathy but will also explore how they impact other diseases.

Diabetic Vitrectomy

Diabetic retinopathy (DR) in its advanced stage is a leading cause of blindness and visual impairment. Despite efforts at early detection of DR, disease monitoring, and medical therapy, significant proportions of people living with diabetes still progress to develop the advanced proliferative disease, which is characterized by neovascularization, actively proliferating fibrovascular membranes, and retinal traction. The surgical removal of this proliferating tissue and the treatment of the retinal ischemic drive can be very rewarding, providing significant stability of the retina and in several cases improved retinal anatomy and vision. Diabetic vitrectomy comprises a broad range of surgical techniques and maneuvers, which offer the surgeon and patient opportunity to reverse deranged vitreoretinal anatomy and improve or stabilizes vision. Advances in vitreoretinal technology have contributed greatly to more recent improved outcomes; it is expected that future advances will offer even more benefit.

Diabetic Foot Ulcer: An Easy and Comprehensive Approach

Foot problems are commonly involved in diabetes, and the most common presentation of diabetes is an ulcer. Diabetic foot ulcer is a complex problem caused by reduced blood supply, nerve damage, or infection. But unfortunately in most of cases, these three factors have played a role for impairment of diabetic feet. Sometimes nerve damage or neuropathy is an initial insult, and multiple times ischemia is the leading factor for ulcer formation. After certain period, infection finally supervenes and makes a sterile ulcer to infected leads to loss of limb or foot. This becomes more complicated because of less pronounced ischemic symptoms in diabetic than non-diabetics. Furthermore, the healing of a neuroischemic ulcer is slowed down by microvascular dysfunction. Therefore, some ulcers can get better by revascularization, but pure ischemic ulcers rarely respond to revascularization. Many guidelines have largely ignored these specific demands related to ulcerated neuroischemic diabetic feet. Any diabetic foot ulcer should always be considered to have vascular impairment unless otherwise proven. This chapter highlights the best way to diagnose and treat these patients with diabetic foot ulcer. Most of the studies dealing with neuroischemic diabetic feet are not comparable in terms of patient populations, interventions, or outcomes. Therefore, there is an urgent need for a paradigm shift in diabetic foot care, that is, a new approach and classification of diabetics with foot ulcer in regard to clinical practice and research.

Chronic Limb-Threatening Ischemia (CLTI) in Diabetic Patients: Looking at the Big Picture beyond Wound, Ischemia and Foot Infection (WIfI) Classification System

During the 1990s, most diabetic ulcers were considered neuropathic, but the Eurodiale study showed that more than 50% of these were non-plantar (neuro-ischaemic and ischaemic). According to the International Guidelines, the neuro-ischaemic and ischaemic diabetic foot ulcer (DFU) outcomes are connected to factors related to the wound, leg-associated factors and patients’ comorbidities. We used wound, ischaemia and foot infection (WIfI) classification system; Trans-Atlantic Inter-Society Consensus-II (TASC-II) arterial lesion score; and Kaiser Permanente pyramid (stratification of patients according to their complexity) for assessing these parameters. From February 2011 to June 2012, we collected 124 episodes of neuro-ischaemic and ischaemic active ulcer in 100 patients: 18 required major amputation, 14 of them were in WIfI stage 4 and 4 in WIfI stage 3. Ten patients (over 14 in WIfI stage 4) were classified as TASC-II D. Eight patients (over the same 14) were classified as the higher risk of Kaiser Permanente pyramid. In line with other studies, our data support that the WIfI classification correlates well regarding risk of amputation at 1 year. However, when adding TASC-II and Kaiser Permanente pyramid assessment, the outcome is even more accurate not only for limb salvage but also for patients’ survival.

Matrix Metalloproteinases (MMPs) and Diabetic Foot: Pathophysiological Findings and Recent Developments in Their Inhibitors of Natural as well as Synthetic Origin

Management of diabetic foot remains a major challenge for healthcare system. Though wound healing is a multiphase process and involved multiple biomarkers that acts in stepwise manner, pathophysiology diabetic foot ulcers is still not much clear and need standardization. Matrix metalloproteinases (MMPs) are often linked with non-healing characteristic of diabetic foot ulcers. They play vital roles in various phases of healing process. Major functions are removal of damaged extracellular matrix in inflammatory phase, breakdown of capillary basement membrane prior to angiogenesis and facilitation in fibroblast migration during proliferation phase. For efficient healing, these enzymes are needed in certain amount only. Imbalance of these enzymes leads to excessive degradation which has been linked with the non-healing nature of diabetic ulcers. This chapter will shed light on the role of MMP’s in various phases of wound healing and the inhibitors of MMP’s from natural as well as synthetic origin. It would help researchers and physicians to the understand nature of diabetic foot more clearly and design of strategies for diabetic foot management.

Novel Application of Immunomodulatory Mushroom Polysaccharide (β-Glucan) and Triterpenes for Diabetic Wound Care

β-Glucan and triterpenes are two important derivative compounds from traditional medicinal mushroom, such as Ganoderma lucidum and Antrodia cinnamomea. β-glucan and triterpenes are considered to have immunoregulatory properties in disease treatment for long years. The immunoregulatory effects are usually activated through some transcription of pro-inflammatory genes and possess immunomodulatory activity. Difficulty in healing wound now is a common condition that occurred in diabetic patients, and the physiological hyperglycemic status of diabetic patients resulting in the wounds continue to produce an inflammatory response. Thus, we hope to use β-glucan and triterpenes for difficult wound healing that possess immunomodulatory activity on the wound micro-environment and stimulate the positive effects on healing. In this chapter, these two important derivative compounds from traditional medicinal mushroom were examined by diabetic mammal’s wound healing models. In these models, the skin wounds’ microenvironment is expected close to diabetic foot, suffering in hyperglycemic and inflammatory status. The results are clearly presented, with the immunomodulatory effects from mushroom β-glucan and triterpenes that involved in modulating the cell-mediated immune system to cause cellular proliferation and further to introduce healing performance of the chronic inflammation wounds.

Diagnosis, Treatment, Multidisciplinary Collaborative Therapy and Prevention of Diabetic Foot

Diabetic foot (DF) is one of the most common complications of diabetes. Diabetic foot is one of the main causes of disability and death of diabetic patients, and it is also a major public health problem that causes a heavy burden on society. Diabetic foot involves a variety of factors including peripheral nerve tissue lesions, ischemic lesions, and reduced body immunity. With the development of medical standards, clinical knowledge and treatment of diabetic foot are constantly improving. Early diagnosis and intervention is the key to reducing the incidence of diabetic foot and improving the cure rate. This chapter will briefly introduce the diagnosis, the treatment, the multidisciplinary collaborative therapy and prevention of diabetic foot.

Neurocognitive Dysfunction and Diabetic Foot

Diabetic foot ulcers are one of the most serious complications associated with diabetes. People with diabetes experience an accelerated rate of age-related cognitive decline, and comorbid complications increase the likelihood of neurocognitive attenuation. The current body of research into neurocognitive functioning in individuals with diabetic foot ulcers is small, but suggests significantly increased rates of neurocognitive dysfunction, and that up to one quarter of this cohort have cognitive functioning consistent with dementia samples. This has implications for utilising disease self-management as the primary treatment model. Neurocognitive deficits mean that understanding, retaining, and adhering to management recommendations are likely to be difficult in this group. Further research is needed in this area to determine the specific neurocognitive profile associated with diabetic foot, including which cognitive domains are the most impacted. The provision of a framework for tailoring management strategies to assist this group with more efficacious disease management is also required.