Current Diabetes Reviews - Volume 17, Issue 4, 2021

Worldwide, diabetes ranks among the ten leading causes of mortality. Prevalence of diabetes is growing rapidly in low and middle income countries. It is a progressive disease leading to serious co-morbidities, which results in increased cost of treatment and over-all health system of the country. Pathophysiological alterations in Type 2 Diabetes (T2D) progressed from a simple disturbance in the functioning of the pancreas to triumvirate to ominous octet to egregious eleven to dirty dozen model. Due to complex interplay of multiple hormones in T2D, there may be multifaceted approach in its management. The ‘long-term secondary complications’ in uncontrolled diabetes may affect almost every organ of the body, and finally may lead to multi-organ dysfunction. Available therapies are inconsistent in maintaining long term glycemic control and their long term use may be associated with adverse effects. There is need for newer drugs, not only for glycemic control but also for prevention or mitigation of secondary microvascular and macrovascular complications. Increased knowledge of the pathophysiology of diabetes has contributed to the development of novel treatments. Several new agents like Glucagon Like Peptide - 1 (GLP-1) agonists, Dipeptidyl Peptidase IV (DPP-4) inhibitors, amylin analogues, Sodium-Glucose transport -2 (SGLT- 2) inhibitors and dual Peroxisome Proliferator-Activated Receptor (PPAR) agonists are available or will be available soon, thus extending the range of therapy for T2D, thereby preventing its long term complications. The article discusses the pathophysiology of diabetes along with its comorbidities, with a focus on existing and novel upcoming antidiabetic drugs which are under investigation. It also dives deep to deliberate upon the novel therapies that are in various stages of development. Adding new options with new mechanisms of action to the treatment armamentarium of diabetes may eventually help improve outcomes and reduce its economic burden.

Background: Diabetic foot ulcer (DFU) is one of the leading complications of type-2 diabetes mellitus. It is associated with neuropathy and peripheral arterial disease of the lower limb in patients with diabetes. There are four stages of wound healing, namely hemostasis phase, inflammatory phase, proliferative phase and maturation phase. In the case of DFU, all these stages are disturbed which lead to delay in healing and consequently to lower limb amputation. Conventional dosage forms like tablets, creams, ointments, gels and capsules have been used for the treatment of diabetic foot ulcer for many years. Introduction: In this review, the global prevalence as well as etiopathogenesis related to diabetic foot ulcer have been discussed. The potential role of various synthetic and herbal drugs, as well as their conventional dosage forms in the effective management of DFU have been discussed in detail. Methods: Structured search of bibliographic databases from previously published peer-reviewed research papers was explored and data has been represented in terms of various approaches that are used for the treatment of DFU. Results: About 148 papers, including both research and review articles, were included in this review to produce a comprehensive as well as a readily understandable article. A series of herbal and synthetic drugs have been discussed along with their current status of treatment in terms of dose and mechanism of action. Conclusion: DFU has become one of the most common complications in patients having diabetes for more than ten years. Hence, understanding the root cause and its successful treatment is a big challenge because it depends upon multiple factors such as the judicious selection of drugs as well as proper control of blood sugar level. Most of the drugs that have been used so far either belong to the category of antibiotics, antihyperglycaemic or they have been repositioned. In clinical practice, much focus has been given to dressings that have been used to cover the ulcer. The complete treatment of DFU is still a farfetched dream to be achieved and it is expected that combination therapy of herbal and synthetic drugs with multiple treatment pathways could be able to offer better management of DFU.

Diabetic Mellitus (DM) is a metabolic disorder that is concerning for people all over the world. DM is caused due to lack of insulin or ineffective production of insulin in the pancreas. A total of 463 million people were reported to have diabetes mellitus in 2019 and this number is predicted to rise up to 578 million by the year 2030 and 700 million by 2045. High blood sugar gives rise to many complications like diabetic retinopathy, diabetic nephropathy, atherosclerosis, hypercoagulability, cardiovascular disease, coronary heart disease, abdominal obesity, hypertension, hyperlipidemia, cerebrovascular disease, coronary artery disease, foot damage, skin complications, Alzheimer’s disease, hearing impairment, and depression. These life-threatening complications make diabetes more severe than other diseases. Many synthetic drugs have been developed, but still, a complete cure is not provided by any of the molecules. Continuous use of some synthetic agents causes severe side effects, and thus the demand for non-toxic, affordable drugs still persists. Traditional treatments have been an extremely valued source of medicine all over human history. These are extensively used throughout the world, indicating that herbs are a growing part of modern and high-tech medicines. The World Health Organization (WHO) has listed a total of 21,000 plants, which are used for medicinal purposes around the world. Among them, more than 400 plants are available for the treatment of diabetes. Despite the fact that there are many herbal drugs available for treating diabetes, only a small number of these plants have undergone scientific and medical evaluation to assess their efficacy. Trigonella foenum-graecum, Allium sativum, Caesalpinia bonduc, Ferula assafoetida,etc., are some of the medicinal plants used for antidiabetic therapy. The presence of phenolic compounds, flavonoids, terpenoids, and coumarins is responsible for the antidiabetic nature of the medicinal plants. These constituents have shown a reduction in blood glucose levels. Pycnogenol, acarbose, miglitol, and voglibose are some of the examples of marketed drugs, which are obtained from natural origin and used as antidiabetic drugs. The active principles derived from the plants work through many antidiabetic mechanisms, which include inhibition of α-glucosidase, α-amylase, and protein tyrosine phosphatase 1B activities. One of the major advantages of herbal drugs is the low level of side effects attributed to these medicines, and this attracted various researchers to develop new molecules for the treatment of diabetes. In this review, recent advances in the field of herbal drugs to treat diabetes, prevent secondary complications from arising due to diabetes, and various herbal molecules in different stages of clinical trials will be emphasized upon.

Modern lifestyle, changing eating habits and reduced physical work have been known to culminate into making diabetes a global pandemic. Hyperglycemia during the course of diabetes is an important causative factor for the development of both microvascular (retinopathy, nephropathy and neuropathy) and macrovascular (coronary artery disease, stroke and peripheral artery disease) complications. In this article, we summarize several mechanisms accountable for the development of both microvascular and macrovascular complications of diabetes. Several metabolic and cellular events are linked to the augmentation of oxidative stress like the activation of advanced glycation end products (AGE) pathway, polyol pathway, Protein Kinase C (PKC) pathway, Poly-ADP Ribose Polymerase (PARP) and hexosamine pathway. Oxidative stress also leads to the production of reactive oxygen species (ROS) like hydroxyl radical, superoxide anion and peroxides. Enhanced levels of ROS rescind the anti-oxidant defence mechanisms associated with superoxide dismutase, glutathione and ascorbic acid. Moreover, ROS triggers oxidative damages at the level of DNA, protein and lipids, which eventually cause cell necrosis or apoptosis. These physiological insults may be related to the microvascular complications of diabetes by negatively impacting the eyes, kidneys and the brain. While underlying pathomechanism of the macrovascular complications is quite complex, hyperglycemia associated atherosclerotic abnormalities like changes in the coagulation system, thrombin formation, fibrinolysis, platelet and endothelial function and vascular smooth muscle are well proven. Since hyperglycemia also modulates the vascular inflammation, cytokines, macrophage activation and gene expression of growth factors, elevated blood glucose level may play a central role in the development of macrovascular complications of diabetes. Taken collectively, chronic hyperglycemia and increased production of ROS are the miscreants for the development of microvascular and macrovascular complications of diabetes.

In developed countries, the prevalence of persons with diabetes and peripheral arterial disease (PAD) is approximately 50%. The presence of PAD is associated with non-healing ulcers, major amputation, cardiovascular morbidity, and mortality. It is estimated that persons with diabetes, foot ulceration and PAD have 50% of 5-years mortality rate. Therefore, subjects with ischemic diabetic foot ulcers (DFUs) should be considered a special group of patients with specific clinical characteristics, general health status and prognosis. In persons with ischemic DFUs, an early diagnosis and treatment are mandatory to reduce the risk of worse outcomes such as major amputation. Revascularization of occluded lower extremity arteries is the main treatment to restore blood flow in the foot and promote wound healing. Nonetheless, there are several unmet needs in the management of diabetic subjects with PAD and foot ulceration as medical therapy, diagnostic criteria and indications for revascularization, revascularization strategy and technical approach as well as the management of no-option critical limb ischemia patients. It is a common opinion that there is an evolution of PAD features in diabetic persons, which seems to present a more aggressive pattern. This may be related to the frequent presence of concomitant comorbidities such as renal failure which could influence the characteristics of atherosclerotic plaques and their distribution. The aim of this review is to commence a complete overview and state of the art in the treatment of patients with diabetes, PAD, and foot ulceration and to describe the current challenges and future perspectives.

Conventional delivery of antidiabetic drugs faces many problems like poor absorption, low bioavailability, and drug degradation. Nanoemulsion is a unique drug technology, which is very suitable for the delivery of antidiabetic drugs. In recent years, the flaws of delivering anti-hypoglycaemic drugs have been overcome by choosing nanoemulsion drug technology. They are thermodynamically stable and also provide the therapeutic agent for a longer duration. Generally, nanoemulsions are made up of either oil-in-water or water-in-oil and the size of the droplets is from fifty to thousand nanometer. Surfactants are critical substances that are added in the manufacturing of nanoemulsions. Only the surfactants which are approved for human use can be utilized in the manufacturing of nanoemulsions. Generally, the preparation of emulsions includes mixing of the aqueous phase and organic phase and using surfactant with proper agitation. Nanoemulsions are used for antimicrobial drugs, and they are also used in the prophylaxis of cancer. Reduction in the droplet size may cause variation in the elastic and optical behaviour of nanoemulsions.

Background: Diabetes mellitus is a metabolic disease that requires immediate attention. Oxidative stress that leads to the generation of reactive oxygen species is a contributing factor to the disease progression. Yttrium oxide nanoparticles (Y2O3 NPs) have a profound effect on alleviating oxidative damage. Methods: The literature related to Y2O3 NPs and oxidative stress has been thoroughly searched using PubMed and Scopus databases and relevant studies from inception until August 2020 were included in this scoping review. Results: Y2O3 NPs altered oxidative stress-related biochemical parameters in different disease models including diabetes. Conclusion: Although Y2O3 NPs are a promising antidiabetic agent due to their antioxidant and anti- inflammatory properties, more studies are required to further elucidate the pharmacological and toxicological properties of these nanoparticles.

Introduction: Patients with type 2 diabetes mellitus (T2DM) are at significantly higher risk of developing cardiovascular diseases (CVD). There is a scarcity of literature reviews that describe and summarize T2DM patients' knowledge and perception about CVD prevention. Objectives: To describe and summarize the assessment of knowledge and perceptions about CVD risk and preventive approaches among patients with T2DM. Methods: A scoping review methodology was adopted, and three scientific databases, Google Scholar, Science Direct, and PubMed were searched using predefined search terms. A multistage screening process that considered relevancy, publication year (2009-2019), English language, and article type (original research) was followed. We formulated research questions focused on the assessment of levels of knowledge and perceptions of the illness relevant to CVD prevention and the identification of associated patients' characteristics. Results: A total of 16 studies were included. Patients were not confident to identify CVD risk and other clinical consequences that may occur in the prognostic pathway of T2DM. Furthermore, patients were less likely to identify all CV risk factors indicating a lack of understanding of the multi-- factorial contribution of CVD risk. Patients' beliefs about medications were correlated with their level of adherence to medications for CVD prevention. Many knowledge gaps were identified, including the basic disease expectations at the time of diagnosis, identification of individuals' CVD risk factors, and management aspects. Knowledge and perceptions were affected by patients' demographic characteristics, e.g., educational level, race, age, and area of residence. Conclusion: There are knowledge gaps concerning the understanding of CVD risk among patients with T2DM. The findings necessitate educational initiatives to boost CVD prevention among patients with T2DM. Furthermore, these should be individualized based on patients' characteristics, knowledge gaps, disease duration, and estimated CVD risk.

Introduction: Diabetic foot ulcer (DFU) is a major complication of diabetes mellitus, as it can physically and emotionally impact the person. Its management can be challenging and expensive, depending on the severity of the wound and the presence of infection. Background: The fat-soluble molecule, vitamin D, has gained great importance ever since its pleiotropism has been recognized. Its efficacy could be attributed to the presence of vitamin D receptors in most of the body tissues. Vitamin D plays a significant role in cell proliferation, differentiation, and immune modulation. It modulates the T and B cells resulting in the suppression of the immunoglobulins, autoimmunity, and inflammation. Methods: We performed a literature search with the objective to highlight the role of vitamin D in peripheral vascular disease and peripheral neuropathy, which are the major risk factors for DFU, as well as evidences of its role in wound healing and management of DFU. Results: Preclinical and clinical studies have shown that vitamin D influences multiple phases of wound healing and thereby accelerates the process. It modulates various cells involved in proliferation and remodelling phases. Vitamin D also enhances the expression of antimicrobial peptides that help to eliminate the microbes, as well as suppress the proinflammatory responses while enhancing the anti-inflammatory responses. Conclusion: This review concludes vitamin D to have a protective role in the immune and vascular system, improve glycaemic outcomes, and wound healing. Therefore, vitamin D could be a preferred adjuvant in the management of DFU.