Role of vasopressin signaling in the pathogenesis of diabetic nephropathy

The diabetic kidney disease (also known as diabetic nephropathy) is a major complication of diabetes mellitus and also the most common cause of chronic kidney disease. Elevated plasma levels of vasopressin are consistently observed in patients with either type 1 and type 2 diabetes mellitus and in animal models of diabetes mellitus. A role of enhanced vasopressin signaling in progression of the diabetic nephropathy to chronic kidney disease has been suggested in several epidemiological studies but the underlying pathogenetic mechanisms remain largely unclear and are the subject of current scientific research.

GP73 is a glucogenic hormone that contributes to SARS-CoV-2-induced hyperglycemia

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces new-onset diabetes and severe metabolic complications of pre-existing diabetes. The pathogenic mechanism underlying this is incompletely understood. Here, we provided evidence linking circulating GP73 with the exaggerated gluconeogenesis triggered by SARS-CoV-2 infection. We found that SARS-CoV-2 infection or glucotoxic conditions increased GP73 production and secretion. Secreted GP73 then trafficked to the liver and kidney to stimulate gluconeogenesis through the cAMP/PKA pathway. By using global phosphoproteomics, we found a drastic remodeling of the PKA kinase hub exerted by GP73. Notably, plasma GP73 levels were elevated and positively correlated with blood glucose in patients with COVID19 and diabetes. Neutralization of circulating GP73 in serum of individuals infected with SARS-CoV-2 or with diabetes reduced excessive gluconeogenesis in cultured hepatocytes, and lowered blood glucose levels in animal models of diabetes. Ablation of GP73 from whole animals has a profound glucose-lowering effect secondary to reduced gluconeogenesis. Thus, GP73 is a key glucogenic hormone contributing to SARS-CoV-2-induced glucose abnormality.

Dedicator of Cytokinesis 5 Regulates Keratinocyte Function and Promotes Diabetic Wound Healing

Cutaneous wound healing is a fundamental biological and coordinated process, and failure to maintain this process contributes to the dysfunction of tissue homeostasis, increasing the global burden of diabetic foot ulcerations. However, the factors that mediate this process are not fully understood. Here, we identify dedicator of cytokinesis 5 (Dock5) a pivotal role in keratinocyte functions contributing to the process of skin wound healing. Specifically, Dock5 is highly upregulated during the proliferative phase of wound repair and is predominantly expressed in epidermal keratinocytes. It regulates keratinocyte adhesion, migration and proliferation, and influences the functions of extracellular matrix (ECM) deposition by facilitating the ubiquitination of transcription factor ZEB1 to activate laminin-332/integrin signaling. Genetic ablation of Dock5 in mice leads to attenuated re-epithelialization and granulation tissue formation, while Dock5 overexpression-improved skin repair can be abrogated by LAMA3 knockdown. Importantly, Dock5 expression in the skin edge is reduced in patients and animal models of diabetes, further suggesting a direct correlation between its abundance and healing capability. The rescue of Dock5 expression in diabetic mice causes a significant improvement in re-epithelialization, collagen deposition, ECM production and granulation. Our study provides a potential therapeutic target for wound healing impairment during diabetes.

Dedicator of Cytokinesis 5 Regulates Keratinocyte Function and Promotes Diabetic Wound Healing

Cutaneous wound healing is a fundamental biological and coordinated process, and failure to maintain this process contributes to the dysfunction of tissue homeostasis, increasing the global burden of diabetic foot ulcerations. However, the factors that mediate this process are not fully understood. Here, we identify dedicator of cytokinesis 5 (Dock5) a pivotal role in keratinocyte functions contributing to the process of skin wound healing. Specifically, Dock5 is highly upregulated during the proliferative phase of wound repair and is predominantly expressed in epidermal keratinocytes. It regulates keratinocyte adhesion, migration and proliferation, and influences the functions of extracellular matrix (ECM) deposition by facilitating the ubiquitination of transcription factor ZEB1 to activate laminin-332/integrin signaling. Genetic ablation of Dock5 in mice leads to attenuated re-epithelialization and granulation tissue formation, while Dock5 overexpression-improved skin repair can be abrogated by LAMA3 knockdown. Importantly, Dock5 expression in the skin edge is reduced in patients and animal models of diabetes, further suggesting a direct correlation between its abundance and healing capability. The rescue of Dock5 expression in diabetic mice causes a significant improvement in re-epithelialization, collagen deposition, ECM production and granulation. Our study provides a potential therapeutic target for wound healing impairment during diabetes.

Use of a Hybrid Adeno-Associated Viral Vector Transposon System to Deliver the Insulin Gene to Diabetic NOD Mice

Previously, we used a lentiviral vector to deliver furin-cleavable human insulin (INS-FUR) to the livers in several animal models of diabetes using intervallic infusion in full flow occlusion (FFO), with resultant reversal of diabetes, restoration of glucose tolerance and pancreatic transdifferentiation (PT), due to the expression of beta (β)-cell transcription factors (β-TFs). The present study aimed to determine whether we could similarly reverse diabetes in the non-obese diabetic (NOD) mouse using an adeno-associated viral vector (AAV) to deliver INS-FUR ± the β-TF Pdx1 to the livers of diabetic mice. The traditional AAV8, which provides episomal expression, and the hybrid AAV8/piggyBac that results in transgene integration were used. Diabetic mice that received AAV8-INS-FUR became hypoglycaemic with abnormal intraperitoneal glucose tolerance tests (IPGTTs). Expression of β-TFs was not detected in the livers. Reversal of diabetes was not achieved in mice that received AAV8-INS-FUR and AAV8-Pdx1 and IPGTTs were abnormal. Normoglycaemia and glucose tolerance were achieved in mice that received AAV8/piggyBac-INS-FUR/FFO. Definitive evidence of PT was not observed. This is the first in vivo study using the hybrid AAV8/piggyBac system to treat Type 1 diabetes (T1D). However, further development is required before the system can be used for gene therapy of T1D.

Noninvasive, wearable, and tunable electromagnetic multisensing system for continuous glucose monitoring, mimicking vasculature anatomy

Painless, needle-free, and continuous glucose monitoring sensors are needed to enhance the life quality of diabetic patients. To that extent, we propose a first-of-its-kind, highly sensitive, noninvasive continuous glycemic monitoring wearable multisensor system. The proposed sensors are validated on serum, animal tissues, and animal models of diabetes and in a clinical setting. The noninvasive measurement results during human trials reported high correlation (>0.9) between the system’s physical parameters and blood glucose levels, without any time lag. The accurate real-time responses of the sensors are attributed to their unique vasculature anatomy–inspired tunable electromagnetic topologies. These wearable apparels wirelessly sense hypo- to hyperglycemic variations with high fidelity. These components are designed to simultaneously target multiple body locations, which opens the door for the development of a closed-loop artificial pancreas.

Animal Models of Diabetes-Associated Renal Injury

Diabetic nephropathy (DN) is the main factor leading to end-stage renal disease (ESRD) and subsequent morbidity and mortality. Importantly, the prevalence of DN is continuously increasing in developed countries. Many rodent models of type 1 and type 2 diabetes have been established to elucidate the pathogenesis of diabetes and examine novel therapies against DN. These models are developed by chemical, surgical, genetic, drug, and diet/nutrition interventions or combination of two or more methods. The main characteristics of DN including a decrease in renal function, albuminuria and mesangiolysis, mesangial expansion, and nodular glomerulosclerosis should be exhibited by an animal model of DN. However, a rodent model possessing all of the abovementioned features of human DN has not yet been developed. Furthermore, mice of different genetic backgrounds and strains show different levels of susceptibility to DN with respect to albuminuria and development of glomerular and tubulointerstitial lesions. Therefore, the type of diabetes, development of nephropathy, duration of the study, cost of maintaining and breeding, and animals’ mortality rate are important factors that might be affected by the type of DN model. In this review, we discuss the pros and cons of different rodent models of diabetes that are being used to study DN.

Diabetes and Hyperglycemia Affect Platelet GPIIIa Expression: Effects on Adhesion Potential of Blood Platelets from Diabetic Patients under In Vitro Flow Conditions

Blood platelets play a crucial role in the early stages of atherosclerosis development. The process is believed to require firm adhesion of platelets to atherosclerosis-prone sites of the artery. However, little evidence exists regarding whether the blood platelets of individuals with pathological conditions associated with atherosclerosis have higher potential for adhesion. This process is to a large extent dependent on receptors present on the platelet membrane. Therefore, the aim of the presented study was to determine whether blood platelets from diabetic patients have higher capacity of adhesion under flow conditions and how diabetes affects one of the crucial platelet receptors involved in the process of adhesion—GPIIIa. The study compares the ability of platelets from non-diabetic and diabetic humans to interact with fibrinogen and von Willebrand factor, two proteins found in abundance on an inflamed endothelium, under flow conditions. The activation and reactivity of the blood platelets were also characterized by flow cytometry. Platelets from diabetic patients did not demonstrate enhanced adhesion to either studied protein, although they presented increased basal activation and responsiveness towards low concentrations of agonists. Platelets from diabetic patients were characterized by lower expression of GPIIIa, most likely due to an enhanced formation of platelet-derived microparticles PMPs, as supported by the observation of elevated concentration of this integrin and of GPIIIa-positive PMPs in plasma. We conclude that altered functionality of blood platelets in diabetes does not increase their adhesive potential. Increased glycation and decrease in the amount of GPIIIa on platelets may be partially responsible for this effect. Therefore, higher frequency of interactions of platelets with the endothelium, which is observed in animal models of diabetes, is caused by other factors. A primary cause may be a dysfunctional vascular wall.

Benefits of micronutrient supplementation for reducing the risk of wet age-related macular disease and diabetic retinopathy

Age-related macular disease and diabetic retinopathy are chronic degenerative diseases characterised by progressive visual impairment. In Europe, age-related macular disease accounts for over 15% of blindness in adults over 50 years of age, and although the burden of diabetic retinopathy in terms of vision impairment is lower, vision loss associated with diabetic retinopathy is increasing with the rising prevalence of diabetes mellitus and the ageing of the population. Late-stage age-related macular disease can be subdivided into dry (non-neovascular) or wet (neovascular or exudative) forms. The large Age-Related Eye Disease Study 2 showed that supplementation with antioxidant nutrients reduces choroids neovascularisation and reduces the risk of progression of neovascular age-related macular disease. Antioxidant micronutrient supplements have also shown promising results in preventing the pathogenesis of retinopathy in animal models of diabetes. Age-related macular disease and diabetic retinopathy are understood to share some common pathophysiological characteristics, suggesting that micronutrients have an important role in ocular health in both conditions. This article will review the current evidence for the utility of micronutrients in preventing the development and progression of neovascular age-related macular disease and diabetic retinopathy.