Secondary Complications Of Diabetes Research Articles

Tonabersat suppresses priming/activation of the NOD-like receptor protein-3 (NLRP3) inflammasome and decreases renal tubular epithelial-to-macrophage crosstalk in a model of diabetic kidney disease

BackgroundAccompanied by activation of the NOD-like receptor protein 3 (NLRP3) inflammasome, aberrant connexin 43 (Cx43) hemichannel-mediated ATP release is situated upstream of inflammasome assembly and inflammation and contributes to multiple secondary complications of diabetes and associated cardiometabolic comorbidities. Evidence suggests there may be a link between Cx43 hemichannel activity and inflammation in the diabetic kidney. The consequences of blocking tubular Cx43 hemichannel-mediated ATP release in priming/activation of the NLRP3 inflammasome in a model of diabetic kidney disease (DKD) was investigated. We examined downstream markers of inflammation and the proinflammatory and chemoattractant role of the tubular secretome on macrophage recruitment and activation.MethodsAnalysis of human transcriptomic data from the Nephroseq repository correlated gene expression to renal function in DKD. Primary human renal proximal tubule epithelial cells (RPTECs) and monocyte-derived macrophages (MDMs) were cultured in high glucose and inflammatory cytokines as a model of DKD to assess Cx43 hemichannel activity, NLRP3 inflammasome activation and epithelial-to-macrophage paracrine-mediated crosstalk. Tonabersat assessed a role for Cx43 hemichannels.ResultsTranscriptomic analysis from renal biopsies of patients with DKD showed that increased Cx43 and NLRP3 expression correlated with declining glomerular filtration rate (GFR) and increased proteinuria. In vitro, Tonabersat blocked glucose/cytokine-dependant increases in Cx43 hemichannel-mediated ATP release and reduced expression of inflammatory markers and NLRP3 inflammasome activation in RPTECs. We observed a reciprocal relationship in which NLRP3 activity exacerbated increased Cx43 expression and hemichannel-mediated ATP release, events driven by nuclear factor kappa-B (NFκB)-mediated priming and Cx43 hemichannel opening, changes blocked by Tonabersat. Conditioned media (CM) from RPTECs treated with high glucose/cytokines increased expression of inflammatory markers in MDMs, an effect reduced when macrophages were pre-treated with Tonabersat. Co-culture using conditioned media from Tonabersat-treated RPTECs dampened macrophage inflammatory marker expression and reduced macrophage migration.ConclusionUsing a model of DKD, we report for the first time that high glucose and inflammatory cytokines trigger aberrant Cx43 hemichannel activity, events that instigate NLRP3-induced inflammation in RPTECs and epithelial-to-macrophage crosstalk. Recapitulating observations previously reported in diabetic retinopathy, these data suggest that Cx43 hemichannel blockers (i.e., Tonabersat) may dampen multi-system damage observed in secondary complications of diabetes.

416 The Impact of Pancreas Transplantation on Secondary Diabetic Complications: A Systematic Review

Abstract Aim Pancreas transplantation (PT) provides diabetic cure for patients with complicated Type 1 Diabetes Mellitus (T1DM). We aimed to examine the impact of PT on secondary diabetic complications, including retinopathy, neuropathy, and cardiovascular disease. Method A database search using MedLINE for publications up to April 2023 was conducted employing MeSH terms ‘Pancreas Transplantation’ AND ‘Diabetes Mellitus, Type 1’ AND ‘Diabetic Retinopathy’ OR ‘Heart Disease’ OR ‘Cardiovascular Diseases’ OR ‘Peripheral Vascular Disease’ OR “Amputation’ OR ‘Neuropathy.” Results 223 articles were screened, with 172 excluded as per study design (total included 51). 64.7% (n=33) of studies were retrospective case control studies, 35.3% (n=18) of studies were retrospective cohort studies. A total of 5616 patients with a mean of 99.1 (SD± 262.4) simultaneous kidney transplant (SPK) patients and 48.2 (SD± 262.4) pancreas transplant alone (PTA) patients per article were studied. All articles examining diabetic retinopathy concluded that retinopathy improved or stabilized. 69% (n=11) of papers demonstrated no significant change to visual acuity. An equal number of articles (n=4) demonstrated increased peripheral nerve conduction velocity after SPK and PTA. 40% (n=2) of articles examining vibration perception studies demonstrated an increase post-transplantation. Improvements in cardiac events incidence, metabolic factors, and heart structure were seen in 79% (n=15) of cardiovascular articles. Conclusions Despite significant heterogeneity in outcome measures observed, PT provides benefits in mitigating the complication profile of T1DM. Standardised outcome measurement should be adopted to allow assessment of the impact of beta-cell replacement with the potential for objective evidence reversibility of secondary complications.

Unveiling the crucial role of intercellular adhesion molecule-1 in secondary diabetic complications.

Diabetes mellitus is associated with secondary complications such as diabetic retinopathy (DR), nephropathy (DN), and cardiomyopathy (DCM), all of which significantly impact patient health. Intercellular adhesion molecule-1 (ICAM-1) has been implicated in inflammatory responses and endothelial dysfunction, both crucial in the pathogenesis of these complications. The goal of this review is to investigate at potential therapy methods that target ICAM-1 pathways and to better understand the multifaceted role of ICAM-1 in secondary diabetic problems. A meticulous analysis of scholarly literature published globally was conducted to examine ICAM-1involvement in inflammatory processes, endothelial dysfunction, and oxidative stress related to diabetes and its complications. Elevated ICAM-1 levels are strongly associated with augmented leukocyte adhesion, compromised microvascular function, and heightened oxidative stress in diabetes. These pathways contribute significantly to DR, DN, and DCM pathogenesis, highlighting ICAM-1 as a key player in their progression. Understanding ICAM-1 role in secondary diabetic complications offers insights into novel therapeutic strategies. Targeting ICAM-1 pathways may mitigate inflammation, improve endothelial function, and ultimately attenuate diabetic complications, thereby enhancing patient health outcomes. Continued research in this area is crucial for developing effective targeted therapies.

Protective Effect of Curcumin on the Tight Junction Integrity and Cellular Senescence in Human Retinal Pigment Epithelium of Early Diabetic Retinopathy.

Diabetic retinopathy (DR) is a secondary complication of diabetes that can lead to visual impairment and blindness. The retinal pigment epithelium (RPE) is a monolayer of pigment cells that forms the blood-retinal barrier (BRB) via tight junction (TJ) proteins and plays a crucial role in the physiological function of the retina. Hyperglycemia induces RPE death and BRB breakdown, which accelerates the process of DR. Curcumin, an active extract of Curcuma longa , has anti-inflammatory, antioxidant, antiapoptotic, and neuroprotective properties. However, the effect of Curcumin on the BRB under high glucose conditions remains unknown. This study aimed to investigate the protective effects of Curcumin on RPE physiology in vitro and in vivo . Curcumin significantly alleviated cell viability inhibition under high glucose conditions. Moreover, high glucose reduced extracellular signal-regulated kinase and Akt pathways activation to diminish RPE cell growth but reversed by Curcumin treatment. Curcumin protected not only TJ integrity but also retinoid regeneration through TJ proteins and isomerase modulation in diabetic retina. Furthermore, Curcumin decreased the expression of angiogenic factor to inhibit retinal neovascularization. Finally, Curcumin treatment markedly reduced apoptosis during hyperglycemia. In conclusion, Curcumin can alleviate the progression of DR by promoting RPE survival, TJ integrity, retinoid isomerase activity, RPE senescence inhibition, and neovascularization. Therefore, Curcumin exhibits high potential for use as a therapeutic agent for early DR.

Specific features of anesthetic management in simultaneous pancreas and kidney transplantation in a recipient with morbid obesity

Introduction. Anesthetic management in simultaneous pancreas and kidney transplantation in recipients has some specific features. In addition to the presence of underlying pathology in the form of type 1 diabetes mellitus and secondary diabetic complications, pronounced comorbidities can often make some difficulties for an anesthesiologist.Aim. We have reported a clinical case showing the specific features of anesthetic support for simultaneous pancreas and kidney transplantation in a recipient with morbid obesity.Clinical Case Report. Specific features of the anesthetic management of a 42-year-old patient L. with morbid obesity (body mass index 43.3 kg/m2) and hypertension who underwent simultaneous pancreas and kidney transplantation have been described. A preoperative examination of this patient revealed predictors of difficult airways, so endoscopically assisted intubation was performed. The Trendelenburg position of the patient during surgical intervention due to an excess body weight led to the increased intrathoracic pressure intraoperatively. The pressure ventilation mode, the neutral position of the patient on the operating table, and the monitoring of ventilation efficiency made it possible to return the elevated intrathoracic pressure to normal. A preoperative examination by a cardiologist, timely diagnosis and treatment of hypertension at the stage of placing the patient on the waiting list made it possible to exclude adverse hemodynamic reactions at the main stages of the operation. The patient was extubated on surgery completion in the Operating Room. The pancreatic graft function and the kidney graft function were satisfactory.Conclusion. Our approaches ensured the safety and efficacy of anesthesiological support and contributed to the successful implementation of simultaneous pancreas and kidney transplantation in the recipient having the concomitant pathology in the form of morbid obesity.

EVALUATION OF ANTIDIABETIC, ANTI-INFLAMMATORY, AND ANTIOXIDANT ACTIVITIES OF DIFFERENT FRACTIONS OF ETHANOLIC EXTRACT OF LEAVES OF Bauhinia variegata BY In vitro METHOD AND ISOLATION OF PHYTOCONSTITUENTS

Today, diabetes is a common morbidity, and the occurrence of the disease is attributed to various pathophysiological states of the human body, including inflammation and free radical oxidants. Previous types of research also reported the involvement of free radical oxidants in the development of secondary complications of diabetes. The scavenging of free radicals by antioxidants turns out to be a defense mechanism and can also alter disease states. Therefore, the study was designed to evaluate the properties of Bauhinia variegata L. leaves in controlling diabetes, inflammation, and free radicals. The ethanolic leaf extract was prepared and the extract was then fractionated with solvents, which were further used to perform pharmacological screening by in vitro methods. The IC50 values of the chloroform fraction (BVC) of leaf extract were recorded as the lowest among the test materials for all in vitro studies. The IC50 values of BVC in the study of inhibition of α-amylase and α-glucosidase enzymes were 31.08±1.53 and 25.33±1.52 g/mL, respectively. In the study of inhibition of bovine serum albumin and egg albumin denaturation, BVC showed efficacy with IC50 values of 23.75±1.35 and 28.15±1.32 g/mL, respectively. The fraction showed free radical scavenging activity in DPPH and nitric oxide assay, with IC50 values of 27.78±1.61 and 34.93±1.49 g/mL, respectively. In addition, two pure compounds, namely chrysoeriol and β-amyrin palmitate, were isolated from this bioactive fraction. Thus, the results proved all the claimed pharmacological effects of the leaves of Bauhinia variegata L. and also justified the hypothesis of the current study.

Efficacy of adipose-derived mesenchymal stem cell therapy in the treatment of chronic micro- and macrovascular complications of diabetes.

Diabetes mellitus is a highly prevalent disease characterized by hyperglycaemia that damages the vascular system, leading to micro- (retinopathy, neuropathy, nephropathy) and macrovascular diseases (cardiovascular disease). There are also secondary complications of diabetes (cardiomyopathy, erectile dysfunction or diabetic foot ulcers). Stem cell-based therapies have become a promising tool targeting diabetes symptoms and its chronic complications. Among all stem cells, adipose-derived mesenchymal stem cells (ADMSCs) are of great importance because of their abundance, non-invasive isolation and no ethical limitations. Characteristics that make ADMSCs good candidates for cell-based therapy are their wide immunomodulatory properties and paracrine activities through the secretion of an array of growth factors, chemokines, cytokines, angiogenic factors and anti-apoptotic molecules. Besides, after transplantation, ADMSCs show great ex vivo expansion capacity and differentiation to other cell types, including insulin-producing cells, cardiomyocytes, chondrocytes, hepatocyte-like cells, neurons, endothelial cells, photoreceptor-like cells, or astrocytes. Preclinical studies have shown that ADMSC-based therapy effectively improved visual acuity, ameliorated polyneuropathy and foot ulceration, arrested the development and progression of diabetic kidney disease, or alleviated the diabetes-induced cardiomyocyte hypertrophy. However, despite the positive results obtained in animal models, there are still several challenges that need to be overcome before the results of preclinical studies can be translated into clinical applications. To date, there are several clinical trials or ongoing trials using ADMSCs in the treatment of diabetic complications, most of them in the treatment of diabetic foot ulcers. This narrative review summarizes the most recent outcomes on the usage of ADMSCs in the treatment of long-term complications of diabetes in both animal models and clinical trials.

Role of Innate Immune and Inflammatory Responses in the Development of Secondary Diabetic Complications.

Increased hyperglycemia due to uncontrolled diabetes is the major cause of secondary diabetic complications such as retinopathy, neuropathy, nephropathy, and cardiovascular diseases. Although it is well known that increased oxidative stress, activation of the polyol pathway, protein kinase C and increased generation of advanced glycation end products could contribute to the development of diabetic complications, recent studies implicated the role of innate immunity and its related inflammatory responses in the pathophysiology of secondary diabetic complications. Increased activation of oxidative stress signaling could regulate NLRP3 inflammasome-mediated innate immune responses as well as NF-κB signalosome-mediated pro-inflammatory responses. This review article focused on the pathogenic role of innate immune and inflammatory responses in the progression of hyperglycemia-induced secondary diabetic complications. Specifically, we discussed in depth how deregulated innate immune and inflammatory responses could lead to an aggravated release of cytokines, chemokines, and growth factors resulting in the development of various secondary complications of diabetes.

Analysis of multi-disease targeting effect of phytochemicals by AMPK stimulation– diabetes: A computational approach

Diabetes is a silent killer and a metabolic syndrome characterized by hyperglycemia that has been exponentially increasing in recent years. There is a need to develop therapeutic agents to control hyperglycemia and its secondary complications as well as protect and revive beta cells in diabetic patients. The target for first-line diabetes treatment is the adenosine monophosphate protein kinase (AMPK), which participates in cellular energy metabolism through phosphorylation of metabolic enzymes and transcription regulators. This study examined the drug-related properties as well as lead preparation of Catharanthus roseus alkaloids and testing molecular interaction at the AMPK targets to confirm their anti-diabetic effect. A control drug metformin and a library of 85 molecules of C. roseus alkaloids were crossed with the ADMET test, followed by the investigation of molecular interaction tested on AMPK1 and AMPK2 targets through an in silico docking process. Vindolinine (CID: 24148538), vindoline (CID: 425978), (+)-vindorosine (CID: 261578), Cr-1 (CID: 5315746), and Cr-2 (CID: 59908094) had passed the ADMET test. Molecular interaction of the tested C. roseus alkaloids on AMPK1 and AMPK2 targets had potential energy that varied from −7.4 to −5.3 kcal/mol, whereas binding energies of −4.0 kcal/mol for AMPK1-metformin interaction and −4.2 kcal/mol for AMPK2-metformin interaction were observed. The tested C. roseus alkaloids were shown to be more potent activators of AMPK than the control drug. All five biomolecules of C. roseus acted as modulators that have the potential to stimulate AMPK, reduce glucose production, and increase glucose utilization in hepatocytes. In addition, they diminished insulin resistance and secondary complications of diabetes by inhibiting acetyl-CoA carboxylase, regulating cholesterol levels and macrophage, and reviving beta cells in Type 2 diabetes. These results provided the foundation for developing new multi-disease-targeting drugs that can treat diabetes, obesity, cardiovascular disease, cancer, and other diseases by the stimulation of AMPK1 and AMPK2 targets.

Antidiabetic effects of polyherbal mixture made of Centaurium erythraea, Cichorium intybus and Potentilla erecta

Ethnopharmacological relevanceThe polyherbal mixture made of Centaurium erythraea aerial parts and Cichorium intybus roots and Potentilla erecta rhizomes has been used for centuries to treat both the primary and secondary complications of diabetes. Aim of the studyAs a continuation of our search for the most effective herbal mixture used as an ethnopharmacological remedy for diabetes, this study aimed to compare the in vitro biological activities of this polyherbal mixture and its individual ingredients, and, most importantly, to validate the ethnopharmacological value of the herbal mixture through evaluation of its phytochemical composition, its potential in vivo toxicity and its effect on diabetes complications. Materials and methodsPhytochemical analysis was performed using HPLC-UV. Antioxidant activity was estimated via the DPPH test. Potential cytotoxicity/anticytotoxicity was assessed using an in vitro RBCs antihemolytic assay and an in vivo sub-chronic oral toxicity method. Antidiabetic activity was evaluated using an in vitro α-amylase inhibition assay and in vivo using a chemically induced diabetic rat model. ResultsThe HPLC-UV analysis revealed the presence of p-hydroxybenzoic acid, p-hydroxybenzoic acid derivative, catechin, five catechin derivatives, epicatechin, isoquercetin, hyperoside, rutin, four quercetin derivatives, caffeic acid, and four caffeic acid derivatives in the polyherbal mixture decoction. Treatment with the decoction has shown no toxic effects. The antioxidant and cytoprotective activities of the polyherbal mixture were higher than the reference's ones. Its antidiabetic activity was high in both in vitro and in vivo studies. Fourteen days of treatment with the decoction (15 g/kg) completely normalized blood glucose levels of diabetic animals, while treatments with insulin and glimepiride only slightly lowered glycemic values. In addition, lipid status of treated animals as well as levels of serum AST, ALT, ALP, creatinine, urea and MDA were completely normalized. In addition, the polyherbal mixture completely restored the histopathological changes of the liver, kidneys and all four Cornu ammonis regions of the hippocampus. ConclusionsThe polyherbal mixture was effective in the prevention of both primary and secondary diabetic complications such as hyperlipidemia, increased lipid peroxidation, non-alcoholic fatty liver disease, nephropathy and neurodegeneration.

Metabolic Outcomes After Pancreas Transplant Alone From Donation After Circulatory Death Donors-The UK Transplant Registry Analysis.

Extrapolating data from early DCD (donation after circulatory death) kidney transplantation, pancreas transplants from DCD grafts were feared to have worse metabolic outcomes. Hence, we aimed to address the question of pancreas transplant alone (PTA) from DCD donors-are our concerns justified? A UK transplant registry analysis of 185 PTA performed between 2005 and 2018 was done. All early graft losses (<3months) were excluded to allow focus on the metabolic outcomes (HbA1c, weight gain and incidence of secondary diabetic macrovascular complications). The aim was to compare the metabolic outcomes, rejection rates (including the need for steroids), patient and graft survival between DBD (Donation after brainstem death) and DCD groups. After excluding early graft losses, data from 162 PTA (DBD = 114 and DCD = 48) were analyzed. Body mass index of the donor was less in DCD group (DBD = 23.40 vs. DCD = 22.25, p = 0.006) and the rest of the baseline transplant characteristics were comparable. There were no significant differences in the HbA1c, weight gain, rejection rate, and incidence of secondary diabetic macrovascular complications post-transplant between DBD and DCD recipients. The 1-, 5-, and 10-year patient and graft survival were similar in both the groups. PTA from DCD donors have equivalent metabolic outcomes and survival (patient/graft) as that of DBD donors.

Carnosine-Based Reversal of Diabetes-Associated Cognitive Decline via Activation of the Akt/mTOR Pathway and Modulation of Autophagy in a Rat Model of Type 2 Diabetes Mellitus

Introduction: Carnosine can suppress secondary complications in diabetes and show robust neuroprotective activity against neurodegenerative diseases. Here, we report that carnosine ameliorates diabetes-associated cognitive decline in vivo through the modulation of autophagy. Methods: A high-fat diet (HFD) and one intraperitoneal injection of 30 mg/kg streptozotocin (STZ) were used to induce type 2 diabetes mellitus in Sprague-Dawley rats. The rats were randomly divided into five groups: control (CON), HFD/STZ, and three intragastric carnosine treatment groups receiving low (100 mg/kg), medium (300 mg/kg), and high (900 mg/kg) doses over 12 weeks. Body weight, blood glucose levels, and cognitive function were continuously monitored. From excised rat hippocampi, we determined superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels; carnosine concentration; protein expressions of Akt, mTOR and the autophagy markers LC3B and P62 and performed histopathological evaluations of the cornu ammonis 1 region. Results: The HFD/STZ group showed increased blood glucose levels and decreased body weight compared to the CON group. However, there were no significant differences in body weight and blood glucose levels between carnosine-treated and -untreated HFD-STZ-induced diabetic rats. Diabetic animals showed obvious learning and memory impairments in the Morris water maze test compared to the CON group. Compared to those in the HFD/STZ group, carnosine increased SOD activity and decreased MDA levels, increased hippocampal carnosine concentration, increased p-Akt and p-mTOR expression, decreased LC3B and P62 expression, alleviated neuronal injuries, and improved cognitive performance in a dose-dependent manner. Conclusion: Independent of any hyperglycemic effect, carnosine may improve mild cognitive impairments by mitigating oxidative stress, activating the Akt/mTOR pathway, and modulating autophagy in the hippocampus of type 2 diabetic rats.

Association of circulatory PCSK-9 with biomarkers of redox imbalance and inflammatory cascades in the prognosis of diabetes and associated complications: a pilot study in the Indian population

s Besides the profound role of proprotein convertase subtilisin/kexin type-9 (PCSK-9) in LDL-C regulation, its association with other metabolic complications cannot be disregarded. The co-existence of redox imbalance and inflammatory cascades has greatly reflected the etiology of hyperglycemia. Therefore, we studied the association of PCSK-9 with inflammation and oxidative stress biomarkers to predict its role in the prognosis of diabetes and its associated complications in the Indian population. This pilot study examined a total of n = 187 subjects: healthy controls (HC; n = 50), diabetic without complication (T2DM; n = 49), diabetic nephropathy (T2DM-N; n = 43), and diabetic dyslipidemic (T2DM-DL; n = 45) subjects. The relationship between circulatory PCSK-9 levels and inflammation and redox imbalance biomarkers has been explored. The significant positive association of elevated PCSK-9 level with the inflammatory (i.e. IL-1β, IL-6, TNF-α, and CRP) and oxidative stress marker (i.e. XOD, CD, LOOH, and MDA) was observed in T2DM-N and T2DM-DL subjects. Whereas single regression analysis depicted that PCSK-9 was inversely associated with the FRAP and PON-1 in T2DM-N and T2DM-DL subjects. Furthermore, no significant correlation was detected in both T2DM and HC subjects. We found a significant relationship between these prognostic biomarkers with an elevated level of PCSK-9 in T2DM-N and T2DM-DL subjects. PCSK-9 is a nontraditional biomarker in diabetes that may help identify patients at risk of developing secondary complications of diabetes in the Indian population. However, further large cohort validation studies are needed.

Harnessing Genomic Analysis to Explore the Role of Telomeres in the Pathogenesis and Progression of Diabetic Kidney Disease.

The prevalence of diabetes is increasing globally, and this trend is predicted to continue for future decades. Research is needed to uncover new ways to manage diabetes and its co-morbidities. A significant secondary complication of diabetes is kidney disease, which can ultimately result in the need for renal replacement therapy, via dialysis or transplantation. Diabetic kidney disease presents a substantial burden to patients, their families and global healthcare services. This review highlights studies that have harnessed genomic, epigenomic and functional prediction tools to uncover novel genes and pathways associated with DKD that are useful for the identification of therapeutic targets or novel biomarkers for risk stratification. Telomere length regulation is a specific pathway gaining attention recently because of its association with DKD. Researchers are employing both observational and genetics-based studies to identify telomere-related genes associated with kidney function decline in diabetes. Studies have also uncovered novel functions for telomere-related genes beyond the immediate regulation of telomere length, such as transcriptional regulation and inflammation. This review summarises studies that have revealed the potential to harness therapeutics that modulate telomere length, or the associated epigenetic modifications, for the treatment of DKD, to potentially slow renal function decline and reduce the global burden of this disease.

Pancreas Transplantation Alone for Brittle Diabetes Mellitus

Only about 8% of all pancreas transplants for insulin-dependent diabetes mellitus are performed in the Pancreas Transplant Alone (PTA) category. PTAs are primarily performed in diabetic, non-uremic patients with unstable glucose control, hypoglycemia unawareness, and an increased risk of diabetes-related mortality, and who have failed all of the more traditional approaches to glycemic control. Tremendous, yet not widely noticed, progress in PTA outcome has been made over the past two decades. PTA is a very safe procedure with 1-and 5-year patient survival rates of 98.3% and 90.5% according to International Pancreas Transplant Registry (IPTR) data. Since the introduction of tacrolimus and mycophenolate mofetil maintenance therapy in the 1990s and the use of depleting antibody induction therapy, PTA graft survival rates at 1-and 5-years posttransplant are 87.2% and 65.0%. To avoid the need for a future kidney after pancreas (KAP) transplant due to impaired pretransplant native kidney function and the posttransplant use of calcineurin inhibitors, the estimated Glomerular Filtration Rate (eGFR) of PTA candidates should be well within the normal range and preferably &gt; 80 mL/min/1.73m². PTAs with stable, long-term function have been shown to have a positive impact on secondary complications of diabetes mellitus. Considering the significantly improved outcome results, PTA should become the pancreas transplant option of choice before the manifestation of devastating secondary complications (kidney failure, cardio-cerebrovascular events, and blindness) that require simultaneous pancreas and kidney (SPK) transplants in qualified candidates, but with higher morbidity and mortality risks. It is important for diabetologists, endocrinologists, and other health professionals involved in the care of diabetic patients to learn about these positive PTA outcome results. Despite improvements in intensive insulin therapy, insulin-delivering devices, bioartificial pancreas, and islet transplantation, a successful PTA is the only treatment option for patients with brittle diabetes that consistently restores normal glucose homeostasis long-term without exposing recipients to the risks of severe hypoglycemia and prevents, halts, or reverses the development or progression of secondary diabetes complications.

Effectiveness and safety of stem cells in the treatment of diabetes

Diabetes mellitus type 1 (DM1) and type 2 (DM2) is one of the most common chronic diseases with high rates of morbidity and mortality. Insulin replacement therapy and other various hypoglycemic means have been used for more than 90 years to control high blood glucose levels, but they cannot accurately mimic the secretion of endogenous insulin, can cause reactive hypoglycemia, and do not exclude the risk of secondary complications of diabetes (nephropathy, neuropathy, retinopathy, vascular pathology). The introduction of new scientific achievements into clinical practice in the future allows optimizing the treatment for diabetes and its complications, which can significantly improve the quality of life of many patients. A very promising method of DM therapy is the use of stem cells (SC) as an almost unlimited source of physiologically competent substitute for primary islets of Langerhans. SC can transform (specialize) into any cell of the body and, unlike others, can divide an indefinite number of times. This allows SC to maintain a certain number of their population and allows for the formation of a whole hierarchy of SC in the body, which are stored in certain depots. And, finally, SC are characterized by the Homing effect— the ability to find the damaged zone and fix itself in it, filling the lost function when introduced into the body. A number of studies and recent meta-analyses suggest that C-peptide, HbA1c levels, and daily insulin requirements improve after treatment of DM with stem cells, meaning that SC therapy may be a safe and effective intervention for some individuals with DM. In DM1, bone marrow hematopoietic SC are a good source of SC transplantation. In DM2, HbA1c and daily insulin requirements were significantly improved after mesenchymal SC therapy, and bone marrow mononuclear cell therapy significantly reduced insulin requirements and improved C-peptide levels. These encouraging results require confirmation in large, randomized, double-blind studies, as well as with longer follow-up periods to clearly recommend stem cell-based therapy as the standard of DM management.

Therapeutic Efficacy of Natural Product 'C-Phycocyanin' in Alleviating Streptozotocin-Induced Diabetes via the Inhibition of Glycation Reaction in Rats.

Diabetes is a long-term metabolic disorder characterized by persistently elevated blood sugar levels. Chronic hyperglycemia enhances glucose-protein interactions, leading to the formation of advanced glycation end products (AGEs), which form irreversible cross-links with a wide variety of macromolecules, and accumulate rapidly in the body tissues. Thus, the objective of this study was to assess the therapeutic properties of C-phycocyanin (C-PC) obtained from Plectonema species against oxidative stress, glycation, and type 2 diabetes mellitus (T2DM) in a streptozotocin (STZ)-induced diabetic Wistar rat. Forty-five days of C-PC administration decreased levels of triglycerides (TGs), blood glucose, glycosylated hemoglobin, (HbA1c), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), liver and kidney function indices, and raised body weight in diabetic rats. C-PC suppressed biochemical glycation markers, as well as serum carboxymethyllysine (CML) and fluorescent AGEs. Additionally, C-PC maintained the redox state by lowering lipid peroxidation and protein-bound carbonyl content (CC), enhancing the activity of high-density lipoprotein cholesterol (HDL-C) and renal antioxidant enzymes, and preserving retinal and renal histopathological characteristics. Thus, we infer that C-PC possesses antidiabetic and antiglycation effects in diabetic rats. C-PC may also act as an antidiabetic and antiglycation agent in vivo that may reduce the risk of secondary diabetic complications.

Treatment strategies in diabetic nephropathy - Update 2022

A new classification of patients with diabetes mellitus into so-called clusters can be used to assess the risk of developing diabetic nephropathy. Up to date treatment of patients with diabetic nephropathy includes not only glycemic control, but focuses on a holistic approach with prevention of (progression of) secondary diabetic complications and reduction of the patient's cardiovascular mortality. To achieve this treatment goals, it requires comprehensive management of the patient to implement lifestyle interventions (regarding diet, physical activity, weight loss, smoking cessation) and selection of the medication with the greatest individual benefit. Part of lifestyle intervention is adherence to a dietary regimen that has again been shown in recent studies to be relevant in inhibiting progression of chronic kidney disease and reducing cardiovascular risk. In particular, this includes protein restriction with preference for plant sources of protein, and salt restriction. Adjustment of drug therapy is no longer based on antihyperglycemic effects alone, but takes into account inhibition of progression of nephropathy and cardiac risk, as well as support of body weight control. For this purpose, in addition to RAAS inhibitors from the field of antihypertensives, the antidiabetic classes of SGLT2 inhibitors and GLP-1 receptor agonists as well as the non-steroidal aldosterone antagonist finerenone are now available.

Glycation of Immunoglobulin-G from Pentose Sugar: A Cause for Structural Perturbations.

Glycation of immunoglobulin-G (IgG) molecules with monosaccharides may cause significant structural disability, thus resulting in their loss of function. The accumulation of AGEs formed from glycation plays an important role in the aliments associated with metabolic diseases. Therefore, excess sugar in plasma interferes with the functioning of IgG and may contribute to a wide range of diabetes-associated complications. The long-term formation of these heterogeneous AGEs may accumulate and affect plasma proteins, especially long-lived proteins. In this study, we analyze immunoglobulin-G (IgG) glycation with 2'-deoxyribose (deoxyribose) instigated modification in IgG structure and AGEs formation. This study aims to glycate IgG from varying concentrations of pentose sugar, 2'-deoxyribose (deoxyribose). Various physicochemical methods and techniques characterized post glycation of IgG, both the native and its glycated analogue. The glycated protein will be assessed for its stability and perturbations by UV-VIS., fluorescence and FT-IR spectroscopic techniques. Moreover, the early glycation product will be done by NBT assay, and other biochemical parameters like HMF, carbonyl content and thioflavin-T assays were also performed to see the biochemical changes induced in the glycated IgG macromolecule. Glycation of protein macromolecules generates stable early glycation products (Amadori products). Later, these Amadori products involved a series of chemical reactions to form more stable advanced glycation end products (AGEs). Our experimental study results could validate the modification in IgG structure and AGEs formation. The formation of IgG-AGEs from glycation of IgG with deoxyribose could exert cellular toxicity, and might initiates secondary complications of diabetes. Therefore, this study emphasized the glycation reaction of IgG from deoxyribose, which has not been reported yet.

Anti-diabetic efficacy and selective inhibition of methyl glyoxal, intervention with biogenic Zinc oxide nanoparticle

Non-enzymatic glycation of biomolecules results in advanced glycation end products (AGEs), which are responsible for secondary complications in diabetes. Inhibiting methyl glyoxal (MGO) induced advanced glycation end product (AGE) formation is the only way to alleviate diabetic complications. This study aimed to look into the abilities of herbal extract Kigelia africana and K. africana synthesized zinc oxide nanoparticles (ZnONPs) to inhibit the emergence of MG-derived AGEs. The study intended to determine antioxidant and AGE inhibition of the plant extract and ZnONPs. ZnONPs were tested for the efficiency of anti-diabetic activity in streptozotocin-induced diabetic Wister rats. We discovered that the MGO-trapping effects on the prevention of AGE production were mediated by the downregulation of the amplification of MGO-trapping impacts on the hypoglycemic and antihyperlipidemic mechanisms of ZnONPs. According to histological findings, the treatment with ZnONPs also successfully lowers inflammation in the hepatic and renal tissues. Overall, future mechanistic research could establish ZnONPs potential anti-diabetic properties.