Multiple Diabetic Complications Research Articles

Association of Sudomotor Dysfunction With Risk of Subclinical Carotid Atherosclerosis in Patients With Type 2 Diabetes

ABSTRACTObjectivePrevious studies suggested that sudomotor dysfunction is closely related to multiple diabetic microvascular complications. We aimed to investigate the association between sudomotor dysfunction and subclinical carotid atherosclerosis (SCAS) in people with type 2 diabetes.MethodsA total of 1788 participants were included in this cross‐sectional study. Sudomotor function was assessed using the SUDOSCAN device, and sudomotor dysfunction was defined as feet electrochemical skin conductance (FESC) < 60 μs. The carotid artery was evaluated by high‐resolution B‐mode ultrasonography. SCAS was defined as mean carotid intima‐media thickness ≥ 1.0 mm and/or the presence of carotid plaque. A logistic regression model was used to evaluate the relationship between sudomotor dysfunction and the risk of SCAS.ResultsAmong the enrolled 1788 participants, 1094 (61.2%) were male. The median age was 60.0 (51.0–66.0) years, and the median glycated haemoglobin (HbA1c) level was 8.3% (7.1%–9.9%). Four hundred twenty‐nine individuals had sudomotor dysfunction, equivalent to 24.0% of all subjects. Compared to people with normal sudomotor function, those with sudomotor dysfunction had a significantly higher prevalence of SCAS (68.1% vs. 58.3%, p < 0.05). Meanwhile, we found that people with SCAS had a lower median FESC level (76.8 μs vs. 74.4 μs) (p = 0.003) and a higher proportion of abnormal sudomotor function (26.9% vs. 19.5%) (p < 0.001). After adjusting for confounding factors including HbA1c, sudomotor dysfunction was significantly associated with the risk of SCAS (odd ratio [OR] = 1.48, 95%CI 1.13–1.95). Furthermore, When FESC was considered as a continuous variable, the multivariable‐adjusted OR of SCAS was 1.17 (95%CI 1.04–1.32) for per 1‐SD decrease in FESC.ConclusionsSudomotor dysfunction was significantly related to SCAS in people with type 2 diabetes.

Redefining C-peptide: Therapeutic Potential in Mitigating Diabetic Microvascular Complications

This review examines the changing insights into C-peptide and its potential for therapeutic actions against the backdrop of diabetic microvascular complications. C-peptide, formerly regarded as just a byproduct of insulin production, has recently surfaced as a bioactive peptide with important physiological effects. Findings indicate that C-peptide has anti-inflammatory and antioxidant capabilities, strengthens glucose utilization, and raises insulin sensitivity. Trial results for C-peptide replacement therapy show hope for treating diabetic neuropathy and nephropathy conditions. The article reviews the influence of C-peptide on cells, focusing on interactions with cell surface receptors and the stimulation of signaling molecules inside cells. C-peptide's role in generating nitric oxide, activating Na+K+ATPase, and improving the flow of blood in microvessels is emphasized. The review explores how C-peptide affects red blood cell deformability and its potential capabilities in reducing multiple diabetic complications. Besides, the article examines current research into C-peptide analogs that have a long-lasting effect and clinical trials that assess C-peptide replacement therapy. ErsattaTM, a new generation of weekly dosage disease-modifying replacement peptides, is seen as a promising advance in the treatment of chronic diabetes complications. Overall, this review stresses the increased acceptance of C-peptide as a powerful agent for the management of microvascular complications in diabetes, giving hope for superior results in patients with both type 1 and potentially type 2 diabetes.

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.

Identification of circRNAs expression profiles and functional networks in parotid gland of type 2 diabetes mouse

BackgroundCircular RNAs (circRNAs) are a novel kind of non-coding RNAs proved to play crucial roles in the development of multiple diabetic complications. However, their expression and function in diabetes mellitus (DM)-impaired salivary glands are unknown.ResultsBy using microarray technology, 663 upregulated and 999 downregulated circRNAs companied with 813 upregulated and 525 downregulated mRNAs were identified in the parotid glands (PGs) of type2 DM mice under a 2-fold change and P < 0.05 cutoff criteria. Gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) analysis of upregulated mRNAs showed enrichments in immune system process and peroxisome proliferator-activated receptor (PPAR) signaling pathway. Infiltration of inflammatory cells and increased inflammatory cytokines were observed in diabetic PGs. Seven differently expressed circRNAs validated by qRT-PCR were selected for coding-non-coding gene co-expression (CNC) and competing endogenous RNA (ceRNA) networks analysis. PPAR signaling pathway was primarily enriched through analysis of circRNA-mRNA networks. Moreover, the circRNA-miRNA-mRNA networks highlighted an enrichment in the regulation of actin cytoskeleton.ConclusionThe inflammatory response is elevated in diabetic PGs. The selected seven distinct circRNAs may attribute to the injury of diabetic PG by modulating inflammatory response through PPAR signaling pathway and actin cytoskeleton in diabetic PGs.

New therapeutic directions in type II diabetes and its complications: mitochondrial dynamics.

As important organelles of energetic and metabolism, changes in the dynamic state of mitochondria affect the homeostasis of cellular metabolism. Mitochondrial dynamics include mitochondrial fusion and mitochondrial fission. The former is coordinated by mitofusin-1 (Mfn1), mitofusin-2 (Mfn2), and optic atrophy 1 (Opa1), and the latter is mediated by dynamin related protein 1 (Drp1), mitochondrial fission 1 (Fis1) and mitochondrial fission factor (MFF). Mitochondrial fusion and fission are generally in dynamic balance and this balance is important to preserve the proper mitochondrial morphology, function and distribution. Diabetic conditions lead to disturbances in mitochondrial dynamics, which in return causes a series of abnormalities in metabolism, including decreased bioenergy production, excessive production of reactive oxygen species (ROS), defective mitophagy and apoptosis, which are ultimately closely linked to multiple chronic complications of diabetes. Multiple researches have shown that the incidence of diabetic complications is connected with increased mitochondrial fission, for example, there is an excessive mitochondrial fission and impaired mitochondrial fusion in diabetic cardiomyocytes, and that the development of cardiac dysfunction induced by diabetes can be attenuated by inhibiting mitochondrial fission. Therefore, targeting the restoration of mitochondrial dynamics would be a promising therapeutic target within type II diabetes (T2D) and its complications. The molecular approaches to mitochondrial dynamics, their impairment in the context of T2D and its complications, and pharmacological approaches targeting mitochondrial dynamics are discussed in this review and promise benefits for the therapy of T2D and its comorbidities.

Endothelial Insulin Resistance Exacerbates Experimental Periodontitis

Epidemiological studies suggest that the severity of periodontitis is higher in people with diabetes than in healthy individuals. Insulin resistance might play a crucial role in the pathogenesis of multiple diabetic complications and is reportedly induced in the gingiva of rodents with type 2 diabetes; however, the molecular mechanisms underlying the pathogenesis of diabetes-related periodontitis remain unclear. Therefore, we aimed to investigate whether endothelial insulin resistance in the gingiva may contribute to the pathogenesis of periodontitis as well as elucidate its underlying molecular mechanisms. We demonstrated that insulin treatment downregulated lipopolysaccharide (LPS)–induced or tumor necrosis factor α (TNFα)–induced VCAM1 expression in endothelial cells (ECs) via the PI3K/Akt activating pathway, resulting in reduced cellular adhesion between ECs and leukocytes. Hyperglycemia-induced selective insulin resistance in ECs diminished the effect of insulin on LPS- or TNFα-stimulated VCAM1 expression. Vascular endothelial cell–specific insulin receptor knockout (VEIRKO) mice exhibited selective inhibition of the PI3K/Akt pathway in the gingiva and advanced experimental periodontitis-induced alveolar bone loss via upregulation of Vcam1, Tnfα, Mcp-1, Rankl, and neutrophil migration into the gingiva compared with that in the wild-type (WT) mice despite being free from diabetes. We also observed that insulin-mediated activation of FoxO1, a downstream target of Akt, was suppressed in the gingiva of VEIRKO and high-fat diet (HFD)–fed mice, hyperglycemia-treated ECs, and primary ECs from VEIRKO. Further analysis using ECs transfected with intact and mutated FoxO1, with mutations at 3 insulin-mediated phosphorylation sites (T24A, S256D, S316A), suggested that insulin-mediated regulation of VCAM1 expression and cellular adhesion of ECs with leukocytes was attenuated by mutated FoxO1 overexpression. These results suggest that insulin resistance in ECs may contribute to the progression of periodontitis via dysregulated VCAM1 expression and cellular adhesion with leukocytes, resulting from reduced activation of the PI3K/Akt/FoxO1 axis.

Purtscher-like retinopathy in a 19-year-old with maturity-onset diabetes of the young: a case report

BackgroundWe report the first case of Purtscher-like retinopathy in a patient with 17q12 deletion-associated maturity-onset diabetes of the young.Case presentationA 19-year-old diabetic Hispanic male with history of cataracts and toe amputations presented with sudden onset of painless bilateral vision loss for 1 week with no associated trauma. Visual acuity was counting fingers at six feet in both eyes. Dilated retinal examination revealed bilateral peripapillary cotton wool spots and intraretinal hemorrhages, and significant subretinal and intraretinal fluid on optical coherence tomography. Fluorescein angiography revealed arteriolar staining and leakage around the disc with areas of capillary nonperfusion, supporting the diagnosis of Purtscher-like retinopathy. Systemic workup revealed multiple diabetic complications including chronic osteomyelitis of multiple toes, nonhealing diabetic foot ulcers, neurogenic bladder and bowel, and bilateral lower-extremity muscular neuropathies. Genetic evaluation revealed a 17q12 deletion, which is associated with maturity-onset diabetes of the young 5. On follow-up examination, he received a single intravitreal antivascular endothelial growth factor injection in the left eye (off label) for persistent macular edema. Although his retinal edema improved, his visual acuity remained poor.ConclusionsThe presentation of our patient’s multiple diabetic complications along visual symptoms suggests Purtscher-like retinopathy can be a sequela of uncontrolled diabetes. Purtscher-like retinopathy is a rare but possible consideration in diabetic patients who present with acute-onset vision loss.

Potential Mechanisms of Yiqi Jiedu Huayu Decoction in the Treatment of Diabetic Microvascular Complications Based on Network Analysis, Molecular Docking, and Experimental Validation.

Diabetic microvascular complications are the main causes of organ dysfunction and even death in diabetic patients. Our previous studies confirmed the beneficial effects of Yiqi Jiedu Huayu Decoction (YJHD) on diabetic cardiomyopathy and diabetic nephropathy. It is not clear whether YJHD can treat multiple diabetic microvascular complications including diabetic retinopathy, diabetic cardiomyopathy, and diabetic nephropathy through some common mechanisms. TCMSP, SymMap, STITCH, Swiss Target Prediction, and SEA databases were used to collect and analyze the components and targets of YJHD. GeneCards, DrugBank, DisGeNET, OMIM, and GEO databases were used to obtain target genes for diabetic retinopathy, diabetic cardiomyopathy, and diabetic nephropathy. The GO and KEGG enrichment analyses were performed on the DAVID and STRING platforms. Molecular docking was used to evaluate the binding sites and affinities of compounds and target proteins. Animal experiments were designed to validate the network pharmacology results. Through network pharmacological analysis, oxidative stress, inflammatory response, and apoptosis were identified as key pathological phenotypes for the treatment of diabetic microvascular complications with YJHD. In addition, JNK, p38, and ERK1/2 were predicted as key targets of YJHD in regulating the abovementioned pathological phenotypes. The results of animal experiments showed that YJHD could ameliorate retinal pathological changes of diabetes rats. YJHD can inhibit oxidative stress and inflammation in heart and kidney of diabetic rats. Molecular docking showed strong binding between compounds and JNK, p38, and ERK1/2. Berlambine may play a key role in the treatment process and is considered as a promising regulator of MAPK protein family. The regulatory effects of YJHD on JNK, p38, and ERK1/2 were demonstrated in animal experiments. YJHD may play a therapeutic role in diabetic microvascular complications by regulating oxidative stress, inflammatory response, and apoptosis. The regulation of JNK, p38, and ERK1/2 phosphorylation may be the key to its therapeutic effect.

The combination of type 1 diabetes and eating disorder during pregnancy

The problem of eating disorders currently holds a special place in clinical practice. Bulimia nervosa is one of the main forms of eating disorders, characterized by the difficulty in its treatment and a long, recurrent course. Eating disorders are common in patients with type 1 diabetes mellitus (T1D), especially in adolescent girls.In this article, we present a clinical case of a patient with T1D and bulimia nervosa, which developed before the manifestation of T1D and progressed against its background. The patient is overly concerned with controlling body weight, specifically restricted the intake of carbohydrates, forcibly caused vomiting. During pregnancy fasting ketonuria («low-carb ketone») was repeatedly detected. The minimum weight was 37 kg (BMI 15.2 kg/m2). Particular interest of this case is the course of pregnancy, which ended in the antenatal death. The possible cause could be the restriction on carbohydrate food and prolonged stay in ketosis, that might lead to the development of pregnancy pathology. Additional examination also revealed multiple complications of diabetes and recurrent depressive disorder, which requires conjoint monitoring by an endocrinologist and a psychiatrist.Combination of T1D and eating disorder in a pregnant patient should be considered as an atypical course of the disease.

Artificial intelligence based prediction models for individuals at risk of multiple diabetic complications: A systematic review of the literature.

The aim of this review is to examine the effectiveness of artificial intelligence in predicting multimorbid diabetes-related complications. In diabetic patients, several complications are often present, which have a significant impact on the quality of life; therefore, it is crucial to predict the level of risk for diabetes and its complications. International databases PubMed, CINAHL, MEDLINE and Scopus were searched using the terms artificial intelligence, diabetes mellitus and prediction of complications to identify studies on the effectiveness of artificial intelligence for predicting multimorbid diabetes-related complications. The results were organized by outcomes to allow more efficient comparison. Based on the inclusion/exclusion criteria, 11 articles were included in the final analysis. The most frequently predicted complications were diabetic neuropathy (n = 7). Authors included from two to a maximum of 14 complications. The most commonly used prediction models were penalized regression, random forest and Naïve Bayes model neural network. The use of artificial intelligence can predict the risks of diabetes complications with greater precision based on available multidimensional datasets and provides an important tool for nurses working in preventive health care. Using artificial intelligence contributes to a better quality of care, better autonomy of patients in diabetes management and reduction of complications, costs of medical care and mortality.

TFEB-Mediated Lysosomal Restoration Alleviates High Glucose-Induced Cataracts Via Attenuating Oxidative Stress.

PurposeDiabetic cataract (DC) is a visual disorder arising from diabetes mellitus (DM). Autophagy, a prosurvival intracellular process through lysosomal fusion and degradation, has been implicated in multiple diabetic complications. Herein, we performed in vivo and in vitro assays to explore the specific roles of the autophagy-lysosome pathway in DC.MethodsStreptozotocin-induced DM and incubation in high glucose (HG) led to rat lens opacification. Protein Simple Wes, Western blot, and immunoassay were utilized to investigate autophagic changes in lens epithelial cells (LECs) and lens fiber cells (LFCs). RNA-sequencing (RNA-seq) was performed to explore genetic changes in the lenses of diabetic rats. Moreover, autophagy-lysosomal functions were examined using lysotracker, Western blot, and immunofluorescence analyses in HG-cultured primary rabbit LECs.ResultsFirst, DM and HG culture led to fibrotic LECs, swelling LFCs, and eventually cataracts. Further analysis showed aberrant autophagic degradation in LECs and LFCs during cataract formation. RNA-seq data revealed that the differentially expressed genes (DEGs) were enriched in the lysosome pathway. In primary LECs, HG treatment resulted in decreased transcription factor EB (TFEB) and cathepsin B (CTSB) activity, and increased lysosomal size and pH values. Moreover, TFEB-mediated dysfunctional lysosomes resulted from excessive oxidative stress in LECs under HG conditions. Furthermore, TFEB activation by curcumin analog C1 alleviated HG-induced cataracts through enhancing lysosome biogenesis and activating protective autophagy, thereby attenuating HG-mediated oxidative damage.ConclusionsIn summary, we first identified that ROS-TFEB-dependent lysosomal dysfunction contributed to autophagy blockage in HG-induced cataracts. Additionally, TFEB-mediated lysosomal restoration might be a promising therapeutic method for preventing and treating DC through mitigating oxidative stress.

Deep Personal Multitask Prediction of Diabetes Complication with Attentive Interactions Predicting Diabetes Complications by Multitask-Learning.

Objective Diabetic complications have brought a tremendous burden for diabetic patients, but the problem of predicting diabetic complications is still unresolved. Our aim is to explore the relationship between hemoglobin A1C (HbA1c), insulin (INS), and glucose (GLU) and diabetic complications in combination with individual factors and to effectively predict multiple complications of diabetes. Methods This was a real-world study. Data were collected from 40,913 participants with an average age of 48 years from the Department of Endocrinology of Ruijin Hospital in Shanghai. We proposed deep personal multitask prediction of diabetes complication with attentive interactions (DPMP-DC) to predict the five complication models of diabetes, including diabetic retinopathy, diabetic nephropathy, diabetic peripheral neuropathy, diabetic foot disease, and diabetic cardiovascular disease. Results Our model has an accuracy rate of 88.01% for diabetic retinopathy, 89.58% for diabetic nephropathy, 85.77% for diabetic neuropathy, 80.56% for diabetic foot disease, and 82.48% for diabetic cardiovascular disease. The multitasking accuracy of multiple complications is 84.67%, and the missed diagnosis rate is 9.07%. Conclusion We put forward the method of interactive integration with individual factors of patients for the first time in diabetic complications, which reflect the differences between individuals. Our multitask model using the hard sharing mechanism provides better prediction than prior single prediction models.

Joint analysis of multivariate failure time data with latent variables.

We propose a joint modeling approach to investigate the observed and latent risk factors of the multivariate failure times of interest. The proposed model comprises two parts. The first part is a distribution-free confirmatory factor analysis model that characterizes the latent factors by correlated multiple observed variables. The second part is a multivariate additive hazards model that assesses the observed and latent risk factors of the failure times. A hybrid procedure that combines the borrow-strength estimation approach and the asymptotically distribution-free generalized least square method is developed to estimate the model parameters. The asymptotic properties of the proposed estimators are derived. Simulation studies demonstrate that the proposed method performs well for practical settings. An application to a study concerning the risk factors of multiple diabetic complications is provided.

Static Magnetic Fields Reduce Oxidative Stress to Improve Wound Healing and Alleviate Diabetic Complications.

Although some studies have shown that some static magnetic fields (SMFs) can promote wound healing in diabetic mice, it is not clear whether the other diabetes complications, such as liver disease and diabetic nephropathy, can also be alleviated. Here, we constructed two simple magnetic plates using neodymium permanent magnets to examine the comprehensive effects of moderate SMFs on genetically obese leptin receptor-deficient db/db diabetic mice. We found that although the blood glucose was not obviously reduced by these two SMF settings, both of the glycated serum protein (GSP) and malondialdehyde (MDA) levels were significantly decreased (Cohen’s d = 2.57–3.04). Moreover, the wound healing, liver lipid accumulation, and renal defects were all significantly improved by SMF treatment (Cohen’s d = 0.91–2.05). Wound tissue examination showed obvious nuclear factor erythroid 2-related factor 2 (NRF2) level decrease (Cohen’s d = 2.49–5.40) and Ki-67 level increase (Cohen’s d = 2.30–3.40), indicating decreased oxidative stress and increased cell proliferation. In vitro cellular studies with fibroblast NIH3T3 cells showed that SMFs could reduce high glucose-induced NRF2 nucleus translocation (Cohen’s d = 0.87–1.15) and cellular reactive oxygen species (ROS) elevation (Cohen’s d = 0.92), indicating decreased oxidative stress. Consequently, high glucose-induced impairments in cell vitality, proliferation, and migration were all improved by SMF treatment. Therefore, our results demonstrate that these simple SMF devices could effectively reduce oxidative stress in diabetic mice and may provide a cost-effective physical therapy strategy to alleviate multiple diabetic complications in the future.

Correlation between metabolic status and diabetic retinopathy evolution in type 1 diabetes.

Out of the multiple vascular complications of diabetes, retinopathy is the easiest to diagnose and monitor as the examination of the eye fundus is an easy investigation to perform, does not require expensive medical equipment and can be repeated without any risk to the patient. The appearance of the retinal vessels, the optic nerve and the retina can provide useful information on the coronary and cerebral circulation, plasma lipid levels, renal function, and the quality of the arteries of the lower limbs. It is known that visual acuity changes variably depending on the macular alteration and may decrease when edema is installed in the macular region or is altered by the appearance of hemorrhages or the presence of foveolar neovascular tissues resulting from traction retinal detachment. In the absence of proper treatment, diabetes leads to blindness. The lesions that appear are not specific to diabetes, but by combining them they create a clinical picture characteristic of this disease.

Senolytics: Potential for Alleviating Diabetes and Its Complications.

Therapeutics that target cellular senescence, including novel “senolytic” compounds, hold significant promise for treating or preventing obesity-induced metabolic dysfunction, type 2 diabetes, and the multiple complications of diabetes and obesity. Senolytics selectively clear senescent cells, which accumulate with aging and obesity and represent a fundamental mechanism of aging that contributes to metabolic dysfunction and diabetes pathogenesis. In addition to improving metabolic function, targeting senescent cells holds promise as a preventive strategy to reduce the incidence and severity of diabetes complications. The intermittent administration schedule used for senolytic therapy may confer benefits in terms of improving adherence and limiting adverse effects. It is necessary to design effective clinical trials that will safely translate discoveries from preclinical models into human studies that may pave the way for a novel therapeutic class for treating obesity, diabetes, and their complications. In this review, we outline what is known regarding the role of cellular senescence in the pathogenesis of type 2 diabetes and its complications, present evidence from preclinical models that targeting cellular senescence is beneficial, review senolytic drugs, and outline the features of clinical trials investigating the role of targeting senescent cells for diabetes.

RAGE signaling is required for AMPA receptor dysfunction in the hippocampus of hyperglycemic mice

Diabetes in humans has been associated for a long time with cognitive dysfunction. In rodent animal models, cognitive dysfunction can manifest as impaired hippocampal synaptic plasticity. Particular attention has been concentrated on the receptor for advanced glycation end products (RAGE), which is implicated in multiple diabetic complications involving the development of vascular and peripheral nerve abnormalities. In this study, we hypothesize that RAGE signaling alters glutamate receptor function and expression, impairing synaptic transmission in the hippocampus. Using preparations of hippocampal slices from male mice, we show a RAGE-dependent decrease in long-term potentiation (LTP) and an increase in paired-pulse facilitation (PPF) following streptozotocin (STZ)-induced diabetes. Consistently, in hippocampal cultures from male and female neonatal mice, high glucose caused a RAGE-dependent reduction of AMPA- but not NMDA-evoked currents, and an increase in cytosolic reactive oxygen species (ROS). Consistently, when cultures were co-treated with high glucose and the RAGE antagonist FPS-ZM1, AMPA-evoked currents were unchanged. Hippocampi from STZ-induced hyperglycemic wild type (WT) mice showed increased RAGE expression concomitant with a decrease of both expression and phosphorylation (Ser 831 and 845) of the AMPA GluA1 subunit. We found these changes correlated to activation of the MAPK pathway, consistent with decreased pJNK/JNK ratio and the JNK kinase, pMEK7. As no changes in expression or phosphorylation of regulatory proteins were observed in hippocampi from STZ-induced hyperglycemic RAGE-KO mice, we report a RAGE-dependent impairment in the hippocampi of hyperglycemic WT mice, with reduced AMPA receptor expression/function and LTP deficits.

Diagnosis and treatment of osteoporosis in elderly patients with type 2 diabetes

Osteoporosis, falls and low-energy fractures have a high prevalence in elderly, which is increasing in the presence of diabetes mellitus type 2 (T2DM). Patients with T2DM have a low rate of bone metabolism, a pronounced change in bone microarchitecture. The use of trabecular bone score in evaluating of densitometry and the FRAX scale improves the sensitivity of the methods in patients with diabetes. Integrated approach is required in elderly patient with type 2 diabetes and includes assessment of geriatric status, diabetes status, correction of multiple complications of diabetes, carbohydrate metabolism, vitamin D deficiency, selection of the most effective hypoglycemic and anti-osteoporetic therapy and development of preventive and treatment methods aimed to reduce falls risk and fractures rate.

Primary Arthrodesis for Diabetic Ankle Fractures.

Background:Treatment of ankle fractures in patients with diabetes is associated with increased complication rates. Ankle arthrodesis is considered a salvage procedure after failed ankle fracture fixation, yet primary ankle arthrodesis has been proposed as a treatment option for patients with significant diabetes-related complications. To date, the characteristics of patients who undergo primary ankle arthrodesis and the associated outcomes have not been described.Methods:A retrospective review was performed of 13 patients with diabetes who underwent primary arthrodesis for traumatic ankle fracture. Patient demographics were characterized in addition to their diabetes complications, Adelaide Fracture in the Diabetic Ankle (AFDA) score, and fracture type. Outcomes assessed included reoperation rates, infection rates, wound complications, nonunion/malunion, amputation, and development of Charcot arthropathy postoperatively.Results:Patients who underwent primary arthrodesis had high rates of diabetes complications, average AFDA scores of 6.4, and high rates of severe injuries, including 38.5% open fractures and 69.2% fracture dislocations. The overall complication rate for primary arthrodesis of ankle fractures in diabetes patients was more than 75% in this cohort. Complications included a 38.5% reoperation rate, 38.5% infection rate, 53.8% wound complication rate, and 23.1% amputation rate. Despite a high nonunion rate at the attempted fusion sites, 89.9% of fractures healed and patients had a stable extremity.Conclusion:This review is the first to characterize the epidemiology and complications of diabetes patients undergoing primary ankle arthrodesis for ankle fractures. In this cohort, patients with multiple diabetic complications and severe injuries underwent primary arthrodesis, which led to an overall high complication rate. Further research is needed to determine the appropriate treatment option for these high-risk patients, and tibiotalocalcaneal stabilization without arthrodesis may be beneficial.Level of Evidence:Level IV, retrospective case series.

4178Insulin treatment is associated with increased risk of device-treated ventricular tachyarrhythmia in patients with diabetes and heart failure

Abstract Background It is debated whether insulin use is associated with a pro-arrhythmic effect. There is paucity of studies investigating this aspect in patients with heart failure (HF), where use of insulin is associated with an increased mortality risk. Purpose We aimed to investigate whether patients receiving insulin had higher risk of device-treated ventricular tachyarrhythmia (VTA) in a population of HF patients with medically treated diabetes and primary prevention implantable cardioverter defibrillator (ICD) or cardiac resynchronization therapy with defibrillator (CRT-D). Methods Information on ICD/CRT-D implantation and therapy, comorbidities, diabetes, diabetes-related complications and medication were obtained through Danish nationwide registers. From 2007 through 2016 we identified all primary prevention ICD/CRT-D implantations in HF patients with diabetes, defined as treatment with antidiabetic medication within one year prior to implantation. Patients were divided into two groups; Insulin treated vs. non-insulin treated patients. Endpoints of interest were VTA, defined as appropriate ICD therapy, and all-cause mortality. Cumulative incidence curves and adjusted Cox proportional Hazards regression analyses were used to assess risk of outcomes. Adjustment variables included age, gender, ischemic heart disease (IHD), left ventricular ejection fraction (LVEF), ICD vs. CRT-D, diuretic use (as a proxy for severity of HF), prior VTA and diabetes-related complications, identified from diagnosis codes for diabetic nephro-, retino-, and neuropathy, multiple diabetic complications and unspecified diabetic complications. Results We identified 1240 patients with HF and diabetes with a primary prevention ICD/CRT-D. The majority of patients had type 2 diabetes (94%). Of these 479 patients (39%) were treated with insulin and 761 (61%) were not. Patients were primarily male (85%) with mean age of 66.9±8.3 years, mean LVEF of 25.6±7.5%, 42% had CRT-D and 58% ICD, without differences between the groups. The insulin-treated group had a higher occurrence of diabetes-related complications (81% vs. 42%, p&lt;0.01) and IHD (95% vs. 90%, p&lt;0.01). During a mean follow-up of 3.1±2.1 years, 74 insulin treated patients (16%) and 86 non-insulin treated patients (11%) experienced VTA (p=0.034), with higher 5-year cumulative incidence of VTA in the insulin group. Insulin treatment was associated with significantly increased risk of VTA (HR = 1.45; 95% CI [1.04–2.03], p=0.031) and all-cause mortality (HR=1.27; 95% CI [1.03–1.58], p=0.027), as compared with non-insulin treated patients. Figure 1 Conclusion In HF patients with diabetes implanted with a primary prevention ICD/CRT-D, treatment with insulin was associated with a significant 45% increased risk of device-treated ventricular tachyarrhythmias and 27% increased risk of all-cause mortality. These findings support further clinical trials to evaluate the safety of insulin in patients with HF and type 2 diabetes.