TCERG1L hypermethylation is a risk factor of diabetic retinopathy in Chinese children with type 1 diabetes

●AIM:To identify the differential methylation sites(DMS)and their according genes associated with diabetic retinopathy(DR)development in type 1 diabetes(T1DM)children.●METHODS:This study consists of two surveys.A total of 40 T1DM children was included in the first survey.Because no participant has DR,retina thinning was used as a surrogate indicator for DR.The lowest 25%participants with the thinnest macular retinal thickness were included into the case group,and the others were controls.The DNA methylation status was assessed by the Illumina methylation 850K array BeadChip assay,and compared between the case and control groups.Four DMS with a potential role in diabetes were identified.The second survey included 27 T1DM children,among which four had DR.The methylation patterns of the four DMS identified by 850K were compared between participants with and without DR by pyrosequencing.●RESULTS:In the first survey,the 850K array revealed 751 sites significantly and differentially methylated in the case group comparing with the controls(|Δβ|>0.1 and Adj.P<0.05),and 328 of these were identified with a significance of Adj.P<0.01.Among these,319 CpG sites were hypermethylated and 432 were hypomethylated in the case group relative to the controls.Pyrosequencing revealed that the transcription elongation regulator 1 like(TCERG1L,cg07684215)gene was hypermethylated in the four T1DM children with DR(P=0.018),which was consistent with the result from the first survey.The methylation status of the other three DMS(cg26389052,cg25192647,and cg05413694)showed no difference(all P>0.05)between participants with and without DR.●CONCLUSION:The hypermethylation of the TCERG1L gene is a risk factor for DR development in Chinese children with T1DM.

Mannogalactoglucan from mushrooms protects pancreatic islets via restoring UPR and promotes insulin secretion in TIDM mice

Type 1 diabetes mellitus(T1DM) lacks insulin secretion due to autoimmune deficiency of pancreaticβ-cells.Protecting pancreatic islets and enhancing insulin secretion has been therapeutic approaches.Mannogalactoglucan is the main type of polysaccharide from natural mushroom,which has potential medicinal prospects.Nevertheless,the antidiabetic property of mannogalactoglucan in T1DM has not been fully elucidated.In this study,we obtained the neutral fraction of alkali-soluble Armillaria mellea polysaccharide(AAMP-N) with the structure of mannogalactoglucan from the fruiting body of A.mellea and investigated the potential therapeutic value of AAMP-N in T1DM.We demonstrated that AAMP-N lowered blood glucose and improved diabetes symptoms in T1DM mice.AAMP-N activated unfolded protein response(UPR) signaling pathway to maintain ER protein folding homeostasis and promote insulin secretion in vivo.Besides that,AAMP-N promoted insulin synthesis via upregulating the expression of transcription factors,increased Ca^(2+) signals to stimulate intracellular insulin secretory vesicle transport via activating calcium/calmodulin-dependent kinase Ⅱ(CamkⅡ) and cAMP/PKA signals,and enhanced insulin secretory vesicle fusion with the plasma membrane via vesicle-associated membrane protein 2(VAMP2).Collectively,these studies demonstrated that the therapeutic potential of AAMP-N on pancreatic islets function,indicating that mannogalactoglucan could be natural nutraceutical used for the treatment of T1DM.

Gestational diabetes mellitus combined with fulminant type 1 diabetes mellitus, four cases of double diabetes: A case report

BACKGROUND Fulminant type 1 diabetes mellitus(FT1DM)that occurs during pregnancy or the perinatal period is known as pregnancy-related FT1DM(PF),always without history of abnormal glucose metabolism.Here,we present four patients who developed FT1DM during treatment but were first diagnosed with gestational diabetes mellitus(GDM).CASE SUMMARY The clinical data of four patients with GDM combined with FT1DM admitted to our hospital between July 2018 and April 2021 were collected,and the patients and their infants were followed up.All patients were diagnosed with GDM during the second trimester and were treated.The blood glucose level elevated suddenly during the third trimester and then were diagnosed with FT1DM.Two patients had an insulin allergy,and two had symptoms of upper respiratory tract infection before onset.One patient developed ketoacidosis,and three developed ketosis.Two patients had cesarean section deliveries,and two had vaginal deliveries.The growth and development of the infants were normal.C-peptide levels were lower than those at onset,suggesting progressive impairment of islet function.The frequencies of the DRB109:01,DQB103:03,DQA103:02,DPA101:03,DPA102:02,DPB105:01,DRB401:03,G 01:01,and G 01:04 human leukocyte antigen(HLA)-G alleles were high in the present study.CONCLUSION In comparison with pregnancy-associated FT1DM(PF),patients with GDM combined with FT1DM had an older age of onset,higher body mass index,slower onset,fewer prodromal symptoms,and less acidosis.The pathogenesis may be due to various factors affecting the already fragileβ-cells of GDM patients with genetically susceptible class II HLA genotypes.We speculate that GDM combined with FT1DM during pregnancy,referred to as“double diabetes,”is a subtype of PF with its own unique characteristics that should be investigated further.

Honeymoon phase in type 1 diabetes mellitus: A window of opportunity for diabetes reversal?

The knowledge of the pathogenesis of type 1 diabetes mellitus(T1DM)continues to rapidly evolve.The natural course of the disease can be described in four clinical stages based on the autoimmune markers and glycemic status.Not all individuals of T1DM progress in that specific sequence.We hereby present a case of T1DM with a classical third phase(honeymoon phase)and discuss the intri-cacies of this interesting phase along with a possible future promise of“cure”with the use of immunotherapies.We now know that the course of T1DM may not be in only one direction towards further progression;rather the disease may have a waxing and waning course with even reversal of type 1 diabetes concept being discussed.The third phase popularly called the“honeymoon phase”,is of special interest as this phase is complex in its pathogenesis.The honeymoon phase of T1DM seems to provide the best window of opportunity for using targeted therapies using various immunomodulatory agents leading to the possibility of achieving the elusive“diabetes reversal”in T1DM.Identifying this phase is therefore the key,with a lot of varying criteria having been proposed.

Association of autoimmune thyroid disease with type 1 diabetes mellitus and its ultrasonic diagnosis and management

As a common hyperglycemic disease,type 1 diabetes mellitus(T1DM)is a complicated disorder that requires a lifelong insulin supply due to the immunemediated destruction of pancreaticβcells.Although it is an organ-specific autoimmune disorder,T1DM is often associated with multiple other autoimmune disorders.The most prevalent concomitant autoimmune disorder occurring in T1DM is autoimmune thyroid disease(AITD),which mainly exhibits two extremes of phenotypes:hyperthyroidism[Graves'disease(GD)]and hypothyroidism[Hashimoto's thyroiditis,(HT)].However,the presence of comorbid AITD may negatively affect metabolic management in T1DM patients and thereby may increase the risk for potential diabetes-related complications.Thus,routine screening of thyroid function has been recommended when T1DM is diagnosed.Here,first,we summarize current knowledge regarding the etiology and pathogenesis mechanisms of both diseases.Subsequently,an updated review of the association between T1DM and AITD is offered.Finally,we provide a relatively detailed review focusing on the application of thyroid ultrasonography in diagnosing and managing HT and GD,suggesting its critical role in the timely and accurate diagnosis of AITD in T1DM.

Roles of fibroblast growth factors in the treatment of diabetes

Diabetes affects about 422 million people worldwide,causing 1.5 million deaths each year.However,the incidence of diabetes is increasing,including several types of diabetes.Type 1 diabetes(5%-10%of diabetic cases)and type 2 diabetes(90%-95%of diabetic cases)are the main types of diabetes in the clinic.Accumulating evidence shows that the fibroblast growth factor(FGF)family plays important roles in many metabolic disorders,including type 1 and type 2 diabetes.FGF consists of 23 family members(FGF-1-23)in humans.Here,we review current findings of FGFs in the treatment of diabetes and management of diabetic complications.Some FGFs(e.g.,FGF-15,FGF-19,and FGF-21)have been broadly investigated in preclinical studies for the diagnosis and treatment of diabetes,and their therapeutic roles in diabetes are currently under investigation in clinical trials.Overall,the roles of FGFs in diabetes and diabetic complications are involved in numerous processes.First,FGF intervention can prevent high-fat diet-induced obesity and insulin resistance and reduce the levels of fasting blood glucose and triglycerides by regulating lipolysis in adipose tissues and hepatic glucose production.Second,modulation of FGF expression can inhibit renal and cardiac fibrosis by regulating the expression of extracellular matrix components,promote diabetic wound healing process and bone repair,and inhibit cancer cell proliferation and migration.Finally,FGFs can regulate the activation of glucoseexcited neurons and the expression of thermogenic genes.

Icariin accelerates bone regeneration by inducing osteogenesisangiogenesis coupling in rats with type 1 diabetes mellitus

BACKGROUND Icariin(ICA),a natural flavonoid compound monomer,has multiple pharmacological activities.However,its effect on bone defect in the context of type 1 diabetes mellitus(T1DM)has not yet been examined.AIM To explore the role and potential mechanism of ICA on bone defect in the context of T1DM.METHODS The effects of ICA on osteogenesis and angiogenesis were evaluated by alkaline phosphatase staining,alizarin red S staining,quantitative real-time polymerase chain reaction,Western blot,and immunofluorescence.Angiogenesis-related assays were conducted to investigate the relationship between osteogenesis and angiogenesis.A bone defect model was established in T1DM rats.The model rats were then treated with ICA or placebo and micron-scale computed tomography,histomorphometry,histology,and sequential fluorescent labeling were used to evaluate the effect of ICA on bone formation in the defect area.RESULTS ICA promoted bone marrow mesenchymal stem cell(BMSC)proliferation and osteogenic differentiation.The ICA treated-BMSCs showed higher expression levels of osteogenesis-related markers(alkaline phosphatase and osteocalcin)and angiogenesis-related markers(vascular endothelial growth factor A and platelet endothelial cell adhesion molecule 1)compared to the untreated group.ICA was also found to induce osteogenesis-angiogenesis coupling of BMSCs.In the bone defect model T1DM rats,ICA facilitated bone formation and CD31hiEMCNhi type H-positive capillary formation.Lastly,ICA effectively accelerated the rate of bone formation in the defect area.CONCLUSION ICA was able to accelerate bone regeneration in a T1DM rat model by inducing osteogenesis-angiogenesis coupling of BMSCs.

Glucagon-like peptide-1 receptor agonists as a possible intervention to delay the onset of type 1 diabetes:A new horizon

Type 1 diabetes(T1D)is a chronic autoimmune condition that destroys insulinproducing beta cells in the pancreas,leading to insulin deficiency and hyperglycemia.The management of T1D primarily focuses on exogenous insulin replacement to control blood glucose levels.However,this approach does not address the underlying autoimmune process or prevent the progressive loss of beta cells.Recent research has explored the potential of glucagon-like peptide-1 receptor agonists(GLP-1RAs)as a novel intervention to modify the disease course and delay the onset of T1D.GLP-1RAs are medications initially developed for treating type 2 diabetes.They exert their effects by enhancing glucose-dependent insulin secretion,suppressing glucagon secretion,and slowing gastric emptying.Emerging evidence suggests that GLP-1RAs may also benefit the treatment of newly diagnosed patients with T1D.This article aims to highlight the potential of GLP-1RAs as an intervention to delay the onset of T1D,possibly through their potential immunomodulatory and anti-inflammatory effects and preservation of beta-cells.This article aims to explore the potential of shifting the paradigm of T1D management from reactive insulin replacement to proactive disease modification,which should open new avenues for preventing and treating T1D,improving the quality of life and long-term outcomes for individuals at risk of T1D.

Evaluation of hybrid closed-loop insulin delivery system in type 1 diabetes in real-world clinical practice:One-year observational study

BACKGROUND In 2016,the Food and Drug Administration approved the first hybrid closed-loop(HCL)insulin delivery system for adults with type 1 diabetes(T1D).There is limited information on the impact of using HCL systems on patient-reported outcomes(PROs)in patients with T1D in real-world clinical practice.In this independent study,we evaluated glycemic parameters and PROs over one year of continuous use of Medtronic’s 670G HCL in real-world clinical practice.AIM To assess the effects of hybrid closed loop system on glycemic control and quality of life in adults with T1D.METHODS We evaluated 71 patients with T1D(mean age:45.5±12.1 years;59%females;body weight:83.8±18.7 kg,body mass index:28.7±5.6 kg/m2,A1C:7.6%±0.8%)who were treated with HCL at Joslin Clinic from 2017 to 2019.We measured A1C and percent of glucose time-in-range(%TIR)at baseline and 12 months.We measured percent time in auto mode(%TiAM)for the last two weeks preceding the final visit and assessed PROs through several validated quality-of-life surveys related to general health and diabetes management.RESULTS At 12 mo,A1C decreased by 0.3%±0.1%(P=0.001)and%TIR increased by 8.1%±2.5%(P=0.002).The average%TiAM was only 64.3%±32.8%and was not associated with A1C,%TIR or PROs.PROs,provided at baseline and at the end of the study,showed that the physical functioning submodule of 36Item Short-Form Health Survey increased significantly by 22.9%(P<0.001).Hypoglycemia fear survey/worry scale decreased significantly by 24.9%(P<0.000);Problem Areas In Diabetes reduced significantly by-17.2%(P=0.002).The emotional burden submodules of dietary diversity score reduced significantly by-44.7%(P=0.001).Furthermore,analysis of Clarke questionnaire showed no increase in awareness of hypoglycemic episodes.WHO-5 showed no improvements in subject’s wellbeing among participants after starting the 670G HCL system.Finally,analysis of Pittsburgh Sleep Quality Index showed no difference in sleep quality,sleep latency,or duration of sleep from baseline to 12 mo.CONCLUSION The use of HCL in real-world clinical practice for one year was associated with significant improvements in A1C,%TIR,physical functioning,hypoglycemia fear,emotional distress,and emotional burden related to diabetes management.However,these changes were not associated with time in auto mode.

Epidemiological, Clinical, and Evolutionary Profile of Type 1 Diabetics in the Internal Medicine Department of the Abass Ndao Hospital from 2010 to 2021 (about 659 Cases)

Introduction: Type 1 diabetes can have acute complications, sometimes requiring hospitalization. The aim of this study was to describe the epidemiological, clinical and evolutionary aspects of type 1 diabetes in patients at the Abass Ndao National Hospital in Dakar. Patients and Methods: This was a cross-sectional, descriptive and analytical study conducted from January 01, 2010 to December 31, 2021. It focused on hospitalized type 1 diabetic patients. Epidemiological, clinical and evolutionary data were evaluated. Results: Six hundred and fifty-nine (659) patients were enrolled, representing a frequency of 11.5%. The mean age was 29.47 years, giving a sex ratio (m/f) of 0.95. Average hospital stay was 6.1 days. One hundred and forty-four (144) patients (21.8%) had inaugural diabetes. The average consultation time was 14.89 days. Acute metabolic complications were ketoacidosis in 353 patients (56%), and hypoglycemia in 1.2%. Simple hyperglycemia was noted in 113 patients (18.0%). Infection was present in 522 patients (58.3%), of whom 95 (28.2%) had a skin infection.55 patients (16.3%) had a respiratory infection. 12.3% had a dietary imbalance.176 cases (27.7%) had no imbalance.26 patients (3.9%) died, with infectious pathologies accounting for the majority of decompensation factors among the deceased (57.7%). Conclusion: Type 1 diabetes is a cause of morbidity and mortality. It is essential to develop and implement a prevention and management program.

Continuous glucose monitoring metrics in pregnancy with type 1 diabetes mellitus

Managing diabetes during pregnancy is challenging,given the significant risk it poses for both maternal and foetal health outcomes.While traditional methods involve capillary self-monitoring of blood glucose level monitoring and periodic HbA1c tests,the advent of continuous glucose monitoring(CGM)systems has revolutionized the approach.These devices offer a safe and reliable means of tracking glucose levels in real-time,benefiting both women with diabetes during pregnancy and the healthcare providers.Moreover,CGM systems have shown a low rate of side effects and high feasibility when used in pregnancies complicated by diabetes,especially when paired with continuous subcutaneous insulin infusion pump as hybrid closed loop device.Such a combined approach has been demonstrated to improve overall blood sugar control,lessen the occurrence of preeclampsia and neonatal hypoglycaemia,and minimize the duration of neonatal intensive care unit stays.This paper aims to offer a comprehensive evaluation of CGM metrics specifically tailored for pregnancies impacted by type 1 diabetes mellitus.

Pressure pain sensitivity: A new stress measure in children and adolescents with type 1 diabetes?

Type 1 diabetes(T1D)is associated with general-and diabetes-specific stress which has multiple adverse effects.Hence measuring stress is of great importance.An algometer measuring pressure pain sensitivity(PPS)has been shown to correlate to certain stress measures in adults.However,it has never been investigated in children and adolescents.The aim of our study was to examine associations between PPS and glycated hemoglobin(HbA1c),salivary cortisol and two questionnaires as well as to identify whether the algometer can be used as a clinical tool among children and adolescents with T1D.Eighty-three participants aged 6-18 years and diagnosed with T1D were included in this study with data from two study visits.Salivary cortisol,PPS and questionnaires were collected,measured,and answered on site.HbA1c was collected from medical files.We found correlations between PPS and HbA1c(rho=0.35,P=0.046),cortisol(rho=-0.25,P=0.02)and Perceived Stress Scale(rho=-0.44,P=0.02)in different subgroups based on age.Males scored higher in PPS than females(P<0.001).We found PPS to be correlated to HbA1c but otherwise inconsistent in results.High PPS values indicated either measurement difficulties or hypersensibility towards pain.

The Improving Effects of Diabetes Education on Diabetes Awareness and Management in Children and Adolescents with T1DM

Background: Diabetes education is crucial in empowering persons with Type 1 diabetes (T1DM) and their families to properly manage the condition by providing comprehensive knowledge, tools, and support. It boosts one’s belief in their ability to succeed, encourages following medical advice, and adds to the general enhancement of health. Objective: This study is to investigate the effectiveness of diabetes education in empowering individuals with Type 1 Diabetes Mellitus (T1DM) and their families to effectively manage the condition. Furthermore, it strives to improve nursing care for families whose children have been diagnosed with Type 1 Diabetes Mellitus (T1DM). Design: This research study investigates the efficacy of diabetes education in empowering individuals with Type 1 Diabetes Mellitus (T1DM) and their families to effectively handle the condition. Materials and Methods: A systematic search was conducted between the years 2000 and 2022, utilizing the Medline and Google Scholar databases. The purpose of the search was to uncover relevant papers pertaining to diabetes education, management of Type 1 Diabetes Mellitus (T1DM), nurse care, and empowerment. The search focused on peer-reviewed research, clinical trials, and scholarly articles that evaluated the efficacy of diabetes education in empowering individuals and families. Results: Diabetes education is crucial for understanding and controlling T1DM. It includes personalized sessions, webinars, group classes, and clinics that provide customized therapies. Comprehensive education enhances glycemic control and family dynamics. Nevertheless, the implementation of diabetes education for families requires specific standards, especially in the field of nursing. Conclusion: Diabetes education is essential for effectively managing Type 1 Diabetes Mellitus (T1DM), providing patients and families with crucial knowledge, resources, and confidence. It encourages independence in-home care and provides explicit guidelines for diabetic nurses to improve nursing care.

Effects of gradient high-field static magnetic fields on diabetic mice

Although 9.4 T magnetic resonance imaging(MRI) has been tested in healthy volunteers,its safety in diabetic patients is unclear.Furthermore,the effects of high static magnetic fields(SMFs),especially gradient vs.uniform fields,have not been investigated in diabetics.Here,we investigated the consequences of exposure to 1.0-9.4 T high SMFs of different gradients(>10 T/m vs.0-10 T/m)on type 1 diabetic(T1D) and type 2 diabetic(T2D) mice.We found that 14 h of prolonged treatment of gradient(as high as 55.5 T/m) high SMFs(1.0-8.6 T) had negative effects on T1D and T2D mice,including spleen,hepatic,and renal tissue impairment and elevated glycosylated serum protein,blood glucose,inflammation,and anxiety,while 9.4 T quasi-uniform SMFs at 0-10 T/m did not induce the same effects.In regular T1D mice(blood glucose>16.7 mmol/L),the>10 T/m gradient high SMFs increased malondialdehyde(P<0.01) and decreased superoxide dismutase(P<0.05).However,in the severe T1D mice(blood glucose≥30.0 mmol/L),the>10 T/m gradient high SMFs significantly increased tissue damage and reduced survival rate.In vitro cellular studies showed that gradient high SMFs increased cellular reactive oxygen species and apoptosis and reduced MS-1 cell number and proliferation.Therefore,this study showed that prolonged exposure to high-field(1.0-8.6 T)>10 T/m gradient SMFs(35-1 380 times higher than that of current clinical MRI)can have negative effects on diabetic mice,especially mice with severe T1D,whereas 9.4 T high SMFs at 0-10T/m did not produce the same effects,providing important information for the future development and clinical application of SMFs,especially high-field MRI.

Rapid correction of hyperglycemia:A necessity but at what price?A brief report of a patient living with type 1 diabetes

BACKGROUND The correction and control of chronic hyperglycemia are the management goals of patients living with diabetes.Chronic hyperglycemia is the main factor inducing diabetes-related complications.However,in certain situations,the rapid and intense correction of chronic hyperglycemia can paradoxically favor the onset of microvascular complications.CASE SUMMARY In this case report,we describe the case of a 25-year-old woman living with type 1 diabetes since the age of 9 years.Her diabetes was chronic and unstable but without complications.During an unplanned pregnancy,her diabetes was intensely managed with the rapid correction of her hyperglycemia.However,over the following 2 years,she developed numerous degenerative microvascular complications:Charcot neuroarthropathy with multiple joint involvement,severe proliferative diabetic retinopathy,gastroparesis,bladder voiding disorders,and end-stage renal failure requiring hemodialysis.CONCLUSION In the literature to date,the occurrence of multiple microvascular complications following the rapid correction of chronic hyperglycemia has been rarely described in the same individual.

Islet transplantation-immunological challenges and current perspectives

Pancreatic islet transplantation is a minimally invasive procedure aiming to reverse the effects of insulin deficiency in patients with type 1 diabetes(T1D)by transplanting pancreatic beta cells.Overall,pancreatic islet transplantation has improved to a great extent,and cellular replacement will likely become the mainstay treatment.We review pancreatic islet transplantation as a treatment for T1D and the immunological challenges faced.Published data demonstrated that the time for islet cell transfusion varied between 2 and 10 h.Approximately 54%of the patients gained insulin independence at the end of the first year,while only 20%remained insulin-free at the end of the second year.Eventually,most transplanted patients return to using some form of exogenous insulin within a few years after the transplantation,which imposed the need to improve immunological factors before transplantation.We also discuss the immunosuppressive regimens,apoptotic donor lymphocytes,anti-TIM-1 antibodies,mixed chimerism-based tolerance induction,induction of antigen-specific tolerance utilizing ethylene carbodiimide-fixed splenocytes,pretransplant infusions of donor apoptotic cells,B cell depletion,preconditioning of isolated islets,inducing local immunotolerance,cell encapsulation and immunoisolation,using of biomaterials,immunomodulatory cells,etc.

PKM2-mediated neuronal hyperglycolysis enhances the risk of Parkinson's disease in diabetic rats

Epidemiological and animal studies indicate that pre-existing diabetes increases the risk of Parkinson's disease(PD).However,the mechanisms underlying this association remain unclear.In the present study,we found that high glucose(HG)levels in the cerebrospinal fluid(CSF)of diabetic rats might enhance the effect of a subthreshold dose of the neurotoxin 6-hydroxydopamine(6-OHDA)on the development of motor disorders,and the damage to the nigrostriatal dopaminergic neuronal pathway.In vitro,HG promoted the 6-OHDA-induced apoptosis in PC12 cells differentiated to neurons with nerve growth factor(NGF)(NGF-PC12).Metabolomics showed that HG promoted hyperglycolysis in neurons and impaired tricarboxylic acid cycle(TCA cycle)activity,which was closely related to abnormal mitochondrial fusion,thus resulting in mitochondrial loss.Interestingly,HG-induced upregulation of pyruvate kinase M2(PKM2)combined with 6-OHDA exposure not only mediated glycolysis but also promoted abnormal mitochondrial fusion by upregulating the expression of MFN2 in NGF-PC12 cells.In addition,we found that PKM2 knockdown rescued the abnormal mitochondrial fusion and cell apoptosis induced by HGþ6-OHDA.Furthermore,we found that shikonin(SK),an inhibitor of PKM2,restored the mitochondrial number,promoted TCA cycle activity,reversed hyperglycolysis,enhanced the tolerance of cultured neurons to 6-OHDA,and reduced the risk of PD in diabetic rats.Overall,our results indicate that diabetes promotes hyperglycolysis and abnormal mitochondrial fusion in neurons through the upregulation of PKM2,leading to an increase in the vulnerability of dopaminergic neurons to 6-OHDA.Thus,the inhibition of PKM2 and restoration of mitochondrial metabolic homeostasis/pathways may prevent the occurrence and development of diabetic PD.

Key elements determining the intestinal region-specific environment of enteric neurons in type 1 diabetes

Diabetes,as a metabolic disorder,is accompanied with several gastrointestinal(GI)symptoms,like abdominal pain,gastroparesis,diarrhoea or constipation.Serious and complex enteric nervous system damage is confirmed in the background of these diabetic motility complaints.The anatomical length of the GI tract,as well as genetic,developmental,structural and functional differences between its segments contribute to the distinct,intestinal region-specific effects of hyperglycemia.These observations support and highlight the importance of a regional approach in diabetes-related enteric neuropathy.Intestinal large and microvessels are essential for the blood supply of enteric ganglia.Bidirectional morpho-functional linkage exists between enteric neurons and enteroglia,however,there is also a reciprocal communication between enteric neurons and immune cells on which intestinal microbial composition has crucial influence.From this point of view,it is more appropriate to say that enteric neurons partake in multidirectional communication and interact with these key players of the intestinal wall.These interplays may differ from segment to segment,thus,the microenvironment of enteric neurons could be considered strictly regional.The goal of this review is to summarize the main tissue components and molecular factors,such as enteric glia cells,interstitial cells of Cajal,gut vasculature,intestinal epithelium,gut microbiota,immune cells,enteroendocrine cells,prooxidants,antioxidant molecules and extracellular matrix,which create and determine a gut region-dependent neuronal environment in diabetes.

Exercise interventions for patients with type 1 diabetes mellitus:A narrative review with practical recommendations

Type 1 diabetes mellitus(T1DM)is a chronic endocrine disease that results from autoimmune destruction of pancreatic insulin-producingβcells,which can lead to microvascular(e.g.,retinopathy,neuropathy,and nephropathy)and macrovascular complications(e.g.,coronary arterial disease,peripheral artery disease,stroke,and heart failure)as a consequence of chronic hyperglycemia.Despite the widely available and compelling evidence that regular exercise is an efficient strategy to prevent cardiovascular disease and to improve functional capacity and psychological well-being in people with T1DM,over 60%of individuals with T1DM do not exercise regularly.It is,therefore,crucial to devise approaches to motivate patients with T1DM to exercise,to adhere to a training program,and to inform them of its specific characteristics(e.g.,exercise mode,intensity,volume,and frequency).Moreover,given the metabolic alterations that occur during acute bouts of exercise in T1DM patients,exercise prescription in this population should be carefully analyzed to maximize its benefits and to reduce its potential risks.

Human pluripotent stem cell-derivedβcells:Truly immature isletβcells for type 1 diabetes therapy?

A century has passed since the Nobel Prize winning discovery of insulin,which still remains the mainstay treatment for type 1 diabetes mellitus(T1DM)to this day.True to the words of its discoverer Sir Frederick Banting,“insulin is not a cure for diabetes,it is a treatment”,millions of people with T1DM are dependent on daily insulin medications for life.Clinical donor islet transplantation has proven that T1DM is curable,however due to profound shortages of donor islets,it is not a mainstream treatment option for T1DM.Human pluripotent stem cell derived insulin-secreting cells,pervasively known as stem cell-derivedβcells(SC-βcells),are a promising alternative source and have the potential to become a T1DM treatment through cell replacement therapy.Here we briefly review how isletβcells develop and mature in vivo and several types of reported SC-βcells produced using different ex vivo protocols in the last decade.Although some markers of maturation were expressed and glucose stimulated insulin secretion was shown,the SC-βcells have not been directly compared to their in vivo counterparts,generally have limited glucose response,and are not yet fully matured.Due to the presence of extra-pancreatic insulin-expressing cells,and ethical and technological issues,further clarification of the true nature of these SC-βcells is required.