Heterogeneously elevated branched-chain/aromatic amino acids among new-onset type-2 diabetes mellitus patients are potentially skewed diabetes predictors

BACKGROUND The lack of specific predictors for type-2 diabetes mellitus(T2DM)severely impacts early intervention/prevention efforts.Elevated branched-chain amino acids(BCAAs:Isoleucine,leucine,valine)and aromatic amino acids(AAAs:Tyrosine,tryptophan,phenylalanine)show high sensitivity and specificity in predicting diabetes in animals and predict T2DM 10-19 years before T2DM onset in clinical studies.However,improvement is needed to support its clinical utility.AIM To evaluate the effects of body mass index(BMI)and sex on BCAAs/AAAs in new-onset T2DM individuals with varying body weight.METHODS Ninety-seven new-onset T2DM patients(<12 mo)differing in BMI[normal weight(NW),n=33,BMI=22.23±1.60;overweight,n=42,BMI=25.9±1.07;obesity(OB),n=22,BMI=31.23±2.31]from the First People’s Hospital of Yunnan Province,Kunming,China,were studied.One-way and 2-way ANOVAs were conducted to determine the effects of BMI and sex on BCAAs/AAAs.RESULTS Fasting serum AAAs,BCAAs,glutamate,and alanine were greater and high-density lipoprotein(HDL)was lower(P<0.05,each)in OB-T2DM patients than in NW-T2DM patients,especially in male OB-T2DM patients.Arginine,histidine,leucine,methionine,and lysine were greater in male patients than in female patients.Moreover,histidine,alanine,glutamate,lysine,valine,methionine,leucine,isoleucine,tyrosine,phenylalanine,and tryptophan were significantly correlated with abdominal adiposity,body weight and BMI,whereas isoleucine,leucine and phenylalanine were negatively correlated with HDL.CONCLUSION Heterogeneously elevated amino acids,especially BCAAs/AAAs,across new-onset T2DM patients in differing BMI categories revealed a potentially skewed prediction of T2DM development.The higher BCAA/AAA levels in obese T2DM patients would support T2DM prediction in obese individuals,whereas the lower levels of BCAAs/AAAs in NW-T2DM individuals may underestimate T2DM risk in NW individuals.This potentially skewed T2DM prediction should be considered when BCAAs/AAAs are to be used as the T2DM predictor.

Minimizing tacrolimus decreases the risk of new-onset diabetes mellitus after liver transplantation

AbstractAIM： To investigate the impact of minimum tacrolimus（TAC） on new-onset diabetes mellitus （NODM） afterliver transplantation （LT）.METHODS： We retrospectively analyzed the data of973 liver transplant recipients between March 1999and September 2014 in West China Hospital LiverTransplantation Center. Following the exclusion ofineligible recipients, 528 recipients with a TAC-dominantregimen were included in our study. We calculatedand determined the mean trough concentration ofTAC （cTAC） in the year of diabetes diagnosis in NODMrecipients or in the last year of the follow-up in non-NODM recipients. A cutoff of mean cTAC value forpredicting NODM 6 mo after LT was identified usinga receptor operating characteristic curve. TAC-relatedcomplications after LT was evaluated by χ^2 test, andthe overall and allograft survival was evaluated usingthe Kaplan-Meier method. Risk factors for NODM afterLT were examined by univariate and multivariate Cox regression.RESULTS： Of the 528 transplant recipients, 131（24.8%） developed NODM after 6 mo after LT, andthe cumulative incidence of NODM progressivelyincreased. The mean cTAC of NODM group recipientswas significantly higher than that of recipients in thenon-NODM group （7.66 ± 3.41 ng/mL vs 4.47 ± 2.22ng/mL, P 〈 0.05）. Furthermore, NODM group recipientshad lower 1-, 5-, 10-year overall survival rates （86.7%,71.3%, and 61.1% vs 94.7%, 86.1%, and 83.7%, P 〈0.05） and allograft survival rates （92.8%, 84.6%, and75.7% vs 96.1%, 91%, and 86.1%, P 〈 0.05） thanthe others. The best cutoff of mean cTAC for predictingNODM was 5.89 ng/mL after 6 mo after LT. Multivariateanalysis showed that old age at the time of LT （〉 50years）, hypertension pre-LT, and high mean cTAC （≥5.89 ng/mL） after 6 mo after LT were independent riskfactors for developing NODM. Concurrently, recipientswith a low cTAC （〈 5.89 ng/mL） were less likely tobecome obese （21.3% vs 30.2%, P 〈 0.05） or todevelop dyslipidemia （27.5% vs 44.8%, P 〈0.05）,chronic kidney dysfunction （14.6% vs 22.7%, P 〈 0.05）,and moderate to severe infection （24.7% vs 33.1%, P〈 0.05） after LT than recipients in the high mean cTACgroup. However, the two groups showed no significantdifference in the incidence of acute and chronicrejection, hypertension, cardiovascular events and newonsetmalignancy.CONCLUSION： A minimal TAC regimen can decreasethe risk of long-term NODM after LT. Maintaining a cTACvalue below 5.89 ng/mL after LT is safe and beneficial.

New-onset diabetes after kidney transplantation:Incidence and associated factors

AIM To determine the incidence and associated factors of new-onset diabetes after transplantation(NODAT) in a Portuguese central hospital. METHODS This single-center retrospective study involved consecutive adult nondiabetic transplant recipients, who had undergone kidney transplantation between January 2012 and March 2016. NODAT was diagnosed according to the criteria of the American Diabetes Association. Data were collected from an institutional database of the Nephrology and Kidney Transplantation Department(Santa Maria Hospital, Lisbon, Portugal) and augmented with data of laboratorial parameters collected from the corresponding patient electronic medical records. Exclusion criteria were preexisting diabetes mellitus, missing information and follow-up period of less than 12 mo. Data on demographic and clinical characteristics as well as anthropometric and laboratorial parameters were also collected. Patients were divided into two groups: With and without NODAT-for statistical comparison.RESULTS A total of 156 patients received kidney transplantduring the study period, 125 of who were included in our analysis. NODAT was identified in 27.2% of the patients(n = 34; 53% female; mean age: 49.5 ± 10.8 years; median follow-up: 36.4 ± 2.5 mo). The incidence in the first year was 24.8%. The median time to diagnosis was 3.68 ± 5.7 mo after transplantation, and 76.5% of the patients developed NODAT in the first 3 mo. In the group that did not develop NODAT(n = 91), 47% were female, with mean age of 46.4 ± 13.5 years and median follow-up of 35.5 ± 1.6 mo. In the NODAT group, the pretransplant fasting plasma glucose(FPG) levels were significantly higher [101(96.1-105.7) mg/d L vs 92(91.4-95.8) mg/d L, P = 0.007] and pretransplant impaired fasting glucose(IFG) was significantly more frequent(51.5% vs 27.7%, P = 0.01). Higher pretransplant FPG levels and pretransplant IFG were found to be predictive risk factors for NODAT development [odds ratio(OR): 1.059, P = 0.003; OR: 2.772, P = 0.017, respectively]. CONCLUSION NODAT incidence was high in our renal transplant recipients, particularly in the first 3 mo posttransplant, and higher pretransplant FPG level and IFG were risk factors.

Association between ADIPOQ gene polymorphisms and the risk of new-onset diabetes mellitus after liver transplantation

BACKGROUND:New-onset diabetes after transplantation(NODAT) has become one of the major factors that affect the overall survival and long-term life quality in liver transplantation(LT) recipients. Previous studies found that the serum adiponectin concentration of diabetic patients is significantly lower than that of healthy subjects. Adiponectin regulates the blood glucose level by increasing body sensitivity to insulin through various mechanisms. In this study, we aimed to investigate the impact of diabetes related gene polymorphisms on the development of NODAT in liver recipients.METHODS:A total of 256 LT patients in a single-center were selected retrospectively for the study. Genomic DNA was extracted from explanted liver tissues, and tested for twelve diabetes mellitus associated single nucleotide polymorphisms by Sequenom Mass ARRAY. Modified clinical models in predicting NODAT were established and evaluated.RESULTS:The GG genotype of ADIPOQ rs1501299 gene polymorphism was significantly more frequent in NODAT than non-NODAT LT patients(56% vs 39%, P=0.014). Dominant model(GG vs GT+TT, P=0.030) and recessive model(GT+GG vs TT, P=0.005) also confirmed the genotype distribution difference between NODAT and non-NODAT groups. Age(OR=1.048, P=0.004), BMI(OR=1.107, P=0.041), and blood tacrolimus level at 1-month LT(OR=1.170, P=0.003) were clinical independent risk factors of NODAT. Furthermore, rs1501299 could improve the ability of clinical model in predicting NODAT(AUROC=0.743, P<0.001).CONCLUSION:ADIPOQ rs1501299 gene polymorphism is associated with an increased risk of NODAT, which should be added to the clinical models in predicting the occurrence of NODAT in LT recipients.

Recent advances in new-onset diabetes mellitus after kidney transplantation

A common challenge in managing kidney transplant recipients(KTR)is posttransplant diabetes mellitus(PTDM)or diabetes mellitus(DM)newly diagnosed after transplantation,in addition to known pre-existing DM.PTDM is an important risk factor for post-transplant cardiovascular(CV)disease,which adversely affects patient survival and quality of life.CV disease in KTR may manifest as ischemic heart disease,heart failure,and/or left ventricular hypertrophy.Available therapies for PTDM include most agents currently used to treat type 2 diabetes.More recently,the use of sodium glucose co-transporter 2 inhibitors(SGLT2i),glucagon-like peptide-1 receptor agonists(GLP-1 RA),and dipeptidyl peptidase 4 inhibitors(DPP4i)has cautiously extended to KTR with PTDM,even though KTR are typically excluded from large general population clinical trials.Initial evidence from observational studies seems to indicate that SGLT2i,GLP-1 RA,and DPP4i may be safe and effective for glycemic control in KTR,but their benefit in reducing CV events in this otherwise high-risk population remains unproven.These newer drugs must still be used with care due to the increased propensity of KTR for intravascular volume depletion and acute kidney injury due to diarrhea and their single-kidney status,pre-existing burden of peripheral vascular disease,urinary tract infections due to immunosuppression and a surgically altered urinary tract,erythrocytosis from calcineurin inhibitors,and reduced kidney function from acute or chronic rejection.

New-onset diabetes mellitus after kidney transplantation:Current status and future directions

A diagnosis of new-onset diabetes after transplantation(NODAT) carries with it a threat to the renal allograft,as well as the same short-and long-term implications of type 2 diabetes seen in the general population.NODAT usually occurs early after transplantation,and is usually diagnosed according to general population guidelines.Non-modifiable risk factors for NODAT include advancing age,African American,Hispanic,or South Asian ethnicity,genetic background,a positive family history for diabetes mellitus,polycystic kidney disease,and previously diagnosed glucose intolerance.Modifiable risk factors for NODAT include obesity and the metabolic syndrome,hepatitis C virus and cytomegalovirus infection,corticosteroids,calcineurin inhibitor drugs(especially tacrolimus),and sirolimus.NODAT affects graft and patient survival,and increases the incidence of post-transplant cardiovascular disease.The incidence and impact of NODAT can be minimized through pre-and post-transplant screening to identify patients at higher risk,including by oral glucose tolerance tests,as well as multi-disciplinary care,lifestyle modification,and the use of modified immunosuppressive regimens coupled with glucose-lowering therapies including oral hypoglycemic agents and insulin.Since NODAT is a major cause of post-transplant morbidity and mortality,measures to reduce its incidence and impact have the potential to greatly improve overall transplant success.

Risk factors for new onset diabetes mellitus after liver transplantation: A meta-analysis

AIM: To determine the risk factors for new-onset diabetes mellitus(NODM) after liver transplantation by conducting a systematic review and meta-analysis.METHODS: We electronically searched the databases of MEDLINE, EMBASE and the Cochrane Library from January 1980 to December 2013 to identify relevant studies reporting risk factors for NODM after liver transplantation. Two authors independently assessed the trials for inclusion and extracted the data. Discrepancies were resolved in consultation with a third reviewer. All statistical analyses were performed with the Rev Man5.0 software(The Cochrane Collaboration, Oxford, United Kingdom). Pooled odds ratios(OR) or weighted mean differences(WMD) with 95% confidence intervals(CIs) were calculated using either a fixed effects or a random effects model, based on the presence(I2 < 50%) or absence(I2 > 50%) of significant heterogeneity. RESULTS: Twenty studies with 4580 patients were included in the meta-analysis, all of which were retrospective. The meta-analysis identified the following significant risk factors: hepatitis C virus(HCV) infection(OR = 2.68; 95%CI: 1.92-3.72); a family history of diabetes(OR = 1.69, 95%CI: 1.09-2.63, P < 0.00001); male gender(OR = 1.53; 95%CI: 1.24-1.90; P < 0.0001); impaired fasting glucose(IFG; OR = 3.27; 95%CI: 1.84-5.81; P < 0.0001); a family history of diabetes(OR = 1.69; 95%CI: 1.09-2.63; P = 0.02); use of tacrolimus(OR = 1.34; 95%CI: 1.03-1.76; P = 0.03) and body mass index(BMI)(WMD = 1.19, 95%CI: 0.69-1.68, P < 0.00001). Other factors, such as hepatitis B virus infection and alcoholism, were not found to be associated with the incidence of NODM.CONCLUSION: The study showed that HCV infection, IFG, a family history of diabetes, male gender, tacrolimus and BMI are risk factors for NODM after liver transplantation.

Post-transplant diabetes mellitus in liver transplantation:Hangzhou experience

BACKGROUND: Diabetes mellitus (DM) is a frequent and serious complication in patients with liver diseases. We aimed to assess the prevalence and consequences of post-transplant DM (PTDM) in Chinese patients with HBV-related liver diseases and to determine the possible risk factors. METHODS: Altogether 165 patients with HBV infection and undergoing cadaveric related liver transplantation (LT) were enrolled. The clinical data of patients with (PTDM group) and without PTDM (non-PTDM group) were compared. RESULTS: Of the 165 patients, 28 had DM and 12 had impaired fasting glucose (IFG) before LT. Patients with pre-transplant DM or IFG had a survival rate similar to that of the others. Forty patients (24.2%) developed PTDM with a mean time of 36 17 days (range 2-300 days) after LT. Of those, 32 developed PTDM within 3 months post-LT and 29 needed insulin treatment. Pre-transplant hepatic encephalopathy and tacrolimus application were found more frequently in the PTDM group than in the non-PTDM group. The plasma tacrolimus levels were notably higher at I and 3 months post-LT in the PTDM group than those in the non-PTDM group. Compared to the non-PTDM group, the PTDM group showed remarkably poorer survival and tumor-free survival in patients with hepatocellular carcinoma, and significantly higher incidence of sepsis, fungal infection, chronic kidney diseases and biliary complications after LT. CONCLUSIONS: Pre-transplant DM did not affect the patient survival after LT. Since PTDM is common, it has a negative impact on outcome and may contribute to tumor recurrence. Pre-transplant hepatic encephalopathy, a tacrolimus-based regimen, and high levels of tacrolimus are clearly associated with the occurrence of PTDM.

WJSC 6^(th) Anniversary Special Issues(2):Mesenchymal stem cells Mesenchymal stem cells help pancreatic islet transplantation to control type 1 diabetes

Islet cell transplantation has therapeutic potential to treat type 1 diabetes,which is characterized by autoimmune destruction of insulin-producing pancreatic isletβcells.It represents a minimal invasive approach forβcell replacement,but long-term blood control is still largely unachievable.This phenomenon can be attributed to the lack of islet vasculature and hypoxic environment in the immediate post-transplantation period that contributes to the acute loss of islets by ischemia.Moreover,graft failures continue to occur because of immunological rejection,despite the use of potent immunosuppressive agents.Mesenchymal stem cells(MSCs)have the potential to enhance islet transplantation by suppressing inflammatory damage and immune mediated rejection.In this review we discuss the impact of MSCs on islet transplantation and focus on the potential role of MSCs in protecting islet grafts from early graft failure and from autoimmune attack.

Islet cell transplantation as a cure for insulin dependent diabetes: current improvements in preserving islet cell mass and function

OBJECTIVE: To review the current progress of islet cell transplantation in patients with insulin-dependent diabetes, emphasizing on the difficulties with recovering and preserving islet cell mass and function, 30% of which is lost during the peri-transplantation period. RESULTS: The islet-cell isolation technique is perfected, but improvements are still progressing in two major directions: preservation of islet cells and tolerance induction. Optimum islet cell viability and function depends on appropriate revascularization of the islet graft and blockade of thrombus formation as well as cytokine and free radical release. Conditioning the islet cells in-vitro prior to transplantation to either upregulate VEGF expression or downregulate NF-kappa B transcription factor has proven to improve revascularization and to prevent islet cell apoptosis and cytokine-mediated damage. Tolerance induction is currently being best achieved by selecting and combining immunosuppressive agents such as monoclonal antibodies which target the major signaling molecules during immune activation, but which are least toxic to islet cells. CONCLUSIONS: Patients with insulin-dependent diabetes will greatly benefit from current developments in effective approaches to protect islets during the peritransplant period. Emerging interest in stem cell biology and differentiation may provide the ultimate solution to the problem of organ scarcity and islet cell protection from the peritransplant induced damage.

Diabetes mellitus is a risk factor of acute kidney injury in liver transplantation patients

Background: Diabetes mellitus has become an increasing global health burden with rapid growing prevalence. Patients with diabetes have higher susceptibility to acute kidney injury(AKI). Liver transplantation(LT) predisposes the kidney to injury. However, the association between diabetes and AKI in LT patients remains unclear. Methods: We conducted a retrospective cohort study examining risk factors for AKI in patients undergone orthotopic LT. Potential risk factors including baseline estimated glomerular filtration rate(e GFR), the model for end-stage liver disease(MELD) score, diabetes, hypertension and intraoperative blood loss were screened. The primary endpoint was AKI occurrence. Multivariate logistic regression was used to analyze the association between potential risk factors and AKI. Results: A total of 291 patients undergone orthotopic LT were included in the present study. Among them, 102 patients(35.05%) developed AKI within 5 days after LT. Diabetes was identified as an independent risk factor for AKI. Patients who developed AKI had worse graft function recovery and higher mortality within 14 days after LT compared to those who did not develop AKI. AKI patients with diabetes had a significant decline of e GFR within the first postoperative year, compared with patients who did not develop AKI and who developed AKI but without diabetes. Conclusions: Diabetes is an independent risk factor for AKI after orthotopic LT. AKI is associated with delayed graft function recovery and higher mortality in short-term postoperative period. Diabetic patients who developed AKI after LT experience a faster decline of e GFR within the first year after surgery.

Transplant options for patients with type 2 diabetes and chronic kidney disease

Chronic kidney disease(CKD) has become a real epidemic around the world, mainly due to ageing and diabetic nephropathy. Although diabetic nephropathy due to type 1 diabetes mellitus(T1DM) has been studied more extensively, the vast majority of the diabetic CKD patients suffer from type 2 diabetes mellitus(T2DM). Renal transplantation has been established as a first line treatment for diabetic nephropathy unless there are major contraindications and provides not only a better quality of life, but also a significant survival advantage over dialysis. However, T2 DM patients are less likely to be referred for renal transplantation as they are usually older, obese and present significant comorbidities. As pre-emptive renal transplantation presents a clear survival advantage over dialysis, all T2 DM patients with CKD should be referred for early evaluation by a transplant center. The transplant center should have enough time in order to examine their eligibility focusing on special issues related with diabetic nephropathy and explore the best options for each patient. Living donor kidney transplantation should always be considered as the first line treatment. Otherwise, the patient should be listed for deceased donor kidney transplantation. Recent progress in transplantation medicine has improved the "transplant menu" for T2 DM patients with diabetic nephropathy and there is an ongoing discussion aboutthe place of simultaneous pancreas kidney(SPK) transplantation in well selected patients. The initial hesitations about the different pathophysiology of T2 DM have been forgotten due to the almost similar short- and long-term results with T1 DM patients. However, there is still a long way and a lot of ethical and logistical issues before establishing SPK transplantation as an ordinary treatment for T2 DM patients. In addition recent advances in bariatric surgery may offer new options for severely obese T2 DM patients with CKD. Nevertheless, the existing data for T2 DM patients with advanced CKD are rather scarce and bariatric surgery should not be considered as a cure for diabetic nephropathy, but only as a bridge for renal transplantation.

Transplantation for the treatment of type 1 diabetes

Transplantation of pancreatic tissue, as either the intact whole pancreas or isolated pancreatic islets has become a clinical option to be considered in the treatment of patients with type 1 insulin-dependant diabetes mellitus. A successful whole pancreas or islet transplant offers the advantages of attaining normal or near normal blood glucose control and normal hemoglobin Alc levels without the risks of severe hypoglycemia associate with intensive insulin therapy. Both forms of transplants are also effective at eliminating the occurrence of significant hypoglycemic events （even with only partial islet function evident）. Whereas whole pancreas transplantation has also been shown to be very effective at maintaining a euglycemic state over a sustained period of time, thus providing an opportunity for a recipient to benefit from improvement of their blood glucose control, it is associated with a significant risk of surgical and post-operative complications. Islet transplantation is attractive as a less invasive alternative to whole pancreas transplant and offers the future promise of immunosuppression-free transplantation through pretransplant culture. Islet transplantation however, may not always achieve the sustained level of tight glucose control necessary for reducing the risk of secondary diabetic complications and exposes the patient to the adverse effects of immunosuppression. Although recent advances have led to an increased rate of obtaining insulin-independence following islet transplantation, further developments are needed to improve the longterm viability and function of the graft to maintain improved glucose control over time.

Diabetes mellitus may affect the long-term survival of hepatitis B virus-related hepatocellular carcinoma patients after liver transplantation

AIM to determine whether diabetes mellitus(DM) affects prognosis/recurrence after liver transplantation(Lt) for hepatitis B virus(HBV)-related hepatocellular carcinoma(HCC). METHODS A retrospective study was conducted between January 2000 and August 2013 on 1631 patients with HBV-related HCC who underwent Lt with antiviral prophylaxis. Patient data were obtained from the China Liver transplant Registry(https://www.cltr.org/). to compare the outcomes and tumor recurrence in the HBV-related HCC patients with or without DM, statistical analyses were conducted using χ2 tests, Mann-Whitney tests, the Kaplan-Meier method, log-rank tests and multivariate step-wise Cox regression analysis. RESULTS Univariate analysis of 1631 patients who underwent Lt found overall 1-, 3- and 5-year survival rates of 79%, 73% and 71% respectively in the DM patients, and 84%, 78% and 76% in the non-DM patients respectively. Overall survival rate differences after Lt between the two groups were significant(P = 0.041), but recurrence-free survival rates were not(P = 0.096). By stratified analysis, the overall survival rates in DM patients for age > 50 years(P = 0.002), the presence of vascular invasion(P = 0.096), tumors ≤ 3 cm(P = 0.047), two to three tumor nodules(P = 0.007), Child-Pugh grade B(P = 0.018), and preLt alanine aminotransferase levels between 40 and 80 IU/L(P = 0.017) were significantly lower than in non-DM patients. Additionally, serum α-fetoprotein level > 2000 ng/m L(P = 0.052) was associated with a significant survival difference trend between DM and non-DM patients. Multivariate analysis showed that the presence of DM(P < 0.001, HR = 1.591; 95%CI: 1.239-2.041) was an independent predictor associated with poor survival after Lt. CONCLUSION HBV-related HCC patients with DM have decreased long-term overall survival and poor Lt outcomes. Prevention strategies for HCC patients with DM are recommended.

Simultaneous liver, pancreas-duodenum and kidney transplantation in a patient with hepatitis B cirrhosis, uremia and insulin dependent diabetes mellitus

Simultaneous liver,pancreas-duodenum,and kidney transplantation has been rarely reported in the literature. Here we present a new and more efficient en bloc technique that combines classic orthotopic liver and pancreas-duodenum transplantation and heterotopic kidney transplantation for a male patient aged 44 years who had hepatitis B related cirrhosis,renal failure,and insulin dependent diabetes mellitus(IDDM). A quadruple immunosuppressive regimen including induction with basiliximab and maintenance therapy with tacrolimus,mycophenolate mofetil,and steroids was used in the early stage post-transplant. Postoperative recovery was uneventful and the patient was discharged on the 15 th postoperative day with normal liver and kidney function. The insulin treatment was completely withdrawn 3 wk after operation,and the blood glucose level remained normal. The case findings support that abdominal organ cluster and kidney transplantation is an effective method for the treatment of end-stage liver disease combined with uremia and IDDM.

Post-transplant diabetes mellitus and preexisting liver disease-a bidirectional relationship affecting treatment and management

Liver cirrhosis and diabetes mellitus(DM)are both common conditions with significant socioeconomic burden and impact on morbidity and mortality.A bidirectional relationship exists between DM and liver cirrhosis regarding both etiology and disease-related complications.Type 2 DM(T2DM)is a wellrecognized risk factor for chronic liver disease and vice-versa,DM may develop as a complication of cirrhosis,irrespective of its etiology.Liver transplantation(LT)represents an important treatment option for patients with end-stage liver disease due to non-alcoholic fatty liver disease(NAFLD),which represents a hepatic manifestation of metabolic syndrome and a common complication of T2DM.The metabolic risk factors including immunosuppressive drugs,can contribute to persistent or de novo development of DM and NAFLD after LT.T2DM,obesity,cardiovascular morbidities and renal impairment,frequently associated with metabolic syndrome and NAFLD,may have negative impact on short and long-term outcomes following LT.The treatment of DM in the context of chronic liver disease and post-transplant is challenging,but new emerging therapies such as glucagon-like peptide-1 receptor agonists(GLP-1RAs)and sodium–glucose cotransporter 2 inhibitors(SGLT2i)targeting multiple mechanisms in the shared pathophysiology of disorders such as oxidative stress and chronic inflammation are a promising tool in future patient management.

Autoimmune diabetes recurrence should be routinely monitored after pancreas transplantation

Autoimmune type 1 diabetes recurrence in pancreas grafts was first described 30 years ago, but it is not yet completely understood. In fact, the number of transplants affected and possibly lost due to this disease may be falsely low. There may be insufficient awareness to this entity by clinicians, leading to underdiagnosis. Some authors estimate that half of the immunological losses in pancreas transplantation are due to autoimmunity. Pancreas biopsy is the gold standard for the definitive diagnosis. However, as an invasive procedure, it is not the ideal approach to screen the disease. Pancreatic autoantibodies which may be detected early before graft dysfunction, when searched for, are probably the best initial tool to establish the diagnosis. The purpose of this review is to revisit the autoimmune aspects of type 1 diabetes and to analyse data about the identified autoantibodies, as serological markers of the disease. Therapeutic strategies used to control the disease, though with unsatisfactory results, are also addressed. In addition, the author's own experience with the prospective monitoring of pancreatic autoantibodies after transplantation and its correlation with graft outcome will be discussed.

Pancreas transplantation in type Ⅱ diabetes mellitus

Although the diagnosis of type 2 diabetes mellitus was once considered a contraindication to simultaneous pancreas-kidney transplantation, a growing body of evidence has revealed that similar graft and patient survival can be achieved when compared to type 1 diabetes mellitus recipients. A cautious strategy regarding candidate selection may limit appropriate candidates from additional benefits in terms of quality of life and potential amelioration of secondary side effects of the disease process. Although our current understanding of the disease has changed, uniform listing characteristics to better define and study this population have limited available data and must be established.

Gut microbiome:A revolution in typeⅡdiabetes mellitus

TypeⅡdiabetes mellitus(T2DM)has experienced a dramatic increase globally across countries of various income levels over the past three decades.The persistent prevalence of T2DM is attributed to a complex interplay of genetic and environmental factors.While numerous pharmaceutical therapies have been developed,there remains an urgent need for innovative treatment approaches that offer effectiveness without significant adverse effects.In this context,the exploration of the gut microbiome presents a promising avenue.Research has increasingly shown that the gut microbiome of individuals with T2DM exhibits distinct differences compared to healthy individuals,suggesting its potential role in the disease’s pathogenesis and progression.This emerging field offers diverse applications,particularly in modifying the gut environment through the administration of prebiotics,probiotics,and fecal microbiome transfer.These interventions aim to restore a healthy microbiome balance,which could potentially alleviate or even reverse the metabolic dysfunctions associated with T2DM.Although current results from clinical trials have not yet shown dramatic effects on diabetes management,the groundwork has been laid for deeper investigation.Ongoing and future clinical trials are critical to advancing our understanding of the microbiome’s impact on diabetes.By further elucidating the mechanisms through which microbiome alterations influence insulin resistance and glucose metabolism,researchers can develop more targeted interventions.The potential to harness the gut microbiome in developing new therapeutic strategies offers a compelling prospect to transform the treatment landscape of T2DM,potentially reducing the disease’s burden significantly with approaches that are less reliant on traditional pharmaceuticals and more focused on holistic,systemic health improvements.

Don´t give up on mitochondria as a target for the treatment of diabetes and its complications

In this editorial,we discuss an article by Wang et al,focusing on the role of mitochondria in peripheral insulin resistance and insulin secretion.Despite numerous in vitro and pre-clinical studies supporting the involvement of mitochondrial dysfunction and oxidative stress in the pathogenesis of diabetes and its complications,efforts to target mitochondria for glycemic control in diabetes using mitochondria-targeted antioxidants have produced inconsistent results.The intricate functionality of mitochondria is summarized to underscore the challenges it poses as a therapeutic target.While mitochondria-targeted antioxidants have demonstrated improvement in mitochondrial function and oxidative stress in pre-clinical diabetes models,the results regarding glycemic control have been mixed,and no studies have evaluated their hypoglycemic effects in diabetic patients.Nonetheless,pre-clinical trials have shown promising outcomes in ameliorating diabetes-related complications.Here,we review some reasons why mitochondria-targeted antioxidants may not function effectively in the context of mitochondrial dysfunction.We also highlight several alternative approaches under development that may enhance the targeting of mitochondria for diabetes treatment.