Anatomical basis for pancreas transplantation via isolated splenic artery perfusion:A literature review

The variability of vascular anatomy of the pancreas underlines the difficulty of its transplantation.Research regarding the consistency of anatomical variations shows splenic arterial dominance in most cases.This can significantly improve transplantation success.A systematic literature review was performed according to the quality standards described in the AMSTAR measurement tool and the PRISMA guidelines.We valuated existing literature regarding the vascularization and blood perfusion patterns of the pancreas in terms of dominance and variability.The collected data was independently analyzed by two researchers.Variance of vascular anatomy was seen to be underreported in literature,though significant findings have been included and discussed in this study,providing valuable insight into the dynamics of pancreatic perfusion and feasibility of transplantation on several different supplying arteries.The splenic artery(SA)has a high percentage of consistency in all found studies(over 90%).High frequency of anastomoses between arterial pools supplying the pancreas can mediate sufficient blood supply through a dominant vessel,such as the SA,which is present in most cases.Pancreatic transplantation with isolated SA blood supply can provide sufficient arterial perfusion of the pancreas for stable transplant viability due to high anatomical consistency of the SA and vast communications with other arterial systems.

Donor risk factors in pancreas transplantation

The aim of the work was to analyze and expose the donor and recipient riskfactors in pancreas transplantation. In the following paper, we exposed the 2018Spanish Consensus Document on Donor and Recipient Selection Criteria forPancreas Transplantation. An assessment of the previous Selection Criteria forDonors and Recipients of Pancreas Transplantation, published in 2005 by theSpanish Pancreas Transplant Group (GETP) and the National TransplantOrganization (ONT) was performed. A literature review was performed usingCochrane Library, PubMed and Google Scholar databases. Some of the followingterms were used for the literature search: “Diabetes Mellitus,” “PancreasTransplantation,” “Insulin-Secreting Cells,” “Pancreas Allograft Thrombosis,”“Allograft Pancreatitis,” “Donors’ Risk Factors,” “Recipients’ Risk Factors,”“Pancreas Allograft Rejection” and “Pancreas Allograft Survival.” After anextended search, different inclusion criteria were established. Articles anddocuments with abstracts of full text and in English or Spanish language wereselected. Subsequently, different scientific meetings took place during 2015 and2016 by the GETP. Finally, the updated criteria were published by the GETP andONT in 2018. Several risk factors have been described in pancreas transplantationthat can be divided into donor risk factors: Advanced age (> 50 years);high bodymass index (BMI) (> 30 kg/m2);cause of death (e.g., stroke);previoushyperglycemia;hyperamylasemia;cold ischemia time (greater than 8 or 12 h,depending on the type of donation);the use of vasopressors in the intensive careunit or cardiac arrest;and the macroscopic aspect of the pancreas allograft. Thefollowing are recipient risk factors: Advanced age (> 50 years);active smoking;high BMI (> 30 kg/m2);and peripheral artery disease or sensorimotorpolyneuropathy. Based on the aforementioned parameters, different selectioncriteria have been established for the recipients depending on the type of pancreastransplantation. Knowledge of the risk factors for pancreas transplantation allowsthe establishment of reliable selection criteria for choosing donors and recipients.

Challenges of pancreas transplantation in developing countries,exploring the Turkey example

Pancreas transplantation significantly improves the quality of life for people with type 1 diabetes,primarily by eliminating the need for insulin and frequent blood glucose measurements.Despite the growing numbers of solid organ transplantations worldwide,number of pancreas transplantations in the developing countries`remain significantly low.This difference of pancreas transplantation practices was striking among the participating countries at the 1st International Transplant Network Meeting which was held in Turkey on 2018.In this meeting more than 40 countries were represented.Most of these counties were developing countries located in Africa,Middle East or Asia.The aim of this article is to identify the challenges and limiting factors for pancreas transplantations in these developing countries,by exploring the Turkish example.The challenges faced by the developing countries are broadly classified in four categories;wait-listing,donor pool,team work and follow up.Under these categorical titles,issues are further discussed in detail,giving examples from Turkish practice of pancreas transplantation.Additionally,several solutions to these challenges have been proposed-some of which have already been undertaken by the Turkish Ministry of Health.With the insight and methods presented in this article,pancreas transplantation should be made possible for the potential recipients in the developing countries.

Predicting early graft loss in pancreas transplantation using novel imaging techniques: are we there yet?

Since its inception in 1966 at the University of Minnesota,pancreas transplantation has witnessed major milestones in evolution of surgical techniques,immunosuppression regimen and more recently,machine perfusion for optimising graft utilisation(1).

Human parvovirus B19-associated early postoperative acquired pure red cell aplasia in simultaneous pancreas-kidney transplantation:A case report

BACKGROUND Acquired pure red cell aplasia(aPRCA)related to human parvovirus B19(HPV B19)is rarely reported in simultaneous pancreas-kidney transplantation(SPKT)recipients;there has yet to be a case report of early postoperative infection.In this current study,we report the case of a Chinese patient who experienced the disease in the early postoperative period.CASE SUMMARY A 63-year-old man,with type 2 diabetes and end-stage renal disease,received a brain dead donor-derived SPKT.Immunosuppression treatment consisted of tacrolimus,prednisone,enteric-coated mycophenolate sodium(EC-MPS),and thymoglobulin combined with methylprednisolone as induction.The hemoglobin(Hb)level declined due to melena at postoperative day(POD)3,erythropoietinresistant anemia persisted,and reticulocytopenia was diagnosed at POD 20.The bone marrow aspirate showed decreased erythropoiesis and the presence of giant pronormoblasts at POD 43.Metagenomic next-generation sequencing(mNGS)of a blood sample identified HPV B19 infection at POD 66.EC-MPS was withdrawn;three cycles of intravenous immunoglobulin(IVIG)infusion therapy were administered;and tacrolimus was switched to cyclosporine.The HPV B19-associated aPRCA resolved completely and did not relapse within the 1-year follow-up period.The diminution in mNGS reads was correlated with Hb and reticulocyte count improvements.CONCLUSION HPV B19-associated aPRCA can occur at an early period after SPKT.An effective therapy regimen includes IVIG infusion and adjustment of the immunosuppressive regimen.Moreover,mNGS can be used for the diagnosis and to reflect disease progression.

Anticoagulation in simultaneous pancreas kidney transplantation - On what basis?

BACKGROUND Despite technical refinements,early pancreas graft loss due to thrombosis continues to occur.Conventional coagulation tests(CCT)do not detect hypercoagulability and hence the hypercoagulable state due to diabetes is left untreated.Thromboelastogram(TEG)is an in-vitro diagnostic test which is used in liver transplantation,and in various intensive care settings to guide anticoagulation.TEG is better than CCT because it is dynamic and provides a global hemostatic profile including fibrinolysis.AIM To compare the outcomes between TEG and CCT(prothrombin time,activated partial thromboplastin time and international normalized ratio)directed anticoagulation in simultaneous pancreas and kidney(SPK)transplant recipients.METHODS A single center retrospective analysis comparing the outcomes between TEG and CCT-directed anticoagulation in SPK recipients,who were matched for donor age and graft type(donors after brainstem death and donors after circulatory death).Anticoagulation consisted of intravenous(IV)heparin titrated up to a maximum of 500 IU/h based on CCT in conjunction with various clinical parameters or directed by TEG results.Graft loss due to thrombosis,anticoagulation related bleeding,radiological incidence of partial thrombi in the pancreas graft,thrombus resolution rate after anticoagulation dose escalation,length of the hospital stays and,1-year pancreas and kidney graft survival between the two groups were compared.RESULTS Seventeen patients who received TEG-directed anticoagulation were compared against 51 contemporaneous SPK recipients(ratio of 1:3)who were anticoagulated based on CCT.No graft losses occurred in the TEG group,whereas 11 grafts(7 pancreases and 4 kidneys)were lost due to thrombosis in the CCT group(P=0.06,Fisher’s exact test).The overall incidence of anticoagulation related bleeding(hematoma/gastrointestinal bleeding/hematuria/nose bleeding/re-exploration for bleeding/post-operative blood transfusion)was 17.65%in the TEG group and 45.10%in the CCT group(P=0.05,Fisher’s exact test).The incidence of radiologically confirmed partial thrombus in pancreas allograft was 41.18%in the TEG and 25.50%in the CCT group(P=0.23,Fisher’s exact test).All recipients with partial thrombi detected in computed tomography(CT)scan had an anticoagulation dose escalation.The thrombus resolution rates in subsequent scan were 85.71%and 63.64%in the TEG group vs the CCT group(P=0.59,Fisher’s exact test).The TEG group had reduced blood product usage{10 packed red blood cell(PRBC)and 2 fresh frozen plasma(FFP)}compared to the CCT group(71 PRBC/10 FFP/2 cryoprecipitate and 2 platelets).The proportion of patients requiring transfusion in the TEG group was 17.65%vs 39.25%in the CCT group(P=0.14,Fisher’s exact test).The median length of hospital stay was 18 days in the TEG group vs 31 days in the CCT group(P=0.03,Mann Whitney test).The 1-year pancreas graft survival was 100%in the TEG group vs 82.35%in the CCT group(P=0.07,log rank test)and,the 1-year kidney graft survival was 100%in the TEG group vs 92.15%in the CCT group(P=0.23,log tank test).CONCLUSION TEG is a promising tool in guiding judicious use of anticoagulation with concomitant prevention of graft loss due to thrombosis,and reduces the length of hospital stay.

Two-layer cold storage method for pancreas and islet cell transplantation

The two-layer cold storage method (TLM) was f irst reported in 1988, consisting of a perfluorochemical (PFC) and initially Euro-Collins' solution, which was later replaced by University of Wisconsin solution (UW). PFC is a biologically inert liquid and acts as an oxygen-supplying agent. A pancreas preserved using the TLM is oxygenated through the PFC and substrates are supplied by the UW solution. This allows the pancreas preserved using the TLM to generate adenosine triphosphate during storage, prolonging the preservation time. In a canine model, the TLM was shown to repair and resuscitate warm ischemically damaged pancreata during preservation, improve pancreas graft survival after transplantation, and also improve the islet yield after isolation. Clinical trials using the TLM in pancreas preservation before whole-pancreas transplantation and islet isolation have shown promising outcomes. We describe the role of the TLM in pancreas and islet transplantation.

Back-table surgery pancreas allograft for transplantation:Implications in complications

To describe the main aspects of back-table surgery in pancreatic graft and the problems arising from poor technique.Back-table surgery for pancreatic graft is a complex,meticulous and laborious technique on which the success of implant surgery and perioperative results depends.The technique can be described in the following steps:Preparation of the sterile table,ex-situ inspection of the pancreasspleen block,management of the duodenum,identification of the bile duct,preparation of the portal vein,preparation of the own graft arteries and anastomosis to the arterial graft,spleen management and graft preservation prior to implantation in the recipient.A careful inspection of the pancreas-spleen block should be performed.It is important to identify the stump of the main bile duct,the portal vein cuff,and the arrangement of the superior mesenteric artery and splenic artery.The redundant duodenum must be removed.The availability of a good venous cuff facilitates the portal vein anastomosis and the positioning of the graft,two key points to prevent thrombosis.The section line of the arteries must be clean,without atherosclerosis,to prevent arterial thrombosis.The superior and splenic mesenteric arteries are generally separated by dense fibrolymphatic tissue.The artery can be reconstructed by interposing a"Y"graft from the donor iliac artery;or with an end-to-end anastomosis between the splenic artery and the superior mesenteric artery.An exquisite technique of bench work helps to prevent the most feared complications of pancreas transplantation:Thrombosis and graft pancreatitis.

Surgical complications after pancreatic transplantation:A computed tomography imaging pictorial review

Pancreatic transplantation is considered by the American Diabetes Association and the European Association for the Study of Diabetes an acceptable surgical procedure in patients with type 1 diabetes also undergoing kidney transplantation in pre-final or end-stage renal disease if no contraindications are present.Pancreatic transplantation,however,is a complex surgical procedure and may lead to a range of postoperative complications that can significantly impact graft function and patient outcomes.Postoperative computed tomography(CT)is often adopted to evaluate perfusion of the transplanted pancreas,identify complications and as a guide for interventional radiology procedures.CT assessment after pancreatic transplantation should start with the evaluation of the arterial Y-graft,the venous anastomosis and the duodenojejunostomy.With regard to complications,CT allows for the identification of vascular complications,such as thrombosis or stenosis of blood vessels supplying the graft,the detection of pancreatic fluid collections,including pseudocysts,abscesses,or leaks,the assessment of bowel complications(anastomotic leaks,ileus or obstruction),and the identification of bleeding.The aim of this pictorial review is to illustrate CT findings of surgical-related complications after pancreatic transplantation.The knowledge of surgical techniques is of key importance to understand postoperative anatomic changes and imaging evaluation.Therefore,we first provide a short summary of the main techniques of pancreatic transplantation.Then,we provide a practical imaging approach to pancreatic transplantation and its complications providing tips and tricks for the prompt imaging diagnosis on CT.

Mortality assessment for pancreas transplants in the United States over the decade 2008-2018

BACKGROUND Pancreas transplant is the only treatment that establishes normal glucose levels for patients diagnosed with diabetes.However,since 2005,no comprehensive analysis has compared survival outcomes of:(1)Simultaneous pancreas-kidney(SPK)transplant;(2)Pancreas after kidney(PAK)transplant;and(3)Pancreas transplant alone(PTA)to waitlist survival.AIM To explore the outcomes of pancreas transplants in the United States during the decade 2008-2018.METHODS Our study utilized the United Network for Organ Sharing Standard Transplant Analysis and Research file.Pre-and post-transplant recipient and waitlist characteristics and the most recent recipient transplant and mortality status were used.We included all patients with type I diabetes listed for pancreas or kidneypancreas transplant between May 31,2008 and May 31,2018.Patients were grouped into one of three transplant types:SPK,PAK,or PTA.RESULTS The adjusted Cox proportional hazards models comparing survival between transplanted and non-transplanted patients in each transplant type group showed that patients who underwent an SPK transplant exhibited a significantly reduced hazard of mortality[hazard ratio(HR)=0.21,95%confidence intervals(CI):0.19-0.25]compared to those not transplanted.Neither PAK transplanted patients(HR=1.68,95%CI:0.99-2.87)nor PTA patients(HR=1.01,95%CI:0.53-1.95)experienced significantly different hazards of mortality compared to patients who did not receive a transplant.CONCLUSION When assessing each of the three transplant types,only SPK transplant offered a survival advantage compared to patients on the waiting list.PKA and PTA transplanted patients demonstrated no significant differences compared to patients who did not receive a transplant.

Late complications of pancreas transplant

To summarize the long-term complications after pancreas transplantation that affect graft function,a literature search was carried out on the long-term complications of pancreatic transplantation,namely,complications from postoperative 3rd mo onwards,in terms of loss of graft function,late infection and vascular complications as pseudoaneurysms.The most relevant reviews and studies were selected to obtain the current evidence on these topics.The definition of graft failure varies among different studies,so it is difficult to evaluate,a standardized definition is of utmost importance to know the magnitude of the problem in all worldwide series.Chronic rejection is the main cause of long-term graft failure,occurring in 10%of patients.From the 3rd mo of transplantation onwards,the main risk factor for late infections is immunosuppression,and patients have opportunistic infections like:Cytomegalovirus,hepatitis B and C viruses,Epstein-Barr virus and varicella-zoster virus;opportunistic bacteria,reactivation of latent infections as tuberculosis or fungal infections.Complete preoperative studies and serological tests should be made in all recipients to avoid these infections,adding perioperative prophylactic treatments when indicated.Pseudoaneurysm are uncommon,but one of the main causes of late bleeding,which can be fatal.The treatment should be performed with radiological endovascular approaches or open surgery in case of failure.Despite all therapeutic options for the complications mentioned above,transplantectomy is a necessary option in approximately 50%of relaparotomies,especially in lifethreatening complications.Late complications in pancreatic transplantation threatens long-term graft function.An exhaustive follow-up as well as a correct immunosuppression protocol are necessary for prevention.

Machine perfusion in abdominal organ transplantation: Current use in the Netherlands

Scarcity of donor organs and the increment in patients awaiting a transplant increased the use of organs from expanded criteria donors or donation after circulatory death.Due to the suboptimal outcomes of these donor organs,there is an increased interest in better preservation methods,such as ex vivo machine perfusion or abdominal regional perfusion to improve outcomes.This state-ofthe-art review aims to discuss the available types of perfusion techniques,its potential benefits and the available evidence in kidney,liver and pancreas transplantation.Additionally,translational steps from animal models towards clinical studies will be described,as well as its application to clinical practice,with the focus on the Netherlands.Despite the lack of evidence from randomized controlled trials,currently available data suggest especially beneficial effects of normothermic regional perfusion on biliary complications and ischemic cholangiopathy after liver transplantation.For ex vivo machine perfusion in kidney transplantation,hypothermic machine perfusion has proven to be beneficial over static cold storage in a randomized controlled trial,while normothermic machine perfusion is currently under investigation.For ex vivo machine perfusion in liver transplantation,normothermic machine perfusion has proven to reduce discard rates and early allograft dysfunction.In response to clinical studies,hypothermic machine perfusion for deceased donor kidneys has already been implemented as standard of care in the Netherlands.

Complications during multiorgan retrieval and pancreas preservation

In pancreas transplantation, complications can arise at each step of the process,from the initial selection of donors and recipients through the surgical techniqueitself and the post-operative period, when lifelong immunosuppression isrequired. In the early steps, careful retrieval and preservation of the pancreas arecrucial for the viability of the organ and ultimate success of the transplant. Thepancreas is a low-flow gland, making it highly sensitive to transplantationconditions and presenting risk of pancreatitis due to periods of ischemia. The twogroups of donors - after brain death (DBD) or after cardiac arrest (DCD) - requiredifferent strategies of retrieval and preservation to avoid or reduce the risk ofcomplications developing during and after the transplantation. For DBD donortransplantation, multiorgan retrieval and cold preservation is the conventionaltechnique. Asystole donor (DCD) transplantation, in contrast, can benefit from thenewest technologies, such as hypothermic and especially normothermicpreservation machines (referred to as NECMO), to optimize organ preservation.The latter has led to an increase in the pool of donors by facilitating recuperationof organs for transplantation that would have been discarded otherwise.

Parvovirus B19 status in liver,kidney and pancreas transplant candidates:A single center experience

BACKGROUND Parvovirus B19(B19V)is associated with a wide range of clinical manifestations.The major presentation is erythema infectiosum.However,a persistent infection may cause pure red cell aplasia and chronic anemia in immunocompromized patients.The B19V seroprevalence varies with age and geographical location.AIM To determine the B19V serological status and DNAemia in kidney,liver,and pancreas transplant candidates.METHODS Patients who underwent kidney,liver,or simultaneous kidney and pancreas/liver transplantation between January 2021 and May 2022 were included in the study.The serum samples were collected before transplantation.For detection of B19V DNA,a LightMix Kit B19V EC(TIB MOLBIOL,Berlin,Germany)was used.B19V IgM and IgG antibodies were detected using a commercial ELISA test(Euroimmun,Lübeck,Germany).RESULTS One hundred and thirty-one transplant candidates were included in the study,71.0%male,with an average age of 53.27 years±12.71 years.There were 68.7%liver,27.5%kidney,3.0%simultaneous pancreas/kidney transplant(SPKT),and 0.8%simultaneous liver/kidney transplant recipients.No patients had detectable B19V DNA.B19V IgG seroprevalence was 77.1%.No acute or recent infections were detected(IgM antibodies).There was no difference in the mean age of seronegative and seropositive patients(51.8 years±12.9 years vs 53.7 years±12.7 years,t=-0.603;P=0.548).Although seropositivity was lower in patients aged less than 30 years(66.6%)compared to the patients aged 30-59 years and>60 years(80.4%and 78.1%,respectively),this difference was not significant.In addition,there was no difference in seropositivity between male and female transplant candidates,76.3%and 78.9%(χ^(2)=0.104;P=0.748).The seroprevalence did not differ among organ recipients,with 77.8%,80.6%,and 50.0%for liver,kidney,and SPKT,respectively,(χ^(2)=5.297;P=0.151).No significant difference was found in the seroprevalence in kidney transplant patients according to dialysis modality.Seroprevalence was 71.1%in hemodialysis patients,and 100%in peritoneal dialysis patients(χ^(2)=0.799;P=0.372).CONCLUSION The B19V seroprevalence is expectedly high among kidney,liver,and pancreas transplant candidates,but there are still 22.9%of seronegative individuals who remain at risk for primary disease and severe manifestations.Further research should elucidate the necessity of B19V screening in peri-transplant management.

Pancreatic transplant surgery and stem cell therapy:Finding the balance between therapeutic advances and ethical principles

The latest achievements in the field of pancreas transplantation and stem cell therapy require an effort by the scientific community to clarify the ethical implications of pioneering treatments,often characterized by high complexity from a surgical point of view,due to transplantation of multiple organs at the same time or at different times,and from an immunological point of view for stem cell therapy.The fundamental value in the field of organ transplants is,of course,a solidarity principle,namely that of protecting the health and life of people for whom transplantation is a condition of functional recovery,or even of survival.The nature of this value is that of a concept to which the legal discipline of transplants entrusts its own ethical dignity and for which it has ensured a constitutional recognition in different systems.The general principle of respect for human life,both of the donor and of the recipient,evokes the need not to put oneself and one’s neighbor in dangerous conditions.The present ethical reflection aims to find a balance between the latest therapeutic advances and several concepts including the idea of the person,the respect due to the dead,the voluntary nature of the donation and the consent to the same,the gratuitousness of the donation,the scientific progress and the development of surgical techniques,and the policies of health promotion.

Immediate post-operative complications(I):Post-operative bleeding;vascular origin:Thrombosis pancreatitis

Simultaneous pancreas-kidney transplantation is the treatment of choice forinsulin-dependent diabetes that associates end-stage diabetic nephropathy, sinceit achieves not only a clear improvement in the quality of life, but also provides along-term survival advantage over isolated kidney transplant. However, pancreastransplantation still has the highest rate of surgical complications among organtransplants. More than 70% of early graft losses are attributed to technical failures,that is, to a non-immunological cause. The so-called technical failures includegraft thrombosis, bleeding, infection, pancreatitis, anastomotic leak and pancreaticfistula. Pancreatic graft thrombosis leads these technical complications as the mostfrequent cause of early graft loss. Currently most recipients receive postoperativeanticoagulation with the aim of reducing the rate of thrombosis. Hemoperitoneumin the early postoperative period is a frequent cause of relaparotomy, but it is notusually associated with graft loss. The incidence of hemoperitoneum is clearlyrelated to the use of anticoagulation in the postoperative period. Post-transplantpancreatitis is another cause of early postoperative complications, less frequentthan the previous. In this review, we analyze the most common surgicalcomplications that determine pancreatic graft losses.

Intraoperative reperfusion assessment of human pancreas allografts using hyperspectral imaging(HSI)

Background:The most common causes of early graft loss in pancreas transplantation are insufficient blood supply and leakage of the intestinal anastomosis.Therefore,it is critical to monitor graft perfusion and oxygenation during the early post-transplant period.The goal of our pilot study was to evaluate the utility of hyperspectral imaging(HSI)in monitoring the microcirculation of the graft and adequate perfusion of the intestinal anastomosis during pancreatic allotransplantation.Methods:We imaged pancreatic grafts and intestinal anastomosis in real-time in three consecutive,simultaneous pancreas-kidney transplantations using the TIVITA®HSI system.Further,the intraoperative oxygen saturation(StO_(2)),tissue perfusion(near-infrared perfusion index,NIR),organ hemoglobin index(OHI),and tissue water index(TWI)were measured 15 minutes after reperfusion by HSI.Results:All pancreas grafts showed a high and homogeneous StO_(2)(92.6%±10.45%).Intraoperative HSI analysis of the intestinal anastomosis displayed significant differences of StO_(2)(graft duodenum 67.46%±5.60%vs.recipient jejunum:75.93%±4.71%,P<0.001)and TWI{graft duodenum:0.63±0.09[I(Index)]vs.recipient jejunum:0.72±0.09[I],P<0.001}.NIR and OHI did not display remarkable differences{NIR duodenum:0.68±0.06[I]vs.NIR jejunum:0.69±0.04[I],P=0.747;OHI duodenum:0.70±0.12[I]vs.OHI jejunum:0.68±0.13[I],P=0.449}.All 3 patients had an uneventful postoperative course with one displaying a Banff 1a rejection which was responsive to steroid treatment.Conclusions:Our study shows that contact-free HSI has potential utility as a novel tool for real-time monitoring of human pancreatic grafts after reperfusion,which could improve the outcome of pancreas transplantation.Further investigations are required to determine the predictive value of intraoperative HSI imaging.

Alternative therapeutic strategies in diabetes management

Diabetes is a heterogeneous metabolic disease characterized by elevated blood glucose levels resulting from the destruction or malfunction of pancreaticβcells,insulin resistance in peripheral tissues,or both,and results in a non-sufficient production of insulin.To adjust blood glucose levels,diabetic patients need exogenous insulin administration together with medical nutrition therapy and physical activity.With the aim of improving insulin availability in diabetic patients as well as ameliorating diabetes comorbidities,different strategies have been investigated.The first approaches included enhancing endogenousβcell activity or transplanting new islets.The protocol for this kind of intervention has recently been optimized,leading to standardized procedures.It is indicated for diabetic patients with severe hypoglycemia,complicated by impaired hypoglycemia awareness or exacerbated glycemic lability.Transplantation has been associated with improvement in all comorbidities associated with diabetes,quality of life,and survival.However,different trials are ongoing to further improve the beneficial effects of transplantation.Furthermore,to overcome some limitations associated with the availability of islets/pancreas,alternative therapeutic strategies are under evaluation,such as the use of mesenchymal stem cells(MSCs)or induced pluripotent stem cells for transplantation.The cotransplantation of MSCs with islets has been successful,thus providing protection against proinflammatory cytokines and hypoxia through different mechanisms,including exosome release.The use of induced pluripotent stem cells is recent and requires further investigation.The advantages of MSC implantation have also included the improvement of diabetes-related comorbidities,such as wound healing.Despite the number of advantages of the direct injection of MSCs,new strategies involving biomaterials and scaffolds have been developed to improve the efficacy of mesenchymal cell delivery with promising results.In conclusion,this paper offered an overview of new alternative strategies for diabetes management while highlighting some limitations that will need to be overcome by future approaches.