Insulin Independence Research Articles

Clinical Outcomes of 27-Gauge Pars Plana Vitrectomy for Diabetic Tractional Retinal Detachment Repair.

Purpose: To analyze the clinical outcomes of 27-gauge pars plana vitrectomy (PPV) repair of diabetic tractional retinal detachment (TRD) of various severities. Methods: This retrospective case series examined the outcomes of 27-gauge PPV to repair diabetic TRD from 2016 to 2020. The effect of medical and ophthalmologic history parameters and baseline detachment characteristics on visual acuity (VA) and retinal reattachment was analyzed. A grading system was established to stage the severity of the baseline vitreoretinal traction or detachment and compare the visual and anatomic outcomes between stages. Results: The study comprised 79 eyes (79 patients). The overall redetachment rate was 10.1% (8/79). The proportion of eyes with severe visual impairment (worse than 20/200) decreased from 81.0% (64/79) preoperatively to 56.9% (37/65) 6 months postoperatively (P < .001). Worse preoperative logMAR VA was associated with greater odds of redetachment (P = .017) and worse postoperative VA (P < .001). Insulin dependence was associated with better VA at 6 months (P = .017). A shorter known duration of diabetes (P = .026) and evidence of neovascularization of the iris (NVI) or angle (P = .004) were associated with worse visual outcomes. Eyes with detachment involving the posterior pole extending beyond the equator had worse VA at 6 months (P = .048). Conclusions: The primary reattachment rate after 27-gauge PPV was 89.9%. There was significant VA improvement, with a roughly 40% reduction in the number of eyes with severe visual impairment by the final follow-up. Insulin dependence, duration of diabetes, presence of NVI before surgery, and baseline posterior pole detachment extending beyond the equator were predictors of visual outcomes.

Outcomes of Pancreas Transplantation for Lower-Ranked Candidates

To perform more pancreas transplantation (PTx), our center sometimes performs pancreas transplantation for candidates ranked sixth place or lower. In this study, we analyzed the outcomes of PTx performed in our center to compare the outcomes of higher- and lower-ranked candidates. Seventy-two cases in which PTx was performed at our center were divided into 2 groups according to the candidate's rank. Cases in which PTx was performed for candidates up to fifth place were classified into the higher rank candidate group (HRC group; n=48), whereas PTx for candidates who were ranked sixth place or lower were classified into the lower rank candidate group (LRC group; n=24). The outcomes of PTx were retrospectively compared. Although the LRC group included a greater number of older donors (age ≥60 years), a greater number of donors with deteriorated renal function, and a greater number of HLA mismatches, the 1- and 5-year patient survival rates in the HRC group were 91.6% and 91.6%, respectively, compared with 95.8% and 87.0%, respectively, in the LRC group (P=.755). In terms of both pancreas and kidney graft survival, there were no significant differences between the 2 groups. Additionally, there were no significant differences between the 2 groups regarding the glucagon stimulation test and 75 g OGTT results, insulin independence rate, HbA1c, or serum creatinine level after transplantation. In Japan, where there is a severe donor shortage, the performance of transplantation for lower-ranked candidates would increase the number of opportunities for patients to receive PTx.

Human hypoimmune primary pancreatic islets avoid rejection and autoimmunity and alleviate diabetes in allogeneic humanized mice.

Transplantation of allogeneic pancreatic donor islets has successfully been performed in selected patients with difficult-to-control insulin-dependent diabetes and impaired awareness of hypoglycemia (IAH). However, the required systemic immunosuppression associated with this procedure prevents this cell replacement therapy from more widespread adoption in larger patient populations. We report the editing of primary human islet cells to the hypoimmune HLA class I- and class II-negative and CD47-overexpressing phenotype and their reaggregation into human HIP pseudoislets (p-islets). Human HIP p-islets were shown to survive, engraft, and ameliorate diabetes in immunocompetent, allogeneic, diabetic humanized mice. HIP p-islet cells were further shown to avoid autoimmune killing in autologous, diabetic humanized autoimmune mice. The survival and endocrine function of HIP p-islet cells were not impaired by contamination of unedited or partially edited cells within the p-islets. HIP p-islet cells were eliminated quickly and reliably in this model using a CD47-targeting antibody, thus providing a safety strategy in case HIP cells exert toxicity in a future clinical setting. Transplantation of human HIP p-islets for which no immunosuppression is required has the potential to lead to wider adoption of this therapy and help more diabetes patients with IAH and history of severe hypoglycemic events to achieve insulin independence.

Clinical outcomes of immune checkpoint inhibitor diabetes mellitus at a comprehensive cancer center.

Introduction: Immune checkpoint inhibitor-associated diabetes mellitus (ICI-DM) is a rare adverse event. In this study, we characterize clinical outcomes of patients with ICI-DM and evaluate survival impact of this complication on melanoma patients. Research design & methods: We conducted a retrospective review of 76 patients diagnosed with ICI-DM from April 2014 to December 2020. Results: 68% of patients presented in diabetic ketoacidosis, 16% had readmissions for hyperglycemia, and hypoglycemia occurred in 70% of patients after diagnosis. Development of ICI-DM did not impact overall survival or progression-free survival in melanoma patients. Conclusion: Development of ICI-DM is associated with long-term insulin dependence and pancreatic atrophy; the use of diabetes technology in this patient population can help improve glycemic control.

Human Hematopoietic Stem/Progenitor Cells in Type One Diabetes Mellitus Treatment: Is There an Ideal Candidate?

Type 1 diabetes mellitus (T1DM) is a highly prevalent autoimmune disease causing the destruction of pancreatic islet β-cells. The resulting insulin production deficiency leads to a lifelong need for insulin re-placement therapy, systemic complications, and reduced life quality and expectancy. Cell therapy has been extensively attempted to restore insulin independence (IID), and autologous nonmyeloablative hematopoietic stem cell transplantation (AHST) has appeared to give the most promising results, but with a highly variable quote of patients achieving IID across the studies. We performed a comprehensive review of the trials involving stem cells, and in particular AHST, for the treatment of T1DM. We then pooled the patients enrolled in the different trials and looked for the patient characteristics that could be associated with the achievement of IID. We found a significantly higher probability of achieving IID in older patients (OR 1.17, 95%CI 1.06-1.33, p = 0.002) and a significantly lower probability in patients with a history of ketoacidosis (OR 0.23, 95%CI 0.06-0.78, p = 0.023). This suggests that there could be a population of patients more likely to benefit from AHST, but further data would be required to depict the profile of the ideal candidate.

Consensus Paper: Latent Autoimmune Cerebellar Ataxia (LACA).

Immune-mediated cerebellar ataxias (IMCAs) have diverse etiologies. Patients with IMCAs develop cerebellar symptoms, characterized mainly by gait ataxia, showing an acute or subacute clinical course. We present a novel concept of latent autoimmune cerebellar ataxia (LACA), analogous to latent autoimmune diabetes in adults (LADA). LADA is a slowly progressive form of autoimmune diabetes where patients are often initially diagnosed with type 2 diabetes. The sole biomarker (serum anti-GAD antibody) is not always present or can fluctuate. However, the disease progresses to pancreatic beta-cell failure and insulin dependency within about 5 years. Due to the unclear autoimmune profile, clinicians often struggle to reach an early diagnosis during the period when insulin production is not severely compromised. LACA is also characterized by a slowly progressive course, lack of obvious autoimmune background, and difficulties in reaching a diagnosis in the absence of clear markers for IMCAs. The authors discuss two aspects of LACA: (1) the not manifestly evident autoimmunity and (2) the prodromal stage of IMCA's characterized by a period of partial neuronal dysfunction where non-specific symptoms may occur. In order to achieve an early intervention and prevent cell death in the cerebellum, identification of the time-window before irreversible neuronal loss is critical. LACA occurs during this time-window when possible preservation of neural plasticity exists. Efforts should be devoted to the early identification of biological, neurophysiological, neuropsychological, morphological (brain morphometry), and multimodal biomarkers allowing early diagnosis and therapeutic intervention and to avoid irreversible neuronal loss.

Matching for HLA-DR excluding diabetogenic HLA-DR3 and HLA-DR4 predicts insulin independence after pancreatic islet transplantation.

In pancreatic islet transplantation, the exact contribution of human leukocyte antigen (HLA) matching to graft survival remains unclear. Islets may be exposed to allogenic rejection but also the recurrence of type 1 diabetes (T1D). We evaluated the HLA-DR matching, including the impact of diabetogenic HLA-DR3 or HLA-DR4 matches. We retrospectively examined the HLA profile in 965 transplant recipients and 2327 islet donors. The study population was obtained from patients enrolled in the Collaborative Islet Transplant Registry. We then identified 87 recipients who received a single-islet infusion. Islet-kidney recipients, 2nd islet infusion, and patients with missing data were excluded from the analysis (n=878). HLA-DR3 and HLA-DR4 were present in 29.7% and 32.6% of T1D recipients and 11.6% and 15.8% of the donors, respectively. We identified 52 T1D islet recipients mismatched for HLA-DR (group A), 11 with 1 or 2 HLA-DR-matches but excluding HLA-DR3 and HLA- DR4 (group B), and 24 matched for HLA-DR3 or HLA-DR4 (group C). Insulin-independence was maintained in a significantly higher percentage of group B recipients from year one through five post-transplantation (p<0.01). At five-year post-transplantation, 78% of group B was insulin-independent compared to 24% (group A) and 35% (group C). Insulin-independence correlated with significantly better glycemic control (HbA1c <7%), fasting blood glucose, and reduced severe hypoglycemic events. Matching HLA-A-B-DR (≥3) independently of HLA- DR3 or HLA-DR4 matching did not improve graft survival. This study suggests that matching HLA-DR but excluding the diabetogenic HLA-DR3 and/or 4 is a significant predictor for long-term islet survival.

No Time to Die-How Islets Meet Their Demise in Transplantation.

Islet transplantation represents an effective treatment for patients with type 1 diabetes mellitus (T1DM) and severe hypoglycaemia unawareness, capable of circumventing impaired counterregulatory pathways that no longer provide protection against low blood glucose levels. The additional beneficial effect of normalizing metabolic glycaemic control is the minimisation of further complications related to T1DM and insulin administration. However, patients require allogeneic islets from up to three donors, and the long-term insulin independence is inferior to that achieved with solid organ (whole pancreas) transplantation. This is likely due to the fragility of islets caused by the isolation process, innate immune responses following portal infusion, auto- and allo-immune-mediated destruction and β-cell exhaustion following transplantation. This review covers the specific challenges related to islet vulnerability and dysfunction that affect long-term cell survival following transplantation.

Bioengineered omental transplant site promotes pancreatic islet allografts survival in non-human primates

The transplanting islets to the liver approach suffers from an immediate posttransplant loss of islets of more than 50%, progressive graft dysfunction over time, and precludes recovery of grafts should there be serious complications such as the development of teratomas with grafts that are stem cell-derived islets (SC-islets). The omentum features an attractive extrahepatic alternative site for clinical islet transplantation. We explore an approach in which allogeneic islets are transplanted onto the omentum, which is bioengineered with a plasma-thrombin biodegradable matrix in three diabetic non-human primates (NHPs). Within 1week posttransplant, each transplanted NHP achieves normoglycemia and insulin independence and remains stable until termination of the experiment. Success was achieved in each case with islets recovered from a single NHP donor. Histology demonstrates robust revascularization and reinnervation of the graft. This preclinical study can inform the development of strategies for β cell replacement including the use of SC-islets or other types of novel cells in clinical settings.

Comment on: Pancreatectomy With Islet-Autotransplantation As Alternative for Pancreatoduodenectomy in Patients With a High-Risk for Postoperative Pancreatic Fistula: The Jury Is Still Out.

We would like to congratulate Balzano et al1 on their randomized controlled bicenter PAN-IT trial wherein total pancreatectomy (TP) with islet-autotransplantation (IAT) was studied as an alternative for patients undergoing pancreatoduodenectomy (PD) with a high-risk for developing postoperative pancreatic fistula (POPF). However, we have some concerns regarding the authors’ final conclusions that TP-IAT may become the standard treatment in candidates for PD with a high risk for POPF. Our concerns center on (1) the primary endpoint of the PAN-IT trial, (2) the lack of assessment of patient-reported outcomes, and (3) the quality of diabetes control. First, it is questionable if postoperative morbidity is the optimal endpoint in a trial that aims to elucidate the role of TP(-IAT) as alternative to PD with a high risk for POPF. How much morbidity should be prevented to justify a lifelong apancreatic state? Indeed, TP-IAT improved the primary endpoint (ie, 90-day overall complication rate) by avoiding POPF, but the 90-day mortality did not differ statistically significant despite a clinically relevant difference (9.7% after PD vs 3.3% after TP-IAT), which is line with recent retrospective single-center series.2,3 However, the mortality after TP(-IAT) in the daily clinical practice may be substantially higher. A recent prospective European international multicenter study including 277 patients who underwent TP found a 90-day mortality rate of 7.6%, which increased to even 11.9% in centers performing less than 60 PDs per year.4 Moreover, the recent Dutch PORSCH trial demonstrated that postoperative mortality can be reduced after PD regardless of hospital volume due to the implementation of an algorithm for early detection and treatment of POPF.5 As a consequence, the vast majority of the clinically relevant POPF can be managed either conservatively or with minimally invasive interventions.5 Second, patient-reported outcomes including quality of life over time are highly relevant endpoints when determining the role of TP(-IAT) in our opinion. Surprisingly, quality of life was not evaluated over time, while the prospective nature of the PAN-IT trial offered a unique opportunity to investigate this properly. This should be included in future prospective studies. Although the interest in TP for this indication has been renewed in recent years by the improved morbidity and mortality after TP in high-volume centers4,6 and more adequate management of the associated metabolic insufficiencies, the related adverse events remain substantial.7 Quality of life on the middle- and long-term after TP is reduced in comparison to the general population.8,9 IAT after TP only (mostly temporarily) controls the endocrine insufficiency partially, whereas exocrine insufficiency remains a challenge. This is especially relevant for the currently studied indication of TP(-IAT) since patients with a high risk for POPF after PD often have long-term survival because of benign/ premalignant pancreatic diseases. Third, the quality of diabetes control and insulin independence obtained by TP-IAT. Already after 1 month, glycemic control as measured by hemoglobin A1c was worse in the TP-IAT group and at the end of follow-up (median follow-up of 388 days), only 6.7% of patients after TP-IAT were independent of insulin versus 80.6% of patients after high-risk PD. The authors argue that the absence of serious hypoglycemic events is explained by the remaining graft function. However, long-term results are missing, while these are highly important considering the likelihood that the graft function will further decrease over time. An alternative for or additive to IAT might be the bihormonal artificial pancreas, for which we recently demonstrating promising results.10 In summary, the PAN-IT is a high quality randomized trial that provides quite relevant insights, but in our opinion does not confirm that TP-IAT may become the standard treatment in patients with a high risk for POPF after PD. We question whether a 30% absolute risk reduction of short-term postoperative morbidity justifies a 73% absolute risk increase of lifelong insulin dependence and, most likely, decreased quality of life. Furthermore, early POPF recognition and step-wise minimally invasive management have an important role in the improvement of both morbidity and mortality after PD. Only future large, randomized studies with mortality and quality of life as primary outcome can answer this question.

Stem Cell Therapy in Combination with Naturopathy: Current Progressive Management of Diabetes and Associated Complications.

Diabetes is a chronic metabolic disorder having a global prevalence of nearly doubled over the last 30 years and has become one of the major health concerns worldwide. The number of adults with diabetes increased to 537 million in 2021. The overarching goal of diabetic research and treatment has always been to restore insulin independence and an average blood glucose level. Chemotherapeutic antidiabetic agents can manage diabetes but often show toxicity and drug resistance. Natural phytomedicines may be useful along with stem cell therapy for diabetes management. Even if the whole pancreatic organ and islet transplantation, are becoming benchmark techniques for diabetes management and control, a considerable scarcity of eligible donors of pancreatic tissues and organs severely limits their use. Stem cell treatment provides a bunch of possibilities for treating people with diabetes. For this purpose, comprehensive article searching was conducted, with relevant material obtained using search engines such as Scopus, PubMed, MEDLINE, Google, and others, using appropriate keywords. Stem cell therapies, including induced pluripotent stem cells and mesenchymal stem cells, are now becoming a popular area of investigation. Recent advancements in stem cell therapy might provide a feasible treatment option. Furthermore, in recent years, some novel bioactive compounds derived from plants have demonstrated antidiabetic action with higher potency than oral hypoglycaemic medications. Recent regenerative medicine and stem cell treatment advancements might subsequently provide a feasible diabetic management option. On the other hand, medicinal herbs have been considered a better choice for the extensive treatment of diabetes. If proper attention is not given to control diabetes by antidiabetic chemotherapeutic agents, natural phytomedicine, and sophisticated treatment like stem cell therapy, then the lifespan of patients will be decreased, and some associated secondary problems will also arise. So, the present review attempts to discuss naturopathy as an alternative resource in combination with stem cell therapy for the progressive management of diabetes and associated disorders.

Re-considering quantity requirements in islet transplantation

Pancreatic islet transplantation stands to enable patients with type 1 diabetes to become insulin-independent. However, the number of islets required to achieve insulin independence is not yet well-defined and depends on the transplantation approach. Here, we contextualize a ‘rule of thumb’ estimate of the islet quantities required for transplantation, and discuss the estimate’s practical implications.

Determinant of the Frequency of Short-Term Undesirable Events in Diabetes Discharged from the Emergency Department

Correction of hyperglycemia in these patients with nonemergency hyperglycemia is controversial. This study aims to reveal the effect of plasma glucose level and other factors (diabetes type, insulin dependence, age, and gender) on the frequency of revisits to the emergency department (ED) and hospitalization of diabetic patients discharged from the ED. Diabetic patients over the age of 18 who applied to the emergency department were included in the prospective, cross-sectional study. All data of patients who applied to the ED were recorded by the physician providing the patient’s care. There was no statistically significant difference in mean plasma glucose levels of patients who had revisits to the ED and were hospitalized (7–30 days, \(p>0.05\)). In hyperglycemic (\(n\): 104) and normoglycemic (\(n\): 125) DM patients, no significant difference was found in terms of frequency of revisit to the ED and hospitalization (respectively, revisit and hospitalization within 7 and 30 days/\(p=0.738\), 0.805, 0.130, and 0.697). When we evaluated the outcomes of revisit to the ED and hospitalization, it was found that the frequency of revisits within 7 and 30 days and hospitalization within 7 days increased significantly in IDDM patients (Table 3). Other factors such as gender, age, admission glucose level, and diabetes type were not found to be effective. In nonemergency hyperglycemic patients admitted to the emergency department, blood plasma glucose levels are not determinative in ED revisits and hospitalizations. However, the management and follow-up of IDDM patients should be done more carefully.

C-peptide Targets and Patient-centered Outcomes of Relevance to Cellular Transplantation for Diabetes.

C-peptide levels are a key measure of beta-cell mass following islet transplantation, but threshold values required to achieve clinically relevant patient-centered outcomes are not yet established. We conducted a cross-sectional retrospective cohort study evaluating patients undergoing islet transplantation at a single center from 1999 to 2018. Cohorts included patients achieving insulin independence without hypoglycemia, those with insulin dependence without hypoglycemia, and those with recurrent symptomatic hypoglycemia. Primary outcome was fasting C-peptide levels at 6 to 12 mo postfirst transplant; secondary outcomes included stimulated C-peptide levels and BETA-2 scores. Fasting and stimulated C-peptide and BETA-2 cutoff values for determination of hypoglycemic freedom and insulin independence were evaluated using receiver operating characteristic curves. We analyzed 192 patients, with 122 (63.5%) being insulin independent without hypoglycemia, 61 (31.8%) being insulin dependent without hypoglycemia, and 9 (4.7%) experiencing recurrent symptomatic hypoglycemia. Patients with insulin independence had a median (interquartile range) fasting C-peptide level of 0.66 nmol/L (0.34 nmol/L), compared with 0.49 nmol/L (0.25 nmol/L) for those being insulin dependent without hypoglycemia and 0.07 nmol/L (0.05 nmol/L) for patients experiencing hypoglycemia ( P < 0.001). Optimal fasting C-peptide cutoffs for insulin independence and hypoglycemia were ≥0.50 nmol/L and ≥0.12 nmol/L, respectively. Cutoffs for insulin independence and freedom of hypoglycemia using stimulated C-peptide were ≥1.2 nmol/L and ≥0.68 nmol/L, respectively, whereas optimal cutoff BETA-2 scores were ≥16.4 and ≥5.2. We define C-peptide levels and BETA-2 scores associated with patient-centered outcomes. Characterizing these values will enable evaluation of ongoing clinical trials with islet or stem cell therapies.

Artificial Intelligence Software for Diabetic Eye Screening: Diagnostic Performance and Impact of Stratification.

To evaluate the MONA.health artificial intelligence screening software for detecting referable diabetic retinopathy (DR) and diabetic macular edema (DME), including subgroup analysis. The algorithm's threshold value was fixed at the 90% sensitivity operating point on the receiver operating curve to perform the disease classification. Diagnostic performance was appraised on a private test set and publicly available datasets. Stratification analysis was executed on the private test set considering age, ethnicity, sex, insulin dependency, year of examination, camera type, image quality, and dilatation status. The software displayed an area under the curve (AUC) of 97.28% for DR and 98.08% for DME on the private test set. The specificity and sensitivity for combined DR and DME predictions were 94.24 and 90.91%, respectively. The AUC ranged from 96.91 to 97.99% on the publicly available datasets for DR. AUC values were above 95% in all subgroups, with lower predictive values found for individuals above the age of 65 (82.51% sensitivity) and Caucasians (84.03% sensitivity). We report good overall performance of the MONA.health screening software for DR and DME. The software performance remains stable with no significant deterioration of the deep learning models in any studied strata.

Insulin Dependence Is Associated With Poor Long-term Outcomes But Equivalent Perioperative Outcomes Following AAA Repair

While diabetes is often a risk factor for vascular disease, its protective effects on abdominal aortic aneurysm (AAA) development have been well documented. Much less is known about the impact of diabetes-and in particular insulin dependence-on long-term outcomes following AAA repair. We aim to evaluate the role of diabetes on perioperative outcomes, mortality, and reintervention following both endovascular and open AAA repair.

Predictive Value of C-Peptide Measures for Clinical Outcomes of β-Cell Replacement Therapy in Type 1 Diabetes: Report From the Collaborative Islet Transplant Registry (CITR).

To determine C-peptide measures and levels associated with positive glycemic control outcomes following islet transplant (ITx) in type 1 diabetes. We evaluated Collaborative Islet Transplant Registry (CITR) islet-alone recipients with pretransplant C-peptide <0.1 nmol/L and mean follow-up of 4.6 ± 1.1 years (n = 677). Receiver operating characteristic area under the curve (ROC-AUC) was used to evaluate the predictive value of fasting and stimulated glucose and C-peptide measures for seven primary outcomes: 1) absence of severe hypoglycemic events (ASHEs); 2) HbA1c <7.0%; 3) HbA1c <7.0% and ASHEs; 4) HbA1c ≤6.5%; 5) HbA1c ≤6.5% and ASHEs; 6) insulin independence; and 7) ASHEs, HbA1c ≤6.5%, and insulin independence (the optimal outcome). Measures with the highest ROC-AUC were selected for determination of optimal cut points. Fasting C-peptide was highly predictive for ASHE (ROC-AUC 0.906; optimal cut point 0.070 nmol/L) and the optimal outcome (ROC-AUC 0.845; optimal cut point 0.33 nmol/L). Mixed-meal tolerance test (MMTT)-stimulated C-peptide-to-glucose ratio (CPGR) outperformed both fasting and stimulated C-peptide for all outcomes except ASHE. The optimal cut point for the optimal outcome was 0.12 nmol/mmol for MMTT-stimulated CPGR and 0.97 nmol/L for MMTT-stimulated C-peptide. Fasting C-peptide reliably predicts ITx primary outcomes. MMTT-stimulated CPGR provides marginally better prediction for composite ITx outcomes, including insulin independence. In the absence of an MMTT, a fasting C-peptide ≥0.33 nmol/L is a reassuring measure of optimal islet graft function. C-peptide targets represent excellent and easily determinable means to predict glycemic control outcomes after ITx and should be considered as potential goals of β-cell replacement.

The future treatment for type 1 diabetes: Pig islet- or stem cell-derived β cells?

Replacement of β cells is only a curative approach for type 1 diabetes (T1D) patients to avoid the threat of iatrogenic hypoglycemia. In this pursuit, islet allotransplantation under Edmonton's protocol emerged as a medical miracle to attain hypoglycemia-free insulin independence in T1D. Shortage of allo-islet donors and post-transplantation (post-tx) islet loss are still unmet hurdles for the widespread application of this therapeutic regimen. The long-term survival and effective insulin independence in preclinical studies have strongly suggested pig islets to cure overt hyperglycemia. Importantly, CRISPR-Cas9 technology is pursuing to develop "humanized" pig islets that could overcome the lifelong immunosuppression drug regimen. Lately, induced pluripotent stem cell (iPSC)-derived β cell approaches are also gaining momentum and may hold promise to yield a significant supply of insulin-producing cells. Theoretically, personalized β cells derived from a patient's iPSCs is one exciting approach, but β cell-specific immunity in T1D recipients would still be a challenge. In this context, encapsulation studies on both pig islet as well as iPSC-β cells were found promising and rendered long-term survival in mice. Oxygen tension and blood vessel growth within the capsules are a few of the hurdles that need to be addressed. In conclusion, challenges associated with both procedures, xenotransplantation (of pig-derived islets) and stem cell transplantation, are required to be cautiously resolved before their clinical application.

Automated pancreatic islet viability assessment for transplantation using bright-field deep morphological signature

Islets transplanted for type-1 diabetes have their viability reduced by warm ischemia, dimethyloxalylglycine (DMOG; hypoxia model), oxidative stress and cytokine injury. This results in frequent transplant failures and the major burden of patients having to undergo multiple rounds of treatment for insulin independence. Presently there is no reliable measure to assess islet preparation viability prior to clinical transplantation. We investigated deep morphological signatures (DMS) for detecting the exposure of islets to viability compromising insults from brightfield images. Accuracies ranged from 98 % to 68 % for; ROS damage, pro-inflammatory cytokines, warm ischemia and DMOG. When islets were disaggregated to single cells to enable higher throughput data collection, good accuracy was still obtained (83–71 %). Encapsulation of islets reduced accuracy for cytokine exposure, but it was still high (78 %). Unsupervised modelling of the DMS for islet preparations transplanted into a syngeneic mouse model was able to predict whether or not they would restore glucose control with 100 % accuracy. Our strategy for constructing DMS' is effective for the assessment of islet pre-transplant viability. If translated into the clinic, standard equipment could be used to prospectively identify non-functional islet preparations unable to contribute to the restoration of glucose control and reduce the burden of unsuccessful treatments.

Diagnostic Dilemmas and Current Treatment Approaches in Latent Onset Autoimmune Diabetes in Adults: A Concise Review.

Latent Onset Autoimmune Diabetes in Adults (LADA) is an autoimmune disorder between T1DM and T2DM and is often misdiagnosed as T2DM due to its late onset. The disease is characterized by β-cell failure and slow progression to insulin dependence. Early diagnosis is significant in limiting disease progression. C-peptide levels and autoantibodies against β-cells are the most critical diagnostic biomarkers in LADA. The review aims to understand the biomarkers used to diagnose LADA, and the treatment approaches followed. We have summarized LADA's pathophysiology and the autoantibodies involved in the condition, diagnostic approaches, and challenges. There are clear shortcomings concerning the feasibility of autoantibody testing. Finally, we explored the treatment strategies involved in the management of LADA. In Conclusion, the usual management includes treatment with metformin and the addition of low doses of insulin. The scope of newer oral hypoglycaemic agents such as GLP-1RA and DPP-4 inhibitors are brought into use. Since the disease is not entirely understood in the research level and clinical practice, we hope to encourage further research in this field to find the prevalence. Large randomized controlled trials are required to compare the efficacy of different treatment options available.