Exogenous Insulin Administration Research Articles

Mesenchymal Stem Cell‐Laden Composite β Cell Porous Microgel for Diabetes Treatment

AbstractType 1 diabetes mellitus is a chronic metabolic condition characterized by the autoimmune damage of pancreatic β cells. As an alternative to continuous exogenous insulin administration of insulin, β cell transplantation is shown to provide an alternative approach for controlling hyperglycemia in diabetes. However, β cell transplantation faces significant challenges of low β cell proliferation and immunologic insults. Thus, novel approaches capable of promoting the islet microenvironment for sustainability is highly desired. This study develops mesenchymal stem cell (MSC)‐laden composite β cell porous microgels (MGs) to address sustainability for the treatment of diabetes. The MGs are prepared via microfluidic droplet templates encapsulating both MSCs and β cells with porogen for creating a porous structure. In addition to offering a suitable microenvironment for nutrient delivery, the porous structure promoted β cell growth and insulin secretion. The outstanding anti‐apoptotic and immunomodulatory roles of MSCs further provide a favorable environment for β cell survival and function. On this basis, the therapeutic performance of the MGs in reducing hyperglycemia and achieving sustained glycemic control in diabetic mice is demonstrated. Collectively, these results show that the novel MGs have great potential for the treatment of diabetes providing a promising platform for clinical β cell transplantation.

Characterization of Perinatal Stem Cell Spheroids for the Development of Cell Therapy Strategy

Type 1 diabetes mellitus (T1DM) is a complex metabolic disease characterized by a massive loss of insulin-producing cells due to an autoimmune reaction. Currently, daily subcutaneous administration of exogenous insulin is the only effective treatment. Therefore, in recent years considerable interest has been given to stem cell therapy and in particular to the use of three-dimensional (3D) cell cultures to better reproduce in vivo conditions. The goal of this study is to provide a reliable cellular model that could be investigated for regenerative medicine applications for the replacement of insulin-producing cells in T1DM. To pursue this aim we create a co-culture spheroid of amniotic epithelial cells (AECs) and Wharton's jelly mesenchymal stromal cells (WJ-MSCs) in a one-to-one ratio. The resulting co-culture spheroids were analyzed for viability, extracellular matrix production, and hypoxic state in both early- and long-term cultures. Our results suggest that co-culture spheroids are stable in long-term culture and are still viable with a consistent extracellular matrix production evaluated with immunofluorescence staining. These findings suggest that this co-culture may potentially be differentiated into endo-pancreatic cells for regenerative medicine applications in T1DM.

Non-alcoholic fatty liver disease in type 1 diabetes: Prevalence and pathophysiology.

Non-alcoholic fatty liver disease (NAFLD) is the most frequent chronic liver disease in the general population with a global prevalence of 25%. It is often associated with metabolic syndrome and type 2 diabetes, as insulin resistance and hyperinsulinemia are known to be favoring factors. Recent studies have described growing incidence of NAFLD in type 1 diabetes (T1D) as well. Although increasing prevalence of metabolic syndrome in these patients seems to explain part of this increase in NAFLD, other underlying mechanisms may participate in the emergence of NAFLD. Notably, some genetic factors are more associated with fatty liver disease, but their prevalence in T1D has not been evaluated. Moreover, oxidative stress, poor glucose control and long-lasting hyperglycemia, as well as exogenous insulin administration play an important role in intrahepatic fat homeostasis. The main differential diagnosis of NAFLD in T1D is glycogenic hepatopathy, which needs to be considered mostly in T1D patients with poor glycemic control. This article aims to review the prevalence and pathophysiology of NAFLD in T1D and open perspectives for clinicians taking care of T1D patients with potential hepatopathy.

Pluripotent stem cells: a new strategy for the treatment of diabetes

Diabetes is now one of the most prevalent diseases in the world. Over the next twenty years, the number of affected individuals could reach 693 million. Diabetes is a group of chronic carbohydrate metabolism disorders responsible for increased blood glucose levels. It has several effects on the human body, and over the years can even become disabling, greatly impacting the patient’s quality of life. The most common therapy is based on daily and chronic administration of exogenous insulin, but this is associated with a series of dangerous and potentially fatal complications. Unsurprisingly therefore, over time, studies have explored various alternatives for the treatment of diabetes, not involving the use of insulin, primarily transplantation of the whole pancreas and of the islets of Langerhans. However, neither of these solutions can be applied on a large scale, mainly due to the lack of donors. In recent years, a viable alternative to insulin and to transplantation has emerged through exploration of the use of pluripotent stem cells and their properties. In this review we analyze the state of the art in this field, and the advantages and disadvantages of cell therapies used for reconstruction of the functional unit of the pancreas, the islets of Langerhans.

Challenges with Cell-based Therapies for Type 1 Diabetes Mellitus.

Type 1 diabetes (T1D) is a chronic, lifelong metabolic disease. It is characterised by the autoimmune-mediated loss of insulin-producing pancreatic β cells in the islets of Langerhans (β-islets), resulting in disrupted glucose homeostasis. Administration of exogenous insulin is the most common management method for T1D, but this requires lifelong reliance on insulin injections and invasive blood glucose monitoring. Replacement therapies with beta cells are being developed as an advanced curative treatment for T1D. Unfortunately, this approach is limited by the lack of donated pancreatic tissue, the difficulties in beta cell isolation and viability maintenance, the longevity of the transplanted cells in vivo, and consequently high costs. Emerging approaches to address these limitations are under intensive investigations, including the production of insulin-producing beta cells from various stem cells, and the development of bioengineered devices including nanotechnologies for improving islet transplantation efficacy without the need for recipients taking toxic anti-rejection drugs. These emerging approaches present promising prospects, while the challenges with the new techniques need to be tackled for ultimately clinical treatment of T1D. This review discussed the benefits and limitations of the cell-based therapies for beta cell replacement as potential curative treatment for T1D, and the applications of bioengineered devices including nanotechnology to overcome the challenges associated with beta cell transplantation.

Diabetes Mellitusta Metabolik Hafızanın Rolü

Diabetes Mellitus, morbidite ve mortalitenin artmasına neden olan, önemli bir halk sağlığı problemidir. Diyabete spesifik hiperglisemi, çeşitli ilaçlar veya ekzojen insülin uygulaması yolu ile klinik olarak kontrol edilmeye çalışılmaktadır fakat gerek tedavi gerekse takipteki gelişmelere rağmen diyabetli birçok hastada vasküler komplikasyon gelişme durumunun önüne hâlen tam anlamı ile geçilememiştir. Çeşitli epidemiyolojik ve geniş kapsamlı çalışmalar, erken ve yoğun hiperglisemi kontrolünün diyabet ile ilişkili komplikasyon riskini azalttığını göstermiştir ve ilgili çalışmaların tamamı, erken glisemik kontrolün gerekliliğini vurgulamaktadır. Erken dönemdeki hiperglisemi kontrolü yakın zamanda “metabolik hafıza” olarak tanımlanmıştır. Mitokondri ve endotel hücrelerinde serbest oksijen radikallerinin aşırı üretimi, mitokondriyal deoksiribonükleik asit (DNA) hasarı, protein kinaz C aktivasyonu, poliol ve hekzoamin yolağı aktivasyonu, ileri glikozilasyon son ürünlerinin ve reseptörlerinin artışı gibi birçok mekanizma metabolik hafıza patogenezinde önemli rol oynamaktadır. Bu mekanizmalar, gen ekspresyonunu kalıcı olarak indükleyerek epigenetik değişikliklere neden olmaktadır. Metabolik hafıza; histon modifikasyonu, DNA metilasyonu ve mikro-ribonükleik asit (RNA) ile ilişkili mekanizmalar gibi epigenetik değişiklikler ile gerçekleşir. Klinik açıdan değerlendirildiğinde ise metabolik hafıza teorisi, metabolik kontrolü en kısa sürede sağlamak için erken ve yoğun tedavi rejiminin gerekliliğini vurgulamaktadır. Uzun süreli diyabetik komplikasyonları en aza indirgemek amacıyla erken ve yoğun hiperglisemi kontrolünün yanı sıra, reaktif oksijen türleri ve glikozilasyonu azaltabilen terapötik ajanlardan ve/veya epigenetik tedaviden de yararlanılabilir. Bu derlemede; metabolik hafıza teorisine, metabolik hafızanın tanımı ve patogenezine, epigenetik mekanizmalara ve terapötik yaklaşımlara yer verilmiştir.

Symbolic Control Design of an Artificial Pancreas for Type-2 Diabetes

Diabetes is a widespread disease characterized by chronic hyperglycemia so that diabetic individuals usually require the administration of exogenous insulin for survival. As a consequence, in the context of the so-called artificial pancreas, many glucose control methods have been presented in the last few years. In this work, we focus on type-2 diabetes and propose a novel model-based glucose control technique based on the use of symbolic models, which are finite approximations of complex dynamical systems. This framework allows taking into account nonlinearities and delays in the dynamics, uncertainties, and input bounds, as well as nonidealities coming from the interaction between physical plant and digital environment. The methodology is extensively validated over a virtual patient model, broadly accepted as a substitute to animal trials in the preclinical testing of closed-loop glucose control strategies. The results show the effectiveness and the robustness of the approach.

Host-microbiota interactions shaping T-cell response and tolerance in type 1 diabetes.

Type-1 Diabetes (T1D) is a complex polygenic autoimmune disorder involving T-cell driven beta-cell destruction leading to hyperglycemia. There is no cure for T1D and patients rely on exogenous insulin administration for disease management. T1D is associated with specific disease susceptible alleles. However, the predisposition to disease development is not solely predicted by them. This is best exemplified by the observation that a monozygotic twin has just a 35% chance of developing T1D after their twin's diagnosis. This makes a strong case for environmental triggers playing an important role in T1D incidence. Multiple studies indicate that commensal gut microbiota and environmental factors that alter their composition might exacerbate or protect against T1D onset. In this review, we discuss recent literature highlighting microbial species associated with T1D. We explore mechanistic studies which propose how some of these microbial species can modulate adaptive immune responses in T1D, with an emphasis on T-cell responses. We cover topics ranging from gut-thymus and gut-pancreas communication, microbial regulation of peripheral tolerance, to molecular mimicry of islet antigens by microbial peptides. In light of the accumulating evidence on commensal influences in neonatal thymocyte development, we also speculate on the link between molecular mimicry and thymic selection in the context of T1D pathogenesis. Finally, we explore how these observations could inform future therapeutic approaches in this disease.

259-OR: Stem Cell–Derived, Fully Differentiated Islet Cells for Type 1 Diabetes

Cadaveric islet transplantation can achieve glycemic control in T1D, but cadaveric islet quantity and quality are limiting. We report the first patient-administered VX-880, an investigational allogeneic stem cell–derived, fully differentiated, pancreatic islet cell replacement therapy. A 64-year-old male with a 40-year history of T1D complicated by impaired awareness of hypoglycemia with 5 severe hypoglycemic events (SHEs) the year before VX-880 was receiving 34U insulin/day at baseline (HbA1c 8.6%; undetectable fasting and stimulated C-peptide) . After a single VX-880 infusion at half target dose, fasting C-peptide was detected by Day 29 and increased rapidly; HbA1c and daily insulin decreased in parallel. At Day 90, robust increases in fasting and stimulated C-peptide, improved glycemic control, and a substantial reduction in exogenous insulin administration were observed and continued to improve through last time point assessed (Table) . VX-880 was generally safe and well tolerated; most AEs were mild or moderate and consistent with immunosuppression. The most common AEs were SHEs (not serious or related to VX-880) , which occurred in the perioperative period. There was 1 serious AE of rash (mild, unrelated to VX-880) , which resolved. These unprecedented results are the first evidence that stem cell–derived islets can restore insulin production and glucose control in T1D. The study continues to enroll and dose patients. Disclosure J.F.Markmann: Consultant; Vertex Pharmaceuticals Incorporated. L.S.Kean: Advisory Panel; HiFiBio, Mammoth Biosciences, Other Relationship; Bristol-Myers Squibb Company, Research Support; Bluebird Bio, Gilead Sciences, Inc., Magenta Therapeutics, Merck & Co., Inc., Novartis AG, Regeneron Therapeutics. A.L.Peters: Advisory Panel; Abbott Diabetes, AstraZeneca, Eli Lilly and Company, Novo Nordisk, Shouti, Vertex Pharmaceuticals Incorporated, Zealand Pharma A/S, Other Relationship; Omada Health, Inc., Research Support; Abbott Diabetes, Dexcom, Inc., Insulet Corporation, Leona M. and Harry B. Helmsley Charitable Trust, Stock/Shareholder; Teladoc Health. P.Witkowski: Advisory Panel; Sernova, Corp., Vertex Pharmaceuticals Incorporated. C.Ricordi: Advisory Panel; Vertex Pharmaceuticals Incorporated. A.Naji: None. M.R.Rickels: Advisory Panel; Sernova, Corp., Vertex Pharmaceuticals Incorporated, Zealand Pharma A/S, Consultant; L-Nutra Inc. M.Alba: None. G.Marigowda: None. L.Ross: Employee; Vertex Pharmaceuticals Incorporated. C.Wang: Employee; Vertex Pharmaceuticals Incorporated. F.Pagliuca: Employee; Vertex Pharmaceuticals Incorporated, Other Relationship; Vertex Pharmaceuticals Incorporated, Stock/Shareholder; Vertex Pharmaceuticals Incorporated. B.Sanna: Employee; Vertex Pharmaceuticals Incorporated.

364-OR: Apolipoprotein A-I and Clinical Remission in Adults with Type 1 Diabetes-InLipoDiab1 Study

Introduction: Apolipoprotein A-I (Apo A-I) , the main protein in high-density lipoproteins, improves beta-cell function and insulin sensitivity in experimental models and in people with type 2 diabetes. In those with type 1 diabetes (DM1) , clinical remission (CR) is a key factor for improved prognosis. However, predictors of CR in DM1 are not well described. Whether Apo A-I predicts CR in patients with DM1 remains unknown. Aim To assess the relationship between baseline Apo A-I at the time of diagnosis of DM1 with the presence of CR after 12 months of the disease. Methods: The participants of Insulin Therapy and Lipoproteins' Profile in Type 1 Diabetes Study (InLipoDiab1; NCT02306005) were prospectively observed from the onset of the disease (the blood collection was performed before exogenous insulin administration) through 12 months. The final observation included 53 adults (62% men, age at onset 27±6 years) . DM1 was confirmed with guideline-based criteria on the presence of specific autoantibodies. The endpoint was the presence of pCR at the end of observation, which was defined as IDAA1C ≤ 9, according to the definition by Mortensen et al.: A1C (%) + [4 × insulin dose (U/kg/day) ]. Apo A-I was measured in serum with an ELISA kit. The group was divided into two according to the presence and absence of pCR. Results: At 12 months, pCR was present in 43 participants (81%) . Baseline serum Apo A-I was significantly lower in participants without pCR versus those with the presence of pCR [0.79 (0.39-1.58) vs. 4.51 (0.95-5.93) mg/dl, p=0.002, respectively]. In multiple logistic regression, higher baseline Apo A-I was associated with the presence of pCR after 12 months, adjusted for sex, age, weight and the presence of diabetic ketoacidosis at onset (OR 1.74 (CI 95% 1.02-2.96) , p=0.03) . Conclusion: The higher Apo A-I serum concentration at onset of DM1 the higher chance is for pCR in adults with DM1, after 12 months of observation. Higher serum Apo A-I levels seem to be a good prognostic factor for pCR of DM1. Disclosure A.Uruska: Other Relationship; Lilly, Novo Nordisk. A.Rohatgi: Speaker's Bureau; CSL Behring. A.Cieluch: None. A.Grzelka-wozniak: Other Relationship; Novo Nordisk, Roche Diabetes Care. J.Flotynska: None. A.Pypec: None. D.Zozulinska-ziolkiewicz: Advisory Panel; Dexcom, Inc., Medtronic, Speaker's Bureau; Abbott Diabetes, Ascensia Diabetes Care, AstraZeneca, BIOTON S.A., Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk, Sanofi. Funding Kosciuszko Foundation and Poznan University of Medical Sciences

Exogenous insulin promotes the expression of B-cell translocation gene 1 and 2 in chicken pectoralis

B-cell translocation genes (BTG) have been proved to play important roles in carbohydrate metabolism through modifying insulin homeostasis and glucose metabolism. This study, therefore, was conducted to investigate the effects of exogenous insulin on the expression of BTG1 and BTG2 in chickens. Twenty-four-day-old broilers and layers were fasted for 16 h and randomly assigned to insulin treatment group (subcutaneously injected with 5 IU/kg body weight) or control group (received an equivalent volume of phosphate-buffered saline). Blood glucose concentration was measured, and it showed that the blood glucose concentrations in the layers were significantly (P < 0.05) higher than that in the broilers under fasting state. Response to exogenous insulin, the blood glucose concentrations were greatly reduced in both breeds. Of note, the blood glucose concentration restored to 62% of the basal state at 240 min (P < 0.05) after insulin stimulation in layers, whereas it was still in low level until 240 min in broilers (under fast state). Tissue profiling revealed that both BTG1 and BTG2 were abundantly expressed in the skeletal muscles of broilers. A negative correlation was observed between blood glucose and BTG1 (ρ = −0.289, P = 0.031) /BTG2 (ρ = −0.500, P < 0.001) in pectoralis, and BTG1 (ρ = −0.462, P < 0.001) in pancreas. As blood glucose decreased due to exogenous insulin administration (under fast state), the expression of both BTG1 and BTG2 notably upregulated in birds’ pectoralis at 120 min and/or 240 min, meanwhile pancreas BTG1 was also upregulated. Re-feeding at 120 min elevated the blood glucose and reduced the expression of BTG genes in pectoralis generally. In addition, the change of BTG1 and BTG2 expression showed distinct difference between layers and broilers at 120 min and 240 min after insulin stimulation in pectoralis, pancreas and heart tissue; even after re-feeding at 120 min, BTG2 expression at 240 min after insulin injection was downregulated in the pectoralis of layers, while it was upregulated in that broilers. Collectively, these results indicated that response to exogenous insulin, chicken blood glucose exhibited breed-specific dynamic change, and meanwhile the expressions of both BTG1 and BTG2 genes in chickens were significantly altered by exogenous insulin in a breed- and tissue-specific manner. BTG1 and BTG2 genes may negatively regulate bird's blood glucose by promoting the glucose uptake corporately in pectoralis, and through regulating the insulin secretion in pancreas (especially BTG1).

Physiological and pharmacological actions of glucagon like peptide-1 (GLP-1) in domestic animals

Analogues of glucagon like peptide-1 (GLP-1) and other drugs that increase this peptide half-life are used worldwide in human medicine to treat type 2 diabetes mellitus (DM) and obesity. These molecules can increase insulin release and satiety, interesting effects that could also be useful in the treatment of domestic animals pathologies, however their use in veterinary medicine are still limited. Considering the increasing incidence of DM and obesity in cats and dogs, the aim of this review is to summarize the available information about the physiological and pharmacological actions of GLP-1 in domestic animals and discuss about its potential applications in veterinary medicine. In diabetic dogs, the use of drugs based on GLP-1 actions reduced blood glucose and increased glucose uptake, while in diabetic cats they reduced glycemic variability and exogenous insulin administration. Thus, available evidence indicates that GLP-1 based drugs could become alternatives to DM treatment in domestic animals. Nevertheless, current data do not provide enough elements to recommend these drugs widespread clinical use.

An Adolescent With Munchausen's Syndrome: A Case Report

Munchausen syndrome is factitious disorders with unknown etiology. It is characterized by fabrication of signs or symptoms of the disease, as well as alteration of laboratory investigations. People with this syndrome pretend that they are sick and tend to seek treatment at different hospitals. We report this 15-year-old adolescent Saudi girl who came to endocrinology clinic with recurrent hypoglycemic attacks for the last 6 months. Laboratory showed exogenous insulin administration by the patient herself. Munchausen syndrome was diagnosed and patient was referred to psychiatry for follow up.

Lyophilized insulin micelles for long-term storage and regulation of blood glucose for preventing hypoglycemia

The administration of exogenous insulin is an important treatment for improving diabetic patients’ health but involves multiple daily subcutaneous injections. The development of insulin formulations for long-acting effects has been hampered by short pharmacokinetics and reduced bioactivity due to long-term storage. To solve this, we developed a formulation with a high insulin loading efficiency achieved via the self-assembly of an amphiphilic polymer (P1M10) and insulin. In a type 1 diabetic rat model, P1M10@insulin micelles quickly and continuously controlled the blood glucose level without risk of hypoglycemia, showing a better therapeutic index than the commercial long-acting insulin glargine. In addition, the P1M10 polymer could protect insulin in solution at room temperature in the long term. Owing to this protection, P1M10@insulin micelles could be lyophilized and reconstituted without any loss of insulin bioactivity, allowing for convenient transportation and storage of therapeutic proteins under normal conditions, which would greatly expand their application scenarios.

Finding Eden - alternative transplantation sites for pancreatic islets.

Pancreatic islets transplantation is an established treatment method for type 1 diabetic patients with the hypoglycemia unawareness syndrome in whom a therapy with modern technologies fails. Islet transplantation is most commonly done using an interventional radiology method: a tissue suspension of pancreatic islets is applied into a branch of the portal vein through a percutaneously installed catheter. Although being minimally invasive unlike pancreas organ transplant, this method is associated with many technical difficulties. Possible complications of the procedure include hemorrhage and portal vein thrombosis. Unlike their natural dispersed localization in exocrine pancreas, isolated pancreatic islets are exposed to hypoxia, toxins and immunosuppressive drugs in the liver parenchyma. Direct contact with the recipients blood causes an instant blood mediated inflammatory reaction (IBMIR) resulting in the death of more than half of the pancreatic islets shortly after their application. Therefore the size of the islet graft is often insufficient and a number of transplanted patients require administration of exogenous insulin. All of these are reasons for seeking an alternative transplantation site with more hospitable conditions for long-term islet survival. Various transplantation sites have been tested in experimental and clinical research. The advantages and disadvantages of some of them are summarized in this paper. Currently, transplantation into the greater omentum seems most promising, which has already been used in clinical practice at several institutions.

Quantification of Insulin Analogs by Liquid Chromatography-High-Resolution Mass Spectrometry.

Administration of exogenous insulin or insulin analogs is a common cause of hypoglycemia. The etiology of hypoglycemic episodes can be investigated by the measurement of insulin. However, frequently used synthetic insulin analogs show variable reactivity with immunoassays designed for the quantification of human insulin and may produce misleading results. To overcome this challenge, mass spectrometric methods can be applied to differentiate and accurately quantify insulin and its analogs. Here we describe a liquid chromatography-tandem high-resolution accurate mass (LC-HRAM) for the highly specific and independent quantification of insulin and its synthetic analogs including aspart, detemir, glargine, glulisine, and lispro. This method utilizes antibody affinity extraction followed by analysis on a high-resolution accurate mass spectrometer.

Modeling Intraperitoneal Insulin Absorption in Patients with Type 1 Diabetes.

Standard insulin therapy to treat type 1 diabetes (T1D) consists of exogenous insulin administration through the subcutaneous (SC) tissue. Despite recent advances in insulin formulations, the SC route still suffers from delays and large inter/intra-subject variability that limiting optimal glucose control. Intraperitoneal (IP) insulin administration, despite its higher invasiveness, was shown to represent a valid alternative to the SC one. To date, no mathematical model describing the absorption and distribution of insulin after IP administration is available. Here, we aim to fill this gap by using data from eight patients with T1D, treated by implanted IP pump, studied in a hospitalized setting, with frequent measurements of plasma insulin and glucose concentration. A battery of models describing insulin kinetics after IP administration were tested. Model comparison and selection were performed based on model ability to predict the data, precision of parameters and parsimony criteria. The selected model assumed that the insulin absorption from the IP space was described by a linear, two-compartment model, coupled with a two-compartment model of whole-body insulin kinetics with hepatic insulin extraction controlled by hepatic insulin. Future developments include model incorporation into the UVa/Padova T1D Simulator for testing open- and closed-loop therapies with IP insulin administration.

Improved Kidney Function Following Physiologic Insulin Resensitization Treatment Modality

Diabetes affects millions of people worldwide and is a leading cause of amputation, blindness, neuropathy, and chronic kidney disease. Chronic kidney disease results in the prolonged impairment of kidney function. Common medications and lifestyle modifications do not eliminate the long-term complications of diabetes, because they lack the ability to restore the periodic cycle of insulin that exists in healthy physiology. Our study used a precise administration of exogenous insulin, mimicking the physiologic profile of insulin secretion, which is more effective at stabilizing cellular blood glucose uptake and reducing diabetic complications than current drug and lifestyle modifications alone. In this case study report, we evaluated three diabetic or pre-diabetic patients who showed improvements in kidney function after beginning this treatment modality. We monitored their chronic kidney disease symptoms before and after the physiological insulin resensitization (PIR) process. We showed that the patients improved in kidney function after several months based on their laboratory metrics and CKD stage classification.

Decellularized Matrix Bioscaffolds: Implementation of Native Microenvironment in Pancreatic Tissue Engineering.

Type 1 diabetes is an autoimmune disease, and its incidence is usually estimated in the range of 5% to 10%. Currently, the administration of exogenous insulin is the standard of care therapy. However, this therapy is not effective in some patients who may develop some chronic complications. Islet transplantation into the liver is another therapy with promising outcomes; however, the long-term efficacy of this therapeutic option is limited to a small number of patients. Because native extracellular matrix (ECM) components provide a suitable microenvironment for islet functions, engineering a 3-dimensional construct that recapitulates the native pancreatic environment could address these obstacles. Many attempts have been conducted to mimic an in vivo microenvironment to increase the survival of islets or islet-like clusters. With the advent of decellularization technology, it is possible to use a native ECM in organ engineering. Pancreatic decellularized bioscaffold provides proper cell-cell and cell-ECM interactions and retains growth factors that are critical in the determination of cell fate within a native organ. This review summarizes the current knowledge of decellularized matrix technology and addresses its possible limitations before use in the clinic.

Placenta derived Mesenchymal Stem Cells transplantation in Type 1 diabetes: preliminary report of phase 1 clinical trial.

Type 1 Diabetes Mellitus (T1DM) is an auto immune reaction against insulin secreting beta cells. Exogenous insulin administration is the only standard treatment for T1DM. However, despite tight glycemic control many patients will develop chronic life-threatening complications. Recently, stem cell transplantation has been suggested as a novel treatment for eliminating the beta cell damage and promoting their regeneration by modulating auto-immunity. To our knowledge; this is the first preliminary report of placenta derived MSCs (PLMSCs) transplantation in juvenile T1DM. An Open label non-randomized phase 1 clinical trial was designed to evaluate the safety of PLMSCs transplantation in new onset juvenile T1DM (IRCT20171021036903N2). PLMSCs were manufactured in our clean room facility using a Xeno-free/GMP compliant protocol. The first series of patients (n = 4) received one dose of1 × 106 PLMSCs/kg intravenously. Diabetic clinical and laboratory parameters and side effects were evaluated weekly for the first month, monthly for 6 months, and then every 3 month till 1 year. Serious adverse events were not seen during 1 year follow-up. Partial remission and hypoglycemic attacks were happened one month after transplantation in two patients. ZnT8-Ab decreased till month 3 and then increased again in all patients. Anti Gad-Ab decreased till month 3 of follow up then increased. This preliminary report of our phase I clinical trial demonstrated the short term safety of PLMSCs transplantation in juvenile T1DM. To prove the long term safety and probable efficacy of this treatment more investigations are needed. Iranian Registry of Clinical Trials: IRCT20171021036903N2.