Long-term efficacy of encapsulated xenogeneic islet transplantation: Impact of encapsulation techniques and donor genetic traits.

Aims/introduction: To investigate the long-term efficacy of various encapsulated xenogeneic islet transplantation, and to explore the impact of different donor porcine genetic traits on islet transplantation outcomes.

Materials And Methods: Donor porcine islets were obtained from wild-type, α1,3-galactosyltransferase knockout (GTKO) and GTKO with overexpression of membrane cofactor protein genotype. Naked, alginate, alginate-chitosan (AC), alginate-perfluorodecalin (A-PFD) and AC-perfluorodecalin (AC-PFD) encapsulated porcine islets were transplanted into diabetic mice.

Dysregulation of autophagy activation induced by atorvastatin contributes to new-onset diabetes mellitus in western diet-fed mice.

Background And Aims: The incidence of statin-induced new-onset diabetes (NOD) is increasing but its underlying mechanisms remain unclear. We aimed to investigate the effects of various doses of atorvastatin (ATO)-induced autophagy on the development of NOD.

Methods And Results: The isolated rat islets and MIN6 cells-treated with ATO, exhibited impaired glucose-stimulated insulin secretion, reduced insulin content, and induced apoptosis.

Differentiation of Microencapsulated Neonatal Porcine Pancreatic Cell Clusters in Vitro Improves Transplant Efficacy in Type 1 Diabetes Mellitus Mice.

Background: Neonatal porcine pancreatic cell clusters (NPCCs) have been proposed as an alternative source of β cells for islet transplantation because of their low cost and growth potential after transplantation. However, the delayed glucose lowering effect due to the immaturity of NPCCs and immunologic rejection remain as a barrier to NPCC's clinical application. Here, we demonstrate accelerated differentiation and immune-tolerant NPCCs by in vitro chemical treatment and microencapsulation.

Suppression of Fibrotic Reactions of Chitosan-Alginate Microcapsules Containing Porcine Islets by Dexamethasone Surface Coating.

Background: The microencapsulation is an ideal solution to overcome immune rejection without immunosuppressive treatment. Poor biocompatibility and small molecular antigens secreted from encapsulated islets induce fibrosis infiltration. Therefore, the aims of this study were to improve the biocompatibility of microcapsules by dexamethasone coating and to verify its effect after xenogeneic transplantation in a streptozotocin-induced diabetes mice.

Generation of iPSC-derived insulin-producing cells from patients with type 1 and type 2 diabetes compared with healthy control.

For alternative sources of β cells, patient-specific induced pluripotent stem cells (iPSCs) could be promising, as cells derived from the "self" allow autologous transplantation. However, only a few studies have investigated insulin-producing cells (IPCs) using iPSCs of patients with type 1 diabetes (T1D). In this study, we generated IPCs using iPSCs derived from patients with T1D and type 2 diabetes (T2D) and compared them with IPCs from a non-diabetic (ND) individual.

Role of sirtuin-1 (SIRT1) in hypoxic injury in pancreatic β-cells.

Islet transplantation (ITx) is being developed as a treatment for type 1 diabetes mellitus, but hypoxic damage to transplanted islet grafts is an important factor affecting successful transplantation. To investigate the role of sirtuin-1 (SIRT1) under hypoxic injury in INS-1 cells, one type of pancreatic β-cell lines, we used SRT1720 and GW4064 for SIRT1 activation. The small interfering RNA SIRT1 (si-SIRT1) was used to suppress SIRT1 gene expression.

Effect of sodium-glucose cotransporter 2 inhibitor, empagliflozin, and α-glucosidase inhibitor, voglibose, on hepatic steatosis in an animal model of type 2 diabetes.

Objective: We investigated the effects of sodium-glucose cotransporter 2 inhibitor, empagliflozin, and α-glucosidase inhibitor, voglibose, on hepatic steatosis in an animal model of type 2 diabetes (T2DM).

Methods: Empagliflozin (OLETF-EMPA) or voglibose (OLETF-VOG) was administered to Otsuka Long-Evans Tokushima fatty (OLETF) rats once daily for 12 weeks. Control Long-Evans Tokushima Otsuka (LETO) and OLETF (OLETF-C) rats received saline.

Effect of resveratrol treatment on graft revascularization after islet transplantation in streptozotocin-induced diabetic mice.

We evaluated the effect of resveratrol (RSV) on graft survival after islet transplantation (ITx) in diabetic mice. Isolated islets from Balb/c mice (200 IEQ) were transplanted under the kidney capsule of diabetic Balb/c mice. Vehicle or RSV (200 mg/kg/day, orally) was given for 14 days after ITx.

Suppression of ROS Production by Exendin-4 in PSC Attenuates the High Glucose-Induced Islet Fibrosis.

Pancreatic stellate cells (PSCs) play a major role to fibrotic islet destruction observed in diabetic patients and animal model of diabetes. Exendin-4 (Ex-4) is a potent insulinotropic agent and has been approved for the treatment of type 2 diabetes. However, there have been no reports demonstrating the effects of Ex-4 on pancreatic islet fibrosis.

Long-term Efficacy and Biocompatibility of Encapsulated Islet Transplantation With Chitosan-Coated Alginate Capsules in Mice and Canine Models of Diabetes.

Background: Clinical application of encapsulated islet transplantation is hindered by low biocompatibility of capsules leading to pericapsular fibrosis and decreased islet viability. To improve biocompatibility, we designed a novel chitosan-coated alginate capsules and compared them to uncoated alginate capsules.

Methods: Alginate capsules were formed by crosslinking with BaCl2, then they were suspended in chitosan solution for 10 minutes at pH 4.

Reversal of Hypoglycemia Unawareness with a Single-donor, Marginal Dose Allogeneic Islet Transplantation in Korea: A Case Report.

Pancreatic islet transplantation is a physiologically advantageous and minimally invasive procedure for the treatment of type 1 diabetes mellitus. Here, we describe the first reported case of successful allogeneic islet transplantation alone, using single-donor, marginal-dose islets in a Korean patient. A 59-yr-old patient with type 1 diabetes mellitus, who suffered from recurrent severe hypoglycemia, received 4,163 islet equivalents/kg from a single brain-death donor.

The Paradoxical Effects of AMPK on Insulin Gene Expression and Glucose-Induced Insulin Secretion.

The activation of AMP-activated protein kinase (AMPK) is known to repress the expression of the insulin gene and glucose-stimulated insulin secretion (GSIS). However, the mechanisms by which this occurs, as well as the effects of AMPK activation on glucolipotoxicity-induced β-cell dysfunction, have not been elucidated. To investigate the effects of 5-amino-4-imidazolecarboxamide ribonucleotide (AICAR) and peroxisome proliferator-activated receptorγ-coactivator-1α (PGC-1α) on β-cell-specific genes under glucolipotoxic conditions, we performed real-time PCR and measured insulin secretion by primary islets.

Targeting PGC-1α to overcome the harmful effects of glucocorticoids in porcine neonatal pancreas cell clusters.

Background: Peroxisome proliferator-activated receptor gamma-coactivator-1α (PGC-1α) has recently been implicated as a crucial factor in the glucocorticoid-suppressed expansion and transdifferentiation of porcine neonatal pancreatic cell clusters (NPCCs). However, the molecular mechanism has not been clarified.

Methods: We investigated whether the suppression of PGC-1α expression protects against β-cell dysfunction induced by dexamethasone (Dx) treatment in vitro and in vivo and determined the mechanism of action of PGC-1α in porcine NPCCs.

Pattern of Stress-Induced Hyperglycemia according to Type of Diabetes: A Predator Stress Model.

Background: We aimed to quantify stress-induced hyperglycemia and differentiate the glucose response between normal animals and those with diabetes. We also examined the pattern in glucose fluctuation induced by stress according to type of diabetes.

Methods: To load psychological stress on animal models, we used a predator stress model by exposing rats to a cat for 60 minutes and measured glucose level from the beginning to the end of the test to monitor glucose fluctuation.

Glycated albumin causes pancreatic β-cells dysfunction through autophagy dysfunction.

Growing evidence suggests that advanced glycation end-products (AGEs) are cytotoxic to pancreatic β-cells. The aims of this study were to investigate whether glycated albumin (GA), an early precursor of AGEs, would induce dysfunction in pancreatic β-cells and to determine which kinds of cellular mechanisms are activated in GA-induced β-cell apoptosis. Decreased viability and increased apoptosis were induced in INS-1 cells treated with 2.

Glucocorticoid treatment independently affects expansion and transdifferentiation of porcine neonatal pancreas cell clusters.

The purpose of this study was to determine the effects of duration and timing of glucocorticoid treatment on the expansion and differentiation of porcine neonatal pancreas cell clusters (NPCCs) into β-cells. After transplantation of NPCCs, the ductal cyst area and β-cell mass in the grafts both showed positive and negative correlations with duration of dexamethasone (Dx) treatment. Pdx-1 and HNF-3β gene expression was significantly downregulated following Dx treatment, whereas PGC-1α expression increased.

Adenoviruses Expressing PDX-1, BETA2/NeuroD and MafA Induces the Transdifferentiation of Porcine Neonatal Pancreas Cell Clusters and Adult Pig Pancreatic Cells into Beta-Cells.

Background: A limitation in the number of insulin-producing pancreatic beta-cells is a special feature of diabetes. The identification of alternative sources for the induction of insulin-producing surrogate beta-cells is a matter of profound importance. PDX-1/VP16, BETA2/NeuroD, and MafA overexpression have been shown to influence the differentiation and proliferation of pancreatic stem cells.

Suppression of peroxisome proliferator-activated receptor gamma-coactivator-1alpha normalizes the glucolipotoxicity-induced decreased BETA2/NeuroD gene transcription and improved glucose tolerance in diabetic rats.

Peroxisome proliferator-activated receptor gamma-coactivator-1alpha (PGC-1alpha) is significantly elevated in the islets of animal models of diabetes. However, the molecular mechanism has not been clarified. We investigated whether the suppression of PGC-1alpha expression protects against beta-cell dysfunction in vivo and determined the mechanism of action of PGC-1alpha in beta-cells.