Elevated islet prohormone ratios as indicators of insulin dependency in islet transplant recipients

Autologous pancreatic islet transplantation is an established therapy for patients with chronic pancreatitis. However, the long-term transplant outcomes are modest. Identifying indicators of graft function will aid the preservation of transplanted islets and glycemic control. To this end, we analyzed beta cell prohormone peptide levels in a retrospective cohort of total pancreatectomy autologous islet transplant patients (n=28). Proinsulin-to-C-peptide (PI/C) and proIAPP-to-total IAPP (proIAPP/IAPP) ratios measured at 3 months post-transplant were significantly higher in patients who remained insulin dependent at 1 year follow-up. In a mouse model of human islet transplantation, recipient mice that later became hyperglycemic displayed significantly higher PI/C ratios than mice that remained normoglycemic. Histological analysis of islet grafts showed reduced insulin- and proinsulin-positive area, but elevated glucagon-positive area in grafts that experienced greater secretory demand. Increased prohormone convertase 1/3 was detected in glucagon-positive cells, and glucagon-like peptide 1 (GLP-1) area was elevated in grafts from mice that displayed hyperglycemia or elevated plasma PI/C ratio, demonstrating intra-islet incretin production in metabolically challenged human islet grafts. These data indicate that in failing grafts, alpha cell prohormone processing is likely altered, and incomplete beta cell prohormone processing may be an early indicator of insulin dependency.

Download Full-text

Fewer Islets Survive from a First Transplant than a Second Transplant: Evaluation of Repeated Intraportal Islet Transplantation in Mice

Cell Transplantation ◽

10.1177/0963689719866685 ◽

2019 ◽

Vol 28 (11) ◽

pp. 1455-1460

Author(s):

Hanna Liljebäck ◽

My Quach ◽

Per-Ola Carlsson ◽

Joey Lau

Keyword(s):

Beta Cell ◽

Islet Transplantation ◽

Fluorescent Protein ◽

Angiogenic Factors ◽

Saline Infusion ◽

Control Group ◽

Vascular Density ◽

Exciting Field ◽

Islet Transplant ◽

Second Transplantation

Beta cell replacement is an exciting field where new beta cell sources and alternative sites are widely explored. The liver has been the implantation site of choice in the clinic since the advent of islet transplantation. However, in most cases, repeated islet transplantation is needed to achieve normoglycemia in diabetic recipients. This study aimed to investigate whether there are differences in islet survival and engraftment between a first and a second transplantation, performed 1 week apart, to the liver. C57BL/6 mice were accordingly transplanted twice with an initial infusion of syngeneic islets expressing green fluorescent protein (GFP). The second islet transplant was performed 1 week later and consisted of islets isolated from non-GFP C57BL/6-mice. Animals were sacrificed either 1 day or 1 month after the second transplantation. A control group received a saline infusion instead of GFP-expressing islets, 1 week later obtained a standard non-GFP islet transplant, and was subsequently sacrificed 1 month later. Islet engraftment in the liver was assessed by immunohistochemistry and serum was analyzed for angiogenic factors induced by the first islet transplantation. Almost 70% of islets found in the liver following repeated islet transplantation originated from the second transplantation. The vascular density in the transplanted non-GFP-expressing islets did not differ depending on whether their transplantation was preceded by a primary islet transplantation or saline administration only nor did angiogenic factors in serum prior to the transplantation of non-GFP islets differ between animals that had received a previous islet transplantation or a saline infusion. We conclude that first islet transplantation creates, by unknown mechanisms, favorable conditions for the survival of a second transplant to the liver.

Download Full-text

103. The Novel Caspase Inhibitor EP1013 Promotes Human Islet Survival and Enhances Marginal Islet Graft Function Following Islet Transplantation

Journal of Surgical Research ◽

10.1016/j.jss.2007.12.117 ◽

2008 ◽

Vol 144 (2) ◽

pp. 223-224

Author(s):

Juliet Emamaullee ◽

Sui Xiong Cai Cai ◽

Ben Tseng ◽

A.M. James Shapiro

Keyword(s):

Islet Transplantation ◽

Graft Function ◽

Human Islet ◽

The Novel ◽

Caspase Inhibitor ◽

Islet Graft ◽

Islet Survival

Download Full-text

Human islet graft function in NOD-SCID mice predicts clinical response in islet transplant recipients

Transplantation Proceedings ◽

10.1016/j.transproceed.2004.04.055 ◽

2004 ◽

Vol 36 (4) ◽

pp. 1108-1110 ◽

Cited By ~ 24

Author(s):

A.O Gaber ◽

D Fraga ◽

M Kotb ◽

A Lo ◽

O Sabek ◽

...

Keyword(s):

Clinical Response ◽

Graft Function ◽

Human Islet ◽

Scid Mice ◽

Islet Graft ◽

Transplant Recipients ◽

Islet Transplant

Download Full-text

IGF2: an endocrine hormone to improve islet transplant survival

Journal of Endocrinology ◽

10.1530/joe-13-0557 ◽

2014 ◽

Vol 221 (2) ◽

pp. R41-R48 ◽

Cited By ~ 10

Author(s):

Amy Hughes ◽

Darling Rojas-Canales ◽

Chris Drogemuller ◽

Nicolas H Voelcker ◽

Shane T Grey ◽

...

Keyword(s):

Cell Death ◽

Islet Transplantation ◽

Inflammatory Cytokine ◽

Apoptotic Cell ◽

Apoptotic Cell Death ◽

Pancreatic Islet Transplantation ◽

Post Transplant ◽

Islet Transplant ◽

Clinical Islet Transplantation ◽

Islet Survival

In the week following pancreatic islet transplantation, up to 50% of transplanted islets are lost due to apoptotic cell death triggered by hypoxic and pro-inflammatory cytokine-mediated cell stress. Thus, therapeutic approaches designed to protect islet cells from apoptosis could significantly improve islet transplant success. IGF2 is an anti-apoptotic endocrine protein that inhibits apoptotic cell death through the mitochondrial (intrinsic pathway) or via antagonising activation of pro-inflammatory cytokine signalling (extrinsic pathway), in doing so IGF2 has emerged as a promising therapeutic molecule to improve islet survival in the immediate post-transplant period. The development of novel biomaterials coated with IGF2 is a promising strategy to achieve this. This review examines the mechanisms mediating islet cell apoptosis in the peri- and post-transplant period and aims to identify the utility of IGF2 to promote islet survival and enhance long-term insulin independence rates within the setting of clinical islet transplantation.

Download Full-text

Role of Exosomes in Islet Transplantation

Frontiers in Endocrinology ◽

10.3389/fendo.2021.681600 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jordan Mattke ◽

Srividya Vasu ◽

Carly M. Darden ◽

Kenjiro Kumano ◽

Michael C. Lawrence ◽

...

Keyword(s):

Islet Transplantation ◽

Graft Function ◽

Pancreatic Islet Transplantation ◽

Complex Molecules ◽

Wide Range ◽

And Function ◽

Antigen Presenting

Exosomes are known for their ability to transport nucleic acid, lipid, and protein molecules, which allows for communication between cells and tissues. The cargo of the exosomes can have a variety of effects on a wide range of targets to mediate biological function. Pancreatic islet transplantation is a minimally invasive cell replacement therapy to prevent or reverse diabetes mellitus and is currently performed in patients with uncontrolled type 1 diabetes or chronic pancreatitis. Exosomes have become a focus in the field of islet transplantation for the study of diagnostic markers of islet cell viability and function. A growing list of miRNAs identified from exosomes collected during the process of isolating islets can be used as diagnostic biomarkers of islet stress and damage, leading to a better understanding of critical steps of the isolation procedure that can be improved to increase islet yield and quality. Exosomes have also been implicated as a possible contributor to islet graft rejection following transplantation, as they carry donor major histocompatibility complex molecules, which are then processed by recipient antigen-presenting cells and sensed by the recipient immune cells. Exosomes may find their way into the therapeutic realm of islet transplantation, as exosomes isolated from mesenchymal stem cells have shown promising results in early studies that have seen increased viability and functionality of isolated and grafted islets in vitro as well as in vivo. With the study of exosomes still in its infancy, continued research on the role of exosomes in islet transplantation will be paramount to understanding beta cell regeneration and improving long-term graft function.

Download Full-text

Islet Product Characteristics and Factors Related to Successful Human Islet Transplantation From the Collaborative Islet Transplant Registry (CITR) 1999–2010

American Journal of Transplantation ◽

10.1111/ajt.12872 ◽

2014 ◽

Vol 14 (11) ◽

pp. 2595-2606 ◽

Cited By ~ 91

Author(s):

A. N. Balamurugan ◽

B. Naziruddin ◽

A. Lockridge ◽

M. Tiwari ◽

G. Loganathan ◽

...

Keyword(s):

Islet Transplantation ◽

Human Islet ◽

Product Characteristics ◽

Islet Transplant ◽

Transplant Registry ◽

Human Islet Transplantation ◽

Islet Transplant Registry

Download Full-text

The Caspase Selective Inhibitor EP1013 Augments Human Islet Graft Function and Longevity in Marginal Mass Islet Transplantation in Mice

Diabetes ◽

10.2337/db07-1452 ◽

2008 ◽

Vol 57 (6) ◽

pp. 1556-1566 ◽

Cited By ~ 47

Author(s):

J. A. Emamaullee ◽

J. Davis ◽

R. Pawlick ◽

C. Toso ◽

S. Merani ◽

...

Keyword(s):

Islet Transplantation ◽

Graft Function ◽

Selective Inhibitor ◽

Human Islet ◽

Islet Graft

Download Full-text

Regenerative Therapy of Type 1 Diabetes Mellitus: From Pancreatic Islet Transplantation to Mesenchymal Stem Cells

Stem Cells International ◽

10.1155/2016/3764681 ◽

2016 ◽

Vol 2016 ◽

pp. 1-22 ◽

Cited By ~ 15

Author(s):

Nadine E. Rekittke ◽

Meidjie Ang ◽

Divya Rawat ◽

Rahul Khatri ◽

Thomas Linn

Keyword(s):

Stem Cells ◽

Type 1 Diabetes ◽

Mesenchymal Stem Cells ◽

Islet Transplantation ◽

Pancreatic Islet ◽

Graft Function ◽

Individual Therapy ◽

Regenerative Therapy ◽

Pancreatic Islet Transplantation

Type 1 diabetes is an autoimmune disease resulting in the permanent destruction of pancreatic islets. Islet transplantation to portal vein provides an approach to compensate for loss of insulin producing cells. Clinical trials demonstrated that even partial islet graft function reduces severe hypoglycemic events in patients. However, therapeutic impact is restrained due to shortage of pancreas organ donors and instant inflammation occurring in the hepatic environment of the graft. We summarize on what is known about regenerative therapy in type 1 diabetes focusing on pancreatic islet transplantation and new avenues of cell substitution. Metabolic pathways and energy production of transplanted cells are required to be balanced and protection from inflammation in their intravascular bed is desired. Mesenchymal stem cells (MSCs) have anti-inflammatory features, and so they are interesting as a therapy for type 1 diabetes. Recently, they were reported to reduce hyperglycemia in diabetic rodents, and they were even discussed as being turned into endodermal or pancreatic progenitor cells. MSCs are recognized to meet the demand of an individual therapy not raising the concerns of embryonic or induced pluripotent stem cells for therapy.

Download Full-text