Abstract
Pancreatic islet transplantation is a minimally invasive procedure to replace β-cells in a subset of patients with autoimmune type 1 diabetic mellitus, who are extremely sensitive to insulin and lack counter-regulatory measures, and thereby increasing their risk of neuroglycopenia and hypoglycemia unawareness. Thus, pancreatic islet transplantation restores normoglycemia and insulin independence, and prevents long-term surgical complications associated with whole-organ pancreas transplantation. Nonetheless, relative inefficiency of islet isolation and storage process as well as progressive loss of islet function after transplantation due to unvoidable islet inflammation and apoptosis, hinder a successful islet transplantation. Carbon monoxide (CO), a gas which was once feared for its toxicity and death at high concentrations, has recently emerged as a medical gas that seems to overcome the challenges in islet transplantation. This minireview discusses recent findings about CO in preclinical pancreatic islet transplantation and the underlying molecular mechanisms that ensure islet protection during isolation, islet culture, transplantation and post-transplant periods in type 1 diabetic transplant recipients. In addition, the review also discusses clinical translation of these promising experimental findings that serve to lay the foundation for CO in islet transplantation to replace the role of insulin therapy, and thus acting as a cure for type 1 diabetes mellitus and preventing long-term diabetic complications.
Highlights
Pancreatic islet transplantation is a minimally invasive procedure that serves as an alternative strategy to injected insulin therapy with the aim of restoring normoglycemia and insulin independence in a subset of patients with autoimmune type 1 diabetic mellitus without surgical complications associated with whole-organ pancreas transplantation (Shapiro et al, 2017; Rickels and Robertshon, 2019)
In a mouse model of pancreatic allogeneic islet transplantation, exposure of healthy non-diabetic donor mice to 250 ppm Carbon monoxide (CO) gas for 20 h prior to islet isolation and/or 24 h before and continuously to day 13 after transplantation of 350–400 islet equivalents in each of streptozotocin (STZ; 225 mg/kg)-induced type 1 diabetic recipient mice led to markedly decreased pancreatic islet mRNA expression of pro-inflammatory genes such as tumor necrosis factor-alpha (TNF-α), inducible nitric oxide synthase, monocyte chemoattractant protein-1 (MCP-1) and macrophage infiltration into islet grafts as well as decreased apoptotic genes such as granzyme B, Fas and Fas ligand (FasL) while simultaneously increased anti-apoptotic gene Bcl-2 significantly at various days after transplantation compared to untreated controls (Wang et al, 2005) (Figure 1)
Pretreatment with 100 μM CORM-2 during islet isolation and subsequently transplanted (150 in number) into renal subcapsular space of STZ (165 mg/kg)-induced type 1 diabetic recipient mice resulted in significant downregulation of the expression of important proinflammatory genes such as TNF-α, interleukin-1beta (IL-1β), IL6, intercellular adhesion molecule-1 (ICAM-1), Toll-like receptor 4 (TLR4), tissue factor (TF), chemokine ligand 2 (CCL2) and C-X-C motif ligand 10 (CXCL10) (Figure 1), which strongly correlated with markedly reduced apoptosis, improved islet cell viability, and higher glucose-stimulated insulin secretion and transplantation outcomes in comparison with control group (Cai et al, 2020)
Summary
Pancreatic islet transplantation is a minimally invasive procedure that serves as an alternative strategy to injected insulin therapy with the aim of restoring normoglycemia and insulin independence in a subset of patients with autoimmune type 1 diabetic mellitus without surgical complications associated with whole-organ pancreas transplantation (Shapiro et al, 2017; Rickels and Robertshon, 2019). This subpopulation of type 1 diabetic patients refers to those who are extremely sensitive to insulin and lack counter-regulatory measures, increasing their risk of neuroglycopenia (abnormally low glucose level in brain) with hypoglycemia unawareness. This minireview discusses current knowledge of CO gas and CO-RMs in preclinical pancreatic islet transplantation and underlying molecular mechanisms that ensure islet protection during isolation, islet culture, transplantation and post-transplant periods
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