Carbon Monoxide in Pancreatic Islet Transplantation: A New Therapeutic Alternative to Patients With Severe Type 1 Diabetes Mellitus

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.

Neurotransmitters regulate β cells insulin secretion: A neglected factor

“…When β cells are stimulated with sodium nitroprusside (SNP, an extracellular NO donor) alone or both sodium nitroprusside and glucose, glucose is still the main factor that induces insulin secretion; NO alone does not induce insulin secretion but only enhances glucose-induced insulin secretion. The mechanism underlying this effect is not clear, but one hypothesis suggests that it may be related to NO-mediated stimulation of transient Ca 2+ release[ 58 ].…”

Type 1 diabetes – What’s new in prevention and therapeutic strategies?

“…Pancreatic transplantation can be a form of treatment in patients with irreversible complications of diabetes, such as diabetic nephropathy [50]. It is now a more and more widely used treatment in adult patients (>18 years old) with T1D of 5 or more years and experiencing unrecognized severe hypoglycaemic episodes [51][52][53][54]. Human islet isolation and purification require a multi-step process to extract the small islet fraction.…”

Type 1 diabetes and engineering enhanced islet transplantation

“…Lo et al [357] demonstrated that the hypoxia-induced reduction in insulin secretion could be recovered through the modulation of intermittent oxygen levels between 5 % and 21 % in their culture system. Islets preconditioned in carbon monoxide (CO) have been reported to provide protective effects from the hypoxia-induced cell death after transplantation [359] . Studies revealed that patients who received CO-treated islets had reduced serum levels of CCL23, a chemokine that can recruit immune cells and upregulate several inflammatory cytokines, and increased levels of CXCL12, which can induce angiogenesis and mitigate oxidative stress [359] .…”