MedE Distinguished Speaker Seminar

ABSTRACT:

Type 1 diabetes mellitus (T1D) is a chronic, progressive disease that affects genetically-prone individuals, gradually reducing their ability to secrete insulin via the autoimmune destruction of the population of islet cells that reside in the pancreas. Poor glycemic control is associated with the development of both microvascular and macrovascular complications, which can increase morbidity and mortality and negatively affect patient quality of life. The most prevalent method of treatment is the daily injection of recombinant insulin, which significantly increases long-term survival.  Unfortunately, insulin injection does not always prevent the extreme glucose excursions experienced by these patients that result in the long-term diabetic complications of end-stage renal failure, retinopathy, and neuropathy. Insulin replacement also does not affect the underlying autoimmune pathophysiology of diabetes.  Ideally, "curing" T1D would require a two-step process: interference with the autoimmune processes present, and the restoration of beta cell mass. 

Allogeneic islet cell transplantation via infusion of cadaveric islets into the portal vein for the restoration of beta cell mass is an attractive investigational treatment for type T1D as it accomplishes the dual goals of beta cell replacement with immune modulation to protect the islets. The functional islet grafts serve to normalize basal hepatic glucose output, reduce hyperinsulinemia, and normalize plasma concentrations of amino acids. Although long-term freedom from insulin injection has not yet been achieved, islet transplantation has resulted in lasting improvement in glycemic control (such as reduction in the number and severity of hypoglycemic episodes) as well as other metabolic effects in many cases [1-3]. However, donor pancreata are limited in availability, and the need for lifelong immunosuppression to prevent the autoimmune destruction of islets increases the risks for cardiovascular disease, atherosclerosis, dysplipidemia, and is additionally toxic to beta cells, therefore shortening the lifespan of transplanted islets. These represent significant additional obstacles to the widespread implementation of islet transplantation as a treatment for T1D. Therefore, islet cell transplantation is currently reserved for severe cases where the benefit-risk ratio is in favor of the procedure—e.g., those who have already undergone allogeneic kidney transplantation (and are already on a long-term immunosuppressive regimen), or patients with "brittle diabetes" who experience frequent bouts of hypoglycemic unconsciousness, which is extremely dangerous if the patient is unattended at the time.  The typical islet transplant candidate has recurrent hypoglycemia, poor recognition of symptoms, and abnormal HgbA1c.

To date, the use of newer and safer immune suppression strategies, such as T-cell-depleting protocols, has resulted in a far greater number (41%-62%) of patients remaining insulin-independent 5 years after the procedure, which approaches the rate of insulin independence achieved by whole organ pancreas transplant (approximately 50%) [4, 5]. Numerous lines of research, however, are actively being pursued to improve islet transplantation outcomes further. These include the improvement of islet isolation, culture, and quality assessment measures through such methods as gene profiling, non-invasive in vivo islet imaging techniques, in silico modeling to improve estimates of islet requirements prior to transplantation and insulin therapy requirements post-islet transplantation in order to reduce islet exhaustion from high ambient glucose levels, the in vivo expansion of islets after transplantation, the use of alternative transplant sites, differentiation of stem cells into islet cells, co-transplantation with mesenchymal stem cells, the use of novel, stabilizing scaffolds at the transplantation site, and immune tolerance induction. A closed-loop system, or "artiicial endocrine pancreas," is another avenue of research that is currently being investigated in post-transplantation patients for the prevention of glucose toxicity to the islet graft, with the ultimate goal of employing portable, standalone closed-loop systems in T1D patients who have not yet undergone islet transplantation.

A closed-loop system utilizes a continuous glucose sensor and insulin pump designed to emulate the physiological characteristics of the pancreatic beta cell in order to achieve the goal of full glycemic normalization, while minimizing patient interaction with the system. Previous issues that have been considered in the development of an artificial pancreas include the absorption kinetics of subcutaneous insulin delivery, dynamics of carbohydrate metabolism (in terms of plasma, hepatic, and pancreatic concentrations of glucose, insulin, and glucagon), and the interactions between plasma and subcutaneous glucose concentrations.  Further, while a functional beta cell can directly determine real-time plasma insulin concentration via physiologic insulin receptors on the cell surface, in an artificial system, a model prediction of the plasma insulin concentration must be used. The reliability of this control algorithm is of central importance to any artificial system. The external physiological insulin delivery (ePID) system combines an external pump and sensor with a variable insulin infusion rate algorithm. 

In a recent study at City of Hope [6], we attempted to improve the PID algorithm by incorporating the concept of "insulin feedback" (IFB) gain.  In short, the physiologic beta cell is thought to reduce insulin secretion in proportion to the prevailing plasma insulin concentration; although the significance of this feedback mechanism to the beta cell remains unclear, the effect of such a feedback term in a closed-loop system is to compensate for a long, or undesirable, time constant in the control response.  Thus, our approach has been to model the artificial control algorithm after the dynamic behavior of the beta cell. 

Bio:Fouad Kandeel, M.D., Ph.D., is Professor and Chair of the Department of Translational Research & Cellular Therapeutics and the Department of Clinical Diabetes, Endocrinology, & Metabolism at the City of Hope Diabetes & Metabolism Research Institute in Duarte, CA. In a highly productive career that has spanned the better part of four decades, Dr. Kandeel has dedicated his himself to the study of islet biology and the refinement and advancement of cell-based therapies such as islet cell transplantation for the amelioration of type 1 diabetes mellitus (T1D) and the prevention of its complications. Current translational and multidisciplinary collaborations aimed at improving islet cell transplantation outcomes include: the development of in silico insulin modeling software to predict patient responses to therapy and optimize outcomes, methods of detecting early-beta cell death to provide earlier therapeutic interventions, non-invasive islet imaging technology, the in vivo expansion of islet grafts using growth factor treatment and/or stem cells, improved islet quality assessment measures through gene profiling and epigenetics, immune tolerance induction strategies using regulatory T cells and mixed chimerism, co-transplantation of islets with mesenchymal stem cells, the development of alternative transplantation sites and islet encapsulation strategies, and prolonging graft survival by engineering automated, portable closed-loop systems (i.e., an "artificial pancreas") to assist in regulating blood glucose. Dr. Kandeel is also working to implement a global diabetes health initiative for type 2 diabetes to streamline care delivery and optimize patient outcomes on a mass population scale.