Islets of Langerhans



The islets of Langerhans are the regions of the pancreas that contain its endocrine (i.e., hormone-producing) cells. Discovered in 1869 by German pathological anatomist Paul Langerhans at the age of 22, the islets of Langerhans constitute approximately 1 to 2% of the mass of the pancreas. There are about one million islets in a healthy adult human pancreas, which are distributed throughout the organ; their combined mass is 1 to 1.5 grams.

Cell types
Hormones produced in the islets of Langerhans are secreted directly into the blood flow by (at least) five different types of cells. In rat islets, endocrine cell subsets are distributed as follows:


 * Alpha cells producing glucagon (15–20% of total islet cells)
 * Beta cells producing insulin and amylin (65–80%)
 * Delta cells producing somatostatin (3–10%)
 * PP cells producing pancreatic polypeptide (3–5%)
 * Epsilon cells producing ghrelin (<1%)

It has been recognized that the cytoarchitecture of pancreatic islets differs between species. In particular, while rodent islets are characterized by a predominant proportion of insulin-producing beta cells in the core of the cluster and by scarce alpha, delta and PP cells in the periphery, human islets display alpha and beta cells in close relationship with each other throughout the cluster.

Islets can influence each other through paracrine and autocrine communication, and beta cells are coupled electrically to other beta cells (but not to other cell types).

Paracrine feedback
The paracrine feedback system of the islets of Langerhans has the following structure:


 * Insulin: activates beta cells and inhibits alpha cells
 * Glucagon: activates alpha cells which activates beta cells and delta cells
 * Somatostatin: inhibits alpha cells and beta cells

Electrical activity
Electrical activity of pancreatic islets has been studied using patch clamp techniques, and it has turned out that the behavior of cells in intact islets differs significantly from the behavior of dispersed cells.

Islet transplantation as a treatment for type 1 diabetes
Islet cell transplantation has the possibility of restoring beta cell function from diabetes, offering an alternative to a complete pancreas transplantation or an artificial pancreas.

Because the beta cells in the islets of Langerhans are selectively destroyed by an autoimmune process in type 1 diabetes, clinicians and researchers are actively pursuing islet transplantation as a means of restoring physiological beta cell function in patients with type 1 diabetes.

Recent clinical trials have shown that insulin independence and improved metabolic control can be reproducibly obtained after transplantation of cadaveric donor islets into patients with unstable type 1 diabetes.

Islet transplantation for type 1 diabetes currently requires potent immunosuppression to prevent host rejection of donor islets.

An alternative source of beta cells, such insulin-producing cells derived from adult stem cells or progenitor cells would contribute to overcoming the current shortage of donor organs for transplantation. The field of regenerative medicine is rapidly evolving and offers great hope for the nearest future. However, type 1 diabetes is the result of the autoimmune destruction of beta cells in the pancreas. Therefore, an effective cure will require a sequential, integrated approach that combines adequate and safe immune interventions with beta cell regenerative approaches.

Another potential source of beta cells may be xenotransplantation. The most likely source for xenogeneic islets for transplantation into human currently under evaluation is the pig pancreas. Interestingly, human and porcine insulin differ only for one aminoacid, and insulin extracted from porcine pancreata has been used for the treatment of patients with diabetes before the development of recombinant human insulin technology. Several studies in small and large animals models have shown that transplantation of islet cells across species is possible. However, several problems need to be overcome for porcine islet transplantation to become a viable clinical option. The immunogenicity of xenogeneic tissues may be different from and even stronger than allogeneic tissues. For instance, Galalpha1-3Galbeta1-4GlcNAc (alpha galactosidase, alpha-Gal) expressed on porcine cells represents a major barrier to xenotransplantation being the target of preformed antibodies present in human blood. Remarkable progress has been recorded in the development of genetically modified pigs lacking or overexpressing molecules that may improve acceptance of transplanted tissues across into humans. Pigs lacking alpha-Gal or overexpressing human Decay Accelerating Factor (hDAF), amongst others, have been generated to study the impact on transplanted outcome in nonhuman primate models. Another limitation is the risk for transmission of zoonotic infections from pigs to humans, particularly from Porcine Endogenous Retro-Viruses (PERV). Amongst the approaches proposed to overcome islet xenorejection is immunoisolation of the clusters using encapsulation techniques that may shield them from immune attack. Studies in rodents and large animals have shown great promise that justify cautious optimism for the near future. Nonrandomized, uncontrolled pilot clinical trials are current ongoing in subject with insulin-requiring diabetes to test the efficacy of encapsulation techniques to protect xenogeneic islets in the absence of chronic anti-rejection drugs.