We all know that in type 1 juvenile diabetes, the insulin producing cells that reside within spherical entities in the pancreas, called islets of Langerhans, are under an immune attack and are lost. This brings along the disease-defining lack of circulating insulin that is accompanied by injurious glucose levels, and the obvious therapeutical approach of insulin replacement by either injections, or transplantation of healthy insulin producing cells.
The common view of type 2 adult diabetes, on the other hand, holds the blame for disease on the function of insulin in the peripheral tissues, and not on the islets. After all, at the typical time of diagnosis of type 2 diabetes, the patients actually exhibit higher-than-normal circulating insulin levels, as the "resistance" to insulin in these patients is partially overcome by insulin overproduction. Later in the progression of the disease, the production of insulin fails and the islets expire. This can be the result of excess circulating glucose per se, which is known to be toxic to islets. Therefore, the approach for treating type 2 diabetes focuses on controlling glucose levels and not on islet function: diet to reduce intake, medications to reduce liver production of glucose (which is the normal role of the liver between meals), and exercise to improve glucose utilization and lose weight in the case of obesity. Yes, these do a fare job at helping the patients, but as in type 1 diabetes, the optimal control of glucose is rarely achieved. And, yes, bad diet and bad health habits can help in developing type 2 diabetes but recent findings shed some light on the role of islets in type 2 diabetes, too. Not during the late stage, when they're the victims of toxic glucose levels and circulating free fatty acids (when obesity is involved), but rather as the trigger for the disease.
As the human genome project advanced, 27 genes were identified as being associated with type 2 diabetes. Not all are known for their function and much study is still being done. Also, not all are required for the disease to surface, and there are environmental factors that are sometimes required (equals: the food you eat, the frequency you eat, exercise, pollutants, medications, background diseases, stress, oxidants, viruses... the list for environmental factors is rather long, which is good considering these are factors that are more in our hands than any other factors involved). Interestingly, of these 27 genes that were linked to type 2 diabetes, 18 are islet-function related. This means that at the level of the genomic make-up that predisposes individuals to type 2 diabetes, a role for islets is inherent. How could a malfunctioning islet cause insulin resistance?
One theory has to do with the way insulin is released. Essentially, there is an immediate short phase of insulin release, and then a late prolonged phase of insulin release. There actually also is a third phase which we won't discuss here. If all goes well, the first and second phases coordinate glucose control and one can say that the islets did their job well. But what if the first phase fails?
There is the possibility that the second phase will chronically try to compensate. Because it is not the "professional" immediate responder, it might perform in such an aberrant way that results in mildly over-prolonged and out-of-balance circulating insulin levels. The peripheral tissues that are supposed to respond to insulin then start blunting their insulin-sensing molecules, in a way, protecting the cells from insulin abuse. These changes in the molecular framework of cells can be reversible to some extent, or at worst, permanent. When the body refuses to respond to insulin, glucose rises and, unintentionally, the liver generates new free glucose under the false impression that insulin is absent.
Why anti-inflammation? Islets are perhaps the most sensitive entities in our body to inflammation. They shut down insulin production and rapidly die when their environment turns injurious. We know that this reflex, when mild, actually allows glucose to rise in the blood of an injured animal, yet these are modern times, and "stress," be it emotional or molecular, translates to danger and to a cellular danger response. Such responses have the nature of being inflammatory, meaning that they spread like flames in their immediate vicinity; an inflamed islet will spread damage to his neighboring tissue.
A recently re-discovered drug comprised of the protein alpha-1-antitrypsin has generated interest in this context and caught the attention of our group in Ben-Gurion University of the Negev, Israel (BGU). It is a naturally occurring molecule that the liver produces during inflammatory states, and that circulates for a week or so until the disease subsides. It blocks inflammation. It is protective of islets in various experimental setups, including cultured islets under an inflammatory trigger and transplanted islets in diabetic animals. The protection of islets is so vast, that since our 2005 publication, researchers have recorded immediate regain of insulin release in its presence in many other models. It is possible that the conditions that negatively affect aberrant islets in type 2 diabetes, and normal islets in type 1 diabetes or in a transplant setup, can be safely removed by this approach.
Finally, perhaps the most striking evidence for its relevance to diabetes, are the repeated reports of its inactivity when drawn from blood of diabetic individuals. Being inactive implores its replacement. We hope that in the near future we can harness this naturally occurring molecule for the benefit of reviving suffering islets and perhaps, if possible, for curing diabetes.