The Battered β-Cell: Usual Suspects and Guilt by Association

Abstract

Does it not astonish us that diabetes was recognized thousands of years ago and in a single century we rapidly developed life-saving therapies, yet we are still trying to identify initial causes of this disease (1–3)? It is true that we have made much more progress in understanding pathophysiological mechanisms for type 1 diabetes mellitus (T1DM) than we have for type 2 diabetes mellitus (T2DM). Perhaps there is a message in this. T2DM is roughly 20 times more common than T1DM, it has at least several different phenotypes in humans, and its prevalence varies significantly among ethnic and racial groups. This suggests that T2DM is not a disease at all, but rather a syndrome—more like an association of signs and symptoms, such as fever, anemia, or pneumonia. In clinics and scientific literature, we tend to refer to T1DM as a single autoimmune disease, but we are vague about T2DM and refer to it as a multifactorial and polygenic disease. This is a reasonable enough concept, but one that opens the door to the possibility that there is no single gene that will explain T2DM. It is true that there are known important mutations in a few transcription factors in a small number of families of humans. Otherwise, however, it may take the loss of more than one gene's expression to develop T2DM in a single human … or it may take overexpression of more than one gene … or it may take a combination of loss and overexpression of different genes to establish the disease. This picture becomes ever more complicated when one adds epigenetic events as a possibility, especially considering how acutely epigenetic changes can come and then go after DNA repair is completed. Small wonder we have not yet identified the genetic cause of human T2DM. Actually, the term T2DM implies that we know more than we do, i.e. that there are only two forms of diabetes. This term arose by default because we decided to change the name of juvenile-onset or insulin-dependent diabetes to “type 1.” The term “type 2” was invented to cover the other 95% of cases of diabetes. That's a pretty large wastebasket and one that invites even worse tongue-in-cheek imprecision, i.e. terms such as type 1 and 1/2 diabetes, which implies an entity midway between type 1 and type 2. Other diabetes phenotypes, such as late onset of T1DM in adults and T2DM in children, clearly provide important pathophysiological clues.