Researchers’ understanding of type 2 diabetes is being reinvented before our eyes. Some time ago, there was a split among diabetes researchers about whether type 2 diabetes was driven by insufficient insulin production (beta-cell failure) or flawed insulin use in cells (insulin resistance). Eventually a consensus was reached: beta-cell failure and insulin resistance both contribute to the progression of type 2 diabetes, and both abnormalities emerging, typically insulin resistance first. Researchers then identified another problem in type 2 diabetes: the over-production of glucose from the liver (gluconeogensis), especially at inappropriate times such as after meals. For some time, this palpable trio – insulin resistance, beta-cell failure, and increased gluconeogenesis – encompassed the mainstream understanding of the pathology of type 2 diabetes.
This trio is expanding before our eyes to encompass a wide range of newly identified problems associated with type 2 diabetes. Suddenly researchers are paying attention to abnormalities in gut hormones (incretins), mitochondrial dysfunction and oxidative stress, inflammation, and even the brain as drivers of type 2 diabetes. The newest member of the pack, abnormal fat distribution, which has been standing on the sidelines since the earliest descriptions of type 2 diabetes, suddenly finds itself in center field.
When people gain weight, the fat cells that are supposed to act as a fat storage depot become overloaded. Fats begin to float around the body, and often accumulate in tissues where they do not belong (so called” ectopic” fat). Free fats as it turns out can land in the pancreas and directly lead to the loss of insulin producing cells, a process that is termed “lipotoxicity.” Abnormal fat distribution in type 2 diabetes may also be an important cause of insulin resistance. Last month, this fat-centered view of diabetes was highlighted in an article in The Journal of the American Medical Association. We expect to hear much more about the fat-centered view of diabetes in future. As this view of diabetes becomes more recognized, we believe that treatments that cause weight loss or are weight neutral will become more favored. Despite causing some weight gain, the TZDs (Actos and Avandia) may also benefit from this view of diabetes because they help fat tissue store more fat, and therefore may help to prevent fat accumulation in other tissues.