Although the case confirming a critical role for autoimmunity in the pathogenesis of type 1 diabetes is settled, the evidence supporting its relevance in the development of type 2 diabetes is only starting to emerge. This form of diabetes is sweeping the globe and accounts for over 95% of cases.
Type 2 diabetes appears to require some critical immune perturbations in its earliest stages for it to develop into a full-blown metabolic disorder. This begins with the understanding that obesity initiates a profound immune response by recruiting large numbers of macrophages to adipose tissue, accounting for as many as 40% of the cells residing in fat. Chronic caloric excess leads to adipose tissue expansion and enlarging adipocytes secrete chemokines that stimulate even more macrophage migration, initiating the tissue inflammatory response. These macrophages churn out tumor necrosis factor (TNF), a cytokine well known to us that can induce hyperglycemia, stimulate fat production and increase resistance to the effects of insulin and its pro-inflammatory ally, interleukin 1 (IL-1). Together, these cytokines generate the systemic inflammatory response that can be so destructive in type 2 diabetes, one that extends beyond fat cells to involve the pancreas, liver, muscle tissue and the cardiovascular system and results in considerable morbidity.11
What if we turn off this inflammatory cascade? A recent retrospective study by some of our colleagues found that patients with rheumatoid arthritis and psoriasis treated with TNF inhibitors had a significantly decreased risk of developing type 2 diabetes compared with patients taking other anti-rheumatic drugs, suggesting that anti-TNF strategies may be effective in disease prevention.12 Interestingly, hydroxychloroquine showed a similar benefit.
The immune-suppression benefit may extend to some of the drugs being used to manage type 2 diabetes. In one study of 50 obese patients with multiple sclerosis (MS), it was observed that metformin and pioglitazone reduced MS disease activity as measured by brain MRI. Moreover, both treatments decreased the secretion of TNF and IL-6 and increased the numbers and regulatory properties of T regulatory cells.13 In disorders of autoimmunity, one should no longer consider obesity to merely be a passive bystander, away from the fray.14 It’s time to get tough on fat!
In 1922, a child diagnosed with type 1 diabetes carried a life expectancy of only two years.
The Big Picture
The rules of autoimmunity prevail for diabetes as they do for most rheumatologic disorders. The similarities are obvious: Although we can identify the elegant complexity of the immune response following the inception of type 1 diabetes, we are at a loss to explain what initiates the immune cascade that destroys the islet cells. Although the target cell has been identified, the best therapies available can only replenish the missing hormone, insulin. Although insulin pumps are getting better at controlling blood glucose, no technology will replace a normally functioning pancreas. And sadly, islet cell transplantation has been a bust.
