Insulitis is an inflammation of the islets of Langerhans, a collection of endocrine tissue located in the pancreas that helps regulate glucose levels, and is classified by specific targeting of immune cell (T and B lymphocytes, macrophages and dendritic cells) infiltration in the islets of Langerhans. This immune cell infiltration can result in the destruction of insulin-producing beta cells of the islets, which plays a major role in the pathogenesis, the disease development, of type 1 and type 2 diabetes. Insulitis is present in 19% of individuals with type 1 diabetes and 28% of individuals with type 2 diabetes. It is known that genetic and environmental factors contribute to insulitis initiation, however, the exact process that causes it is unknown. Insulitis is often studied using the non-obese diabetic (NOD) mouse model of type 1 diabetes. The chemokine family of proteins may play a key role in promoting leukocytic infiltration into the pancreas prior to pancreatic beta-cell destruction.
Pathophysiology
The pathogenesis of insulitis can be assessed based on the threshold of CD3+ or CD45+ cells surrounding or infiltrating the islets of Langerhans, however, this can only be studied with a pancreatic tissue sample. CD3+ and CD45+ (cluster of differentiation 3 & 45 positive cells) are lymphocytes. Studying non-obese diabetic mice has revealed a correlation between insulitis progression and quantity of insulin autoantibodies production in the blood circulation, as well as a link between certain combinations of present autoantibodies and risk for developing type 1 diabetes and insulitis.
Insulitis, which is present in roughly 19% of type 1 diabetes patients, most prominently occurs in the first year after diagnosis in patients aged 0 to 14 years with a prevalence of 68% (32/47 patients studied). Insulitis prevalence is 4% in young patients with chronic type 1 diabetes (patients who have had the disease for over a year). Only 29% of older patients aged 15 to 39 have shown insulitic lesion within a year after diagnosis. The exact reason for this disparity between age groups is unknown, however it is theorised that adults may have a different or less severe form of type 1 diabetes that progresses slower.
There are 2 different sub-classifications of insulitis, peri-insulitis and intra-insulitis, that differ based on the location of immune cell infiltration. In peri-insulitis, cell infiltration occurs in the periphery of the islets, whereas in intra-insulitis has cell infiltration in the parenchyma, the functional tissue, of the islet. Often, in peri-insulitis, cell infiltration in concentration at 1 pole of the islet.
Diagnosis
There is a significant correlation between insulitis frequency and CD45+, CD3+, CD4+, CD8+, and CD20+ cells within an insulitis lesion, and the general consensus within the scientific community is that a lesion in the islets of Langerhans can be diagnosed as insulitis if it meets the minimum threshold of at least 3 islets infiltrated, each with a minimum of 15 CD45+ cells. One study that was aiming to find the frequency of individuals with type 2 diabetes who fulfilled the insulitis diagnostic requirements found that the current definition and requirements of insulitis could not be used to “distinguish pancreases retrieved from individuals with type 1 diabetes from those with type 2 diabetes,” (Lundberg et al., 2017). This study proposed changing the accepted definition of insulitis to have a positive diagnosis occur when “≥ 15 CD3+ cells, not CD45+ cells, are found in ≥ 3 islets,” (Lundberg et al., 2017) and doing so decreased the percentage of type 2 diabetic patients meeting the criteria for insulitis from 82% to 28%.
A primary challenge to studying the pathogenesis of insulitis and type 1 and 2 diabetes is due to the lack of an agreement in the definition and diagnostic conditions of insulitis. This lack of consensus exists because there are many different immunophenotyping markers and cell infiltrate thresholds used to distinguish insulitis from other inflammatory conditions, and due to the small sample size available to study, there is lots of research focused on more clearly identifying the characteristics of insulitis.