Harnessing Islet Heterogeneity to Trace the Origins of Type 1 Diabetes

Aim:
Type 1 diabetes (T1D) is a chronic debilitating disease caused by an autoimmune attack that destroys insulin producing b-cells in pancreatic islets. Surprisingly, a century after the discovery of insulin T1D remains incurable and the factors which trigger it are largely unknown. In the early stages of the disease, different islets experience varying degrees of the immune attack, and islets infiltrated by immune cells are often adjacent to intact islets. This phenomenon presents a powerful natural experiment which provides an opportunity to find the causes for T1D by asking: “Why is islet X attacked by the immune system, while its neighbor, islet Y, is not?

Methods:
To answer this question, we developed a method to separate attacked and non-attacked islets derived from the same pancreas. This way, we avoid confounding factors which accompany the classical juxtaposition of mice from different genetic backgrounds, or mice at different stages of the disease.

Results:
Single cell RNA sequencing of attacked and non-attacked islets extracted from non-obese diabetic (NOD) mice reveals the full repertoire of immune cells in the islet niche during the pre-symptomatic phases of the disease. This facilitated reconstruction of a crude timeline of the events that lead to beta cell destruction; and revealed a potential regulatory role for a macrophage population specific to non-attacked islets.

Conclusions:
Altogether, investigating the “battlefield” which drives the diabetic process is expected to yield novel markers for early detection and points of intervention in attempt to delay, or even prevent, the eruption of the disease.