T2D is characterized by progressive pancreatic islet dysfunction; however, dissecting causes of this dysfunction in humans is challenging due to disease heterogeneity and the difficulty of obtaining relevant pancreatic samples. To address these challenges, we used an integrated approach to functionally and molecularly study the native pancreas and isolated islets from the same human T2D cadaveric donor. Using associated donor clinical information, we focused on donors with short disease duration (n=10, age 47-66 years, 2-7-year duration, oral medications). Compared to age-matched control islets, T2D islets had dysfunctional insulin (decreased) and glucagon (increased) secretion despite similar insulin and glucagon content. Tissue-section analysis of T2D pancreata showed no difference in relative endocrine (α, β and δ) cell composition. To assess for changes in the islet microenvironment, we analyzed macrophages by staining with Iba1 and endothelial cells with Caveolin-1 and found a 2-fold increase in intraislet macrophages (T2D vs. control: 3.01% vs. 1.45% by area) but no change in intraislet endothelial cell area (T2D vs. control: 8.97% vs. 8.21% by area). Interestingly, costaining with Iba1 and thioflavin S demonstrated that T2D islets with amyloid did not have increased macrophage infiltration compared to T2D islets without amyloid although a close spatial association of macrophages and amyloid deposits was noted. RNA-sequencing analysis of FACS-purified α and β cells from T2D islets showed increased inflammatory signaling pathways in both cell types. Specifically, transcripts for cytokine receptors such as IL6R, IL1R1, and IFNGR1 as well as downstream regulators including NFKB1 and NFKB2 were elevated in T2D α and/or β cells. Together, these data suggest that early in the course of T2D, increased macrophages in the islet microenvironment may lead to elevated α and β cell inflammatory signaling and contribute to human α and β cell dysfunction.


J.T. Walker: None. S. Shrestha: None. N. Prasad: None. T. Richardson: None. R. Aramandla: None. G. Poffenberger: None. R. Bottino: None. M. Brissova: None. A.C. Powers: None.

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