Low-Level Insulin Content Within Abundant Non-β Islet Endocrine Cells in Long-standing Type 1 Diabetes.

Although most patients with type 1 diabetes (T1D) continue to produce small amounts of insulin decades after disease onset, very few β-cells persist within their pancreata. Consequently, the source of persistent insulin secretion within T1D remains unclear. We hypothesized that low-level insulin content within non-β-cells could underlie persistent T1D insulin secretion. We tested for low levels of insulin (insulin) within a large cohort of JDRF Network for Pancreatic Organ Donors With Diabetes (nPOD) human pancreata across a wide range of ages and T1D disease durations. Long exposures, high-throughput imaging, and blinded parallel examiners allowed precise quantification of insulin cells. Of note, abundant islet endocrine cells with low quantities of insulin were present in most T1D pancreata. Insulin islet abundance and composition were not influenced by age, duration of diabetes, or age of onset. Insulin islets also contained β-cell markers at variable levels, including Pdx1, Nkx6.1, GLUT1, and PC1/3. Most insulin cells contained abundant glucagon and other α-cell markers, suggesting that α-cells drive much of the insulin phenotype in T1D. However, pancreatic polypeptide, somatostatin, and ghrelin cells also contributed to the insulin cell population. Insulin cells represent a potential source of persistent insulin secretion in long-standing T1D and a possible target for regenerative therapies to expand β-cell function in disease.