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^low) 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^low cells. Of note, abundant islet endocrine cells with low quantities of insulin were present in most T1D pancreata. Insulin^low islet abundance and composition were not influenced by age, duration of diabetes, or age of onset. Insulin^low islets also contained β-cell markers at variable levels, including Pdx1, Nkx6.1, GLUT1, and PC1/3. Most insulin^low cells contained abundant glucagon and other α-cell markers, suggesting that α-cells drive much of the insulin^low phenotype in T1D. However, pancreatic polypeptide, somatostatin, and ghrelin cells also contributed to the insulin^low cell population. Insulin^low 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.