Low Level Insulin Content Within Abundant Non-Beta Islet Endocrine Cells in Long-Standing Type 1 Diabetes

Although most type 1 diabetes (T1D) patients 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 low-level insulin content within non-β-cells could underlie persistent T1D insulin secretion. We tested for low amounts of insulin (insulin low ) within a large cohort of JDRF 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. Surprisingly, abundant islet endocrine cells with low quantities of insulin were present in most T1D pancreata. Insulin low islet abundance and composition was 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. But, PP-, SS-, and ghrelin cells also contributed to the insulin low cell population. Insulin low cells represent a potential source of persistent insulin secretion in longstanding T1D and a possible target for regenerative therapies to expand β-cell function in disease.