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

Area of Science:

• Endocrinology
• Diabetes Research
• Cell Biology

Background:

• Type 1 diabetes (T1D) is characterized by autoimmune destruction of insulin-producing beta cells.
• Despite beta cell loss, many T1D patients exhibit persistent low-level insulin secretion.
• The source of this residual insulin production in T1D remains largely unknown.

Purpose of the Study:

• To investigate the hypothesis that non-beta cells with low insulin content contribute to persistent insulin secretion in T1D.
• To quantify the presence and characteristics of insulin-low (insulin^low) cells in human pancreata from T1D donors.
• To explore the potential of these insulin^low cells as targets for T1D regenerative therapies.

Main Methods:

• Analysis of a large cohort of human pancreata from the JDRF Network for Pancreatic Organ Donors With Diabetes (nPOD).
• Utilized long exposures and high-throughput imaging for precise quantification of insulin^low cells.
• Employed blinded parallel examiners to ensure accuracy in cell quantification and characterization.

Main Results:

• Abundant islet endocrine cells with low quantities of insulin (insulin^low) were identified in most T1D pancreata.
• The prevalence of insulin^low islets was not significantly affected by patient age, diabetes duration, or age of onset.
• Insulin^low cells co-expressed beta-cell markers (e.g., Pdx1, Nkx6.1) and predominantly alpha-cell markers (e.g., glucagon), with contributions from other endocrine cells.

Conclusions:

• Non-beta islet cells, particularly alpha cells, can exhibit low-level insulin expression in T1D.
• These insulin^low cells represent a potential source of endogenous insulin in long-standing T1D.
• Targeting and expanding these insulin^low cells could offer a novel strategy for beta-cell regenerative therapy in T1D.