Small molecule glucagon release inhibitors with activity in human islets

Area of Science:

• Endocrinology
• Pharmacology
• Diabetes Research

Background:

• Type 1 diabetes (T1D) affects over 1.25 million individuals in the US, characterized by the immune-mediated destruction of insulin-producing beta cells.
• Surviving alpha cells in T1D patients exhibit dysregulated function, contributing to dangerous blood glucose fluctuations (hyperglycemia and hypoglycemia).
• Effective management of T1D requires maintaining long-term blood glucose control, necessitating novel therapeutic strategies targeting alpha cell function.

Purpose of the Study:

• To discover small molecules capable of suppressing alpha cell function for potential preclinical development.
• To validate previously identified glucagon-suppressing compounds from rodent models in human islet systems.
• To identify specific compounds that inhibit glucagon secretion without adversely affecting insulin release.

Main Methods:

• Primary human islet cells were dissociated, replated, and treated with candidate glucagon-suppressing compounds.
• Glucagon accumulation in the medium was measured using reporter assays.
• Insulin secretion was assessed in a MIN6 beta cell reporter assay, and intact human islets were treated to validate findings.

Main Results:

• Compounds SW049164 and SW088799 demonstrated significant inhibition of glucagon release from human alpha cells.
• These compounds had minimal impact on insulin secretion from beta cells.
• SW088799 showed significant glucagon release inhibition with an IC50 of 1.26 µM in concentration-response studies.

Conclusions:

• The identified compounds, particularly SW088799, show conserved mechanisms of action between rodent and human alpha cells.
• SW049164 and SW088799 are promising candidates for further investigation as potential therapeutics for T1D.
• Future studies on SW088799 could elucidate its molecular targets or facilitate its use as an in vitro tool compound.