ADCY5 couples glucose to insulin secretion in human islets

Area of Science:

• Endocrinology
• Molecular Biology
• Genetics

Background:

• Single nucleotide polymorphisms (SNPs) in the ADCY5 gene are associated with elevated fasting glucose and increased type 2 diabetes (T2D) risk.
• The precise mechanisms by which these ADCY5 variants affect pancreatic β-cell function remain largely unknown.

Purpose of the Study:

• To investigate the role of ADCY5 in glucose and GLP-1-stimulated insulin secretion in human islets.
• To elucidate the functional consequences of ADCY5 polymorphisms on β-cell signaling pathways.

Main Methods:

• Quantitative assessment of ADCY5 mRNA expression in human islets.
• In situ imaging of cAMP and calcium dynamics in response to glucose and GLP-1 stimulation.
• Evaluation of glucose metabolism and ATP production in ADCY5-silenced islets.

Main Results:

• Risk allele carriers exhibited reduced ADCY5 mRNA expression in islets.
• ADCY5 is essential for coupling glucose, but not GLP-1, to insulin secretion.
• ADCY5 silencing impaired glucose-induced cAMP production and ATP generation at high glucose concentrations (>8 mmol/L).
• ADCY5 plays a metabolism-independent role, inhibiting calcium transients and β-cell connectivity across all tested glucose levels.
• GLP-1-induced calcium responses remained unaffected in ADCY5-depleted islets.

Conclusions:

• Altered ADCY5 expression and impaired glucose signaling in β-cells likely contribute to the influence of ADCY5 polymorphisms on fasting glucose levels and T2D risk.
• ADCY5 has critical, metabolism-independent roles in human β-cell function beyond its role in glucose sensing.