Adhesion G Protein-Coupled Receptor G1 (ADGRG1/GPR56) and Pancreatic beta-Cell Function

• Context: Adhesion G protein-coupled receptor (GPCR)-G1 (ADGRG1) is the most abundant GPCR in human pancreatic islets, but its role in islet function is unclear. Objective: Investigate how ADGRG1 expression and activation by its ligand, collagen III, impacts beta-cell function in normal and type 2 diabetic (T2D) islets. Design: Genes associated with the ADGRG1 in human islets was probed by RNA-sequencing of human pancreatic islet isolated from cadaveric donors, followed by functional studies on beta-cell proliferation, apoptosis, and insulin secretion in human and mouse islets and in INS-1 cells. Main Outcome Measures: Changes in beta-cell gene expression, proliferation, apoptosis, and insulin secretion were quantified by RNA-sequencing, qPCR, Thymidine incorporation, Western blotting, and RIA, respectively. Results: ADGRG1 is the most abundant GPCR mRNA in both human and mouse islets, and its expression in human islets strongly correlates with genes important for beta-cell function and T2D risk. The expression of ADGRG1 was reduced in islets of T2D donors, in db/db mouse islets, and in isolated human islets exposed to chronic hyperglycemia. Beneficial effects of collagen type III on beta-cell function via activation of the cAMP/protein kinase A pathway, suppression of RhoA and caspase-3 activity, increased beta-cell viability, and proliferation were abolished when ADGRG1 was down-regulated in beta-cells. Conclusions: We demonstrate a mechanistic link between ADGRG1 expression and beta-cell function. Pharmacological agents that promote expression or activation of the ADGRG1 receptor may represent a novel approach for the treatment of T2D.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)

Nyckelord

GLUCOSE-TOLERANCE TEST

INSULIN-SECRETION

HUMAN ISLETS

RNA-SEQ

GPR56

GPCR

DYSFUNCTION

EXPRESSION

PATHWAYS

GROWTH

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