FFAR1 and Type 2 Diabetes Mellitus

The genetic evidence linking FFAR1 to Type 2 diabetes mellitus is limited. In one study, the coding region of FFAR1 was examined in a cohort of 43 patients (PMID:15606695), and additional re‐sequencing in 96 subjects (PMID:17987108) identified candidate variants; however, the association with disease risk remains inconclusive and lacks clear familial segregation. Notably, a candidate variant, c.538G>A (p.Gly180Ser), was found in a subset of subjects (PMID:18583466), yet its impact on the overall genetic architecture of the disease is modest.

Functional evidence from in vitro and in vivo studies provides moderate support for FFAR1’s role in insulin secretion dysregulation. Assays demonstrate that loss‐of‐function mutations, such as the reported R104P mutation that abrogates receptor activity (PMID:26505901), result in impaired intracellular calcium mobilization and reduced insulin release. Though the genetic association is conflicted, the functional data suggest that altered FFAR1 signaling may contribute to beta‑cell dysfunction. Key take‑home sentence: While current genetic findings are limited, the functional deficits observed in FFAR1 variants underscore its potential clinical relevance in Type 2 diabetes mellitus.

References

• Diabetic medicine : a journal of the British Diabetic Association • 2005 • Studies of relationships between variation of the human G protein-coupled receptor 40 Gene and Type 2 diabetes and insulin release PMID:15606695
• PloS one • 2007 • Variants in the FFAR1 gene are associated with beta cell function PMID:17987108
• The Journal of clinical endocrinology and metabolism • 2008 • Loss-of-function mutation of the GPR40 gene associates with abnormal stimulated insulin secretion by acting on intracellular calcium mobilization PMID:18583466
• PloS one • 2015 • A Single Amino Acid Mutation (R104P) in the E/DRY Motif of GPR40 Impairs Receptor Function PMID:26505901

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