ABCC8 – Type 2 Diabetes Mellitus

Common and rare variants in ABCC8 have been investigated extensively for their contribution to type 2 diabetes mellitus risk. Population-based case–control and meta‐analyses, including a UK study of 2 486 subjects, report modest effect sizes for SUR1 polymorphisms (OR ~1.2) and confirm association only for KCNJ11 E23K but not for ABCC8 exon 16–3t/c or exon 18 variants ([PMID:12540637]). A Japanese family with a gain‐of‐function SUR1 missense mutation (c.1819G>A (p.Val607Met)) demonstrated intrafamilial heterogeneity: five carriers across three generations presented with transient neonatal diabetes, impaired glucose tolerance, ketosis‐onset insulin‐dependent diabetes, slowly progressive insulin‐dependent diabetes, and adult‐onset type 2 diabetes ([PMID:30068891]). Conversely, early SSCP screens in Caucasian NIDDM patients found no enrichment of ABCC8 coding variants, arguing against a major role for common SUR1 variants in non‐pancreatic forms of diabetes ([PMID:8897013]).

Functional assays provide moderate support for a pathogenic mechanism: the adult‐onset SUR1 p.Tyr356Cys variant (c.1067A>G) exhibits reduced MgATP sensitivity and altered beta‐cell K(ATP) gating in HEK293 and INS1 cells, impairing glucose‐induced depolarization and Ca²⁺ influx consistent with diabetes susceptibility ([PMID:18346985]). No rare loss‐of‐function ABCC8 variants segregate as a Mendelian trait in type 2 diabetes pedigrees, and the modest functional defects in adult‐onset alleles contrast sharply with the severe channel dysfunction seen in neonatal diabetes or hyperinsulinism.

Key Take-home: ABCC8 harbors common and rare variants that modestly modify type 2 diabetes risk via subtle K(ATP) channel gating alterations; clinical utility lies in distinguishing monogenic neonatal or hyperinsulinism alleles from low‐penetrance adult‐onset risk variants.

References

• Endocrine Journal • 2018 • Heterogeneous nature of diabetes in a family with a gain-of-function mutation in the ATP-binding cassette subfamily C member 8 (ABCC8) gene. PMID:30068891
• Diabetes • 2003 • Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes. PMID:12540637
• Diabetes • 2008 • A rare mutation in ABCC8/SUR1 leading to altered ATP-sensitive K⁺ channel activity and beta-cell glucose sensing is associated with type 2 diabetes in adults. PMID:18346985
• Diabetologia • 1996 • Sequence variations in the human Kir6.2 gene, a subunit of the beta-cell ATP-sensitive K-channel: no association with NIDDM in white Caucasian subjects or evidence of abnormal function when expressed in vitro. PMID:8897013

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