SLC2A2 – Neonatal Diabetes Mellitus

Biallelic mutations in SLC2A2, encoding the GLUT2 glucose transporter, have been identified as a cause of transient and permanent neonatal diabetes mellitus (NDM). In mice, Slc2a2 knockout results in lethal neonatal diabetes, demonstrating a critical role for GLUT2 in pancreatic β-cell glucose uptake and insulin secretion. The human phenotype emerges prior to the classical Fanconi-Bickel syndrome features, highlighting a window of isolated neonatal hyperglycaemia.

In a cohort of 104 patients with NDM of unknown aetiology, five unrelated individuals from consanguineous families were found to harbour homozygous SLC2A2 mutations, including four novel alleles. Four of these presented with transient neonatal diabetes (16% of transient NDM cases) and one with permanent NDM, all before overt Fanconi-Bickel manifestations (5 probands) (PMID:22660720).

Inheritance is autosomal recessive, with segregation of homozygous SLC2A2 variants in multiple consanguineous pedigrees. The spectrum includes splice-site and missense changes such as c.607A>C (p.Ser203Arg) which abolishes GLUT2 function in vitro. No additional affected relatives were reported beyond the probands.

Functional studies corroborate the clinical data: Slc2a2-null mice exhibit neonatal hyperglycaemia and death, and Xenopus oocyte assays of patient variants demonstrate loss of glucose transport activity, confirming a loss-of-function mechanism.

Some data in adult human islets suggest that GLUT2 is not the principal β-cell glucose transporter in mature human cells (PMID:21920790), but the early-onset neonatal diabetes phenotype and animal models strongly support a critical role for GLUT2 during pancreatic development and neonatal insulin secretion.

Overall, SLC2A2 should be included in genetic testing for consanguineous families and transient neonatal diabetes cohorts after exclusion of common NDM genes. Key take-home: Biallelic SLC2A2 variants cause autosomal recessive neonatal diabetes and guide early diagnosis and management.

References

• Diabetologia • 2012 • SLC2A2 mutations can cause neonatal diabetes, suggesting GLUT2 may have a role in human insulin secretion. PMID:22660720
• Molecular genetics and metabolism • 2011 • GLUT2 (SLC2A2) is not the principal glucose transporter in human pancreatic beta cells: implications for understanding genetic association signals at this locus. PMID:21920790

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