SLC2A2 mutations can cause neonatal diabetes, suggesting GLUT2 may have a role in human insulin secretion.
OBJECTIVE
The gene SLC2A2 encodes GLUT2, which is found predominantly in pancreas, liver, kidney and intestine. In mice, GLUT2 is the major glucose transporter into pancreatic beta cells, and biallelic Slc2a2 inactivation causes lethal neonatal diabetes. The role of GLUT2 in human beta cells is controversial, and biallelic SLC2A2 mutations cause Fanconi-Bickel syndrome (FBS), with diabetes rarely reported. We investigated the potential role of GLUT2 in the neonatal period by testing whether SLC2A2 mutations can present with neonatal diabetes before the clinical features of FBS appear.


METHODS
We studied SLC2A2 in patients with transient neonatal diabetes mellitus (TNDM; n = 25) or permanent neonatal diabetes mellitus (PNDM; n = 79) in whom we had excluded the common genetic causes of neonatal diabetes, using a combined approach of sequencing and homozygosity mapping.


RESULTS
Of 104 patients, five (5%) were found to have homozygous SLC2A2 mutations, including four novel mutations (S203R, M376R, c.963+1G>A, F114LfsX16). Four out of five patients with SLC2A2 mutations presented with isolated diabetes and later developed features of FBS. Four out of five patients had TNDM (16% of our TNDM cohort of unknown aetiology). One patient with PNDM remains on insulin at 28 months.


CONCLUSIONS
SLC2A2 mutations are an autosomal recessive cause of neonatal diabetes that should be considered in consanguineous families or those with TNDM, after excluding common causes, even in the absence of features of FBS. The finding that patients with homozygous SLC2A2 mutations can have neonatal diabetes supports a role for GLUT2 in the human beta cell.
Peninsula College of Medicine and Dentistry, University of Exeter, Peninsula Medical School Building, Barrack Road, Exeter, Devon EX2 5DW, UK.
F H
FH
Sansbury
S E
SE
Flanagan
J A L
JA
Houghton
F L
FL
Shuixian Shen
A M S
AM
Al-Senani
A M
AM
Habeb
M
M
Abdullah
A
A
Kariminejad
S
S
Ellard
A T
AT
Hattersley
D001483:Base Sequence; D002239:Carbohydrate Metabolism, Inborn Errors / Q000235:genetics; D017931:DNA Primers; D003920:Diabetes Mellitus / Q000175:diagnosis / Q000235:genetics*; D005198:Fanconi Syndrome / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D051273:Glucose Transporter Type 2 / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D009154:Mutation
D017931:DNA Primers; D051273:Glucose Transporter Type 2; D007328:Insulin; C495680:SLC2A2 protein, human