Reduced second phase insulin secretion in carriers of a sulphonylurea receptor gene variant associating with Type II diabetes mellitus.
OBJECTIVE
The sulphonylurea receptor is a subunit of the ATP-sensitive potassium channel in the pancreatic beta cell. Mutations at nt -3 of the splice acceptor site of exon 16 and a silent mutation in exon 18 of the gene for the sulphonylurea receptor (SUR1) associate with Type II (non-insulin-dependent) diabetes mellitus in several independent populations. We investigated whether these gene variants associate with changes in the pattern of glucose-stimulated insulin secretion.


METHODS
Subjects who had normal glucose tolerance (n = 67) and subjects with an impaired glucose tolerance (n = 94), originating from two independent studies, were included in the study. Beta-cell function and insulin sensitivity were assessed by the hyperglycaemic clamp.


RESULTS
Frequencies of the exon 16 -3t allele in the normal and impaired glucose tolerant groups were 46% and 44% respectively (p = NS). The more rare exon 18 T allele showed frequencies of 5 and 7% respectively (p = NS). We observed an approximately 25% reduced second-phase insulin secretion in carriers of the exon 16 -3t allele in both groups (p < 0.05). Estimates of insulin sensitivity did not show differences between carriers and non-carriers. The variant in exon 18 and the combined presence of variants in exon 16 and exon 18 were not associated with differences in insulin secretion or insulin sensitivity in our study groups.


CONCLUSIONS
The diabetes associated exon 16 -3t variant of the SUR1 gene associates with a functional change of the beta cell as reflected by reduced second-phase insulin secretion in response to a standardized hyperglycaemia in normal and impaired glucose tolerant subjects.
Hart
L M
LM
Leiden University Medical Centre, Department of Molecular Cell Biology, The Netherlands.
Dekker
J M
JM
van Haeften
T W
TW
Ruige
J B
JB
Stehouwer
C D
CD
Erkelens
D W
DW
Heine
R J
RJ
Maassen
J A
JA
D018528:ATP-Binding Cassette Transporters; D000368:Aged; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000503:physiopathology; D005091:Exons; D005787:Gene Frequency; D005838:Genotype; D015309:Glucose Clamp Technique; D018149:Glucose Intolerance; D006801:Humans; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D007700:Kinetics; D008875:Middle Aged; D009154:Mutation; D015221:Potassium Channels / Q000235:genetics*; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug / Q000235:genetics*; D064233:Sulfonylurea Receptors
C577507:ABCC8 protein, human; D018528:ATP-Binding Cassette Transporters; D001786:Blood Glucose; D007328:Insulin; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors