ABCMdb

PMID: 12559865

Huopio H, Otonkoski T, Vauhkonen I, Reimann F, Ashcroft FM, Laakso M
A new subtype of autosomal dominant diabetes attributable to a mutation in the gene for sulfonylurea receptor 1.
Lancet. 2003 Jan 25;361(9354):301-7., [PubMed]

Sentences

No. Mutations Sentence Comment

1 ABCC8 p.Glu1506Lys We have described a dominant heterozygous mutation-E1506K-in the sulfonylurea receptor 1 (SUR1) gene (ABCC8) in a Finnish family, which leads to congenital hyperinsulinaemia due to reduction of KATP-channel activity. Login to comment 2 ABCC8 p.Glu1506Lys We aimed to characterise glucose metabolism in adults heterozygous for the E1506K mutation. Login to comment 3 ABCC8 p.Glu1506Lys Methods Glucose tolerance was assessed by an oral glucose tolerance test, insulin secretion by the intravenous glucose tolerance test and hyperglycaemic clamp, and insulin sensitivity by hyperinsulinaemic euglycaemic clamp in 11 people heterozygous for the E1506K mutation and 19 controls. Login to comment 4 ABCC8 p.Glu1506Lys Findings Four people who were heterozygous for the SUR1 E1506K mutation had diabetes, five had impaired glucose tolerance, one had impaired fasting glucose, and one had normal glucose tolerance. Login to comment 5 ABCC8 p.Glu1506Lys Although glucose-induced, first-phase insulin secretion was normal in children younger than 10 years of age who were heterozygous for the SUR1 E1506K mutation (n=2; 66 and 334 pmol/L), it fell rapidly after puberty (n=3; 12-32 pmol/L), and was almost completely lost in adulthood (n=11; 12-32 pmol/L). Login to comment 7 ABCC8 p.Glu1506Lys By contrast, insulin sensitivity (M/I value) was normal in carriers of the E1506K mutation who did not have diabetes and was reduced by 15% in those who were heterozygous with diabetes (0·07 in those without diabetes and 0·05 in those with the disorder; not significantly different from controls). Login to comment 8 ABCC8 p.Glu1506Lys Interpretation Heterozygous E1506K substitution in the SUR1 gene causes congenital hyperinsulinism in infancy, loss of insulin secretory capacity in early adulthood, and diabetes in middle-age. This variant represents a new subtype of autosomal dominant diabetes. Login to comment 16 ABCC8 p.Glu1506Lys ABCC8 p.Glu1506Lys However, congenital hyperinsulinaemia offers a model to investigate the long-term results of constant depolarisation of the beta-cell membrane and amplified concentrations of intracellular calcium on insulin secretion and risk of diabetes.5,6 We have described a dominant mutation in the SUR1 gene (E1506K) in patients with congenital hyperinsulinaemia. Login to comment 17 ABCC8 p.Glu1506Lys This mutation leads to a reduction, but not complete loss, of KATP channel activity.7 We aimed to investigate glucose homoeostasis in carriers of the SUR1 E1506K mutation in a large Finnish pedigree. Login to comment 18 ABCC8 p.Glu1506Lys Participants and methods Participants Between December, 2000, and May, 2001, we recruited all known relatives of patients who had been diagnosed with congenital hyperinsulinaemia in early infancy7 who were heterozygous for the dominant SUR1 mutation E1506K. Login to comment 35 ABCC8 p.Glu1506Lys ABCC8 p.Glu1506Lys SULFONYLUREA RECEPTOR 1 Regulates insulin secretion in the pancreatic beta-cells * * * † † † † † * * *** * NN * * N N NN N N NN N N N N NN N NN NN NN N N N N N N N N DM DM CHI CHI CHI CHI CHICHI/DM DM DM DM DM Male Female Died Figure 1: Pedigree of patients with the E1506K mutation in the sulfonylurea receptor 1 gene Heterozygous carriers are shown by half-filled symbols and individuals with normal genotype by N. DM indicates people with diabetes and CHI, congenital hyperinsulinaemia. Login to comment 38 ABCC8 p.Glu1506Lys Control People heterozygous for (n=19) the sulfonylurea receptor 1 E1506K mutation No diabetes Diabetes (n=7) (n=4) Sex (male/female) 10/9 3/4 0/4 Age (years, mean [SD]) 41 (6) 45 (15) 50 (15) Systolic blood pressure 128 (14) 130 (16) 128 (32) (mm Hg, mean [SD]) Diastolic blood pressure 86 (9) 83 (10) 76 (9) (mm Hg [SD]) Body-mass index 25·8 (3·8) 24·2 (2·5) 28·8 (3·7) (kg/m2 , mean [SD]) Fasting blood glucose 4·6 (0·4) 5·0 (0·8) 8·3 (2·5) (mmol/L, mean [SD]) Fasting plasma insulin 55·8 (20·2) 34·3 (9·7) 57·5 (21.6) (pmol/L) Fasting C-peptide (pmol/L) 514 (157) 444 (105) 578 (108) Data are mean (SD) or number of participants. Login to comment 39 ABCC8 p.Glu1506Lys ABCC8 p.Glu1506Lys ABCC8 p.Glu1506Lys ABCC8 p.Glu1506Lys ABCC8 p.Glu1506Lys ABCC8 p.Glu1506Lys ABCC8 p.Glu1506Lys ABCC8 p.Glu1506Lys ABCC8 p.Glu1506Lys ABCC8 p.Glu1506Lys Table 1: Clinical and biochemical characteristics of participants 303 0 4 2 0 2 50 100 150 200 250 300 350 400 450 4 6 8 10 11 12 Bloodglucose(mmol/L) Incrementalbloodglucosearea underthecurve(mmol/Lperh) Control E1506K carriers, no diabetes E1506K carriers, diabetes 0 0 Incrementalplasmainsulinarea underthecurve(pmol/Lperh) 500 1000 1500 2000 2500 3000 0 18 20 16 14 12 10 8 6 * ‡ † † † ‡ ‡ ‡ ‡ ‡ ‡ * * 50 200 250 100 150 300 350 400 Plasmainsulin(pmol/L)PlasmaC-peptide(pmol/L) Incrementalplasmainsulinarea underthecurve(pmol/Lperh) Minutes 1200 30 60 90 Control E1506K carriers, no diabetes E1506K carriers, diabetes * * * A B C D E F 400 200 0 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 Figure 2: Oral glucose tolerance test in controls and carriers of the E1506K mutation with or without diabetes Concentrations of blood glucose (A), plasma insulin (C), plasma C-peptide (E), and incremental areas under the curve of blood glucose (B), plasma insulin (D), and plasma C-peptide (F). Login to comment 41 ABCC8 p.Glu1506Lys Longer error bars in C and E represent SDs of E1506K carriers with no diabetes. Login to comment 51 ABCC8 p.Glu1506Lys Results Participants 11 individuals (relatives of patients diagnosed with congenital hyperinsulinaemia7 ) who were heterozygous for the SUR1 E1506K mutation participated in the study (figure 1). Login to comment 59 ABCC8 p.Glu1506Lys ABCC8 p.Glu1506Lys ABCC8 p.Glu1506Lys ABCC8 p.Glu1506Lys ABCC8 p.Glu1506Lys ABCC8 p.Glu1506Lys ABCC8 p.Glu1506Lys ABCC8 p.Glu1506Lys ABCC8 p.Glu1506Lys ABCC8 p.Glu1506Lys To ascertain concentrations of plasma insulin and 18 20 16 14 12 10 8 6 4 2 0 0 0 20 40 60 80 100 0 Minutes 100 1000 2000 3000 4000 5000 200 300 400 500 600 700 800 Bloodglucose(mmol/L) Incrementalbloodglucosearea underthecurve(mmol/Lpermin) Incrementalplasmainsulinarea underthecurve(pmol/Lpermin) Plasmainsulin(pmol/L) 100 2 4 6 8 * Control Control E1506K carriers, no diabetes E1506K carriers, diabetes A B C D ‡ ‡ ‡ ‡‡‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ † † E1506K carriers, no diabetes E1506K carriers, diabetes Figure 3: Intravenous glucose tolerance tests in controls and carriers of the E1506K mutation with or without diabetes Concentrations of blood glucose (A) and plasma insulin (C), and incremental blood glucose (B) and plasma insulin (D) areas under the curve. Login to comment 72 ABCC8 p.Glu1506Lys Glucose response- when expressed as the incremental glucose area under the curve-was significantly higher in participants heterozygous for the E1506K mutation than in controls (p=0·0010 in those without diabetes, p<0·0001 in those with the disease; figure 2, B). Login to comment 77 ABCC8 p.Glu1506Lys Intravenous glucose tolerance test Plasma insulin concentrations at all timepoints measured after intravenous glucose administration, and incremental plasma insulin areas under the curve, were significantly reduced in both groups of individuals with the E1506K mutation (p<0·0001 at 2, 4, 6, 8 min in both groups; p=0·0004 at 10 min in carriers without diabetes; and p=0·0005 in carrier with diabetes; figure 3). Login to comment 78 ABCC8 p.Glu1506Lys First-phase insulin secretion was normal or high in the youngest patients with congenital hyperinsulinaemia, but those older than 10 years of age had impaired first-phase insulin secretion.12 Insulin secretion decreased linearly with age in individuals heterozygous for the E1506K mutation, independently of their glucose tolerance status (regression equation: plasma insulin 1 minϩ3 min= 32·1-0·282ϫage; Pearson correlation coefficient -0·591; figure 4). Login to comment 79 ABCC8 p.Glu1506Lys All controls had higher insulin secretion than did adults heterozygous for the SUR1 E1506K mutation (p<0·0001). Login to comment 80 ABCC8 p.Glu1506Lys ABCC8 p.Glu1506Lys Hyperglycaemic and hyperinsulinaemic euglycaemic clamp In the hyperglycaemic clamp, plasma insulin (p=0·0120 and p<0·0001) and C-peptide responses (p=0·0180 and p<0·0001) were strikingly reduced in all individuals with the E1506K mutation (p values given are for those without and with diabetes, respectively; table 2). Login to comment 82 ABCC8 p.Glu1506Lys ABCC8 p.Glu1506Lys ABCC8 p.Glu1506Lys ABCC8 p.Glu1506Lys ABCC8 p.Glu1506Lys ABCC8 p.Glu1506Lys ABCC8 p.Glu1506Lys ABCC8 p.Glu1506Lys Mean rates of whole-body glucose uptake (M value) did not differ significantly between groups (60·5 [SD 16·5], 64·4 [16·0], and 400 300 200 100 10 20 30 40 50 60 70 80 0 0 E1506K carriers, CHI Controls Plasmainsulinsecretion(pmol/L) Age (years) E1506K carriers, no diabetes E1506K carriers, diabetes Figure 4: Sum of the 1 and 3 min insulin concentrations during intravenous glucose tolerance test in patients with congenital hyperinsulinaemia, controls, and carriers of the E1506K mutation with or without diabetes Line=linear regression line. Login to comment 84 ABCC8 p.Glu1506Lys Controls People heterozygous for the sulfonylurea receptor 1 E1506K mutation No diabetes p Diabetes p Maximum insulin response (pmol/L, mean [SD]) 857 (476) 422 (362) 0·0120 97 (40) <0·0001 Maximum C-peptide response (pmol/L, mean [SD]) 3893 (927) 2887 (1097) 0·0180 1138 (288) <0·0001 M/I value (␮mol kg-1 min-1 Ϭpmol/L, mean [SD]) 0·07 (0·02) 0·07 (0·02) 0·975 0·05 (0·04) 0·824 Data are mean (SD). Login to comment 87 ABCC8 p.Glu1506Lys However, compared with controls, rate of whole-body glucose uptake was reduced by 15% in individuals heterozygous for the SUR1 E1506K mutation with diabetes. Login to comment 89 ABCC8 p.Glu1506Lys Discussion Our results show that the E1506K mutation in the KATP channel subunit (SUR1) had a dominant pattern of inheritance in a large pedigree, leading to development of insulin deficiency and type 2 diabetes. Login to comment 90 ABCC8 p.Glu1506Lys Results of electrophysiological studies have shown that sulfonylurea receptor 1 E1506K mutant channels move to the plasma membrane, but these channels are no longer activated by MgADP.7 As a result, they remain shut even at low blood glucose concentrations, producing continuous membrane depolarisation that leads to maintained Ca2+ influx, which in turn causes the persistent insulin secretion that characterises congenital hyperinsulinaemia. Login to comment 91 ABCC8 p.Glu1506Lys The severely blunted, first-phase, glucose-stimulated insulin secretion and reduced maximum glucose-stimulated insulin secretory capacity we noted in adults heterozygous for the E1506K mutation suggests that these individuals have a defect in insulin secretion, which developed after puberty (figure 4). Login to comment 93 ABCC8 p.Glu1506Lys In most patients with congenital hyperinsulinaemia, and as we saw in all our participants with the E1506K mutation, the clinical course of disease is characterised by slow progressive loss of beta-cell function.13 Results of studies have suggested that this loss may result from beta-cell apoptosis.6 Indeed, patients with congenital hyperinsulinaemia who have had their pancreas removed, and who have mutations in the SUR1 gene, have increased numbers of apoptotic cells in focal lesions.6,14 Although the mechanism has not been completely defined, the concentration of intracellular calcium is likely to be an important determinant of beta-cell apoptosis.15 In transgenic mice with congenital hyperinsulinaemia overexpressing a dominant negative form of KIR6.2 in pancreatic beta-cells, which disrupts KATP channel activity,16 hyperinsulinaemia is evident in the neonatal period, but insulin deficiency, attributed to apoptosis, develops later. Login to comment 94 ABCC8 p.Glu1506Lys ABCC8 p.Glu1506Lys A similar rise in beta-cell apoptosis could explain the diminished insulin secretory capacity of our study individuals with the SUR1 E1506K mutation. Login to comment 96 ABCC8 p.Glu1506Lys Mutations in six different genes are known to cause monogenic maturity-onset diabetes of the young.2 Our results show that the E1506K mutation in the SUR1 gene causes a rare subtype of diabetes that fulfils criteria for this diabetes subtype: the mutation has an autosomal dominant inheritance based on linkage and haplotype analysis,7 and leads to insulin deficiency in early adulthood and to diabetes in middle-age. Login to comment 97 ABCC8 p.Glu1506Lys Moreover, seven of eight women heterozygous for the SUR1 E1506K mutation had abnormal glucose tolerance during pregnancy, which is typical in females with monogenic maturity-onset diabetes of the young.17 However, age of onset of diabetes in our patients was not typical of that seen in patients with this diabetes subtype. Login to comment 100 ABCC8 p.Glu1506Lys ABCC8 p.Glu1506Lys Furthermore, polymorphisms of the SUR1 gene have been linked to low insulin secretory capacity.20,23 We did not find the E1506K mutation in any of the 160 chromosomes of patients with type 2 diabetes.7 Despite their severe insulin deficiency, only four of the 11 individuals with the E1506K mutation fulfilled criteria for diabetes. Login to comment 101 ABCC8 p.Glu1506Lys These four people had almost complete loss of first-phase insulin secretion during the intravenous glucose tolerance test, and their insulin secretory capacity did not differ significantly from that of adults with diabetes who were heterozygous for the SUR1 E1506K mutation. Login to comment 102 ABCC8 p.Glu1506Lys Our findings are closely similar to those from a study of SUR1 knockout mice, in which mice had a complete absence of first-phase insulin secretion and abnormal glucose tolerance.24 In our study, individuals heterozygous for the SUR1 E1506K mutation with diabetes showed a 15% reduction in insulin sensitivity compared with those without diabetes. Login to comment 108 ABCC8 p.Glu1506Lys This pathway for insulin secretion is important, because mice without receptors for the incretins, glucagon-like peptide 1, and gastric inhibitory polypeptide show impaired insulin secretion and abnormal glucose tolerance without insulin resistance.26,27 Incretin-induced insulin secretion in individuals heterozygous for the E1506K mutation in our study could have helped prevent conversion from impaired glucose tolerance to frank diabetes. Login to comment 111 ABCC8 p.Glu1506Lys ABCC8 p.Glu1506Lys When beta cells are no longer able to compensate, the insulin secretory response becomes progressively impaired, gradually leading to a deficiency in early and late phases of insulin secretion and to abnormal glucose tolerance.28 The E1506K mutation in the SUR1 gene in the family we have studied causes congenital hyperinsulinaemia due to continuous overstimulation of insulin secretion, and leads to insulin deficiency and diabetes in middle-age. This mutation results in an autosomal dominant subtype of diabetes. Login to comment