SummaryBackgroundKCNJ11 mutations cause permanent neonatal diabetes through pancreatic ATP-sensitive potassium channel activation. 90% of patients successfully transfer from insulin to oral sulfonylureas with excellent initial glycaemic control; however, whether this control is maintained in the long term is unclear. Sulfonylurea failure is seen in about 44% of people with type 2 diabetes after 5 years of treatment. Therefore, we did a 10-year multicentre follow-up study of a large international cohort of patients with KCNJ11 permanent neonatal diabetes to address the key questions relating to long-term efficacy and safety of sulfonylureas in these patients.MethodsIn this multicentre, international cohort study, all patients diagnosed with KCNJ11 permanent neonatal diabetes at five laboratories in Exeter (UK), Rome (Italy), Bergen (Norway), Paris (France), and Krakow (Poland), who transferred from insulin to oral sulfonylureas before Nov 30, 2006, were eligible for inclusion. Clinicians collected clinical characteristics and annual data relating to glycaemic control, sulfonylurea dose, severe hypoglycaemia, side-effects, diabetes complications, and growth. The main outcomes of interest were sulfonylurea failure, defined as permanent reintroduction of daily insulin, and metabolic control, specifically HbA1c and sulfonylurea dose. Neurological features associated with KCNJ11 permanent neonatal diabetes were also assessed. This study is registered with ClinicalTrials.gov, number NCT02624817.Findings90 patients were identified as being eligible for inclusion and 81 were enrolled in the study and provided long-term (>5·5 years cut-off) outcome data. Median follow-up duration for the whole cohort was 10·2 years (IQR 9·3–10·8). At most recent follow-up (between Dec 1, 2012, and Oct 4, 2016), 75 (93%) of 81 participants remained on sulfonylurea therapy alone. Excellent glycaemic control was maintained for patients for whom we had paired data on HbA1c and sulfonylurea at all time points (ie, pre-transfer [for HbA1c], year 1, and most recent follow-up; n=64)—median HbA1c was 8·1% (IQR 7·2–9·2; 65·0 mmol/mol [55·2–77·1]) before transfer to sulfonylureas, 5·9% (5·4–6·5; 41·0 mmol/mol [35·5–47·5]; p<0·0001 vs pre-transfer) at 1 year, and 6·4% (5·9–7·3; 46·4 mmol/mol [41·0–56·3]; p<0·0001 vs year 1) at most recent follow-up (median 10·3 years [IQR 9·2–10·9]). In the same patients, median sulfonylurea dose at 1 year was 0·30 mg/kg per day (0·14–0·53) and at most recent follow-up visit was 0·23 mg/kg per day (0·12–0·41; p=0·03). No reports of severe hypoglycaemia were recorded in 809 patient-years of follow-up for the whole cohort (n=81). 11 (14%) patients reported mild, transient side-effects, but did not need to stop sulfonylurea therapy. Seven (9%) patients had microvascular complications; these patients had been taking insulin longer than those without complications (median age at transfer to sulfonylureas 20·5 years [IQR 10·5–24·0] vs 4·1 years [1·3–10·2]; p=0·0005). Initial improvement was noted following transfer to sulfo...

PNDM frequency in Slovakia is much higher (one in 215,417 live births) than previously suggested from international estimates (about one in 800,000). We identified one ABCC8 and four KCNJ11 mutation carriers, of whom four were successfully transferred to SU, dramatically improving their diabetes control and quality of life.

OBJECTIVEInactivating mutations in glucokinase (GCK) cause mild fasting hyperglycemia. Identification of a GCK mutation has implications for treatment and prognosis; therefore, it is important to identify these individuals. A significant number of patients have a phenotype suggesting a defect in glucokinase but no abnormality of GCK. We hypothesized that the GCK β-cell promoter region, which currently is not routinely screened, could contain pathogenic mutations; therefore, we sequenced this region in 60 such probands.RESEARCH DESIGN AND METHODSThe β-cell GCK promoter was sequenced in patient DNA. The effect of the identified novel mutation on GCK promoter activity was assessed using a luciferase reporter gene expression system. Electrophoretic mobility shift assays (EMSAs) were used to determine the impact of the mutation on Sp1 binding.RESULTSA novel −71G>C mutation was identified in a nonconserved region of the human promoter sequence in six apparently unrelated probands. Family testing established cosegregation with fasting hyperglycemia (≥5.5 mmol/l) in 39 affected individuals. Haplotype analysis in the U.K. family and four of the Slovakian families demonstrated that the mutation had arisen independently. The mutation maps to a potential transcriptional activator binding site for Sp1. Reporter assays demonstrated that the mutation reduces promoter activity by up to fourfold. EMSAs demonstrated a dramatic reduction in Sp1 binding to the promoter sequence corresponding to the mutant allele.CONCLUSIONSA novel β-cell GCK promoter mutation was identified that significantly reduces gene expression in vitro through loss of regulation by Sp1. To ensure correct diagnosis of potential GCK-MODY (maturity-onset diabetes of the young) cases, analysis of the β-cell GCK promoter should be included.

Diabetes mellitus is associated with hyperglycemia and with accelerated non-enzymatic glycation, increased oxidative stress and free radical production. The aim of the present study was to evaluate the levels of proteins glycation and oxidation parameters, compare them between poorly and well controlled children with type 1 diabetes mellitus, and determine the impact of glycemic control on these parameters. Blood and serum were obtained from 81 patients with type 1 diabetes mellitus (DM1) (20 patients had long-term good glycemic control [GGC], 61 patients had long-term poor glycemic control [PGC]). Thirty-one healthy children were used as controls. Fructosamine (FAM) was determined by a spectrophotometric method, HbA1c was measured by LPLC, serum advanced glycation end-products (s-AGEs) were determined fluorimetrically, and advanced oxidation protein products (AOPP) were measured spectrophotometrically. We observed significantly higher FAM, HbA1c, s-AGEs and AOPP levels in the patients with DM1 compared with controls, and significantly higher FAM, HbA1c and sAGEs levels in the PGC group compared with the GGC group. AOPP was higher in the PGC group than in the GGC group, but not significantly. In the PGC group we observed significant correlations between HbA1c and HDL-C (r = -0.306, p = 0.01), HbA1c and s-AGEs (r = 0.486, p < 0.001), and HbA1c and AOPP (r = 0.447, p < 0.01). s-AGEs significantly correlated with triacylglycerols (TAG) (r = 0.537, p < 0.001) and AOPP with HDL-C (r = -0.336, p < 0.05), TAG (r = 0.739, p < 0.001) and s-AGEs (r = 0.577, p < 0.001). In conclusion, our results showed both glycative and oxidative stress are increased in the PGC diabetic group compared with controls, they are linked with glycemic control, and probably contribute to the development of diabetic complications. We suggest that the measurement of not only HbA1c but also s-AGEs and AOPP may be useful to predict the risk of development of diabetic complications.

Abbreviations: (ANCOVA) analysis of covariance, (AUCH) glucose area >140 mg% normalized to 7 days of the continuous glucose sensor download, (AUCL) glucose area <70 mg% normalized to 7 days of the continuous glucose sensor download, (BAS) basal insulin dose as a percentage of the total daily insulin dose, (BG) weekly mean glucose level, (BOL) number of daily boluses, (CEEGI) Central and Eastern Europe, Greece, and Israel, (CGS) continuous glucose sensing, (DCCT) Diabetes Control and Complications Trial, (GHb) glycosylated hemoglobin, (HEX) number of glucose excursions above 140 mg%, (IFCC) International Federation of Clinical Chemistry and Laboratory Medicine, (INS) total daily insulin dose, (LEX) number of glucose excursions below 70 mg%, (MANOVA) multivariate analysis of variance, (SD) standard deviation, (SDEV) standard deviation glucose