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...

The lifetime of the lowest excited singlet (S 1 ) state of peridinin and many other carbonyl-containing carotenoids and polyenes has been reported depend on the polarity of the solvent. This effect has been attributed to the presence of an intramolecular charge transfer (ICT) state in the manifold of excited states for these molecules. The nature of this ICT state has yet to be elucidated. In the present work, steady-state and ultrafast time-resolved optical spectroscopy have been performed on peridinin and three synthetic analogues, C 33 -peridinin, C 35 -peridinin, and C 39 -peridinin which have different numbers of conjugated carbon-carbon double bonds. Otherwise, the molecules are structurally similar in that they posses the same functional groups. The trends in the positions of the steady-state and transient spectral profiles for this systematic series of molecules allow an assignment of the spectral features to transitions involving the S 0 , S 1 , S 2 and ICT states. A kinetics analysis reveals the lifetimes of the excited states and the dynamics of their excited state deactivation pathways. The most striking observation in the data is that the lifetime of the ICT state converges to the same value of 10.0 ± 2.0 ps in the polar solvent, methanol, for all the peridinin analogues regardless of the extent of π-electron conjugation. This suggests that the ICT state is highly localized on the lactone ring which is a common structural feature in all the molecules. The data further suggest that the S 1 and ICT states behave independently and that the ICT state is populated both from both S 1 and S 2 , the rate and efficiency from S 1 being dependent on the length of the π-electron chain of the carotenoid and the solvent polarity. Keywords peridinin; peridinin analogue; carotenoid; ICT state; excited state; kinetics analysis *Author to whom correspondence should be addressed: Harry A. Frank, Department of Chemistry, 55 North Eagleville Road, University of Connecticut, Storrs,. harry.frank@uconn.edu. Supporting Information available: Overlay of the fluorescence spectra of C 33 -peridinin, C 35 -peridinin and peridinin taken at room temperature in carbon disulfide and n-hexane, NIR transient spectra of all four analogues taken at room temperature in methanol, and steady-state absorption spectra of C 33 -peridinin, C 35 -peridinin, peridinin and C 39 -peridinin taken at room temperature in methanol, extended to high energy to show the "cis-peak" region between 27,000 and 40,000 cm −1 . This material is available free of charge via the Internet at

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