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Aims KCNJ11-related diabetes is the most common form of permanent neonatal diabetes and has been associated with a spectrum of neurodevelopmental problems. We compared neurodevelopmental outcomes in patients with KCNJ11 mutations and their sibling controls. Methods Through our Monogenic Diabetes Registry (), we evaluated 23 patients with KCNJ11 mutations with ( n = 9) and without ( n = 14) global developmental delay successfully treated with sulfonylurea and 20 healthy sibling controls, using a battery of targeted neuropsychological and behavioural assessments with scaled scores that are comparable across a wide range of ages. Results Patients with KCNJ11-related diabetes without global developmental delay had significant differences compared with sibling controls on a range of assessments including IQ, measures of academic achievement and executive function. KCNJ11 patients with global delay exhibited significant differences in behavioural symptoms with a tendency to avoid social contact and displayed a reduced ability to adapt to new circumstances. Parents reported more immature behaviour, gross mood swings, bizarre thoughts, other unusual and severe behaviours, and there were also significant deficits in all subdomains of daily living skills. Conclusions This series represents the largest and most comprehensive study of neuropsychological and behavioural dysfunction of individuals with KCNJ11 diabetes and is the first to compare outcome with sibling controls. Our data demonstrate the variety of neurodevelopmental problems seen in those with KCNJ11 mutations, even in those without recognized global developmental delays. These data can be used to counsel families and guide structured neurodevelopmental assessments and treatments based on the initial genetic diagnosis in patients with neonatal diabetes. [ABSTRACT FROM AUTHOR]

Aims The response to glucagon-like peptide 1 receptor agonist treatment may be influenced by endogenous β-cell function. We investigated whether urinary C-peptide creatinine ratio assessed before or during liraglutide treatment was associated with treatment response. Methods A single, outpatient urine sample for urinary C-peptide creatinine ratio was collected 2 h after the largest meal of the day among two separate groups: (1) subjects initiating liraglutide (0.6 → 1.2 mg daily) or (2) subjects already treated with liraglutide for 20-32 weeks. The associations between pretreatment and on-treatment urinary C-peptide creatinine ratio and HbA1c change at 32 weeks were assessed using univariate and multivariate analyses (the ratio was logarithm transformed for multivariate analyses). Changes in HbA1c according to pretreatment urinary C-peptide creatinine ratio quartiles are shown. Results One hundred and sixteen subjects (70 pretreatment, 46 on treatment) with Type 2 diabetes from 10 diabetes centres were studied. In univariate analyses, neither pretreatment nor on-treatment urinary C-peptide creatinine ratio correlated with HbA1c change (Spearman rank correlation coefficient, r = -0.17, P = 0.17 and r = -0.20, P = 0.19, respectively). In multi-linear regression analyses, entering baseline HbA1c and log urinary C-peptide creatinine ratio, pretreatment and on-treatment log urinary C-peptide creatinine ratio became significantly associated with HbA1c change ( P = 0.048 and P = 0.040, respectively). Mean ( sd) HbA1c changes from baseline in quartiles 1 to 4 of pretreatment urinary C-peptide creatinine ratio were -3 ± 17 mmol/mol (-0.3 ± 1.6%) ( P = 0.52), -12 ± 15 mmol/mol (-1.1 ± 1.4%) ( P = 0.003), -11 ± 13 mmol/mol (-1.0 ± 1.2%) ( P = 0.002) and -12±17 mmol/mol (-1.1±1.6%) ( P=0.016), respectively. Conclusions Postprandial urinary C-peptide creatinine ratios before and during liraglutide treatment were weakly associated with the glycaemic response to treatment. Low pretreatment urinary C-peptide creatinine ratio may be more useful than higher values by predicting poorer glycaemic response. [ABSTRACT FROM AUTHOR]

Aims The aim of this study was to use general practice data to estimate the prevalence of diabetic nephropathy within the registered diabetes patients and examine variation in practice prevalence and management performance since introduction of this initiative. Methods Reported quality indicators from the Northern Ireland General Practice Quality and Outcomes Framework were analysed for diabetes and diabetic nephropathy prevalence and management in the period 2004-2008. Variation in prevalence at practice level was assessed using multiple linear regression adjusting for age, practice size, deprivation and glycaemic control. Results In 2006-2007, 57 454 (4.1%) adult diabetic patients were registered in the denominator population of 1.4 million comparedwith 51 923 (3.8%) in 2004-2005 (mean practice range 0.5-7.7%).Diabetic nephropathy prevalencewas 15.1 and 11.5%, respectively (8688 and 5955 patients). Documented diabetic nephropathy prevalence showed marked variation across practices (range 0-100%) and was significantly negatively correlatedwith diabetes list size, albumin creatinine ratio testing rates and renin-angiotensin-aldosterone system blockade use and positively correlated with exception reporting rates. Specifically, for every increase in 100 diabetic patients to a register, documented diabetic nephropathy prevalence reduced by 40% (P = 0.003). On the positive side, median albumin-creatinine ratio testing rates doubled to 82%compared with figures in the pre-Framework era. Conclusions Implementation of the Northern Ireland General Practice Quality and Outcomes Framework has positively benefitted testing for diabetic nephropathy and increased numbers of detected patients in a short space of time.Large variation in diabetic nephropathy prevalence remains and is associated with diabetes registry size, screening and treatment practices, suggesting that understanding this variation may help detect and better manage diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Aims To establish the safety in terms of insulin sensitivity of a low dose thiazide/ACE inhibitor combination. Methods We examined the effects on insulin sensitivity of captopril either alone or in combination with low-dose bendroflumethiazide (1.25 mg) in 15 hypertensive Type 2 diabetic patients. Insulin action was assessed using an isoglycaemic hyperinsulinaemic clamp in a double-blind, randomised, crossover study after a 6-week placebo run-in and following two 12-week treatment periods with captopril (C) (100 mg) alone or in combination with bendroflumethiazide (CB) (1.25 mg). Results Blood pressure was lower following CB compare to C (138/83 vs. 144/85 mmHg; P < 0.05) and both were lower than baseline (153/92 mmHg; P < 0.01). CB resulted in a significant increase in fasting plasma glucose compared to C (9.6 ± 2.6 vs. 8.5 ± 1.6 mmol/l; P < 0.05). Exogenous glucose infusion rates required to maintain isoglycaemia during hyperinsulinaemia were lower after CB compared to C (25.1 ± 13.3 vs. 34.2 ± 16.8 µmol/kg/min; P < 0.01) as were isotopically determined glucose utilisation rates (29.0 ± 12.4 vs. 36.6 ± 17.3 µmol/kg/min; P < 0.05). There was no significant difference in fasting endogenous glucose production between treatments (CB 9.3 ± 3.3 vs. C 8.6 ± 1.6 µmol/kg/min), nor between suppression following insulin (CB 4.0 ± 2.1 vs. C 4.3 ± 3.1 µmol/kg/min). Conclusions Combination of low-dose bendroflumethiazide with captopril lowered blood pressure but resulted in deleterious effects on insulin action compared to captopril alone. [ABSTRACT FROM AUTHOR]

SummaryAims It has been suggested that the adverse metabolic effects of antihypertensive therapy offset some of the benefits of blood pressure reduction. It has also been suggested that angiotensin converting enzyme (ACE) inhibitors reduce insulin resistance and that, if used together with thiazide diuretics, the adverse effects of thiazides on insulin sensitivity may be eliminated. We examined the effects on insulin sensitivity of captopril either alone or in combination with bendrofluazide in 11 hypertensive Type 2 diabetic patients. Methods Insulin action was assessed using an isoglycaemic hyperinsulinaemic clamp in a double-blind, randomized, crossover study after a 6-week placebo run-in and following two 12-week treatment periods with captopril (C) (100 mg) alone or in combination with bendrofluazide (CB) (2.5 mg). Results Blood pressure was lower following CB compared to C (128/82 vs. 144/88 mmHg; P < 0.005) and both were lower than baseline (162/101 mmHg; P < 0.001). CB resulted in a significant increase in fasting plasma glucose compared to C (9.7 ± 0.8 vs. 8.5 ± 0.6 mmol/l; P < 0.05). Exogenous glucose infusion rates required to maintain isoglycaemia during hyperinsulinaemia were lower after CB compared to C (22.3 ± 2.4 vs. 27.4 ± 4.2 mol.kg-1.min-1; P < 0.05). Suppression of endogenous glucose production was reduced after CB compared to baseline (4.0 ± 0.6 vs. 2.4 ± 0.5 mol.kg-1.min-1; P < 0.05). Conclusions Combination of bendrofluazide with captopril lowered blood pressure but resulted in deleterious effects on insulin action compared to captopril alone. [ABSTRACT FROM AUTHOR]