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Impaired awareness of hypoglycaemia (IAH) is a major risk for severe hypoglycaemia in insulin treatment of type 1 diabetes (T1D). To explore the hypothesis that unhelpful health beliefs create barriers to regaining awareness, we conducted a multi-centre, randomised, parallel, two-arm trial (ClinicalTrials.gov NCT02940873) in adults with T1D and treatment-resistant IAH and severe hypoglycaemia, with blinded analysis of 12-month recall of severe hypoglycaemia at 12 and/or 24 months the primary outcome. Secondary outcomes included cognitive and emotional measures. Adults with T1D, IAH and severe hypoglycaemia despite structured education in insulin adjustment, +/- diabetes technologies, were randomised to the "Hypoglycaemia Awareness Restoration Programme despite optimised self-care" (HARPdoc, n = 49), a psychoeducation programme uniquely focussing on changing cognitive barriers to avoiding hypoglycaemia, or the evidence-based "Blood Glucose Awareness Training" (BGAT, n = 50), both delivered over six weeks. Median [IQR] severe hypoglycaemia at baseline was 5[2-12] per patient/year, 1[0-5] at 12 months and 0[0-2] at 24 months, with no superiority for HARPdoc (HARPdoc vs BGAT incident rate ratios [95% CI] 1.25[0.51, 3.09], p = 0.62 and 1.26[0.48, 3.35], p = 0.64 respectively), nor for changes in hypoglycaemia awareness scores or fear. Compared to BGAT, HARPdoc significantly reduced endorsement of unhelpful cognitions (Estimated Mean Difference for Attitudes to Awareness scores at 24 months, -2.07 [-3.37,-0.560], p = 0.01) and reduced scores for diabetes distress (-6.70[-12.50,-0.89], p = 0.02); depression (-1.86[-3.30, -0.43], p = 0.01) and anxiety (-1.89[-3.32, -0.47], p = 0.01). Despite positive impact on cognitive barriers around hypoglycaemia avoidance and on diabetes-related and general emotional distress scores, HARPdoc was not more effective than BGAT at reducing severe hypoglycaemia.

Background: Podocyte loss is a key event in primary focal segmental glomerulosclerosis (FSGS). Common first-line therapy for patients with primary FSGS involves steroid therapy with or without blood pressure control; however 40-70% of patients achieve no remission. Animal studies have shown that treatment efficacy is achieved partly through preservation of podocyte number, as well as podocyte protective effects. Animal studies have also determined that podocyte number and density are predictive of FSGS severity. Therefore, this study aimed to determine if podocyte number and density can predict the response to therapy in patients with primary FSGS. Method(s): A retrospective cohort study of renal biopsies was conducted from 2009-2020 in Melbourne, Australia at a tertiary hospital (Monash Medical Centre). Patients diagnosed with primary FSGS were screened (n=84). Patients were excluded for lack of consent for samples to be used for research purposes (n=38), risks of other forms of FSGS (n=13), insufficient clinical data available (n=2), no biopsy tissue available (n=7) or <6 glomerular profiles available in the biopsy (n=5). Included patients were allocated into groups of treatment responders (n=11) or non-responders (n=8) based on urinary/serum data 6 months following initial diagnosis and commencement of treatment. Biopsies were immunofluorescently stained for podocyte-specific markers. Model-based stereology was used to estimate podometrics. Sections were re-stained with PAS to measure the glomerulosclerotic index (GSI). Result(s): Podocyte number per glomerulus in responders (347 (215-606); median (IQR)) was 45% higher than in non-responders (190; 143-263) (P=0.03). Podocyte density in responders (76; 58-142 per 106mum3 of glomerular volume) was similar to nonresponders (66; 44-88 per 106mum3 of glomerular volume) (P=0.38). GSI was significantly higher in non-responder patients (1.1; 0.6-2.3) than responders (0.6; 0.2-0.9) (P=0.04), and was significantly and nega

IntroductionThe successful treatment of type 1 diabetes (T1D) requires those affected to employ insulin therapy to maintain their blood glucose levels as close to normal to avoid complications in the long-term. The Dose Adjustment For Normal Eating (DAFNE) intervention is a group education course designed to help adults with T1D develop and sustain the complex self-management skills needed to adjust insulin in everyday life. It leads to improved glucose levels in the short term (manifest by falls in glycated haemoglobin, HbA1c), reduced rates of hypoglycaemia and sustained improvements in quality of life but overall glucose levels remain well above national targets. The DAFNEplus intervention is a development of DAFNE designed to incorporate behavioural change techniques, technology and longer-term structured support from healthcare professionals (HCPs).Methods and analysisA pragmatic cluster randomised controlled trial in adults with T1D, delivered in diabetes centres in National Health Service secondary care hospitals in the UK. Centres will be randomised on a 1:1 basis to standard DAFNE or DAFNEplus. Primary clinical outcome is the change in HbA1c and the primary endpoint is HbA1c at 12 months, in those entering the trial with HbA1c >7.5% (58 mmol/mol), and HbA1c at 6 months is the secondary endpoint. Sample size is 662 participants (approximately 47 per centre); 92% power to detect a 0.5% difference in the primary outcome of HbA1c between treatment groups. The trial also measures rates of hypoglycaemia, psychological outcomes, an economic evaluation and process evaluation.Ethics and disseminationEthics approval was granted by South West-Exeter Research Ethics Committee (REC ref: 18/SW/0100) on 14 May 2018. The results of the trial will be p

Introduction: Glomerular disease accounts for more than 90% of chronic kidney disease (CKD), which is predicted to cost the Australian health care system AUD $20 billion in 2020. There is increasing evidence that podocytes play a vital role in the development of most glomerular disease. In a landmark study by Wharram et al (2005), it was shown that podocyte depletion <20% resulted in remaining podocytes being able to adapt and repair the glomerular filtration barrier, preventing the development of glomerulosclerosis. However more severe podocyte depletion resulted in focal segmental glomerulosclerosis (FSGS), with sustained proteinuria and reduced renal function. This provided strong support for the podocyte depletion hypothesis, which proposes that if sufficient podocyte depletion occurs, the glomerulus will not be able to recover and thus result in progressive FSGS. To investigate this concept, it is important to develop animal models of varying and predictable podocyte depletion and FSGS. Here we describe a mouse model of diphtheria toxin (DT)-induced podocyte depletion that results in differing degrees of podocyte loss, proteinuria and FSGS. Method(s): PodCreiDTR mice that express human DT receptors only in podocytes were injected with varying doses of DT or with saline. Experimental animals received two injections of DT, 12 days apart. The cumulative total dose varied between 100 - 750 ng/kg DT. Urine was collected at regular time points for analysis of urinary total protein/creatinine (UTP/Cre). Peak UTP/Cre was observed at 21 days following the first DT injection. Mice were killed 9 weeks after the first DT injection, and kidneys were harvested. The left kidney was assessed for FSGS (glomerulosclerotic index; GSI) and the right kidney was used for 3D imaging to count the total number of podocytes in individual whole glomeruli. Result(s): Mice presented with a variable peak UTP/Cre between 1946-9244 g/mol when injected with DT. Saline injected mice had UTP/Cre

Aims: The worldwide prevalence of gestational diabetes mellitus (GDM) is increasing. Studies in rodent models indicate that hyperglycaemia during pregnancy alters kidney development, yet few studies have examined if this is so in humans. The objective of this study was to evaluate the association of treated GDM with foetal kidney size. Material(s) and Method(s): Participants were recruited from an Australian tertiary hospital, and clinical data were collected from women without GDM and women diagnosed and treated for GDM and their offspring. Participants underwent an obstetric ultrasound at 32-34 weeks gestation for foetal biometry and foetal kidney volume measurement. Result(s): Sixty-four non-GDM and 64 GDM women participated in the study. Thirty percent of GDM women were diagnosed with fasting hyperglycaemia, while 89% had an elevated 2-hour glucose level. Maternal age, weight and body mass index were similar in women with and without GDM. Estimated foetal weight, foetal kidney dimensions, total foetal kidney volume and birth weight were similar in offspring of women with and without GDM. Conclusion(s): We conclude that a period of mild hyperglycaemia prior to diagnosis of GDM and treatment initiation, which coincides with a period of rapid nephron formation and kidney growth, does not alter kidney size at 32-34 weeks gestation.Copyright © 2019 The Authors. Endocrinology, Diabetes & Metabolism published by John Wiley & Sons Ltd

INTRODUCTION: Severe hypoglycaemia (SH), when blood glucose falls too low to support brain function, is the most feared acute complication of insulin therapy for type 1 diabetes mellitus (T1DM). 10% of people with T1DM contribute nearly 70% of all episodes, with impaired awareness of hypoglycaemia (IAH) a major risk factor. People with IAH may be refractory to conventional approaches to reduce SH, with evidence for cognitive barriers to hypoglycaemia avoidance. This paper describes the protocol for the Hypoglycaemia Awareness Restoration Programme for People with Type 1 Diabetes and Problematic Hypoglycaemia Persisting Despite Optimised Self-care (HARPdoc) study, a trial to assess the impact on hypoglycaemia experience of a novel intervention that addresses cognitive barriers to hypoglycaemia avoidance, compared with an existing control intervention, recommended by the National Institute of Health and Care Excellence. METHODS AND ANALYSIS: A randomised parallel two-arm trial of two group therapies: HARPdoc versus Blood Glucose Awareness Training, among 96 adults with T1DM and problematic hypoglycaemia, despite attendance at education with or without technology use, in four centres providing specialist T1DM services. The primary outcome will be the SH rate at 12 and/or 24 months after randomisation to either course. Secondary outcomes include rates of SH requiring parenteral therapy, involving unconsciousness or needing emergency services; hypoglycaemia awareness status, overall diabetes control and quality of life measures. An implementation study to evaluate how the interventions are delivered and how implementation impacts on clinical effectiveness is planned as a parallel study, with its own protocol. ETHICS AND DISSEMINATION: The protocol was approved by the London Dulwich Research Ethics Committee, the Health Research Authority, National Health Service R&D and the Institutional Review Board of the Joslin Diabetes Center in the USA. Study findings will be dissem