John N Harvey

Prevalence of ketoacidosis at diagnosis of childhood onset Type 1 diabetes in Wales from 1991 to 2009 and effect of a publicity campaign

Diabet. Med. 29, 1506–1509 (2012)

Faster Aspart Versus Insulin Aspart As Part of a Basal-Bolus Regimen in Inadequately Controlled Type 2 Diabetes: The onset 2 Trial

OBJECTIVE This multicenter, double-blind, treat-to-target, phase 3 trial evaluated the efficacy and safety of fast-acting insulin aspart (faster aspart) versus insulin aspart (IAsp) in adults with type 2 diabetes receiving basal insulin and oral antidiabetic agents. RESEARCH DESIGN AND METHODS The primary end point was HbA1c change from baseline after 26 weeks’ treatment. After an 8-week run-in to optimize basal insulin, subjects were randomized (1:1) to mealtime faster aspart (n = 345) or IAsp (n = 344), titrated using a simple daily patient-driven algorithm, plus insulin glargine U100 and metformin. RESULTS HbA1c change was –1.38% (faster aspart) and –1.36% (IAsp); mean HbA1c was 6.6% for both groups. Faster aspart demonstrated noninferiority versus IAsp in reducing HbA1c (estimated treatment difference [ETD] [95% CI] –0.02% [–0.15; 0.10]). Both treatments improved postprandial plasma glucose (PPG) control; the PPG increment (liquid meal test) was statistically significant in favor of faster aspart after 1 h (ETD [95% CI] −0.59 mmol/L [−1.09; −0.09]; −10.63 mg/dL [−19.56; −1.69]; P = 0.0198), but not after 2–4 h. Change from baseline in fasting plasma glucose, body weight, and overall severe/blood glucose–confirmed hypoglycemia rates (rate ratio [RR] [95% CI] 1.09 [0.88; 1.36]) were similar between treatments. Postmeal hypoglycemia (0−2 h) rates were 2.27 (faster aspart) and 1.49 (IAsp) per patient-year of exposure (RR [95% CI] 1.60 [1.13; 2.27]). CONCLUSIONS Faster aspart and IAsp were confirmed noninferior in a basal-bolus regimen regarding change from baseline in HbA1c. Faster aspart improved 1-h PPG with no differences in 2−4-h PPG versus IAsp. Overall hypoglycemia rates were similar except for an increase in 0−2-h postmeal hypoglycemia with faster aspart.

Glycemic control in children with type 1 diabetes in wales: influence of the pediatric diabetes specialist nurse.

OBJECTIVE To determine whether glycemic control is improving in diabetic children in Wales and to identify factors associated with improvement. RESEARCH DESIGN AND METHODS Data were collected in 2001 and 2006. RESULTS Over time A1C was reduced from 9.08 ± 1.66 to 8.88 ± 1.63% (P = 0.012). There were differences among centers (P < 0.001) and differential changes over time (interaction P < 0.001). Since 2001 five centers had appointed a pediatric diabetes specialist nurse (PDSN). A1C improved in these centers from 9.59 ± 1.88 to 8.72 ± 1.61% (P < 0.001). Glycemic control was worse in children aged >10 years compared with younger patients (P < 0.001). Improvement occurred in those aged >10 years. Age (P = 0.003) and insulin dose (P < 0.001) were positively and independently associated with A1C. Thus, any influence of PDSNs was not achieved through increased insulin prescription. CONCLUSIONS Improvement in glycemic control has occurred. Worse control is associated with greater prescribed insulin dose in older children. Appointment of PDSNs was associated with improved glycemic control among adolescents.

Evidence for a persistent, major excess in all cause admissions to hospital in children with type-1 diabetes: results from a large Welsh national matched community cohort study

Objectives To estimate the excess in admissions associated with type1 diabetes in childhood. Design Matched-cohort study using anonymously linked hospital admission data. Setting Brecon Group Register of new cases of childhood diabetes in Wales linked to hospital admissions data within the Secure Anonymised Information Linkage Databank. Population 1577 Welsh children (aged between 0 and 15 years) from the Brecon Group Register with newly-diagnosed type-1 diabetes between 1999–2009 and 7800 population controls matched on age, sex, county, and deprivation, randomly selected from the local population. Main outcome measures Difference in all-cause hospital admission rates, 30-days post-diagnosis until 31 May 2012, between participants and controls. Results Children with type-1 diabetes were followed up for a total of 12 102 person years and were at 480% (incidence rate ratios, IRR 5.789, (95% CI 5.34 to 6.723), p<0.0001) increased risk of hospital admission in comparison to matched controls. The highest absolute excess of admission was in the age group of 0–5 years, with a 15.4% (IRR 0.846, (95% CI 0.744 to 0.965), p=0.0061) reduction in hospital admissions for every 5-year increase in age at diagnosis. A trend of increasing admission rates in lower socioeconomic status groups was also observed, but there was no evidence of a differential rate of admissions between men and women when adjusted for background risk. Those receiving outpatient care at large centres had a 16.1% (IRR 0.839, (95% CI 0.709 to 0.990), p=0.0189) reduction in hospital admissions compared with those treated at small centres. Conclusions There is a large excess of hospital admissions in paediatric patients with type-1 diabetes. Rates are highest in the youngest children with low socioeconomic status. Factors influencing higher admission rates in smaller centres (eg, “out of hours resources”) need to be explored with the aim of targeting modifiable influences on admission rates.

Excess all-cause mortality before age 30 in childhood onset type 1 diabetes: data from the Brecon Group Cohort in Wales

Background Long-term outcomes in young people with type 1 diabetes continue to be of interest, and may help evaluate the effects of changes to the clinical care of children that have occurred in recent decades. Aims To identify mortality and its causes before age 30 years in patients developing type 1 diabetes before age 15 years. Methods Since 1995, paediatricians in Wales have compiled a prospective register of incident cases of type 1 diabetes occurring before age 15 years in Wales (the Brecon Cohort). Their subsequent mortality rates were compared with mortality in the general populations of Wales and England using the patient-years exposure method. Causes of death were ascertained from death certificates and from clinicians. Results The standardised mortality ratio for young people with type 1 diabetes in Wales was 2.91 with no clear evidence of improvement or worsening of mortality risk over time. Most deaths occurred between ages 15 and 30 years although at a slightly younger age than in the general population. There were more deaths with increasing age at diagnosis of diabetes. Ketoacidosis remains the most common cause of death before age 30 years. Hypoglycaemia was difficult to ascertain with certainty but also caused some deaths. In this age group, chronic complications of diabetes were not a cause of mortality. Conclusions Despite the developments in clinical care in recent years, the mortality risk for people developing type 1 diabetes in childhood remains high in young adult life before the onset of chronic complications.

Euglycaemic ketoacidosis in patients with and without diabetes

Ketoacidosis in individuals with diabetes is usually associated with a raised plasma glucose concentration. However, ketoacidosis in diabetes can occur with normal (≤11mmol/L) plasma glucose levels. Ketoacidosis is also seen in patients who do not have diabetes, most commonly in pregnancy or following alcoholic binges, rarely with starvation, anorexia nervosa or inborn errors of metabolism. The aim of this review is to compare the clinical features, pathophysiology and management of these conditions.

Determining diabetic retinopathy screening interval based on time from no retinopathy to laser therapy

Objectives To determine the necessary screening interval for retinopathy in diabetic patients with no retinopathy based on time to laser therapy and to assess long-term visual outcome following screening. Methods In a population-based community screening programme in North Wales, 2917 patients were followed until death or for approximately 12 years. At screening, 2493 had no retinopathy; 424 had mostly minor degrees of non-proliferative retinopathy. Data on timing of first laser therapy and visual outcome following screening were obtained from local hospitals and ophthalmology units. Results Survival analysis showed that very few of the no retinopathy at screening group required laser therapy in the early years compared with the non-proliferative retinopathy group (p < 0.001). After two years, <0.1% of the no retinopathy at screening group required laser therapy, and at three years 0.2% (cumulative), lower rates of treatment than have been suggested by analyses of sight-threatening retinopathy determined photographically. At follow-up (mean 7.8 ± 4.6 years), mild to moderate visual impairment in one or both eyes due to diabetic retinopathy was more common in those with retinopathy at screening (26% vs. 5%, p < 0.001), but blindness due to diabetes occurred in only 1 in 1000. Conclusions Optimum screening intervals should be determined from time to active treatment. Based on requirement for laser therapy, the screening interval for diabetic patients with no retinopathy can be extended to two to three years. Patients who attend for retinal screening and treatment who have no or non-proliferative retinopathy now have a very low risk of eventual blindness from diabetes.

When should screening for diabetic retinopathy begin for children with type 1 diabetes

Visual impairment and blindness as a result of diabetic retinopathy (DR) are amongst the most feared complications of diabetes. However, the prevalence of sight-threatening diabetic retinopathy (STDR) has been slowly decreasing[1–4]. Recently, it has been reported that diabetes is no longer the leading cause of blindness in the working age population in the United Kingdom[5]. These observations may reflect the cumulative impact of better management of diabetes, the introduction of screening programs aiming to identify STDR, and more active and effective ophthalmologic management. Good glycemic and blood pressure control are pivotal in the primary prevention of DR, with some evidence of direct benefit from fibrates when used in those with dyslipidemia[6,7]. The introduction of intensive insulin therapy to optimize glycemic control in children aged 13–17 years with type 1 diabetes (T1DM) was seen to reduce the risk of developing DR by 53%[8]. The benefit of such intensive management in the adolescent years remained evident many years later (legacy effect), even when HbA1c values were similar for the intensively treated and control groups[9]. Currently, the treatment for STDR, which encompasses proliferative DR (PDR) and selected cases of severe non-proliferative DR (pre-proliferative DR (PPDR), and maculopathy, is primarily by laser photocoagulation and, more recently, in conjunction with intravitreal injections of inhibitors of vascular endothelial growth factors (anti-VEGF). The relatively recent addition of anti-VEGF treatment has improved visual outcomes in those with PDR and clinically significant macular edema (CSMO)[10]. If these measures are deemed inadequate then vitrectomy may be required. It is generally acknowledged that DR remains asymptomatic until it reaches an advanced stage (STDR) and that the benefit from treatment with laser photocoagulation is best achieved the earlier the diagnosis and treatment are delivered. This is the basis for the introduction of screening for DR, which has also been shown to be cost-effective, especially in comparison to the societal cost of blindness[11]. The detection of any DR will help to prompt the need for improving and maintaining good glycemic control to prevent progression to STDR. In the context of this review, glycemic control is usually worse in adolescents compared with younger-age children [12] Guidelines for DR screening in children and young persons with diabetes

Functional structure of the promoter regions for the predominant low molecular weight isoforms of tropomyosin in human kidney cells

High and low molecular weight (LMW) tropomyosin isoforms, by regulation of actin filaments, have a major role in the regulation of cell behaviour. They affect malignant transformation, motility, differentiation, metastasis and cell membrane protein presentation. Expression of LMW isoforms from the TPM1 and TPM3 genes have an important role in these effects but the regulation of their expression is unknown. Luciferase assays on a progressively truncated 1.7 kb fragment upstream of the exon 1b translation start site in the TPM1 and TPM3 genes in HEK‐293 cells showed upstream activation sequences in TPM1 between −152 and −139 bp and in TPM3 between −154 and −102 bp. The effect of mutating candidate transcription factor binding sites identified an AML1‐like transcription factor binding site in TPM1 and a cAMP response element in TPM3. Downstream from the primary activation sequence in TPM1 was a repressor region corresponding to two Sp/KLF family binding GC boxes. Band shift assays confirmed that deletion of these sites altered transcription factor binding and ChIP assays confirmed the presence of AML1 and CREB at the TPM1 and TPM3 activation sequences in the respective promoters. Expression of LMW isoforms from TPM1 and TPM3 genes is regulated very differently. This facilitates regulation of the many cell processes involving these proteins. In situations where these proteins have a critical role, such as cancer metastasis, it also facilitates specific intervention. J. Cell. Biochem. 113: 3576–3586, 2012.