Roy J Powell

Genetic cause of hyperglycaemia and response to treatment in diabetes

BACKGROUND Type 2 diabetes shows evidence of underlying heterogeneity. No studies have assessed whether different causes for diabetes change the response to oral hypoglycaemic therapy. In a few cases, patients with diabetes caused by mutations in the hepatocyte nuclear factor 1alpha (HNF-1alpha) gene have been described as sensitive to the hypoglycaemic effects of sulphonylureas. We aimed to see whether the glycaemic response to the sulphonylurea gliclazide and the biguanide metformin differed in HNF-1alpha diabetes and type 2 diabetes, and to investigate the mechanism for differences in sulphonylurea sensitivity. METHODS We did a randomised crossover trial of glicazide and metformin in 36 patients, either with diabetes caused by HNF-1alpha mutations or type 2 diabetes, who were matched for body-mass index and fasting plasma glucose. The primary outcome was reduction in fasting plasma glucose. Analysis was by intention to treat. We assessed possible mechanisms for sulphonylurea sensitivity through insulin sensitivity, insulin secretory response to glucose and tolbutamide, and tolbutamide clearance. FINDINGS Patients with HNF-1alpha diabetes had a 5.2-fold greater response to gliclazide than to metformin (fasting plasma glucose reduction 4.7 vs 0.9 mmol/L, p=0.0007) and 3.9-fold greater response to gliclazide than those with type 2 diabetes (p=0.002). Patients with HNF-1alpha diabetes had a strong insulin secretory response to intravenous tolbutamide despite a small response to intravenous glucose, and were more insulin sensitive than those with type 2 diabetes. Sulphonylurea metabolism was similar in both patient groups. INTERPRETATION The cause of hyperglycaemia changes the response to hypoglycaemic drugs; HNF-1alpha diabetes has marked sulphonylurea sensitivity. This pharmacogenetic effect is consistent with models of HNF-1alpha deficiency, which show that the beta-cell defect is upstream of the sulphonylurea receptor. Definition of the genetic basis of hyperglycaemia has implications for patient management.

Assessing newborn body composition using principal components analysis: differences in the determinants of fat and skeletal size

BackgroundBirth weight is a composite of skeletal size and soft tissue. These components are likely to have different growth patterns. The aim of this paper is to investigate the association between established determinants of birth weight and these separate components.MethodsWeight, length, crown-rump, knee-heel, head circumference, arm circumference, and skinfold thicknesses were measured at birth in 699 healthy, term, UK babies recruited as part of the Exeter Family Study of Childhood Health. Corresponding measurements were taken on both parents. Principal components analysis with varimax rotation was used to reduce these measurements to two independent components each for mother, father and baby: one highly correlated with measures of fat, the other with skeletal size.ResultsGestational age was significantly related to skeletal size, in both boys and girls (r = 0.41 and 0.52), but not fat. Skeletal size at birth was also associated with parental skeletal size (maternal: r = 0.24 (boys), r = 0.39 (girls) ; paternal: r = 0.16 (boys), r = 0.25 (girls)), and maternal smoking (0.4 SD reduction in boys, 0.6 SD reduction in girls). Fat was associated with parity (first borns smaller by 0.45 SD in boys; 0.31 SD in girls), maternal glucose (r = 0.18 (boys); r = 0.27 (girls)) and maternal fat (r = 0.16 (boys); r = 0.36 (girls)).ConclusionPrincipal components analysis with varimax rotation provides a useful method for reducing birth weight to two more meaningful components: skeletal size and fat. These components have different associations with known determinants of birth weight, suggesting fat and skeletal size may have different regulatory mechanisms, which would be important to consider when studying the associations of birth weight with later adult disease.

Can clinical features be used to differentiate type 1 from type 2 diabetes? A systematic review of the literature

Objective Clinicians predominantly use clinical features to differentiate type 1 from type 2 diabetes yet there are no evidence-based clinical criteria to aid classification of patients. Misclassification of diabetes is widespread (7–15% of cases), resulting in patients receiving inappropriate treatment. We sought to identify which clinical criteria could be used to discriminate type 1 and type 2 diabetes. Design Systematic review of all diagnostic accuracy studies published since 1979 using clinical criteria to predict insulin deficiency (measured by C-peptide). Data sources 14 databases including: MEDLINE, MEDLINE in Process and EMBASE. The search strategy took the form of: (terms for diabetes) AND (terms for C-Peptide). Eligibility criteria Diagnostic accuracy studies of any routinely available clinical predictors against a reference standard of insulin deficiency defined by cut-offs of C-peptide concentrations. No restrictions on race, age, language or country of origin. Results 10 917 abstracts were screened, and 231 full texts reviewed. 11 studies met inclusion criteria, but varied by age, race, year and proportion of participants who were C-peptide negative. Age at diagnosis was the most discriminatory feature in 7/9 studies where it was assessed, with optimal cut-offs (>70% mean sensitivity and specificity) across studies being <30 years or <40 years. Use of/time to insulin treatment and body mass index (BMI) were also discriminatory. When combining features, BMI added little over age at diagnosis and/or time to insulin (<1% improvement in classification). Conclusions Despite finding only 11 studies, and considerable heterogeneity between studies, age at diagnosis and time to insulin were consistently the most discriminatory criteria. BMI, despite being widely used in clinical practice, adds little to these two criteria. The criteria identified are similar to the Royal College of General Practitioners National Health Service (RCGP/NHS) Diabetes classification guidelines, which use age at diagnosis <35 years and time to insulin <6 m. Until further studies are carried out, these guidelines represent a suitable classification scheme. Systematic review registration PROSPERO reference CRD42012001736.

Factors determining penetrance in familial atypical haemolytic uraemic syndrome

Background Inherited abnormalities of complement are found in ∼60% of patients with atypical haemolytic uraemic syndrome (aHUS). Such abnormalities are not fully penetrant. In this study, we have estimated the penetrance of the disease in three families with a CFH mutation (c.3643C>G; p. Arg1215Gly) in whom a common lineage is probable. 25 individuals have been affected with aHUS with three peaks of incidence—early childhood (n=6), early adulthood (n=11) and late adulthood (n=8). Eighteen individuals who have not developed aHUS carry the mutation. Methods We estimated penetrance at the ages of 4, 27, 60 and 70 years as both a binary and a survival trait using MLINK and Mendel. We genotyped susceptibility factors in CFH, CD46 and CFHR1 in affected and unaffected carriers. Results and Conclusions We found that the estimates of penetrance at the age of 4 years ranged from <0.01 to 0.10, at the age of 27 years from 0.16 to 0.29, at the age of 60 years from 0.39 to 0.51 and at the age of 70 years from 0.44 to 0.64. We found that the CFH haplotype on the allele not carrying the CFH mutation had a significant effect on disease penetrance. In this family, we did not find that the CD46 haplotypes had a significant effect on penetrance.

Paternal insulin resistance and its association with umbilical cord insulin concentrations

Aims/hypothesisFetal growth is influenced by genetic factors as well as the intra-uterine environment. We hypothesised that some genetic factors may alter fetal insulin secretion and insulin action.Subjects, materials and methodsTo assess this, we analysed plasma insulin concentration in umbilical cord blood from 644 normal, term, UK Caucasian deliveries from the Exeter Family Study of Childhood Health. We tested for associations between cord insulin and each of parental anthropometry, fasting glucose, insulin and lipids.ResultsAs expected, cord insulin concentrations correlated with all measures of birth size (weight, length, head and arm circumferences, sum of skinfold thicknesses, ponderal index: r=0.16–0.4, p<0.01 for all) and maternal BMI (r=0.11, p=0.005), maternal glucose (r=0.25, p<0.001) and maternal insulin resistance (r=0.23, p<0.001). Paternal fasting insulin and insulin resistance were correlated with cord insulin (r=0.15, p=0.006; r=0.13, p=0.001, respectively), and this was independent of paternal BMI. Multiple linear regression analysis revealed paternal insulin resistance to be a predictor of cord insulin concentrations, independently of maternal factors.ConclusionOur results show an independent relationship between paternal insulin resistance and cord insulin concentrations. This is consistent with heritability of insulin resistance from father to offspring and a compensatory increase in fetal insulin secretion, the latter occurring pre-natally before the homeostatic feedback loop between glucose and insulin is established.

Offspring birthweight is not associated with paternal insulin resistance

Aims/hypothesisLow birthweight is associated with insulin resistance and other insulin resistance-related phenotypes: diabetes, hypertension, and vascular disease in later life. The underlying mechanism is unclear. The foetal insulin hypothesis proposes that a single genetic predisposition to beta cell dysfunction/insulin resistance results in both reduced insulin-dependent foetal growth in utero, hence low birthweight, and predisposition to type 2 diabetes. The aim of this study was to test whether, as predicted by the foetal insulin hypothesis, there is an association between measures of paternal insulin resistance and offspring birthweight.Subjects and MethodsThe Exeter Family Study of Childhood Health (EFSOCH) is a community-based study within central Exeter (UK), established to test the foetal insulin hypothesis prospectively. Associations were tested between offspring birthweight and paternal insulin resistance, calculated by homeostasis model assessment analysis in 986 families using data relating to singleton, non-diabetic, UK white pregnancies. Ethics approval was given by the North and East Devon local ethics committee.ResultsOffspring birthweight was not significantly correlated with log paternal insulin resistance (r=0, p=0.91), log HDL cholesterol concentration (r=−0.02, p=0.47) or log triglyceride concentration (r=0, p=0.99) when corrected for paternal BMI and common confounders. Multiple linear regression analysis confirmed that paternal insulin resistance was not an independent predictor of offspring birthweight.Conclusions/interpretationResults from a young, adult, non-diabetic population do not support the foetal insulin hypothesis as an explanation for the association of low birthweight with insulin resistance.

Identifying clinical criteria to predict Type 1 diabetes, as defined by absolute insulin deficiency: a systematic review protocol

Introduction Management of a patients diabetes is entirely dependent upon the type of diabetes they are deemed to have. Patients with Type 1 diabetes are insulin deficient so require multiple daily insulin injections, whereas patients with Type 2 diabetes still have some endogenous insulin production so insulin treatment is only required when diet and tablets do not establish good glycaemic control. Despite the importance of a correct diagnosis, classification of diabetes is based on aetiology and relies on clinical judgement. There are no clinical guidelines on how to determine whether a patient has Type 1 or Type 2 diabetes. We aim to systematically review the literature to derive evidence-based clinical criteria for the classification of the major subtypes of diabetes. Methods and analysis We will perform a systematic review of diagnostic accuracy studies to establish clinical criteria that predict the subsequent development of absolute insulin deficiency seen in Type 1 diabetes. Insulin deficiency will be determined by reference standard C-peptide concentrations. Synthesis of criteria identified will be undertaken using hierarchical summary receiver operating characteristic curves. Ethics and dissemination As this is a systematic review, there will be no ethical issues. We will disseminate results by writing up the final systematic review and synthesis for publication in a peer-reviewed journal and will present at national and international diabetes-related meetings.

Assessing the accuracy of ultrasound estimation of gestational age during routine antenatal care in in vitro fertilization (IVF) pregnancies

Introduction In the UK an accurate gestational age is confirmed by ultrasound measured foetal crown rump length (CRL) at 11 + 2–14 + 1 weeks of gestation. The currently recommended Robinson and Fleming crown rump length reference chart was develop in 1975. Advances in ultrasound technology and standardized crown rump length measurement training could mean this is now out of date. Our study aimed to assess its accuracy in current routine antenatal care. Methods Retrospective data from 178 IVF pregnancies seen for routine antenatal care at a UK Regional Maternity Unit between 1 January 2006 and 1 January 2016 was retrieved. We compared ultrasound calculated crown rump length gestational age taken at the routine First Trimester Screening Clinic (FTSC) with the ‘true’ gestational age calculated from the known IVF fertilization date. Results We identified a systematic overestimation of gestational age by ultrasound using the currently recommended crown rump length reference chart when compared to IVF gestational age. The mean overestimation was 3.0 days (95% CI: 2.7 to 3.4), p < 0.001. A range of alternative ultrasound reference charts also generated a systematic overestimation, ranging from 1.6 to 2.9 days (p < 0.001, for each). Conclusions The current crown rump length reference chart systematically overestimates gestational age by an average of three days when assessed in IVF pregnancies. A systematic overestimation was also identified in alternative crown rump length reference charts. These differences, although slight, were systematic with implications for the accuracy of gestational age estimation particularly in pregnancies at risk of pre-term delivery or growth restriction. Our findings need confirming in larger, non IVF cohorts and could lead to the need for an updated crown rump length reference chart.