Rinki Murphy

Clinical implications of a molecular genetic classification of monogenic |[beta]|-cell diabetes

Monogenic diabetes resulting from mutations that primarily reduce β-cell function accounts for 1–2% of diabetes cases, although it is often misdiagnosed as either type 1 or type 2 diabetes. Knowledge of the genetic etiology of diabetes enables more-appropriate treatment, better prediction of disease progression, screening of family members and genetic counseling. We propose that the old clinical classifications of maturity-onset diabetes of the young and neonatal diabetes are obsolete and that specific genetic etiologies should be sought in four broad clinical situations because of their specific treatment implications. Firstly, diabetes diagnosed before 6 months of age frequently results from mutation of genes that encode Kir6.2 (ATP-sensitive inward rectifier potassium channel) or sulfonylurea receptor 1 subunits of an ATP-sensitive potassium channel, and improved glycemic control can be achieved by treatment with high-dose sulfonylureas rather than insulin. Secondly, patients with stable, mild fasting hyperglycemia detected particularly when they are young could have a glucokinase mutation and might not require specific treatment. Thirdly, individuals with familial, young-onset diabetes that does not fit with either type 1 or type 2 diabetes might have mutations in the transcription factors HNF-1α (hepatocyte nuclear factor 1-α) or HNF-4α, and can be treated with low-dose sulfonylureas. Finally, extrapancreatic features, such as renal disease (caused by mutations in HNF-1β) or deafness (caused by a mitochondrial m.3243A>G mutation), usually require early treatment with insulin.

Antibiotic treatment during infancy and increased body mass index in boys: an international cross-sectional study.

Objective:To investigate whether antibiotic exposure during the first year of life is associated with increased childhood body mass index (BMI).Design:Secondary analysis from a multi-centre, multi-country, cross-sectional study (The International Study of Asthma and Allergies in Childhood Phase Three).Subjects:A total of 74 946 children from 31 centres in 18 countries contributed data on antibiotic use in the first 12 months of life and current BMI.Methods:Parents/guardians of children aged 5–8 years completed questionnaires that included questions about their children’s current height and weight, and whether in the child’s first 12 months of life, they had received any antibiotics, paracetamol, were breastfed or the mother/female guardian smoked cigarettes, and whether the child had wheezed in the past 12 months. A general linear mixed model was used to determine the association of antibiotic exposure with BMI, adjusting for age, sex, centre, BMI measurement type (self-reported or measured), maternal smoking, breastfeeding, paracetamol use, gross national income and current wheeze.Results:There was a significant interaction between sex and early-life antibiotic exposure. Early-life antibiotic exposure was associated with increased childhood BMI in boys (+0.107 kg m−2, P<0.0001), but not in girls (−0.008 kg m−2, P=0.75) after controlling for age, centre and BMI measurement type. The association remained in boys (+0.104 kg m−2, P<0.0007), after adjustment for maternal smoking, breastfeeding, paracetamol use and current wheeze. There was no interaction between age, maternal smoking, breastfeeding, paracetamol use, gross national income and current wheeze in the association between early antibiotic exposure and BMI.Conclusions:Exposure to antibiotics during the first 12 months of life is associated with a small increase in BMI in boys aged 5–8 years in this large international cross-sectional survey. By inference this provides additional support for the importance of gut microbiota in modulating the risk of obesity, with a sex-specific effect.

Newly diagnosed diabetes mellitus after acute pancreatitis: a systematic review and meta-analysis

Background Diabetes mellitus (DM) is common in the general population and it poses a heavy burden to society in the form of long-term disability, healthcare use and costs. The pancreas is a key player in glucose homeostasis, but the occurrence of newly diagnosed DM after acute pancreatitis (AP), the most frequent disease of the pancreas, has never been assessed systematically. The aim of this study was to conduct a systematic literature review to determine the prevalence and time course of DM and related conditions after the first attack of AP as well as the impact of covariates. Methods Relevant literature cited in three electronic databases (Scopus, EMBASE and MEDLINE) was reviewed independently by two authors. The main outcome measures studied were newly diagnosed prediabetes, DM, or DM treated with insulin. Pooled prevalence and 95% CIs were calculated for all outcomes. Results A total of 24 prospective clinical studies, involving 1102 patients with first episode of AP, met all the eligibility criteria. Prediabetes and/or DM was observed in 37% (95% CI 30% to 45%) individuals after AP. The pooled prevalence of prediabetes, DM and treatment with insulin after AP was 16% (95% CI 9% to 24%), 23% (95% CI 16% to 31%), and 15% (95% CI 9% to 21%), respectively. Newly diagnosed DM developed in 15% of individuals within 12 months after first episode of AP and the risk increased significantly at 5 years (relative risk 2.7 (95% CI 1.9 to 3.8)). A similar trend was observed with regard to treatment with insulin. The severity of AP, its aetiology, individuals’ age and gender had minimal effect on the studied outcomes. Conclusions Patients with AP often develop prediabetes and/or DM after discharge from hospital, and have a greater than twofold increased risk of DM over 5 years. Further studies are warranted to determine the optimal strategy for its detection and whether the risk of developing DM after AP can be reduced.

The worldwide association between television viewing and obesity in children and adolescents: cross sectional study.

Background Studies exploring the effect of television viewing on obesity throughout childhood are conflicting. Most studies have been confined to single high-income countries. Our aim was to examine the association between television viewing habits and Body Mass Index (BMI) in adolescents and children in a multicentre worldwide sample. Methods In the International Study of Asthma and Allergies in Children Phase Three, adolescents aged between 12 and 15 years completed questionnaires which included questions on television viewing habits, height and weight. Parents/guardians of children aged between 5 and 8 years completed the same questionnaire on behalf of their children. The questionnaire asked “During a normal week, how many hours a day (24 hours) do you (does your child) watch television?” Responses were categorised as; “short” (<1 hour), “moderate” (1 to ≤3 hours), “long” (3 to ≤5 hours) and “prolonged” (>5 hours). Findings 207,672 adolescents from 37 countries and 77,003 children from 18 countries provided data. Daily television viewing in excess of one hour was reported in 89% of adolescents and 79% of children. Compared with adolescents in the short viewing group, those in the moderate, long and prolonged groups had BMIs that were 0.14 kg/m2, 0.21 kg/m2, 0.30 kg/m2 and 0.08 kg/m2, 0.16 kg/m2 and 0.17 kg/m2 larger for females and males respectively (both P<0.001). Compared with children in the short viewing group, those in the moderate, long and prolonged groups had BMIs that were 0.24 kg/m2, 0.34 kg/m2, 0.36 kg/m2 and 0.19 kg/m2, 0.32 kg/m2 and 0.36 kg/m2 larger for females and males respectively (both P<0.001). Interpretation Increased television viewing hours were positively associated with BMI in both adolescents and children with an apparent dose response effect. These findings extend the evidence that television viewing contributes to increased BMI in childhood.

Obesity and diabetes genes are associated with being born small for gestational age: Results from the Auckland Birthweight Collaborative study

BackgroundIndividuals born small for gestational age (SGA) are at increased risk of rapid postnatal weight gain, later obesity and diseases in adulthood such as type 2 diabetes, hypertension and cardiovascular diseases. Environmental risk factors for SGA are well established and include smoking, low pregnancy weight, maternal short stature, maternal diet, ethnic origin of mother and hypertension. However, in a large proportion of SGA, no underlying cause is evident, and these individuals may have a larger genetic contribution.MethodsIn this study we tested the association between SGA and polymorphisms in genes that have previously been associated with obesity and/or diabetes. We undertook analysis of 54 single nucleotide polymorphisms (SNPs) in 546 samples from the Auckland Birthweight Collaborative (ABC) study. 227 children were born small for gestational age (SGA) and 319 were appropriate for gestational age (AGA).Results and ConclusionThe results demonstrated that genetic variation in KCNJ11, BDNF, PFKP, PTER and SEC16B were associated with SGA and support the concept that genetic factors associated with obesity and/or type 2 diabetes are more prevalent in those born SGA compared to those born AGA. We have previously determined that environmental factors are associated with differences in birthweight in the ABC study and now we have demonstrated a significant genetic contribution, suggesting that the interaction between genetics and the environment are important.

Fast-food consumption and body mass index in children and adolescents: an international cross-sectional study.

Objective To investigate whether reported fast-food consumption over the previous year is associated with higher childhood or adolescent body mass index (BMI). Design Secondary analysis from a multicentre, multicountry cross-sectional study (International Study of Asthma and Allergies in Children (ISAAC) Phase Three). Subjects and methods Parents/guardians of children aged 6–7 completed questionnaires which included questions about their childrens asthma and allergies, fast-food consumption, height and weight. Adolescents aged 13–14 completed the same questionnaire. The questionnaire asked “In the past 12 months, how often on average did you (your child) eat fast-food/burgers?” The responses were infrequent (never/only occasionally), frequent (once/twice a week) or very frequent (three or more times per week). A general linear mixed model was used to determine the association between BMI and fast-food consumption, adjusting for Gross National Income per capita by country, measurement type (whether heights/weights were reported or measured), age and sex. Results 72 900 children (17 countries) and 199 135 adolescents (36 countries) provided data. Frequent and very frequent fast-food consumption was reported in 23% and 4% of children, and 39% and 13% of adolescents, respectively. Children in the frequent and very frequent groups had a BMI that was 0.15 and 0.22 kg/m2 higher than those in the infrequent group (p<0.001). Male adolescents in the frequent and very frequent groups had a BMI that was 0.14 and 0.28 kg/m2 lower than those in the infrequent group (p<0.001). Female adolescents in the frequent and very frequent groups had a BMI that was 0.19 kg/m2 lower than those in the infrequent group (p<0.001). Conclusions Reported fast-food consumption is high in childhood and increases in adolescence. Compared with infrequent fast-food consumption, frequent and very frequent consumption is associated with a higher BMI in children. Owing to residual confounding, reverse causation and likely misreporting, the reverse association observed in adolescents should be interpreted with caution.

Use of HbA1c in the Identification of Patients with Hyperglycaemia Caused by a Glucokinase Mutation: Observational Case Control Studies

Aims HaemoglobinA1c (HbA1c) is recommended for diabetes diagnosis but fasting plasma glucose (FPG) has been useful for identifying patients with glucokinase (GCK) mutations which cause lifelong persistent fasting hyperglycaemia. We aimed to derive age-related HbA1c reference ranges for these patients to determine how well HbA1c can discriminate patients with a GCK mutation from unaffected family members and young-onset type 1 (T1D) and type 2 diabetes (T2D) and to investigate the proportion of GCK mutation carriers diagnosed with diabetes using HbA1c and/or FPG diagnostic criteria. Methods Individuals with inactivating GCK mutations (n = 129), familial controls (n = 100), T1D (n = 278) and T2D (n = 319) aged ≥18years were recruited. Receiver Operating Characteristic (ROC) analysis determined effectiveness of HbA1c and FPG to discriminate between groups. Results HbA1c reference ranges in subjects with GCK mutations were: 38–56 mmol/mol (5.6–7.3%) if aged ≤40years; 41–60 mmol/mol (5.9–7.6%) if >40years. All patients (123/123) with a GCK mutation were above the lower limit of the HbA1c age-appropriate reference ranges. 69% (31/99) of controls were below these lower limits. HbA1c was also effective in discriminating those with a GCK mutation from those with T1D/T2D. Using the upper limit of the age-appropriate reference ranges to discriminate those with a mutation from those with T1D/T2D correctly identified 97% of subjects with a mutation. The majority (438/597 (73%)) with other types of young-onset diabetes had an HbA1c above the upper limit of the age-appropriate GCK reference range. HbA1c ≥48 mmol/mol classified more people with GCK mutations as having diabetes than FPG ≥7 mmol/l (68% vs. 48%, p = 0.0009). Conclusions Current HbA1c diagnostic criteria increase diabetes diagnosis in patients with a GCK mutation. We have derived age-related HbA1c reference ranges that can be used for discriminating hyperglycaemia likely to be caused by a GCK mutation and aid identification of probands and family members for genetic testing.

Deletions and rearrangements of the H19/IGF2 enhancer region in patients with Silver–Russell syndrome and growth retardation

Silver–Russell syndrome (SRS) is characterised by prenatal and postnatal growth retardation, dysmorphic facial features, and body asymmetry. In 35–60% of SRS cases the paternally methylated imprinting control region (ICR) upstream of the H19 gene (H19-ICR) is hypomethylated, leading to downregulation of IGF2 and bi-allelic expression of H19. H19 and IGF2 are reciprocally imprinted genes on chromosome 11p15. The expression is regulated by the imprinted methylation of the ICR, which modulates the transcription of H19 and IGF2 facilitated by enhancers downstream of H19. A promoter element of IGF2, IGF2P0, is differentially methylated equivalently to the H19-ICR, though in a small number of SRS cases this association is disrupted—that is, hypomethylation affects either H19-ICR or IGF2P0. Three pedigrees associated with hypomethylation of IGF2P0 in the probands are presented here, two with paternally derived deletions, and one with a balanced translocation of inferred paternal origin. They all have a breakpoint within the H19/IGF2 enhancer region. One proband has severe growth retardation, the others have SRS. This is the first report of paternally derived structural chromosomal mutations in 11p15 causing SRS. These cases define a novel aetiology of the growth retardation in SRS, namely, dissociation of IGF2 from its enhancers.

Relationship between the exocrine and endocrine pancreas after acute pancreatitis

AIM To determine the prevalence and time course of pancreatic exocrine insufficiency in individuals with newly diagnosed prediabetes or diabetes mellitus after acute pancreatitis. METHODS Relevant literature cited in three major biomedical journal databases (EMBASE, MEDLINE, and Scopus) was reviewed independently by two authors. There were no language constraints but the search was limited to human studies. Studies included were cohort studies of adult patients who were discharged after an attack of acute pancreatitis. Patients were excluded if they were under 18 years of age or had a previous diagnosis of prediabetes or diabetes mellitus, pancreatic exocrine insufficiency, or chronic pancreatitis. The main outcome measure was the prevalence of concomitant pancreatic exocrine insufficiency in patients who were diagnosed with prediabetes and diabetes mellitus after an attack of acute pancreatitis. Subgroup analysis was conducted for patients who were diagnosed with prediabetes only and those who were diagnosed with diabetes mellitus only. Subgroup analysis looking at the time course of concomitant pancreatic exocrine and endocrine insufficiency was also conducted. Pooled prevalence and corresponding 95% confidence intervals were calculated for all outcome measures and P-values < 0.05 were deemed statistically significant. RESULTS Eight clinical studies comprising of 234 patients met all eligibility criteria. The pooled prevalence of newly diagnosed prediabetes or diabetes in individuals after acute pancreatitis was 43% (95%CI: 30%-56%). The pooled prevalence of pancreatic exocrine insufficiency in individuals after acute pancreatitis was 29% (95%CI: 19%-39%). The prevalence of concomitant pancreatic exocrine insufficiency in individuals with newly diagnosed prediabetes or diabetes was 40% (95%CI: 25%-55%). The prevalence of concomitant pancreatic exocrine insufficiency among individuals with prediabetes alone and diabetes mellitus alone was 41% (95%CI: 12%-75%) and 39% (95%CI: 28%-51%), respectively. Further analysis showed that the prevalence of concomitant pancreatic exocrine insufficiency in individuals with prediabetes or diabetes decreases over time after an attack of acute pancreatitis. CONCLUSION Pancreatic exocrine insufficiency occurs in 40% of individuals with newly diagnosed prediabetes or diabetes mellitus after acute pancreatitis. Further studies are needed to investigate the pathogenesis of diabetes in this setting.

Severe Intrauterine Growth Retardation and Atypical Diabetes Associated with a Translocation Breakpoint Disrupting Regulation of the Insulin-Like Growth Factor 2 Gene

CONTEXT IGF-II is an imprinted gene (predominantly transcribed from the paternally inherited allele), which has an important role in fetal growth in mice. IGF2 gene expression is regulated by a complex system of enhancers and promoters that determine tissue-specific and development-specific transcription. In mice, enhancers of the IGF2 gene are located up to 260 kb telomeric to the gene. The role of IGF-II in humans is unclear. OBJECTIVE A woman of short adult stature (1.46 m, -3 sd score) born with severe intrauterine growth retardation (1.25 kg at term, -5.4 SD score) and atypical diabetes diagnosed at the age of 23 yr had a balanced chromosomal translocation t(1;11) (p36.22; p15.5). We hypothesized that her phenotype resulted from disruption of her paternally derived IGF2 gene because her daughter who inherited the identical translocation had normal birth weight. DESIGN Both chromosomal break points were identified using fluorescent in situ hybridization. Sequence, methylation, and expression of the IGF2 gene was examined. Hyperinsulinemic, euglycemic clamp with glucose tracers and magnetic resonance imaging of the thorax, abdomen, and pelvis were performed. RESULTS The 11p15.5 break point mapped 184 kb telomeric of the IGF2 gene. Microsatellite markers confirmed paternal origin of this chromosome. IGF2 gene sequence and methylation was normal. IGF2 gene expression was reduced in lymphoblasts. Clamp studies showed marked hepatic and total insulin resistance. Massive excess sc fat was seen on magnetic resonance imaging despite slim body mass index (21.1 kg/m2). CONCLUSIONS A break point 184 kb upstream of the paternally derived IGF2 gene, separating it from some telomeric enhancers, resulted in reduced expression in some mesoderm-derived adult tissues causing intrauterine growth retardation, short stature, lactation failure, and insulin resistance with altered fat distribution.