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Articles by A. T. Hattersley
Total Records ( 9 ) for A. T. Hattersley
  T. J McDonald , B. A Knight , B. M Shields , P Bowman , M. B Salzmann and A. T. Hattersley
 

Introduction: C-peptide measurement in blood or 24-h urine samples provides useful information regarding endogenous insulin secretion, but problems related to the rapid degradation of C-peptide in blood and difficulty of 24-h urine collection have limited widespread routine clinical use of this test. We assessed the feasibility of measuring urinary C-peptide (UCP) with correction for creatinine concentration in single urine samples.

Methods: We analyzed UCP using a routine electrochemiluminescence immunoassay in samples from 21 healthy volunteers. We investigated the stability of UCP with different preservatives and storage conditions and compared the reproducibility of urinary C-peptide/creatinine ratio (UCPCR) in first- and second-void fasting urines, then assessed correlations with 24-h collections.

Results: UCPCR was unchanged at room temperature for 24 h and at 4 °C for 72 h even in the absence of preservative. UCPCR collected in boric acid was stable at room temperature for 72 h. UCPCR remained stable after 7 freeze-thaw cycles but decreased with freezer storage time and dropped to 82%–84% of baseline by 90 days at –20 °C. Second-void fasting UCPCRs were lower than first-void (median 0.78 vs 1.31, P = 0.0003) and showed less variation (CV 33% vs 52%), as second-void UCPCRs were not influenced by evening food-related insulin secretion. Second-void fasting UCPCR was highly correlated with 24-h UCP (r = 0.8, P = 0.00006).

Conclusions: Second-void fasting UCPCR is a reproducible measure that correlates well with 24-h UCP in normal samples. The 3-day stability of UCPCR at room temperature greatly increases its potential clinical utility.

  R. M Freathy , A. J Bennett , S. M Ring , B Shields , C. J Groves , N. J Timpson , M. N Weedon , E Zeggini , C. M Lindgren , H Lango , J. R.B Perry , A Pouta , A Ruokonen , E Hypponen , C Power , P Elliott , D. P Strachan , M. R Jarvelin , G. D Smith , M. I McCarthy , T. M Frayling and A. T. Hattersley
  OBJECTIVE

Low birth weight is associated with an increased risk of type 2 diabetes. The mechanisms underlying this association are unknown and may represent intrauterine programming or two phenotypes of one genotype. The fetal insulin hypothesis proposes that common genetic variants that reduce insulin secretion or action may predispose to type 2 diabetes and also reduce birth weight, since insulin is a key fetal growth factor. We tested whether common genetic variants that predispose to type 2 diabetes also reduce birth weight.

RESEARCH DESIGN AND METHODS

We genotyped single-nucleotide polymorphisms (SNPs) at five recently identified type 2 diabetes loci (CDKAL1, CDKN2A/B, HHEX-IDE, IGF2BP2, and SLC30A8) in 7,986 mothers and 19,200 offspring from four studies of white Europeans. We tested the association between maternal or fetal genotype at each locus and birth weight of the offspring.

RESULTS

We found that type 2 diabetes risk alleles at the CDKAL1 and HHEX-IDE loci were associated with reduced birth weight when inherited by the fetus (21 g [95% CI 11–31], P = 2 x 10–5, and 14 g [4–23], P = 0.004, lower birth weight per risk allele, respectively). The 4% of offspring carrying four risk alleles at these two loci were 80 g (95% CI 39–120) lighter at birth than the 8% carrying none (Ptrend = 5 x 10–7). There were no associations between birth weight and fetal genotypes at the three other loci or maternal genotypes at any locus.

CONCLUSIONS

Our results are in keeping with the fetal insulin hypothesis and provide robust evidence that common disease-associated variants can alter size at birth directly through the fetal genotype.

  R. Singh , A. T. Hattersley and L. W. Harries
 

Aims  Mitochondrial depletion in pancreatic beta cells is known to reduce glucose stimulated insulin secretion. We aimed to determine whether the offspring of patients with early onset Type 2 diabetes had reduced peripheral blood mitochondrial content relative to control subjects and whether this could lead to a predisposition to type 2 diabetes in later life.

Methods  We measured the levels of mitochondria relative to a single copy genomic target by real time polymerase chain reaction in a series of peripheral blood samples taken from the offspring of Caucasian patients with Type 2 diabetes and matched controls. Measures of insulin sensitivity and beta cell function were also taken.

Results  In contrast with previous studies, mitochondrial DNA content was not decreased in the offspring of patients with Type 2 diabetes relative to matched controls in our cohort. Conversely, we noted a small proliferation in mitochondrial numbers in our case subjects. In agreement with these findings, no correlations with either insulin sensitivity or beta cell function were noted.

Conclusions  Our results indicate that reduced mitochondrial DNA content in peripheral blood is not a risk factor for the development of Type 2 diabetes in the offspring of patients with early onset Type 2 diabetes.

  O. Rubio-Cabezas , E. L. Edghill , J. Argente and A. T. Hattersley
  AimsMonogenic diabetes is frequently misdiagnosed as Type 1 diabetes. We aimed to screen for undiagnosed monogenic diabetes in a cohort of children who had a clinical diagnosis of Type 1 diabetes but were pancreatic autoantibody-negative. MethodsWe studied 252 patients diagnosed clinically with Type 1 diabetes between 6months and 17years of age. Pancreatic autoantibodies [islet cell autoantibodies (ICA), glutamic acid decarboxylase antibodies (GADA) and/or insulinoma-associated antigen-2 antibodies (IA2A)] were absent in 25 cases (9.9%). The most frequent genes involved in monogenic diabetes [KCNJ11 and INS for neonatal diabetes and HNF1A and HNF4A for maturity-onset diabetes of the young (MODY)] were directly sequenced. ResultsTwo of the 25 (8%) antibody-negative patients had de novo heterozygous mutations in INS; c.94G>A (G32S) and c.265C>T (R89C). The two patients presented with non-ketotic hyperglycaemia at 8 and 11months of age. In contrast, the four antibody-positive patients who presented at a similar age (6–12months) had a more severe metabolic derangement, manifested as ketosis in all four cases, with ketoacidosis in two. At ages 15 and 5years, both INS mutation patients were prescribed a replacement dose of insulin with good glycaemic control [glycated haemoglobin (HbA1c) 7.0 and 7.2%]. No mutations were found in KCNJ11, HNF1A or HNF4A. ConclusionsThe identification of patients with monogenic diabetes from children with clinically defined Type 1 diabetes may be helped by clinical criteria including the absence of pancreatic autoantibodies.
  J. Grulich-Henn , V. Wagner , A. Thon , E. Schober , W. Marg , T. M. Kapellen , H. Haberland , K. Raile , S. Ellard , S. E. Flanagan , A. T. Hattersley and R. W. Holl
  Aims The aim of this study was to elucidate the entities and the frequency of neonatal diabetes mellitus (NDM) in a large representative database for paediatric diabetes patients in Germany and Austria.
Methods 
Based on the continuous diabetes data acquisition system for prospective surveillance (DPV), which includes 51 587 patients with onset of diabetes before the age of 18 years from 299 centres in Germany and Austria, we searched for patients with onset of diabetes mellitus in the first 6 months of life.
Results 
Ninety patients were identified, comprising 0.17% of all paediatric cases in the DPV registry. This represented an incidence of approximately one case in 89 000 live births in Germany. A monogenic basis for NDM was established in 30 subjects (seven UPD6, 10 KCNJ11, seven ABCC8, two FOXP3, two PDX1, one INS, one EIF2AK3). Pancreatic hypoplasia or agenesis was reported in 10 patients and seven subjects were classified as having Type 1 diabetes by their centres. Transient neonatal diabetes (TNDM) accounted for approximately 10% of all cases with NDM. No aetiology was defined in 41 subjects, which may reflect incomplete genetic testing or novel genetic aetiologies.
Conclusion 
Based on a large database, we identified a higher rate of NDM in Germany than has been reported previously. Full molecular genetic testing should be performed in all patients diagnosed before 6 months of age.
  A. M. Steele , B. M. Shields , M. Shepherd , S. Ellard , A. T. Hattersley and E. R. Pearson
  Aims: To investigate all-cause and cardiovascular mortality in subjects with diabetes caused by a mutation in the hepatocyte nuclear factor 1α gene (HNF1A).
Methods: We identified 39 British families with HNF1A mutations. Consenting individuals were asked details of age and cause of death of parents and siblings. Copies of death certificates were requested from the family or were obtained via the Offices for National Statistics.
Results: Data were collated on 241 control subjects and 153 mutation carriers. Of those who died, 66% of mutation carriers died from a cardiovascular-related illness compared with 43% of control subjects (P=0.02). Family members with HNF1A mutations died at a younger age than familial control subjects [all-cause hazard ratio, adjusting for sex and smoking status: 1.9 (95% confidence interval 1.2, 2.9, P=0.006; cardiovascular hazard ratio: 2.3, confidence interval 1.3, 4.2, P=0.006)].Conclusions: We have shown that individuals known to have diabetes caused by a mutation in the HNF1A gene have an increased risk of cardiovascular mortality compared with their unaffected family members. As with other forms of diabetes, consideration should be given to early statin therapy despite a seemingly protective lipid profile.
  T. J. McDonald , K. Colclough , R. Brown , B. Shields , M. Shepherd , P. Bingley , A. Williams , A. T. Hattersley and Sian Ellard
  Aim  Maturity-onset diabetes of the young is a monogenic form of familial, young-onset diabetes. It is rare (~1% diabetes) and may be misdiagnosed as Type 1 diabetes and inappropriately treated with insulin. Type 1 diabetes is characterized by the presence of islet autoantibodies, including glutamate decarboxylase (GAD) and islet antigen-2 (IA-2) antibodies. The prevalence of islet autoantibodies is unknown in maturity-onset diabetes of the young and may have the potential to differentiate this form of diabetes from Type 1 diabetes. The aim of this study was to determine the prevalence of GAD and IA-2 antibodies in patients with maturity-onset diabetes of the young and Type 1 diabetes. Methods  We measured plasma GAD and IA-2 antibodies in 508 patients with the most common forms of maturity-onset diabetes of the young (GCK: n = 227; HNF1A: n = 229; HNF4A: n = 52) and 98 patients with newly diagnosed Type 1 diabetes (diagnosed < 6 months). Autoantibodies were considered positive if ≥ 99th centile of 500 adult control subjects. Results  GAD and/or IA-2 antibodies were present in 80/98 (82%) patients with Type 1 diabetes and 5/508 (< 1%) patients with maturity-onset diabetes of the young. In the cohort with Type 1 diabetes, both GAD and IA-2 antibodies were detected in 37.8% of patients, GAD only in 24.5% and IA-2 only in 19.4%. All five patients with maturity-onset diabetes of the young with detectable antibodies had GAD antibodies and none had detectable IA-2 antibodies. Conclusion  The prevalence of GAD and IA-2 antibodies in maturity-onset diabetes of the young is the same as in control subjects (< 1%). The finding of islet autoantibodies, especially IA-2 antibodies, makes the diagnosis of maturity-onset diabetes of the young very unlikely and genetic testing should only be performed if other clinical characteristics strongly suggest this form of diabetes rather than Type 1 diabetes. This supports routine islet autoantibody testing before proceeding to more expensive molecular genetic testing.
  A. G. Jones , R. E. J. Besser , T. J. McDonald , B. M. Shields , S. V. Hope , P. Bowman , R. A. Oram , B. A. Knight and A. T. Hattersley
  Aims  Serum C-peptide measurement can assist clinical management of diabetes, but practicalities of collection limit widespread use. Urine C-peptide creatinine ratio may be a non-invasive practical alternative. The stability of C-peptide in urine allows outpatient or community testing. We aimed to assess how urine C-peptide creatinine ratio compared with serum C-peptide measurement during a mixed-meal tolerance test in individuals with late-onset, insulin-treated diabetes. Methods  We correlated the gold standard of a stimulated serum C-peptide in a mixed-meal tolerance test with fasting and stimulated (mixed-meal tolerance test, standard home meal and largest home meal) urine C-peptide creatinine ratio in 51 subjects with insulin-treated diabetes (diagnosis after age 30 years, median age 66 years, median age at diagnosis 54, 42 with Type 2 diabetes, estimated glomerular filtration rate > 60 ml min−1 1.73 m−2). Results  Ninety-minute mixed-meal tolerance test serum C-peptide is correlated with mixed-meal tolerance test-stimulated urine C-peptide creatinine ratio (r = 0.82), urine C-peptide creatinine ratio after a standard breakfast at home (r = 0.73) and urine C-peptide creatinine ratio after largest home meal (r = 0.71). A stimulated (largest home meal) urine C-peptide creatinine ratio cut-off of 0.3 nmol/mmol had a 100% sensitivity and 96% specificity (area under receiver operating characteristic curve = 0.99) in identifying subjects without clinically significant endogenous insulin secretion (mixed-meal tolerance test-stimulated C-peptide < 0.2 nmol/l). In detecting a proposed serum C-peptide threshold for insulin requirement (stimulated serum C-peptide < 0.6 nmol/l), a stimulated (largest home meal) urine C-peptide creatinine ratio cut-off of 0.6 nmol/mmol had a sensitivity and specificity of 92%. Conclusion  In patients with insulin-treated diabetes diagnosed after age 30 years, urine C-peptide creatinine ratio is well correlated with serum C-peptide and may provide a practical alternative measure to detect insulin deficiency for use in routine clinical practice.
  P. Bowman , T. J. McDonald , B. M. Shields , B. A. Knight and A. T. Hattersley
  Aims Serum C-peptide can be used in Type 2 diabetes as a measure of endogenous insulin secretion, but practicalities of collection limit its routine clinical use. Urine C-peptide creatinine ratio is a non-invasive alternative that is stable for at least 3 days at room temperature in boric acid preservative. We aimed to assess the utility of urine C-peptide creatinine ratio in individuals with Type 2 diabetes as an alternative to serum C-peptide. Methods  We assessed, in 77 individuals with Type 2 diabetes, the reproducibility of, and correlations between, fasting and postprandial urine C-peptide creatinine ratio and serum C-peptide, and the impact of renal impairment (estimated glomerular filtration rate < 60 ml min−1 1.73 m−2) on these correlations. Results Urine C-peptide creatinine ratio was at least as reproducible as serum C-peptide [fasting coefficient of variation mean (95% CI): 28 (21−35)% vs. 38 (26−59)% and 2−h post-meal 26 (18−33)% vs. 27 (20−34)%. Urine C-peptide creatinine ratio 2 h post-meal was correlated with stimulated serum C-peptide, both the 2−h value (r = 0.64, P < 0.001) and the 2-h area under the C-peptide curve (r = 0.63, P < 0.001). The association seen was similar in patients with and without moderate renal impairment (P = 0.6). Conclusions In patients with Type 2 diabetes, a single urine C-peptide creatinine ratio is a stable, reproducible measure that is well correlated with serum C-peptide following meal stimulation, even if there is moderate renal impairment. Urine C-peptide creatinine ratio therefore has potential for use in clinical practice in the assessment of Type 2 diabetes.
 
 
 
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