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Articles by A. T. Hattersley
Total Records ( 10 ) for A. T. Hattersley
  A. S. Slingerland , W. Hurkx , K. Noordam , S. E. Flanagan , J. W. Jukema , L. C. Meiners , G. J. Bruining , A. T. Hattersley and M. Hadders-Algra
  Background KCNJ11 mutations are a common cause of diabetes diagnosed in the first 6 months of life, and approximately 25% of patients have neurological features. Sulphonylureas have been shown to improve glycaemic control and also motor function, but the impact on cognitive function has not been extensively addressed previously.

Methods  The patient had a low birth weight and was found to have diabetes at the age of 2 days. The patient was treated with insulin from diagnosis. The child also had marked developmental delay so that his average functional age was 2.5 years when he was 12 years old. A V59M mutation in KCNJ11 was found on sequencing, resulting in a diagnosis of intermediate developmental delay, epilepsy, neonatal diabetes (DEND) syndrome. Identification of a Kir6.2 mutation allowed insulin injections to be replaced by glibenclamide tablets.

Results  This resulted not only in improved glycaemic control (HbA1c fell from 8.1 to 6.5%), but also an impressive improvement in many aspects of cognitive function, with the functional age increasing to 4 years within 6 months of treatment change.

Conclusions  This is the first clear report of cognitive function improving in a patient with the neurological features associated with a KATP channel mutation following transfer to sulphonylureas. The finding of cognitive improvement suggests that glibenclamide is likely to be acting directly on the brain and not just on nerve and muscle, improving muscle strength.

  E. L. Edghill , L. McCulloch , P. Fulton , N. Beer , A. T. Hattersley and A. L. Gloyn
  Not available
  M. Shepherd , B. Shields , S. Ellard , O. Rubio-Cabezas and A. T. Hattersley
  Background and aims  Hepatocyte nuclear factor-1 alpha (HNF1A) gene mutations are the commonest cause of monogenic diabetes, but patients are often misdiagnosed as having Type 1 diabetes and started on insulin treatment. Patients with HNF1A diabetes are particularly sensitive to the glucose-lowering effect of sulphonylureas, which are the pharmacological treatment of choice. We aimed to assess if patients do change from insulin to sulphonylurea treatment when HNF1A diabetes is confirmed and the impact of this treatment change on long-term glycaemic control.

Methods  We investigated the clinical course of 43 patients who were insulin treated from diagnosis for a median 4 years (range 1-14) before an HNF1A gene mutation was identified.

Results  Thirty-four patients (79%) stopped insulin following genetic testing and transferred to sulphonylureas. Twenty-four of them (71%) remained off insulin at a median 39 months (range 17-90) post-transfer. The 10 patients who recommenced insulin had a trend towards a longer duration of diabetes (18 vs. 7 years, P = 0.066) compared with those remaining on tablets. The median glycated haemoglobin (HbA1c) was good (6.9%; interquartile range 6.3-8.0%) in the patients who remained off insulin and 19/24 patients (79%) achieved HbA1c < 7.5% or improved their pre-genetic diagnosis HbA1c by > 1.0%. Transfer off insulin was not attempted in eight patients: one of these was planning pregnancy and two chose to remain on insulin.

Conclusion  In this observational study we found that a molecular genetic diagnosis of HNF1A diabetes does alter treatment in clinical practice, with 79% attempting transfer to sulphonylureas. Transfer to sulphonylureas was successful in the majority of patients without deterioration in glycaemic control.

  G. Spyer , K. M. Macleod , M. Shepherd , S. Ellard and A. T. Hattersley
  Aim  To assess determinants of fetal growth in the offspring of pregnant women with hyperglycaemia due to a heterozygous glucokinase (GCK) gene mutation.

Methods  Details of gestational age at delivery, fetal birth weight and maternal antenatal treatment were collected from patients and retrospective case note review of 82 offspring born to 42 women with GCK gene mutations and 31 offspring born to 13 unaffected normoglycaemic women with an affected partner. Fetal genotype was determined using direct sequencing from either a mouth swab or a blood sample.

Results  In mothers with GCK mutations, non-mutation-carrying offspring were heavier than mutation-carrying offspring (corrected birth weight 3.9 ± 0.6 vs. 3.2 ± 0.8 kg; P < 0.001) and more likely to be macrosomic (> 4.0 kg; 39% vs. 7%, P = 0.001). There was no difference in corrected birth weight between offspring of insulin- and diet-treated women (3.7 ± 0.7 vs. 3.8 ± 0.6 kg; P = 0.1), although insulin-treated mothers delivered earlier (37.5 ± 1.7 vs. 38.9 ± 2.3 weeks; P < 0.001) due to increased obstetric intervention.

Conclusions  Offspring of women with GCK mutations are at increased risk of macrosomia and its obstetric consequences. Fetal birth weight is predominantly altered by fetal genotype and not treatment of maternal hyperglycaemia with insulin. This probably reflects the large effect of a fetal GCK mutation on fetal insulin secretion and the difficulty in reducing the regulated maternal glycaemia caused by a glucose sensing defect in people with GCK mutations.

  M. A. Stone , J. Camosso-Stefinovic , J. Wilkinson , S. De Lusignan , A. T. Hattersley and K. Khunti
  Aims  To conduct a systematic review to identify types and implications of incorrect or incomplete coding or classification within diabetes or between diabetes and other conditions; also to determine the availability of evidence regarding frequency of occurrence.

Methods  Medical Subject Headings (MeSH) and free-text terms were used to search relevant electronic databases for papers published to the end of August 2008. Two researchers independently reviewed titles and abstracts and, subsequently, the full text of potential papers. Reference lists of selected papers were also reviewed and authors consulted. Three reviewers independently extracted data.

Results  Seventeen eligible studies were identified, including five concerned with distinguishing between Type 1 and Type 2 diabetes. Evidence was also identified regarding: the distinction between diabetes and no-diabetes, failure to specify type of diabetes, and diagnostic errors or difficulties involving maturity-onset diabetes of the young, latent autoimmune diabetes in adults, pancreatic diabetes, persistence of foetal haemoglobin and acquired immune deficiency syndrome (AIDS). The sample was too heterogeneous to derive accurate information about frequency, but our findings suggested that misclassification occurs most commonly in young people. Implications relating to treatment options and risk management were highlighted, in addition to psychological and financial implications and the potential impact on the validity of quality of care evaluations and research.

Conclusions  This review draws attention to the occurrence and implications of incorrect or incomplete coding or classification of diabetes, particularly in young people. A pragmatic and clinically relevant approach to classification is needed to assist those involved in making decisions about types of diabetes.

  R. E. J. Besser , A. G. Jones , T. J. McDonald , B. M. Shields , B. A. Knight and A. T. Hattersley
  Aims  The mixed meal tolerance test is the gold standard measure of endogenous insulin secretion. Practical issues limit the routine clinical use of this test, including omitting insulin prior to the ingestion of a high-carbohydrate liquid mixed meal, which can result in marked hyperglycaemia. We aimed to assess whether insulin omission is necessary during the mixed meal tolerance test and whether fasting C-peptide was a practical alternative to the test.

Methods  Ninety-one adults with insulin-treated diabetes (Type 1 n = 56, Type 2 n = 35) underwent two mixed meal tolerance tests; one standard without insulin and one with the patient's usual morning insulin.

Results  The 90-min serum C-peptide was highly correlated in the standard mixed meal tolerance test and the test with insulin (r = 0.98, P < 0.0001). There was a 20% reduction in the peak C-peptide value when insulin was given {test with insulin [0.39 (0.01-1.16) vs. test without insulin 0.48 (0.01-1.36) nmol/l, P = 0.001]}, but the original serum C-peptide cut-off for significant endogenous insulin secretion (≥ 0.2 nmol/l) still correctly classified 90/91 patients (98% sensitivity/100% specificity). Fasting serum C-peptide was highly correlated to 90-min serum C-peptide during the test (r = 0.97, P < 0.0001). A fasting serum C-peptide ≥ 0.07 nmol/l was the optimal cut-off (100% sensitivity and 97% specificity) for significant endogenous insulin secretion (defined as 90-min stimulated serum C-peptide ≥ 0.2 nmol/l).

Conclusions  Insulin omission may not always be necessary during a mixed meal tolerance test and fasting serum C-peptide may offer a practical alternative in insulin-treated patients.

  A. G. Jones , B. A. Knight , G. C. Baker and A. T. Hattersley
  Not available
  E. L. Edghill , K. Stals , R. A. Oram , M. H. Shepherd , A. T. Hattersley and S. Ellard
  Aims  Hepatocyte nuclear factor 1β (HNF1B) mutations cause a syndrome of renal cysts and diabetes, with whole gene deletions accounting for approximately 50% of cases. The severity of the renal phenotype is variable, from enlarged cystic kidneys incompatible with life to normal renal development and function. We investigated the prevalence of HNF1B deletions in patients with diabetes but no known renal disease.

Methods  We tested 461 patients with familial diabetes diagnosed before 45 years, including 258 probands who met clinical criteria for maturity-onset diabetes of the young (two generations affected and at least one family member diagnosed under 25 years). A fluorescent polymerase chain reaction assay was used to analyse two intragenic polymorphic HNF1B markers and identify heterozygous patients who therefore did not have whole gene deletions. Those patients homozygous for both markers were then tested for an HNF1B deletion using multiplex ligation-dependent probe amplification.

Results  Heterozygous HNF1B intragenic polymorphisms were identified in 337/461 subjects. Multiplex ligation-dependent probe amplification analysis showed an HNF1B gene deletion in three of the remaining 124 probands, all of whom met the criteria for maturity-onset diabetes of the young. Testing of their relatives identified three additional deletion carriers and ultrasound scanning showed renal developmental abnormalities in three of these six patients.

Conclusions  We estimate that HNF1B mutations account for < 1% of cases of maturity-onset diabetes of the young. Although HNF1B mutations are a rare cause of diabetes in the absence of known renal disease, a genetic diagnosis of renal cysts and diabetes syndrome is important as it raises the possibility of subclinical renal disease and the 50% risk of renal cysts and diabetes syndrome in the patient's offspring.

  A. G. Jones and A. T. Hattersley
  C-peptide is produced in equal amounts to insulin and is the best measure of endogenous insulin secretion in patients with diabetes. Measurement of insulin secretion using C-peptide can be helpful in clinical practice: differences in insulin secretion are fundamental to the different treatment requirements of Type 1 and Type 2 diabetes. This article reviews the use of C-peptide measurement in the clinical management of patients with diabetes, including the interpretation and choice of C-peptide test and its use to assist diabetes classification and choice of treatment. We provide recommendations for where C-peptide should be used, choice of test and interpretation of results. With the rising incidence of Type 2 diabetes in younger patients, the discovery of monogenic diabetes and development of new therapies aimed at preserving insulin secretion, the direct measurement of insulin secretion may be increasingly important. Advances in assays have made C-peptide measurement both more reliable and inexpensive. In addition, recent work has demonstrated that C-peptide is more stable in blood than previously suggested or can be reliably measured on a spot urine sample (urine C-peptide:creatinine ratio), facilitating measurement in routine clinical practice. The key current clinical role of C-peptide is to assist classification and management of insulin-treated patients. Utility is greatest after 3-5 years from diagnosis when persistence of substantial insulin secretion suggests Type 2 or monogenic diabetes. Absent C-peptide at any time confirms absolute insulin requirement and the appropriateness of Type 1 diabetes management strategies regardless of apparent aetiology.
  K. Y. Thong , T. J. McDonald , A. T. Hattersley , A. D. Blann , S. Ramtoola , C. Duncan , S. Carr , K. Adamson , A. U. Nayak , R. Khurana , S. J. Hunter , A. Ali , S. Au and R. E. J. Ryder


The response to glucagon-like peptide 1 receptor agonist treatment may be influenced by endogenous β-cell function. We investigated whether urinary C-peptide creatinine ratio assessed before or during liraglutide treatment was associated with treatment response.


A single, outpatient urine sample for urinary C-peptide creatinine ratio was collected 2 h after the largest meal of the day among two separate groups: (1) subjects initiating liraglutide (0.6 [RIGHTWARDS ARROW] 1.2 mg daily) or (2) subjects already treated with liraglutide for 20-32 weeks. The associations between pretreatment and on-treatment urinary C-peptide creatinine ratio and HbA1c change at 32 weeks were assessed using univariate and multivariate analyses (the ratio was logarithm transformed for multivariate analyses). Changes in HbA1c according to pretreatment urinary C-peptide creatinine ratio quartiles are shown.


One hundred and sixteen subjects (70 pretreatment, 46 on treatment) with Type 2 diabetes from 10 diabetes centres were studied. In univariate analyses, neither pretreatment nor on-treatment urinary C-peptide creatinine ratio correlated with HbA1c change (Spearman rank correlation coefficient, = -0.17, = 0.17 and = -0.20, = 0.19, respectively). In multi-linear regression analyses, entering baseline HbA1c and log urinary C-peptide creatinine ratio, pretreatment and on-treatment log urinary C-peptide creatinine ratio became significantly associated with HbA1c change (= 0.048 and = 0.040, respectively). Mean (sd) HbA1c changes from baseline in quartiles 1 to 4 of pretreatment urinary C-peptide creatinine ratio were -3 ± 17 mmol/mol (-0.3 ± 1.6%) (= 0.52), -12 ± 15 mmol/mol (-1.1 ± 1.4%) (= 0.003), -11 ± 13 mmol/mol (-1.0 ± 1.2%) (= 0.002) and -12±17 mmol/mol (-1.1±1.6%) (P=0.016), respectively.


Postprandial urinary C-peptide creatinine ratios before and during liraglutide treatment were weakly associated with the glycaemic response to treatment. Low pretreatment urinary C-peptide creatinine ratio may be more useful than higher values by predicting poorer glycaemic response.

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