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Articles by M. Shepherd
Total Records ( 6 ) for M. Shepherd
  M. Shepherd
  Background Identification of genes causing monogenic diabetes has led to treatment change, from insulin to sulphonylureas for many previously considered insulin dependent. Changing treatment has led to improved glycaemic control and quality of life; however, the impact of a genetic diagnosis and consequent treatment change on identity has not been explored.
Methods This paper examines the experiences of patients and their families using Bury’s theory of biographical disruption in chronic illness to offer insight and comparison with the disruption caused by treatment change following genetic testing. This qualitative study is a longitudinal follow-up using in-depth interviews over time. Thirty-one individuals were interviewed following genetic testing and again 12 months later.
Results Key themes identified were: (i) embodied practices of diabetes; (ii) perceived identity on insulin; (iii) ‘holding on’ to insulin treatment; (iv) challenges and benefits of treatment change; (v) identity reconstruction. Participants were categorized into ‘Transferers’ who successfully transferred to sulphonylureas, ‘Attempters’ who attempted transfer but recommenced insulin and ‘Decliners’ who declined treatment change.
Conclusions Injecting insulin was integral to participant’s lives and fundamental to their identity. Embodied practices of diabetes were deeply embedded in self identity; the possibility of stopping insulin injections was a major challenge contradicting previous beliefs and led to identity reconstruction.
  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.
  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. 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.

  S. V. Hope , A. G. Jones , E. Goodchild , M. Shepherd , R. E. J. Besser , B. Shields , T. McDonald , B. A. Knight and A. Hattersley
 

Aims

To determine the prevalence and clinical characteristics of absolute insulin deficiency in long-standing Type 2 diabetes, using a strategy based on home urinary C-peptide creatinine ratio measurement.

Methods

We assessed the urinary C-peptide creatinine ratios, from urine samples taken at home 2 h after the largest meal of the day, in 191 insulin-treated subjects with Type 2 diabetes (diagnosis age ≥45 years, no insulin in the first year). If the initial urinary C-peptide creatinine ratio was ≤0.2 nmol/mmol (representing absolute insulin deficiency), the assessment was repeated. A standardized mixed-meal tolerance test with 90-min stimulated serum C-peptide measurement was performed in nine subjects with a urinary C-peptide creatinine ratio ≤ 0.2 nmol/mmol (and in nine controls with a urinary C-peptide creatinine ratio >0.2 nmol/mmol) to confirm absolute insulin deficiency.

Results

A total of 2.7% of participants had absolute insulin deficiency confirmed by a mixed-meal tolerance test. They were identified initially using urinary C-peptide creatinine ratio: 11/191 subjects (5.8%) had two consistent urinary C-peptide creatinine ratios ≤ 0.2 nmol/mmol; 9 of these 11 subjects completed a mixed-meal tolerance test and had a median stimulated serum C-peptide of 0.18 nmol/l. Five of these 9 had stimulated serum C-peptide <0.2 nmol/l and 9/9 subjects with urinary C-peptide creatinine ratio >0.2 had endogenous insulin secretion confirmed by the mixed-meal tolerance test. Compared with subjects with a urinary C-peptide creatinine ratio >0.2 nmol/mmol, those with confirmed absolute insulin deficiency had a shorter time to insulin treatment (median 2.5 vs. 6 years, P=0.005) and lower BMI (25.1 vs. 29.1 kg/m2, P=0.04). Two out of the five patients with absolute insulin deficiency were glutamic acid decarboxylase autoantibody-positive.

Conclusions

Absolute insulin deficiency may occur in long-standing Type 2 diabetes, and cannot be reliably predicted by clinical features or autoantibodies. Absolute insulin deficiency in Type 2 diabetes may increase the risk of hypoglycaemia and ketoacidosis, as in Type 1 diabetes. Its recognition should help guide treatment, education and management. The urinary C-peptide creatinine ratio is a practical non-invasive method to aid detection of absolute insulin deficiency, with a urinary C-peptide creatinine ratio > 0.2 nmol/mmol being a reliable indicator of retained endogenous insulin secretion.

 
 
 
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