RESEARCH IN MONOGENIC DIABETES

Researchers here at the Peninsula Medical School are currently conducting a number of studies looking at monogenic diabetes. Monogenic diabetes is diabetes caused by a mutation in a single gene. Two types of diabetes found to have monogenic causes are Maturity Onset Diabetes of the Young (MODY) and Permanent Neonatal Diabetes.

PATIENTS & PROFESSIONALS VIEWS OF GENETIC TESTING IN DIABETES
Maggie Shepherd

Maggie has been conducting research using a qualitative approach into attitudes of patients and professionals to genetic testing in diabetes. This comprised of case studies, in-depth interviews and focus groups with patients with MODY and their families and health care professionals from diabetes and genetics teams involved in their care.

Particular interests include:

• Patients' and professionals' beliefs about inheritance/genetics in diabetes.
• Disseminating 'understandable' information to patients and professionals about the genetics of diabetes
• Qualitative research methodology
• Producing guidelines and advice regarding the introduction of genetic testing in diabetes

Publications directly relating to this research:

1. Shepherd M. 2006. Transforming lives: transferring patients with neonatal diabetes from insulin to sulphonylureas. European Diabetes Nursing. 3, 3, 137-142

2. Shepherd M, Hattersley AT, Ellard S. 2005. Integration of the MODY link nurse project: 20 month evaluation. Journal of Diabetes Nursing, 9, 2, 47-52

3. Dudding S, McMahon H, Shepherd M. 2005. MODY link nurses: pushing the boundaries of diabetes nursing. Journal of Diabetes Nursing, 9, 1, 7-10

4. Dalton J, Shepherd M. 2004. Identification of MODY: the implications for Holly Journal of Diabetes Nursing. 8, 1, 19-21

5. Shepherd M, Hattersley AT. 2004. ‘I don’t feel like a diabetic anymore’: The impact of stopping insulin in patients with maturity onset diabetes of the young (MODY) following genetic testing. Clinical Medicine. 4, 2, 144-147

6. Shepherd M. 2004. Preventing severe hypoglycaemia in Type 1 diabetes (a review of the article by Nordfelt et al 2003 ‘Prevention of severe hypoglycaemia in type 1 diabetes: a randomized controlled population study) International Diabetes Monitor. 16, 2, 27-28

7. Shepherd M. 2003. ‘I’m amazed I’ve been able to come off injections’: Patients’ perceptions of genetic testing in diabetes. Report of the 2003 Janet Kinson Lecture. Practical Diabetes International. 20, 9, 338-343

8. Shepherd M, Pearson ER, Houghton J, Salt G, Ellard S, Hattersley AT. 2003. No deterioration in glycaemic control in HNF1a MODY following transfer from long term insulin to sulphonylureas Diabetes Care. 26, 11, 3191-3192

9. Shepherd M, Stride A, Ellard S, Hattersley AT. 2003. Integrating genetics into diabetes care: a new role for DSNs. Journal of Diabetes Nursing. 7, 8, 289-292

10. Shepherd M, Sparkes A, Hattersley A. 2003. Dimensions of personal loss and gain associated with a rare genetic type of diabetes. Illness, Crisis and Loss. 11, 4, 362-376

11. Shepherd M. 2003. Personal comment: Genetic testing in maturity onset diabetes of the young (MODY) – practical guidelines for professionals. Practical Diabetes International 20, 3, 108-110

12. Shepherd M, Houghton J. 2002. An educational model for the integration of genetics into diabetes care. Practical Diabetes International. 19, 8, 244

Future research will include:

1. Case studies, interviews, and focus groups with patients with Type 2 diabetes to investigate their views of genetic information in diabetes.
2. In-depth interviews with doctors involved in diabetes care regarding their views of genetic information in MODY.

If you would like to take part or find out more about this research, please contact Maggie Shepherd on 01392 403053 or email M.H.Shepherd@ex.ac.uk

COMPLICATIONS ASSOCIATED WITH HNF-1A MODY
Anna Steele - Research Nurse

Anna was involved in the HNF4A birth weight study. The results of this work show that if a baby inherits a copy of a change in the HNF4A gene it could have a large birth weight and also have a hypoglycemic event within 48 hours after birth. For the results of this work and the clinical recommendations that accompany them, please see the following paper:

Pearson ER, Boj SF, Steele AM, Barrett T, Stals K, Shield JP, Ellard S, Ferrer J, Hattersley AT.
Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene.
PLoS Med. 2007 Apr;4(4):e118.

Anna’s main work now investigates if individuals with changes in the glucokinase gene are likely to develop to develop complications associated with hyperglycemia. This work is at the volunteer recruiting stage and patient referrals to the study are welcomed. She would also be interested in looking for volunteers with diabetes due to changes in the HNF1A gene or type 2 diabetes as these people will form a comparison group. Please contact Anna.Steele@pms.ac.uk for more information.

THE ROLE OF MESSENGER RNA (MRNA) PROCESSING IN MONOGENIC DIABETES
Dr Lorna Harries – Diabetes and Metabolism Academic Fellow

Lorna’s research focuses on the role of messenger RNA processing, mRNA surveillance and regulation of gene expression by small regulatory RNA species in the determination of disease mechanisms in monogenic diabetes. She is particularly interested in how mRNA biology can influence developmental pathways and moderate genotype:phenotype relationships in maturity-onset diabetes of the young (MODY).

If you would like to find out more about Lorna’s research, she can be contacted by phone on 01392 406779 or by email at lorna.harries@pms.ac.uk

Recent publications:

Harries LW, Ellard S, Stride A, Morgan NG, Hattersley AT.
Isomers of the TCF1 gene encoding hepatocyte nuclear factor-1 alpha show differential expression in the pancreas and define the relationship between mutation position and clinical phenotype in monogenic diabetes.
Hum Mol Genet. 2006 Jul 15;15(14):2216-24. Epub 2006 Jun 7.

Harries LW, Bingham C, Bellanne-Chantelot C, Hattersley AT, Ellard S.
The position of premature termination codons in the hepatocyte nuclear factor -1 beta gene determines susceptibility to nonsense-mediated decay.
Hum Genet. 2005 Nov;118(2):214-24. Epub 2005 Nov 15

Harries LW, Hattersley AT, Ellard S.
Messenger RNA transcripts of the hepatocyte nuclear factor-1 alpha (HNF-1 alpha) gene containing premature termination codons are subject to nonsense-mediated decay.
Diabetes (2004) 53, pp500 – 504.

Harries LW, Ellard S, Jones RW, Hattersley AT, Bingham C
Abnormal splicing of hepatocyte nuclear factor-1 beta in the renal cysts and diabetes syndrome.
Diabetologia. 2004 May;47(5):937-42. Epub 2004 Apr 15.

Bulman MP, Harries LW, Hansen T, Shepherd M, Kelly WF, Hattersley AT, Ellard S.
Abnormal Splicing of Hepatocyte Nuclear Factor 1 alpha in maturity-onset diabetes of the young.
Diabetologia (2002) 45 pp1463 - 1467.

NEONATAL DIABETES AND CONGENITAL HYPERINSULINISM

Dr Sarah Flanagan – Post-Doctoral Research Fellow

Sarah’s research focuses on the genetics of neonatal diabetes and congenital hyperinsulinism. She has a particular interest in understanding genotype/phenotype relationships associated with mutations in the KCNJ11 and ABCC8 genes which encode the subunits of the K-ATP channel in the pancreatic beta cell.

Sarah is currently involved in research to identify novel genetic causes of neonatal diabetes and congenital hyperinsulinism using genome-wide SNP analysis and next-generation sequencing technology.

If you would like to find out more about Sarah’s research, she can be contacted by phone on 01392 406778 or by email at  Sarah.Flanagan@pms.ac.uk

Selected publications:

1.     Flanagan SE, Patch AM, Locke JM et al. Genome-Wide Homozygosity Analysis Reveals HADH Mutations as a Common Cause of Diazoxide-Responsive Hyperinsulinemic-Hypoglycemia in Consanguineous Pedigrees. J Clin Endocrinol Metab. 2011
2.     Flanagan SE, Patch AM, Ellard S. Using SIFT and PolyPhen to Predict Loss-of-Function and Gain-of-Function Mutations. Genet Test Mol Biomarkers. 2010 14(4):533-7.
3.     Flanagan SE, Kapoor RR et al. Dominantly acting ABCC8 mutations in patients with medically unresponsive hyperinsulinaemic hypoglycaemia. Clin Genet. 2011 79(6):582-7.
4.     Flanagan SE, Kapoor RR, Mali G et al. Diazoxide-responsive hyperinsulinemic hypoglycemia caused by HNF4A gene mutations. Eur J Endocrinol. 2010; 162(5):987-92.

5.     Flanagan SE, Hussain K, Smith VV et al.  An ABCC8 gene mutation and mosaic uniparental isodisomy resulting in atypical diffuse congenital hyperinsulinism. Diabetes 2008; 57:259-63

6.     Flanagan SE, Shield JP, Mackay DJ et al. Mosaic paternal uniparental isodisomy and an ABCC8 gene mutation in a patient with permanent neonatal diabetes and hemihypertrophy. Diabetes. 2008; 57:255-8

7.     Stoy J, Edghill EL, Flanagan SE et al. Insulin gene mutations as a cause of permanent neonatal diabetes. PNAS 2007;104(38):15040-4

8.     Flanagan SE, Ellard S, Girard CA et al. Permanent Neonatal Diabetes Caused by Dominant, Recessive, or Compound Heterozygous SUR1 Mutations with Opposite Functional Effects. Am J Hum Genet. 2007 81(2):375-82

9.     Flanagan SE, Patch AM, Mackay DJ et al. Mutations in KATP Channel Genes cause Transient Neonatal Diabetes and Permanent Diabetes in Childhood or Adulthood. Diabetes. 2007 56(7): 1930-1937

10.  Flanagan SE, Edghill EL, Gloyn AL et al. Mutations in KCNJ11, which encodes Kir6.2, are a common cause of diabetes diagnosed in the first 6 months of life, with the phenotype determined by genotype. Diabetologia. 2006 49(6):1190-7.