Education Resource from the Society for Endocrinology
Professor Andrew Hattersley
Peninsula Medical School, Exeter
Summer School15-18 July 2003
University of Manchester, Hulme Hall, Manchester, UK
There has been considerable emphasis on the molecular genetics of diabetes
in the past decade. There have been considerable scientific advances with most
of the genes for monogenic disorders defined and many predisposing variants
identified for Type1 and Type 2 diabetes. In this talk I aim to answer the question
about whether these scientific advances led to any role for molecular genetics
within the diabetic clinic.
At present defining susceptibility alleles in Type 1 and Type 2 diabetes does
not have sufficient specificity to play a direct role in treatment management
and therefore this lecture will concentrate on monogenic diabetes. The overall
scheme in these genetic subtypes is that by finding a gene mutation it will
enable a specific diagnosis in diabetic patients which in turn will allow improved
understanding about clinical features, clinical course and treatment decisions.
In addition in some cases it is possible to predict the development of diabetes
in non-diabetic family members.
Ten years ago the subdivision of Type 1 and Type 2 diabetes was relatively easy and genetic syndromes could be defined by clinical characteristics. Now there is increasing obesity in Type 2 diabetes occurring in children and young adults and Type 1 diabetic patients are frequently obese as are people with genetic syndromes. This makes clinical criteria much harder to interpret. Fortunately during this past decade there has been considerable advances in defining the monogenic genes with the genes defined in all common monogenic disorders. The commonest type of monogenic diabetes in the diabetic clinic is Maturity Onset Diabetes of the Young (MODY). The clinical definition of this is an early onset of non insulin-dependent diabetes (at least one family member diagnosed under 25 years) with an autosomal dominant inheritance of a single gene defect resulting in ? cell dysfunction. It is now possible for us to identify the genetic subtypes as 6 genes have been defined causing MODY. Diagnostic testing will confirm a diagnosis of MODY meaning for children and adults that it is established that the diagnosis is not Type 2 diabetes.
There is clear evidence that the prognosis of the different subtypes of MODY is completely different as outlined in Table 1. Glucokinase patients are quite unlike any other forms of diabetes in that they have a raised fasting blood glucose from birth which remains stably elevated between 5.5 and 8.5 mmol/l throughout life. In contrast patients with transcription factor mutations are born with normal glucose tolerance and develop diabetes in adolescence or early adult life showing a progressive deterioration in glycaemic control once they become diabetic.
The genetic aetiology determines the treatment response with HNF1? patients being markedly sensitive to sulphonylureas. This finding was confirmed in a randomised control trial and recently patients have been taken off insulin 5-30 years after diagnosis and showed an improvement in HbA1c on oral medication.
Within a MODY family where the genetic aetiology is defined it is possible to perform mutation testing in non-diabetic family members. If this mutation screen is negative they have a population risk of diabetes. However if it is positive for transcription factor diabetes they have a >95% life-time risk of diabetes. There are considerable issues in the practicalities and ethical issues arising and it is crucial that parents making decisions about this are fully informed of all the consequences.
At present not all patients with MODY will have detectable abnormality on sequencing of the coding region. We have found patients who have chromosomal abnormalities leading to MODY and also mutations in a promoter region 46,000 bases away from the rest of the gene. There are many factors that alter the phenotype of mutation carriers. This includes the co-inheritance of a Type 2 diabetes genetic susceptibility and exposure to maternal hypoglycaemia in-utero which leads to a a more severe clinical course and earlier diagnosis of diabetes respectively.
In addition there are practical limitations that although sequencing is both specific and sensitive it is technically difficult, time-consuming and expensive. Rational application of testing is required and this involves using strict criteria to ensure that patients tested are likely to have a mutation. This should involve assessment not only of the characteristics of diabetes but also extra pancreatic fields such as renal cysts which are strong phenotypic marker of HNF1? mutations. It is likely in time that genetic testing will become cheaper and more rapid. Once possible application is the use of DNA chips which we have recently tested in our laboratory.
Molecular genetics can greatly help within the diabetic clinic with diagnosis, prognosis, treatment and prediction of diabetes. However as with all laboratory tests it is important to realise the limitations of this technology the limitations of this technology and clinical skills remain vital for its appropriate use.
Table 1 [PDF]
Andrew Hattersley
Email A.T.Hattersley@ex.ac.uk
Website:
For further details about genetic molecular testing within the UK see the Exeter
Molecular Genetics website www.diabetesgenes.org. This site includes test costs
and patient information
The opinions expressed in this paper are those of the speaker and do not necessarily reflect the views of the Society
Revised:
04-Sep-2003