Opening Lecture
From base change to better care:
the clinical impact of molecular genetics

A. Hattersley, UK

Genetics is one approach that can define the underlying pathophysiology and also heterogeneity in patients with diabetes. 2007 has been a great year for the genetics of diabetes with at least 6 genomewide scans reported resulting in 3 novel Type 1 and 6 novel Type 2 genes. Therefore there has been as much progress in 2007 as there has been in the 15 years before this and the rate of gene discovery is continuing to accelerate. The ultimate aim of all research in diabetes is to prevent diabetes or improve the care of people with diabetes. As almost all of the novel predisposing genes for Type 2 diabetes were not expected there will be considerable work to establish how they predispose to diabetes before novel treatments affecting these pathways can be developed. However there are some genetic discoveries that can already lead to improved clinical care.   In monogenic diabetes the cause of diabetes is a mutation in a single gene so finding a mutation in a causal gene by sequencing the DNA from patients can be used as a diagnostic test. However such a diagnostic test will only be helpful if this information not only helps classification but also helps determine clinical care. At present the choice of diabetic pharmacological agents predominantly depends on the degree of hyperglycaemia rather than the cause of the hyperglycaemia but monogenic diabetes shows this traditional paradigm needs to change.  

Clinically defined maturity-onset diabetes of the young or MODY is now subclassified in to molecular genetic subgroups with very different beta-cell defects and different responses to treatment. Patients with a glucose-sensing beta-cell defect due to glucokinase mutations have regulated, mild, fasting hyperglycaemia. Oral hypoglycaemic agents or low-dose insulin do not affect glycaemic control and so should be discontinued. There is striking evidence of pharmacogenetics in HNF-1alpha MODY where, in a randomised trial, we showed a 4 fold greater fall in fasting glucose than in BMI matched type 2 patients. HNF-1alpha patients control can be improved by taking them off insulin injections after 10-30 years and putting them on sulphonylureas. This reflects that the defect in HNF1alpha deficienct beta-cells precedes the KATP channel where sulphonylureas act. HNF1beta is expressed in pancreatic stem cells before differentiation into endocrine or exocrine cells, so patients with HNF1beta mutations have reduced pancreatic development, resulting in early-onset diabetes and exocrine dysfunction. These patients usually rapidly require insulin and are not sensitive to sulphonylureas. Therefore very different treatments are needed for these three genetic subgroups of MODY. 

The management of neonatal diabetes has been transformed since the discovery that mutations in the genes encoding the Kir6.2 and SUR1 subunits of the beta-cell potassium channel were major causes of diabetes diagnosed before 6 months. All mutations showed reduced channel closure in response to ATP resulting in reduced insulin secretion with the severity determining the severity of the beta-cell defect and whether there are neurological features. A striking result has been that even the insulin dependent patients can discontinue insulin injections and show improved glycaemic control on high dose sulphonylurea tablets which act to close the KATP channel by a non ATP dependent route.   In conclusion, molecular genetics allows us to understand more precisely the pathophysiology and aetiology of the diabetes found in an individual patient. In monogenic diabetes we can already see how this information has identified several specific beta-cell defects each with a specific response to treatment. Diagnostic genetic testing is now available in many countries (see www.diabetesgenes.org) and the associated improvements in treatment have been a driving force in the introduction of genetic testing into clinical care. The next challenge is to use the new genetic information in type 2 diabetes to lead to further individualisation of treatment.