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Submitted on February 6, 2006
Accepted on February 21, 2006
Peninsula Medical School, Exeter, England; Ninewells Hospital and Medical School, Dundee, Scotland
* To whom correspondence should be addressed. E-mail: A.T.Hattersley{at}exeter.ac.uk.
Defining the molecular genetics of diabetes gives new insights into the underlying etiology and so should help improve treatment. The genetic etiology is now known for most patients with 
-cell monogenic diabetes allowing genetic classification. We review how this genetic knowledge alters treatment.
Patients with a glucose sensing -cell defect due to glucokinase mutations have regulated, mild fasting hyperglycaemia. Oral hypoglycaemic agents or low dose insulin rarely improve glycaemic control. Patients with HNF1
mutations have progressive -cell deterioration and need treatment. HNF1 patients are four times more sensitive to sulfonylureas than matched Type 2 diabetic patients. This is partly due to greater insulin secretion, reflecting that the defect in HNF1 deficiency precedes the KATP channel where sulfonylureas act. HNF1 is expressed in pancreatic stem cells before differentiation into endocrine or exocrine cells so patients with HNF1 mutations have reduced pancreatic development resulting in early-onset diabetes and exocrine dysfunction. These patients usually rapidly require insulin and are not sensitive to sulfonylureas.
35-50% of patients diagnosed with diabetes before 6 months have a mutation in Kir6.2. The mutated KATP channel in these patients does not close in response to increased ATP concentrations but can be closed when sulfonylureas bind to the SUR1 subunit of the channel by an ATP independent route. These patients are usually insulin dependent but have excellent glycaemic control on high dose sulfonylureas tablets.
In conclusion the defining of molecular genetic etiology in monogenic diabetes has defined several specific cell defects and these are critical in determining the response to treatment.
•
HNF1 •
Kir6.2 •
pharmacogenetics •
diabetes
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