A podcast about diabetes and genes
With Andrew Hattersley
and Maggie Shepherd
A podcast about diabetes and genes
With Andrew Hattersley
and Maggie Shepherd
Mary Lee was thought to have Type 1 diabetes for over 3 decades; she was finally diagnosed with HNF1A MODY and was able to stop her insulin injections and get excellent blood sugar control with a sulphonylurea tablet. We hear from Ewan Pearson how sulphonylurea tablets were found to be excellent glucose lowering treatment when Andrew’s clinical observations of his HNF1A MODY patients were followed up by Ewan with a clinical trial.
Mary Lee was first diagnosed with diabetes aged 16; she was thought to have Type 1 diabetes as she was young and slim and was treated with insulin injections. Although later it was recognised that the diabetes she had was familial with her 2 siblings, father, paternal aunt and grandmother all being diagnosed with diabetes as young adults she still remined on insulin treatment. When, in her early 50’s she had a genetic test she described it has “the best blood test she had ever had” as it led to a diagnosis of HNF1A MODY and her being taken off insulin and treated with sulphonylurea tablets (gliclazide). Initially she found it hard to believe a tiny tablet could replace her insulin injections, but she was delighted to find her blood sugar control was very good and she did not need her insulin.
Professor Ewan Pearson is now Professor of Diabetic Medicine at the University of Dundee, and an Honorary Consultant in Diabetes and Endocrinology at Ninewells Hospital and Medical School in Dundee. More information is available here:
https://discovery.dundee.ac.uk/en/persons/ewan-pearson
He has now been an author on 300 papers but his very first paper, written when a junior doctor, resulted from joining Andrew in his diabetes clinic in 1999. In the clinic he met one of Andrew’s patients with HNF1A MODY whose glucose control had got dramatically worse when he stopped his sulphonylurea treatment and dramatically improved when he restarted it. Ewan wrote up that HNF1A patients were sensitive to sulphonylureas based on the experience of the 3 patients in Andrew’s clinic. This is the paper:
https://onlinelibrary.wiley.com/doi/10.1046/j.1464-5491.2000.00305.x
Ewan decided to train in diabetes and endocrinology and returned to Exeter as a Wellcome Trust research fellow doing a PhD. He set up a formal clinical trial that compared how well gliclazide and metformin worked in patients with HNF1A MODY and Type 2 diabetes. The result was dramatic; the fall in glucose when on the sulphonylurea treatment in the HNF1A patients was 5 x greater than that seen in Type 2 diabetes. This was published in the Lancet as was the first trial evidence of precision medicine in diabetes. The paper can be found here:
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(03)14571-0/abstract
Maggie Shepherd immediately realised that this marked response to sulphonylurea tablets meant that HNF1A patients who were presently treated with insulin might be able to stop their injections and just take sulphonylurea tablets. She wrote up the first eight patients that she successfully transferred off insulin onto gliclazide tablets:
An unexpected death from a heart attack of an HNF1A family member led to a North Devon family raising money for diabetes research and asking Ewan and Andrew to investigate if heart attacks were more common in HNF1A MODY. It had been thought that because these patients had a high HDL (the protective type of cholesterol) that heart attacks would be unlikely, but this turned out not to be the case. Anna Steele, a research nurse working on a PhD, collected details on the age of death and cause of death from 400 MODY family members and showed that heart attacks were twice as likely in those with HNF1A MODY compared to the unaffected family members. This is the paper
https://onlinelibrary.wiley.com/doi/10.1111/j.1464-5491.2009.02913.x
This has led to cholesterol lowering treatment being very important in HNF1A MODY as it is in Type 1 and Type 2 diabetes.
More details about HNF1A MODY are available on our website
https://www.diabetesgenes.org/what-is-mody/hepatic-nuclear-factor-1-alpha-hnf1a/