Stopping insulin; a life-changing therapeutic intervention for patients with neonatal diabetes
Submitting InstitutionUniversity of Exeter
Unit of AssessmentClinical Medicine
Summary Impact TypeHealth
Research Subject Area(s)
Medical and Health Sciences: Clinical Sciences
Summary of the impact
The treatment of patients with neonatal diabetes has been transformed by
the research of Professors Sian Ellard and Andrew Hattersley at Exeter.
Childhood diabetes usually presages a life-long requirement for insulin
injections and a reduction in quality of life. This research revealed that
~50% of patients with permanent neonatal diabetes have mutations in a
potassium channel regulating insulin secretion. A new diagnostic test was
introduced and relevant patients were switched from insulin injections to
oral therapy. As a result, patients in 77 countries across 5 continents
now benefit from improved care, a better quality of life and reduced
Before this research, most patients diagnosed with diabetes in the first
six months of life faced a lifetime of insulin treatment. In 2002, Prof
Hattersley (FRS; appointed to University of Exeter in 1995) initiated an
international search for patients with neonatal diabetes and Prof Ellard
(appointed in 1997) began the search for disease-causing mutations. As a
result, their postdoctoral fellow, Dr Anna Gloyn, found that the most
common cause was a mutation in a subunit (Kir6.2) of the pancreatic beta
cell ATP-sensitive potassium (KATP) channel [1,2].
The pancreatic KATP channel controls electrical activity,
linking raised blood glucose levels to insulin secretion. Binding of ATP
to the Kir6.2 subunit closes the channel to initiate insulin secretion.
Molecular modelling suggested that the patients' mutations would affect
ATP binding and hence prevent insulin secretion. This was confirmed by
functional studies of isolated potassium channels expressed either in
Xenopus oocytes  or cultured pancreatic beta-cells (with Prof Noel
Morgan in Exeter).
The pivotal stage in the research was recognising the possibility for
pharmaceutical intervention. The KATP channel defect suggested
that, in affected patients, the glucose sensing and insulin
synthesis/secretion processes are intact, but failure to secrete insulin
is due to the channel remaining open in the presence of ATP. Sulphonylurea
drugs used to treat type 2 diabetes act by binding to the sulphonylurea
receptor (SUR1) subunits of the channel to cause their closure,
independently of ATP. Prof Hattersley proposed that sulphonylureas might
close the channels and facilitate insulin secretion when administered to
patients in vivo.
Clinical evidence from "proof of principle" studies supported this
possibility and in 2005 Prof Hattersley and PhD student Dr Ewan Pearson
led an international clinical trial in which >90% of patients with
Kir6.2 mutations were able to stop insulin treatment and achieve better
blood glucose control . The improved glycaemic control predicts a lower
risk of diabetic complications later in life. In 2006, Prof Ellard found
that mutations in the SUR1 subunit also cause neonatal diabetes .
Overall, around 50% of patients with permanent neonatal diabetes have a
mutation in either the Kir6.2 or SUR1 subunits and most patients respond
to sulphonylurea therapy .
Approximately 20% of patients with Kir6.2 or SUR1 mutations also have
impaired neurological function. A small number have severe developmental
delay, epilepsy and neonatal diabetes (named by the Exeter group as DEND
syndrome). Prof FM Ashcroft's group (Oxford) showed that the mutations in
these patients have the greatest effect on channel function. A more common
intermediate form of DEND syndrome with moderate developmental delay was
also recognised and the researchers investigated the responses of these
patients to sulphonylurea treatment. Reports have described improved
cognitive function (particularly speech and concentration), behaviour,
sleeping patterns and motor development . The neurological benefits are
likely to be greatest in those children treated with sulphonylureas from
diagnosis since brain plasticity is greatest in early childhood.
This research has provided one of the first examples of genomic medicine
where detailed knowledge of a patient's genome determines their optimal
References to the research
Evidence of the quality of the research is provided via a
selection of highly-cited, peer reviewed, publications and by the award of
external grant support.
1. Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining GJ, Slingerland
AS, Howard N, Srinivasan S, Silva JM, Molnes J, Edghill EL, Frayling TM,
Temple IK, Mackay D, Shield JP, Sumnik Z, van Rhijn A, Wales JK, Clark P,
Gorman S, Aisenberg J, Ellard S, Njølstad PR, Ashcroft FM, Hattersley AT.
Activating mutations in the gene encoding the ATP-sensitive
potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J
Med. 2004 350: 1838-1849. (692 citations to Oct 13)
2. Flanagan SE, Edghill EL, Gloyn AL, Ellard S, Hattersley AT. 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: 1190-1197. (130 citations to Oct 13)
3. Pearson ER, Flechtner I, Njølstad PR, Malecki MT, Flanagan SE, Larkin
B, Ashcroft FM, Klimes I, Codner E, Iotova V, Slingerland AS, Shield J,
Robert JJ, Holst JJ, Clark PM, Ellard S, Søvik O, Polak M, Hattersley AT;
Neonatal Diabetes International Collaborative Group. Switching from
insulin to oral sulfonylureas in patients with diabetes due to Kir6.2
mutations. N Engl J Med. 2006 355: 467-777. (423 citations to Oct 13)
4: Ellard S, Flanagan SE, Girard CA, Patch AM, Harries LW, Parrish A,
Edghill EL, Mackay DJ, Proks P, Shimomura K, Haberland H, Carson DJ,
Shield JP, Hattersley AT, Ashcroft FM. Permanent neonatal diabetes caused
by dominant, recessive, or compound heterozygous SUR1 mutations with
opposite functional effects. Am J Hum Genet. 2007 81:375-82. (81 citations
to Oct 13)
5: Rafiq M, Flanagan SE, Patch AM, Shields BM, Ellard S, Hattersley AT;
Neonatal Diabetes International Collaborative Group. Effective treatment
with oral sulfonylureas in patients with diabetes due to sulfonylurea
receptor 1 (SUR1) mutations. Diabetes Care. 2008 31:204-9. (76 citations
to Oct 13)
6: Slingerland AS, Nuboer R, Hadders-Algra M, Hattersley AT, Bruining GJ.
Improved motor development and good long-term glycaemic control with
sulfonylurea treatment in a patient with the syndrome of intermediate
developmental delay, early-onset generalised epilepsy and neonatal
diabetes associated with the V59M mutation in the KCNJ11 gene.
Diabetologia. 2006 49:2559-63. (57 citations to Oct 13).
1) Wellcome Trust 2003-2008 £1.13M (Prof Hattersley)
Title: Monogenic and Polygenic Influences on human fetal growth and
development — Wellcome Research Leave Award for Clinical Academics
2) Wellcome Trust 2008-2011 £430K (Prof Frayling co-PI)
Title: An investigation of genes in key beta-cell pathways following the
type 2 diabetes WTCCC genome wide association study.
3) MRC 2007-2010 £1.19M (Prof Frayling co-PI)
Title: Translating Genome-Wide Association Data from the WTCCC Study into
Biological and Clinical Insights in Type 2 Diabetes.
4) European Commission FP7 Initial Training Networks (Marie Curie)
2009-2013 €400K (PI Prof Hatterley and 12 others)
Title: BOLD — Biology of Liver and Pancreatic Development and Disease
5) Wellcome Trust 2012-2019 £2.9M (Joint PIs Prof Ellard and Hattersley)
Title: New insights from neonatal diabetes
Details of the impact
1) Diagnostic genetic testing is now available for all patients
diagnosed with neonatal diabetes. Multiple laboratories in Europe
and the USA have set up testing for neonatal diabetes. However, for those
patients in countries without genetic testing laboratories or for whom the
cost of testing is prohibitive, the Exeter laboratory provides rapid
testing at no cost to the patient or their parents (funded by the Wellcome
Trust). Patients continue to be referred for testing from across the world
and, to October 2013, 1169 referrals had been received from 77 countries
across 5 continents. The number of patients diagnosed with a KATP
channel mutation causing neonatal diabetes had increased from 10 reported
in the first publication (2004) to 454 in October 2013.
2) Public awareness of neonatal diabetes and the need for genetic
testing has been raised. In July 2009, the Royal Society hosted the
first Neonatal Diabetes Open Day for families whose lives have been
changed by this research. 45 families came from across the world to
celebrate the life-changing transformations they have experienced.
Colleagues in Chicago (USA) were inspired to create a US registry and held
their first Neonatal Diabetes Family Meeting in June 2010. Facebook groups
have been created by parents and parent-led meetings have followed.
3) Most patients found to have a KATP channel
mutation can stop insulin treatment and achieve better glucose control
with sulphonylurea tablets. For most patients their glucose control
on insulin was outside treatment targets but on sulphonylureas glucose
levels are maintained within treatment targets and often close to the
levels in people without diabetes. More than 500 patients worldwide have
now had their diabetes therapy changed and many more newly diagnosed
individuals who would otherwise have been prescribed insulin therapy, are
being treated with tablets.
4) Changing from insulin injections to sulphonylurea tablets improves
quality of life by stopping pain at injection sites and removing the
many restrictions on life that are imposed by multi-injection or insulin
pump therapy. The regulation of insulin secretion in response to ingestion
of food means that the patients' diet is no longer tightly restricted.
They also experience fewer hypoglycaemic episodes.
5) The better glycaemic control achieved with sulphonylureas will
reduce the future risk of diabetic complications including heart
attack, stroke, kidney failure, blindness and neuropathy.
6) Many of the 20% of patients with neurological impairment have seen
an improvement in their motor skills, cognitive function, speech,
concentration, sleep and behaviour. Reports from parents have been
substantiated by teachers and healthcare professionals. The early
diagnosis made possible by clinical diagnostic genetic testing means that
the maximum number of patients can benefit from improved neurological
outcome as well as better diabetes control and lifestyle gains.
7) Reduced healthcare costs due to the cheaper treatment
(sulphonylurea tablets vs insulin), reduction in blood glucose monitoring
and reduced risk of diabetic complications later in life. For example,
colleagues in the USA (g; below) estimate that genetic testing followed by
transfer to sulphonylureas and consequent improved glycaemic control saves
$12,528 per patient at 10 years and $30,437 at 30 years.
8) This work has informed public debate on genomic medicine.
Sources to corroborate the impact
Diagnostic genetic testing for all patients diagnosed with neonatal
a) The Exeter website www.diabetesgenes.org
provides information on genetic testing for neonatal diabetes and has
received >115000 hits (at Sept 2013).
Raised public awareness of neonatal diabetes and the need for
b) The Wellcome Trust made a video which is available on their website
c) Diabetes UK includes neonatal diabetes within its website "Guide to
d) A documentary entitled "Journey to a Miracle: Freedom from Insulin" is
in production. A pilot is available at http://www.tmktv.com/result.php?title=Journey-to-a-Miracle:-Freedom-from-Insulin---Pilot
Improved quality of life for patients with a KATP channel
mutation who stop insulin treatment
Transfer from insulin to sulphonylurea tablets has transformed patient
lives. Patients and parents describe the effect this has had on their
lives in the video filmed by the Wellcome Trust and TMKTV Documentary (see
b and d).
e) The Exeter team were awarded the ISPAD (International Society for
Paediatric and Adolescent Diabetes) Prize for Innovation in Pediatric
Diabetes Care in 2012 see http://www.ispad.org/
f) There have been numerous reports on the TV news and in newspapers
about the improved quality of life for patients. One example can be seen
on the BBC website http://news.bbc.co.uk/1/hi/health/8176275.stm
Reduced healthcare costs due to the cheaper treatment
(sulphonylurea tablets vs insulin), reduction in blood glucose monitoring
and reduced risk of diabetic complications later in life.
g) Colleagues in Chicago (USA) demonstrated by modelling that genetic
testing for neonatal diabetes is cost-effective with savings achieved
within 10 years from testing (Greeley et al 2011 Diabetes Care 34,
Informed public debate on genomic medicine
h) The House of Lords Select Committee on Science and Technology
conducted an enquiry into genomic medicine. Their report was published in
2009 and includes the example of neonatal diabetes (see page 18 http://www.parliament.uk/business/committees/committees-archive/lords-s-t-select/genomic/).