Diagnosis, classification, and treatment of diabetes
BMJ 2011; 342 doi: https://doi.org/10.1136/bmj.d3319 (Published 09 June 2011) Cite this as: BMJ 2011;342:d3319
All rapid responses
We read with interest Farmer and Fox's Editorial [1] on the
diagnosis, classification and treatment of diabetes. It highlights an
important point about the high levels of misclassification of diabetes
within primary care which in turn can adversely impact on clinical
management decisions.
Although we agree that 'universal genetic testing for young onset
diabetes remains prohibitively expensive' it is important to note that for
diabetes diagnosed under the age of six months genetic testing is
absolutely necessary to help in the management of neonatal diabetes and
results in better treatment[2] that is clinically cost effective.[3]
We contest the statement that the cost of genetic testing is
prohibitive for routine testing. A test should be done if the pre-test
likelihood warrants it and it will lead to a change in clinical
management. The pre-test likelihood of a positive genetic diagnosis for
diabetes can be greatly improved by considering age of diagnosis, family
history and treatment. Using these clinical factors MODY is currently
confirmed in 27% of referrals for genetic testing. [4]. Further
biochemical tests, such as autoantibody status[5], serum or urine C-
peptide[6] and highly sensitive CRP[7] are likely to refine this process.
The NHS cost for a single gene test for MODY is ?350. A positive
result in 1 in 4 patients means this is good value for money when
considering the potential savings in drugs costs, monitoring, follow-up
and complications, not to mention the patient's quality of life
improvements.[8] Genetic testing should be a key part of routine diabetes
care.
We feel that weighted clinical characteristics are important in
determining which patients should be selected for genetic screening and
have developed a probability calculator model, which is available at:
http://projects.exeter.ac.uk/diabetesgenes/mody/MODYCalc.htm
Ali Chakera, Beverley Shields, Andrew Hattersley, Sian Ellard
References
1. Farmer A, Fox R. Diagnosis, classification, and treatment of
diabetes. BMJ 2011; 342:d3319
2. Pearson ER, Flechtner I, Njolstad 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, Sovik 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 Aug 3;355(5):467-77.
3. Greeley SA, John PM, Winn AN, Ornelas J, Lipton RB, Philipson LH,
Bell GI, Huang ES. The cost-effectiveness of personalized genetic
medicine: the case of genetic testing in neonatal diabetes. Diabetes Care.
2011 Mar;34(3):622-7. Epub 2011 Jan 27
4. Shields BM, Hicks S, Shepherd MH, Colclough K, Hattersley AT,
Ellard S. Maturity-onset diabetes of the young (MODY): how many cases are
we missing? Diabetologia. 2010 Dec;53(12):2504-8. Epub 2010 May 25.
5. McDonald TJ, Colclough K, Brown R, Shields B, Shepherd M, Bingley
P, Williams A, Hattersley AT, Ellard S. Islet autoantibodies can
discriminate maturity-onset diabetes of the young (MODY) from Type 1
diabetes. Diabet Med. 2011 Mar 12. doi: 10.1111/j.1464-5491.2011.03287.x.
[Epub ahead of print]
6. Besser RE, Shepherd MH, McDonald TJ, Shields BM, Knight BA, Ellard
S, Hattersley AT. Urinary C-peptide creatinine ratio is a practical
outpatient tool for identifying hepatocyte nuclear factor 1-
{alpha}/hepatocyte nuclear factor 4-{alpha} maturity-onset diabetes of the
young from long-duration type 1 diabetes. Diabetes Care. 2011 Feb; 34(2):
286-91.
7. McDonald TJ, Shields BM, Lawry J, Owen KR, Gloyn AL, Ellard S,
Hattersley AT. High-Sensitivity CRP Discriminates HNF1A-MODY From Other
Subtypes of Diabetes. Diabetes Care. 2011 Jun 23. [epub ahead of print]
8. Shepherd M, Hattersley AT. 'I don't feel like a diabetic any
more': the impact of stopping insulin in patients with maturity onset
diabetes of the young following genetic testing. Clin Med. 2004 Mar-Apr;
4(2): 144-7.
Competing interests: No competing interests
Dear Editor
We thank Misra and colleagues for their support in highlighting the
serious issue of the misclassification of diabetes type, and the need to
look beyond traditional classifications based on age and body mass index.
However, their proposal that C-peptide and autoantibody testing should be
available to all practitioners is not universally accepted. Indeed the
studies they quote,1;2 although important were, respectively, small (18
patients) and included those with a diagnosis of type 1 diabetes of at
least 5 years duration. Both papers noted the need for further studies
before the tests were incorporated into clinical practice.
A detailed review recently published simultaneously in Diabetes Care
and Clinical Chemistry,3 concluded that there was no role at present for
routine C-peptide testing in the diagnosis or monitoring of diabetes,3 and
that islet cell autoantibody testing should not be used for routine
diagnosis of diabetes. In addition to the reasons given in our editorial,4
they note that that the interlaboratory imprecision for islet cell
autoantibodies is inappropriately high. We grateful to Misra and
colleagues for providing further detail about these developments in
laboratory assessment of diabetes.
Andrew Farmer and Robin Fox
1. Besser REJ, Ludvigsson J, McDonald TJ, Shilds BM, Knight BA and
Hattersley AT. Urine C-peptide creatinine ratio is a non-invasive
alternative to the mixed meal tolerance test in children and adults with
type 1 diabetes. Diabetes Care. 2011; 34:607-609
2. Besser REJ, Shepherd MH, McDonald TJ, Shields BM, Knight BA,
Ellard S & Hattersley AT. Urinary C-peptide creatinine ratio is a
practical outpatient tool for identifying hepatocyte nuclear factor 1-
alpha/hepatocyte nuclear factor 4-alpha maturity-onset diabetes of the
young from long-duration type 1 diabetes. Diabetes Care. 2011; 34:286-291
3. Sacks DB, Arnold M, Bakris GL, Burns DE, Horvath AR, Kirkman MS et
al. Guidelines and Recommendations for Laboratory Analysis in the
Diagnosis and Management of Diabetes Mellitus. Diabetes Care
2011;34(6):e61-e99.
4. Farmer A, Fox R. BMJ 2011;342:doi:10.1136/bmj.d3319
Competing interests: No competing interests
Dear Editor,
The Editorial by Farmer and Fox addresses the serious issue of the
misclassification of diabetes type, seen increasingly in the diabetes
clinic. However, it is important to clarify some of the points raised and
to discuss some additional issues.
The aetiological classification as proposed by the working group(1)
is not universally applicable at diagnosis. Rather than classifying
diabetes with certainty, the critical decision at diagnosis is to
determine whether life-sustaining insulin therapy is required or not. To
this end, the WHO criteria, which is implemented in the UK, specifies four
sub-types and recognises the continual spectrum of glycaemia and insulin
dependency within these cohorts (2). This is a safe approach to adopt at
the point of diagnosis, and classification of diabetes type can then be
reassessed at regular intervals.
The authors underestimate the utility of autoantibody testing as,
whilst they are correct that a positive test doesn't automatically assign
an individual as type 1, as shown in the UKPDS the risk of becoming
insulin dependent is far higher in positive individuals than negative (3)
Therefore in those with uncertain type, autoantibody positivity should be
regarded as a risk factor for future insulin dependency. This reinforces
the need to frequently reassess individuals who are antibody positive but
not on insulin, for development of beta-cell failure.
The laboratory assessment of beta-cell function has been completely
overlooked. C-peptide assessment has often been in the domain of
specialist diabetes clinics. However, recent publications highlight the
utility of urinary C-peptide assessment as a stable and sensitive
alternative to serum stimulated C-peptide for the differentiation of type
1 diabetes and MODY(4,5). Though C-peptide levels are often equivocal in
the very group of individuals in whom beta-cell function assessment is
desirable, the combination of C-peptide levels with autoantibody testing
and clinical suspicion is a powerful discriminatory tool available to all
practitioners.
The cost of genetic testing is often cited as a barrier to routine
testing in the diabetes clinic. It is of course important to select
appropriate patients for testing to improve the pre-test probability but,
in addition to this, the cost of testing should be considered alongside
the potential cost savings from stopping insulin in those with confirmed
mutations. Furthermore one cannot underestimate the improvements in
quality of life and psychological morbidity that young individuals who are
able to stop insulin may receive.
We thank the authors for highlighting this very important problem. It
is imperative that primary and secondary care physicians recognise the
significance of appropriately classifying diabetes. Traditional
classifications based on age and body mass index are increasingly
redundant as phenotypes converge. Clinical assessment is now augmented by
a powerful laboratory toolkit.
Dr Shivani Misra, SpR Metabolic Medicine (smisra@imperial.ac.uk)
Dr Anne Dornhorst, Consultant Diabetologist
Dr Nick S Oliver, Consultant Diabetologist
Imperial Healthcare NHS Trust
1. Royal college of general practitioners and NHS Diabetes. Coding,
classification and diagnosis of diabetes. 2011.
www.diabetes.nhs.uk/our_work_areas/classification_of_diabetes/.
2.http://whqlibdoc.who.int/publications/2006/9241594934_eng.pdf
3. Turner R, Stratton I, Horton V, Manley S, ZImmet P, Mackay IR,
Shattock M, Bottazzo GF, & Holman R. For the UKPDS study. UKPDS 25:
auto antibodies to islet-cell cytoplasm and glutamic acid decarboxylase
for prediction of insulin requirement in type 2 diabetes. Lancet.
1997;350:1288-1293
4. Besser REJ, Ludvigsson J, McDonald TJ, Shilds BM, Knight BA and
Hattersley AT. Urine C-peptide creatinine ratio is a non-invasive
alternative to the mixed meal tolerance test in children and adults with
type 1 diabetes. Diabetes Care. 2011; 34:607-609
5. Besser REJ, Shepherd MH, McDonald TJ, Shields BM, Knight BA,
Ellard S & Hattersley AT. Urinary C-peptide creatinine ratio is a
practical outpatient tool for identifying hepatocyte nuclear factor 1-
alpha/hepatocyte nuclear factor 4-alpha maturity-onset diabetes of the
young from long-duration type 1 diabetes. Diabetes Care. 2011; 34:286-291
Competing interests: No competing interests
Dear Sir,
The Royal College of General Practitioners and NHS
Diabetes seem to suggest making life unduly difficult for many clinic
doctors. They suggest a new nomenclature for the types of diabetes
mellitus so that management may more often be appropriate. If that's the
aim, why not aim at a classification into modes of management?
Choice of management depends primarily on metabolic features, such as
glycaemic levels and weight for height (would that fasting insulinaemia
could be included), and only secondarily on pathogenetic type (eg, a
tendency to prescribe insulin slightly more readily for Type I patients,
but it does a Type I patient with mild hyperglycaemia and normal weight no
favours to use insulin when oral agents might control their glycaemia [and
growth if young] just as well). The report does recognise, even if only in
passing, that under its system assessment of type may alter with time, but
it seems asking for trouble to classify according to 'continual treatment
from diagnosis'. Responses to diet, increased exercise and oral
hypoglycaemic agents can be surprisingly variable, let alone according to
the presence of bacterial infection, large alcohol intake or depression.
It's a wise physician who can decide on the wisdom of the use of insulin
immediately on diagnosis, especially I would hazard for those more than 35
years old (and the thought that the type of one's diabetes will depend on
the exact date of one's 35th birthday is little short of ludicrous).
Metabolic state is one thing, and pathogenetic process another, but
to classify with the aim of improving management from the result of a snap
decision on first diagnosis will produce multiple revisions and so sow
confusion.
Yours sincerely,
Derek Hockaday
Competing interests: No competing interests
Measuring endogenous insulin secretion can help discriminate diabetes subtypes.
Dear Editor
We welcome Farmer and Fox's editorial on the diagnosis of different
types of diabetes and are pleased it has lead to a debate.[1] However, we
should point out that in their recent reply the authors have misquoted the
papers they reference, and it is our opinion that more consideration
should be given to the role of C-peptide as a guide to treatment in
diabetes.
The studies on urine C-peptide:creatinine ratio (UCPCR) mentioned
involved 72 and 200 patients with diabetes, respectively,[2,3] rather than
the 18 quoted. There is now a strong body of evidence that C-peptide and
can be used to discriminate Type 1 from MODY and Type 2 diabetes.[2-5]
Farmer and Fox support the review by Sacks et al [6] that C-peptide
should not be routinely measured, however that review was published before
considering the latest data regarding the ease and utility of testing
UCPCR. The advantages of the urine test are that it is cheap (~10 pounds),
non-invasive and not subject to the stringent collection requirements of
the serum test. It is stable for three days in boric acid preservative at
room temperature. This means that the test can be requested from primary
care and allows direct measurement of the hormone of interest to help
classify type of diabetes.
The clear difference between treating patients with Type 2 and Type 1
diabetes results from whether or not they secrete endogenous insulin. Most
treatment in Type 2 diabetes only works if there is endogenous insulin
secretion. UCPCR is an easy method of determining insulin secretion.
We consider there are several clinical scenarios in which testing C-
peptide is useful. The main clinical use of UCPCR is to determine
endogenous insulin secretion in patients on insulin treatment. It allows
patients treated with insulin from diagnosis to be reclassified from Type
1 to Type 2 diabetes if UCPCR is positive allowing a change to more
appropriate treatment.
The problem with using 'time to continuous insulin treatment' as a
diagnostic criterion is that it results in a circular diagnosis. If
someone has determined a patient to have Type 1 diabetes at diagnosis,
they will be treated with continual insulin, which will subsequently
'confirm' the diagnosis of Type 1 diabetes.
As Farmer and Fox[1] point there is a considerable overlap between
Type 1, Type 2 and MODY diabetes. Farmer and Fox state that in order for
practices to "avoid misclassifying patients with Type 1 and Type 2
diabetes, medical records should be regularly reviewed, preferably by
checking the classification against other information held in the medical
record." Testing UCPCR in patients more than five years after diagnosis
provides a clear, evidence-based way of checking that initial clinical
diagnosis.[5]
Rachel EJ Besser, Ali J Chakera, Angus G Jones, Maggie H Sheppard,
Tim J McDonald, Andrew T Hattersley
References:
1. Farmer A, Fox R. BMJ 2011;342:doi:10.1136/bmj.d3319
2. Besser REJ, Ludvigsson J, McDonald TJ, Shields BM, Knight BA and
Hattersley AT. Urine C-peptide creatinine ratio is a non-invasive
alternative to the mixed meal tolerance test in children and adults with
type 1 diabetes. Diabetes Care. 2011; 34:607-609
3. Besser REJ, Shepherd MH, McDonald TJ, Shields BM, Knight BA,
Ellard S & Hattersley AT. Urinary C-peptide creatinine ratio is a
practical outpatient tool for identifying hepatocyte nuclear factor 1-
alpha/hepatocyte nuclear factor 4-alpha maturity-onset diabetes of the
young from long-duration type 1 diabetes. Diabetes Care. 2011; 34:286-291
4. Bowman P, McDonald TJ, Shields BM, Knight BA, Hattersley AT.
Validation of a single-sample urinary C-peptide creatinine ratio as a
reproducible alternative to serum C-peptide in patients with Type 2
diabetes. Diabet Med. 2011 Aug 26. doi: 10.1111/j.1464-5491.2011.03428.x.
[Epub ahead of print]
5. Jones AG, Besser RE, McDonald TJ, Shields BM, Hope SV, Bowman P,
Oram RA, Knight BA, Hattersley AT. Urine C-peptide creatinine ratio is an
alternative to stimulated serum C-peptide measurement in late-onset,
insulin-treated diabetes. Diabet Med. 2011 Sep;28(9):1034-8. doi:
10.1111/j.1464-5491.2011.03272.x.
6. Sacks DB, Arnold M, Bakris GL, Burns DE, Horvath AR, Kirkman MS et
al. Guidelines and Recommendations for Laboratory Analysis in the
Diagnosis and Management of Diabetes Mellitus. Diabetes Care
2011;34(6):e61-e99.
Competing interests: No competing interests