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morbidity in most countries.Furthermore, 25-50% of people with

non-insulin-requiring diabetes atdiagnosis subsequently progress toinsulin treatment. In some cases, thisprogression results from inadequatetherapy. However, in most people thisis due to the progression of thedisease process itself, with continuingand eventually severe loss of insulin-secretory capacity.

Self-antibodiesIn one sub-group however, circulatingantibodies to the person's owninsulin-producing islet cells can bedetected, the same self-antibodies asare found in Type 1 diabetes.Thosepeople with initially non-insulin-requiring Type 2 diabetes plusdiabetes-associated auto-(self)-antibodies are defined as havingLADA, and are now known to be athigh risk of progression to insulindependency. 1,2

The prevalence of LADA has beenestimated in a number of studies of both European and non-Europeanpopulations. In Europe, LADA isdefined as initially non-insulinrequiring diabetes diagnosed inpeople aged 30-50 years withantibodies to GAD glutamic aciddecarboxylase .This accounts forabout 10% of cases. In populations

Latent autoimmune diabetesin adults (LADA)

David Leslie and Cristina Valeri

December 2003 Volume 48 Issue 4

>>

Diabetes is classified into two major types: Type 1

(in sulin-dependent) diabetes, and Type 2 diabetes.

However, it is apparent that there are some forms of the

condition which do not fit comfortably into these

categories. Indeed, there is one form of diabetes which

appears to straddle the two major types. While it appears

to affect adults with Type 2 diabetes, it shows many of

the genetic, immune, and metabolic features of Type 1

diabetes, and carries a high risk of progression to insulin

dependency. This form of the condition is known as 'latent autoimmune diabetes in adults' (LADA). It is found in

about 10% of initially non-insulin-requiring people with

diabetes, and is therefore probably more prevalent than

Type 1 diabetes. A major European Union initiative

(ACTIONLADA) plans to learn more about LADA.

The development of diabetes isprojected to reach pandemicproportions over the next10-20 years. International DiabetesFederation (IDF) data indicate that bythe year 2025, the number of peopleaffected will reach 333 million 90% of these people will have Type 2diabetes. In most Western societies,

the overall prevalence has reached4-6%, and is as high as 10-12% among60-70-year-old people. The annualhealth costs caused by diabetes and itscomplications account for around6-12% of all health-care expenditure.

Type 2 diabetes plays a major role incontributing to mortality and

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outside Europe the frequency variesfrom zero in Papua New Guinea to16% in the Congo, and to 16% in a

Chinese population.We know thatwhile Type 1 diabetes is relativelyuncommon,Type 2 diabetes is verycommon. Given that an appreciableproportion of non-insulin-requiringpeople with diabetes have GADauto-antibodies, it follows that LADAis probably substantially moreprevalent than classic Type 1diabetes. 1

Autoimmune non-insulin-requiring

diabetes representsa sizeable

proportion of theadult population

with the condition.

GeneticsPeople with LADA often have thetissue-typing (histocompatability

HLA) genes and immune changeswhich are normally associated withType 1 diabetes. 3 Indeed, the HLAgenes associated with LADA arealso the same as those associatedwith Type 1 diabetes.The presenceof GAD auto-antibodies, as notedabove, partly defines LADA. Butpeople with LADA can also haveother diabetes-associated auto-antibodies, including islet cell auto-

antibodies and so-called IA-2 auto-antibodies.Those with GAD andIA-2 auto-antibodies progress morerapidly to insulin dependency thanthose with GAD auto-antibodiesalone. 2,4

Clinical featuresThese genetic and immune features of LADA are consistent with an immune-mediated disease process whichresembles Type 1 diabetes. Peoplewith LADA show many of the other >>

December 2003 Volume 48 Issue 4

Glutamic acid decarboxylase (GAD) is an enzyme which is foundin all human cells. It catalyzes the degradation of glutamic acid,

part of the cycle for the disposal of a waste (ammonia) in the body.The presence in the blood of self-antibodies to GAD is an earlymarker of the process that leads to the destruction of insulin-producing islet cells, and thus of Type 1 diabetes.

Sulfonylureas are one of several different classes of drug which areused in the treatment of Type 2 diabetes to lower the level of glucose in the blood.

About 80% of adults apparently

with recently diagnosed Type 2diabetes but with LADA progressto insulin requirement within6 years.

mauritius

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December 2003 Volume 48 Issue 4

David Leslie andCristina Valeri

David Leslie is Professor of Diabetesand Autoimmunity at Queen Mary College, University of London, UK,and Principle Investigator of the

European Union Study ACTIONLADA.

Cristina Valeri is Research Fellow at Queen Mary College, University of

London, UK.

References1. The Expert Committee on theDiagnosis and Classification of Diabetes Mellitus. Report of theexpert committee on the diagnosisand classification of diabetesmellitus. Diabetes Care 1998; 21(suppl 1): S3-519.

2. Leslie RDG, Atkinson MA,Notkins AL. Autoantigens IA-2 andGAD in type 1 (insulin-dependent)

diabetes. Diabetologia 1999; 42: 3-14.

3. Tuomi T, Carlsson A, Li H,Isomaa B, Miettinen A, Nilsson A,Nissen M, et al. Clinical and geneticcharacteristics of type 2 diabeteswith and without GAD antibodies.

Diabetes 1999; 48: 150-7.

4. Turner R, Stratton I, Horton V,Manley S, Zimmet P, Mackay IR, et al,

for UK Prospective Diabetes Study(UKPDS) Group. UKPDS 25:autoantibodies to islet cytoplasm andglutamic acid decarboxylase forprediction of insulin requirement intype 2 diabetes. Lancet 1997; 350:1288-93.

5. Palmer J. Therapeutic importanceof subset of type 2 diabetes? DiabetesCare 2000; 23: 574-575.

clinical characteristics of Type 1diabetes. For example, they tend notto be obese (unlike most people

with Type 2 diabetes) and show astriking insulin secretory deficiencywhere this is measured.

About 80% of adults apparentlywith recently diagnosed Type 2diabetes but with GAD auto-antibodies (ie LADA) progress toinsulin requirement within 6 years.While the average intervalbetween starting therapy with oral

drugs to lower blood sugar(glucose) levels and progression torequiring insulin is approximately4 years in people with LADA, it isas long as 8 years in people whodo not have diabetes-associatedauto-antibodies. 4 At present,no treatment can stop thisprogression to insulin-requiringdiabetes, but it is clearly of majorpublic health importance sinceLADA is so prevalent. 5

Since the diseasecourse in LADA is

distinct fromclassic Type 2

diabetes,management

strategies mayalso have to

differ.

Management of LADAThere is no establishedmanagement strategy for peoplewho are diagnosed with LADA. 5

The potential value of identifyingthis group at high risk of progression to insulin dependenceincludes:

the avoidance of usingmetformin

treatment theoreticalassociated risks exist ofmetformin in people with

diabetes who becomeinsulin-dependentthe early introduction ofinsulin therapythe application of interventiontrials to arrest or reverse thedestructive disease process.

For those people diagnosed withdiabetes in whom the primarydefect is the loss of insulin

secretion, treatment should aimto restore islet insulin secretion.Therapy to prevent progressiontowards insulin dependency couldinclude immunotherapy, insulin,or oral hypoglycaemic drugs.

The efficacy of sulfonylureas hasnot been formally tested, althoughthey often appear to be effectiveat first in these relatively insulin-sensitive people. However, it isevident that sulfonylureas do notarrest progression to insulindependency in people with LADA.Whether metformin is of benefitis unclear.The drug may becontraindicated in those withLADA as there is a theoreticalrisk of severe metabolicdisturbance in people whoprogress to insulin dependencywhilst taking metformin.