LATENT AUTOIMMUNE DIABETES OF THE ADULTS LADA

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LATENT AUTOIMMUNE DIABETES OF THE ADULTS (LADA)

• Chou Chien-Wen M.D.
• Chi-Mei Medical Center
• 25 April 2003

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Different Terms

• Slow-progressing type 1 diabetes
• Type 1.5 diabetes
• LADA

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DEFINITION

• The term autoimmune diabetes not requiring
  insulin at diagnosis (or LADA) is more
  appropriate in that the concept of latency
  indicates patients of adult age who do not
  require insulin at least for some time after
  diagnosis and who possess immunological and
  genetic features typical of type 1 diabetes.

Pozzilli, Paolo MD Diabetes Care.
24(8)1460-1467, August 2001.
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Type 2 Diabetes or Slow-Onset Type 1 Diabetes ?

• 60 of cases, type 1 diabetes develops after the
  age of 20 years
• A population-based study of insulin-treated
  adults in New Zealand by Scott and Brown (1991)
  showed that 14.4 of all known adults with
  diabetes were insulin-treated, and most of these
  subjects (83) commenced insulin as a permanent
  treatment within 1 year of diagnosis and hence
  were most likely to have type 1 diabetes
• These findings were confirmed in Sweden by
  Hagopian et al.(1993), who reported that of newly
  diagnosed patients with adult-onset diabetes who
  were seropositive for antibodies to GAD
  (anti-GAD) at the time of diagnosis, 60 required
  insulin within 18 months.

Zimmet, Paul MD Diabetes Care. 22(2S)
Supplement59B-64B, March 1999.
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RECOGNITION OF LADA (1)

• slow-onset diabetes in adults could have an
  autoimmune basis came initially from studies in
  the early 1980s
• Groop et al. in 1986 reported a high frequency of
  islet cell antibodies (ICAs) in adult Finnish
  patients with what was thought to be type 2
  diabetes

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RECOGNITION OF LADA (2)

• They selected 102 cases from the register of the
  Helsinki Diabetic Association and the outpatient
  clinic of the Helsinki University Hospital
• the entry criteria included gt35 years of age at
  diagnosis, nonketotic diabetes without insulin
  treatment over at least 6 months of observation,
  and an initial diagnosis of type 2 diabetes

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RECOGNITION OF LADA (3)

• As many as 10-15 of all adults with diabetes may
  have LADA, and LADA may constitute up to 50 of
  cases of nonobese type 2 diabetes.
• This Figure maybe even higher because positivity
  for anti-GAD may not be the sole marker of
  autoimmunity in this group, given that about 25
  may have markers other than anti-GAD
• testing for anti-ICA512 and insulin autoantibody
  actually adds very little

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• Table 2. Characteristics of Finnish adult
  insulin-deficient and non-insulin-deficient
  subjects

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• Table 3. Anti-GAD and ICA in newly diagnosed type
  2 diabetes from the UKPDS

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• Table 4. Characteristics of 3,672 patients and
  factors related to the progression to insulin at
  6 years from baseline in the UKPDS

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• Table 2-Recent European population-based studies
  of GAD antibody positivity in patients with LADA

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RECOGNITION OF LADA (4)

• 94 of patients aged lt35 years positive for ICA
  and 84 of those positive for anti-GAD at
  baseline required insulin therapy after 6 years
  compared with 14 of seronegative cases.

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• Figure 1. Scattergrams of age at diagnosis
  (years) and time from diagnosis (years) to start
  of insulin treatment according to anti-GAD status
  in Tasmanians with adult-onset insulin-treated
  diabetes. phases both asymptomatic and
  symptomatic

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• Table 1. Features of LADA

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PATHOGENESIS

• the pathogenesis of LADA still remains unanswered
  
• typical HLA genetic predisposition to type 1
  diabetes is less marked than that in patients
  diagnosed in younger age.
• Hyperglycemia in type 1 diabetes is thought to be
  the end-stage result of an interaction between
  susceptibility genes and an abnormal immune
  response toward beta-cells after exposure to
  some environmental factors not yet characterized.
  
• in the case of LADA, the qualitative/quantitative
  exposure to such factors is less pronounced.
• T-cell "insulitis," which has been found in a
  patient with GAD antibodies and residual
  beta-cell function who had a pancreas biopsy,
  suggesting that the pathological hallmark of type
  1 diabetes (i.e., insulitis) is present in LADA.
• immune tolerance to beta-cell antigens could
  occur in LADA, which in turn may spontaneously
  protect these patients from extensive T-cell
  destruction of beta-cells

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• Table 1-Pathogenesis of LADA

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• Figure 1-The destruction of beta-cells and the
  appearance of type 1 diabetes according to the
  age of onset and the putative pathogenetic
  mechanisms

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CHARACTERIZATION OF LADA

• LADA patients have several features of classic
  type 1 diabetes in addition to islet cell
  antibody positivity, including high rates of
  HLA-DR3 and DR4.
• Adults with non-insulin-requiring diabetes who
  are positive for GAD and/or islet cell antibodies
  (ICA) require insulin treatment significantly
  earlier after diagnosis than ICA- patients.
• Of the adult diabetic patients considered to be
  insulin-deficient on the basis of their C-peptide
  responses to glucagon, antibodies to GAD are
  detected in 75 compared with 10 in the
  noninsulin-deficient group.
• The type of autoantibodies to islet cell antigens
  distinguish between acute-onset type 1 diabetes
  and LADA because GAD antibodies and ICA indicate
  slow disease progression, whereas the presence of
  IA-2 antibodies is associated with an acute-onset
  clinical phenotype.
• Patients with LADA share insulin resistance with
  type 2 diabetic patients but display a more
  severe defect in maximally stimulated beta-cell
  capacity.

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• Figure 2-Suggested steps for the characterization
  of LADA. AID, autoimmune diseases

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The prevention of diabetes in LADA

• LADA can be identified using the anti-GAD assay
  since a high proportion (70-80 percent) are
  likely to be positive.
• Their identification could lead to the earlier
  institution of insulin therapy, with preservation
  of residual beta-cell function.
• This, in turn, may permit better metabolic
  control of diabetes, possibly reducing the risk
  of long-term microvascular complications of
  diabetes