The Journal for Nurse Practitioners
Volume 4, Issue 9 , Pages 681-687, October 2008

Latent Autoimmune Diabetes in Adults

  • Jane Kapustin

      Affiliations

    • Jane Kapustin, PhD, CRNP, is the assistant dean for master's studies and an associate professor at the University of Maryland School of Nursing and an NP at Joslin Diabetes Center at University of Maryland Medical Center.

Article Outline

Abstract 

Latent autoimmune diabetes in adults (LADA) is a genetically linked, autoimmune form of type 1 diabetes mellitus that is commonly seen after age 30 in patients who often have a normal body mass index without overt signs of metabolic syndrome. They have positive circulating antibodies reflecting the autoimmune nature of beta cell destruction, and they frequently are poorly controlled on oral anti-diabetic agents. Because they are older when first symptomatic, they are often diagnosed with type 2 diabetes. However, it is important to recognize patients with LADA because they often progress quickly to insulin dependence. The characteristics of LADA, pathogenesis, diagnostic work-up, complications, and evidence-based management of the disease will be reviewed. Implications for practice will be included.

Keywords:  GAD antibodies , insulin , LADA , metabolic syndrome , type 1 diabetes mellitus

 

Latent autoimmune diabetes in adults (LADA) is a genetically linked, autoimmune form of type 1 diabetes mellitus that is manifested in adult populations, typically over the age of 30.1 Because many of the affected patients have poor glycemic control and are older when first symptomatic, they are often diagnosed with type 2 diabetes. However, many do not have the typical characteristics of type 2 diabetics such as obesity and insulin resistance.2

Confusion regarding the diagnosis and categorization of LADA exists because patients share symptoms of both types 1 and 2 diabetes, and it is usually diagnosed in adulthood. It has been referred to as “late-onset autoimmune diabetes of adulthood,” “slow onset type 1 diabetes,” and “type 1.5 diabetes.”3 Officially, LADA is classified as type 1 diabetes by the World Health Organization.

The frequency of LADA is underestimated and may range as high as 6% to 50% among type 2 diabetics. Its prevalence is increased among younger patients.4 Given its frequency among the population, it is important to recognize LADA because these patients are at particular high risk for developing insulin dependence. They may require a rapid escalation of oral medications and it may result in multiple medication failure. At that point, they will become insulin dependent earlier than antibody-negative patients.5

The characteristics of LADA, pathogenesis, diagnostic work-up, complications, and evidence-based management of the disease will be reviewed. Emphasis on the clinical signs and symptoms that may prompt a more detailed work-up will be included.

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Background and Incidence 

LADA is associated with circulating antibodies to islet cells and most commonly to glutamic acid decarboxylase (GAD). Because they appear to have a more insidious form of autoimmune beta cell destruction, the patients affected with LADA do not require insulin initially. Eventually, however, most patients with LADA will require insulin within 3 years as beta cell function declines. In particular, those patients with LADA who have positive islet cell antibodies are more likely to experience accelerated beta cell failure.6, 7, 8

Patients with LADA have several characteristics of type 1 and type 2 diabetes (Table 1). The accurate diagnosis of LADA is usually based on 3 criteria: (1) adult onset, typically over the age of 30, (2) presence of circulating antibodies, and (3) requiring insulin no sooner than 6 months after diagnosis.1, 6, 7 This type of diabetes is etiologically associated with environmental and heritable predispositions.7

Table 1. Summary of LADA compared with Type 1 and Type 2 Diabetes Mellitus
CharacteristicType 1 DiabetesType 2 DiabetesLADA
Age of diagnosisChildren to young adults, usually under 25. Most cases occur between early teens and age 20.Older adults but trend is among younger patients, affecting children and adolescents.Children not affected. Typically seen at age 35-40, but can occur at age 25.
OnsetRapid, days to weeksMore insidious, over months to yearsMore insidious than type 1 DM. May progress more quickly.
Associated risks/genetic influencesGenetic factors and environmental triggers, usuallyexposure to virusFamilial/hereditary associations. Associated with PCOS, metabolic syndrome, Hashimoto's thyroiditis. Environmental factors: obesity, sedentary lifestyle, central obesityGenetic predisposition and environmental triggers suspected. Usually absence of type 2 DM in family history.
Serological markers
ICAICA 80% of casesNoPositive indicates LADA vs T2DM
IAAIAA often detectedNoVery often
GADGAD more common in adults than childrenRare; may represent LADAVery often
IA2IA2 50%-70% newly diagnosed casesNoOften
IgAIgA higher incidence than general populationHigher incidence than general populationHigher incidence than general population
C-peptidesLowNormal to highLow
HLAYesNoYes, often
FeaturesDKA, recent weight loss, thin, no insulin resistanceOften diagnosed incidentally, overweight/obese, insulin resistanceOften misdiagnosed as T2 DM, usually thin or normal weight, non-insulin dependent at first, not insulin resistant usually
TreatmentInsulinLifestyle changes, oral agents, insulinOral agents with early failure, insulin

Patients with LADA usually present with low C-peptide levels consistent with the autodestruction of islet cells, thus reducing the amount of insulin produced. Patients with type 2 diabetes usually have normal to high levels of C-peptides. Eventually, as the disease progresses, the patient with LADA will require insulin. Of note, the need for insulin occurs much more rapidly for patients with LADA than for typical type 2 diabetics.7, 8, 9 In essence, patients with LADA tend to be more insulin deficient, not insulin resistant. Like patients with type 2 diabetes, patients with LADA may not require insulin initially but some may have some degree of insulin resistance. Unlike type 2 diabetes, there is often an absence of family history of type 2 diabetes in a LADA patient's family.10

Based on the findings from the United Kingdom Prospective Diabetes Study (UKPDS),11 approximately 10% of adults with diabetes tested positive for GAD antibodies and were determined to have LADA. This can be inferred to represent approximately 375,000 people in the United States.

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Risk Factors 

The risk factors associated with LADA are important to recognize so that health care providers can appropriately conduct antibody testing for proper diagnosis. Because antibody testing is not indicated for every patient with diabetes, other clues can assist with identification.12 Clinical features include age of onset < 50 (typically < 35), acute symptoms of diabetes, BMI < 25 kg/m2, personal history of autoimmune diseases such as autoimmune thyroid disease, and family history of autoimmune disease. LADA should be suspected when a younger adult with uncontrolled hyperglycemia presents without signs of metabolic syndrome, has poor response to oral agents, and has evidence of other autoimmune diseases such as Grave's disease, Hashimoto's thyroiditis, or pernicious anemia.12, 13

Because it is not practical or economical to test all diabetics for LADA, Fourlanos et al14 developed a screening tool to assist with distinguishing patients at high risk for developing LADA from those with type 2 diabetics. In their retrospective study, the authors discovered clinical features associated with LADA: (1) age at onset < 50 (p = 0.00001), (2) acute symptoms of hyperglycemia (p < 0.00001), (3) BMI < 25 kg/m2 (p = 0.00004), (4) personal history of autoimmune disease (p = 0.011), and (5) family history of autoimmune disease (p = 0.024). A majority of patients with LADA had at least 2 of the 5 clinical features, representing 90% sensitivity and 71% specificity for detecting LADA. This high-risk group should have further antibody testing to detect LADA.

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Case Study 

Consider the case of Jodi, a 44-year-old Caucasian female who was referred by her primary care provider for diabetes management. Jodi was hospitalized briefly about a year ago for sudden hyperglycemia. She reported feeling ill 4 weeks earlier, with symptoms such as severe fatigue and rapid heart rate. In the emergency department, she was told that her glucose level was 280. She recalls losing about 7 pounds before her hospitalization. Her primary care provider started her on glipizide and metformin and she quickly gained fair control of her diabetes. Several months later, however, her fasting glucoses and HbA1c levels began to rise steadily in spite of reaching maximum doses of her medications. Her primary care provider questioned her compliance with her treatment plan at one point because she did not seem to respond to her medications.

At the diabetes clinic, Jodi's HbA1c is 9.2%. She reports polydipsia and polyuria and is troubled by nocturia. She is concerned about her poor response to medications and reports taking them faithfully. Her history is negative for any medical illnesses, no prior use of any routine medications, and no family history of diabetes. She is 5 feet 7 1/2 inches tall and weighs 134 pounds. She exercises routinely, is a nonsmoker, and drinks a glass of wine a month on average. She has a 9-year-old daughter who weighed 6 pounds, 12 ounces at birth and is healthy today. Further serological testing reveals a low C-Peptide level and GAD antibody positivity.

One striking feature of Jodi's case is that she does not have the typical risk factors associated with type 2 diabetes or metabolic syndrome, such as being overweight/obese or having co-morbidities such as hypertension or hyperlipidemia.10 Other factors associated with type 2 diabetes, like a sedentary lifestyle, positive family history of diabetes, or having a gestational diabetes event in the past are also missing from her history. Health care providers should be suspicious of a clinical presentation such as Jodi's. None of the typical features of type 2 diabetes are present in this case, yet it would not be unusual for some patients with LADA to present with insulin resistance.

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Pathogenesis 

LADA is thought to represent a slowly progressive beta cell destruction process due to the presence of circulating islet autoimmunity. Patients with LADA demonstrate less progressive beta cell destruction than type 1 diabetics when initially diagnosed, but most LADA patients will require insulin within 3 years at the point of diagnosis.1, 6, 7 As in Jodi's case, many patients with LADA will quickly progress to requiring insulin but do not demonstrate the dramatic decline associated with type 1 diabetes in childhood.

There are 2 distinct forms of type 1 diabetes: immune-mediated and idiopathic (Figure 1). The immune-mediated form of type 1 diabetes is characterized by autoimmune beta cell destruction that leads to insulin deficiency very quickly and is associated with autoantibodies that include glutamic acid decarboxylase (GAD) antibodies, islet cell antibodies (ICA), insulin antibodies (IAA), islet antigen 2 (IA2), and tyrosine phosphatase antibodies. It also has a strong association with the HLA (human leukocyte antigen) system, the major histocompatibility complex. This group of genes, located on chromosome 6, encodes cell-surface antigen-presenting proteins and many other genes, and they are essential elements in immune function. In the case of type 1 diabetes of immune-mediated origin, class II antigens (DR, DP, and DQ) present phagocytosed antigens from outside the cell to T-lymphocytes. This accounts for its role in autoimmunity and beta cell destruction.1, 6

The genetics of LADA is less well defined. LADA is associated with increased frequencies of genetic markers (HLA DR3, DR4, and DR3/4) that are also found in type 1 diabetics. However, HLA DR4 DQ8 antigens are more commonly associated with rapid beta cell destruction as associated with type 1 diabetics and less commonly seen in LADA; this may explain why LADA patients do not require insulin as readily as type 1 diabetics. In addition, LADA patients may display more tolerance to beta cell antigens, which may protect them more from extensive, rapid beta cell destruction.1, 6, 12

LADA is different than Maturity Onset Diabetes of the Young (MODY) in several ways. MODY is a group of disorders that present in children, adolescents, or young adults that demonstrate strong genetic etiology. The primary disorder of asymptomatic hyperglycemia seems to be independent of non-genetic factors such as obesity and sedentary lifestyle. The physiological defects seen in the 6 forms of MODY are related to genetic mutations causing reduced pancreatic insulin release.15

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Diagnosis 

Diagnosis of LADA begins with a high index of suspicion. As defined by Fourlanos, et al,14 clinical indicators of LADA should guide the provider to identification of high-risk patients. Recently diagnosed diabetics under the age of 50 who have acute diabetic symptoms, have BMI less than 25 kg/m2, or have a personal or family history of other autoimmune diseases should trigger further screening. Other clues that should raise suspicion include the absence of metabolic syndrome and poor response to oral medication.14 Features of metabolic syndrome include hypertension, glucose intolerance, dyslipidemia, and central obesity; 3 of these are necessary for the diagnosis of metabolic syndrome.9

Jodi demonstrated a later age at diagnosis, a normal BMI, no personal or family history, and lack of signs of the metabolic syndrome. A high index of suspicion should have been applied in her case.

Serological tests specific for LADA diagnosis will include glutamic acid decarboxylase (GAD) antibody levels, ICAs, and tyrosine phosphatase antibodies. Positive GAD antibodies are the most sensitive indicators of LADA.6, 9, 10, 13 The GAD antibody assay is 84% sensitive and 94% specific. In one study,16 the presence of these 3 antibodies is associated with insulin dependency in 100% of cases.

Measuring C-peptides is important because a low level is associated with a higher degree of beta cell destruction. An oral medication that stimulates the production of insulin would not be an appropriate choice for a patient who has already suffered significant beta cell loss. Earlier initiation of insulin is indicated for the patient with low C-peptide levels.6, 7, 9

Jodi presented with a positive GAD antibody and a very low C-peptide level. Additionally, she did not respond well to oral hypoglycemic medications. This presentation is highly correlated with early requirements for insulin such as in Jodi's case.

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Evidence-Based Management 

The focus for management of patients with LADA should be on controlling hyperglycemia and preventing complications. Because they have a more insidious process of beta cell destruction, patients with LADA can benefit from opportunities to preserve beta cell function. With strict glycemic control, patients with LADA may avert the need for insulin injections and they may suffer fewer microvascular complications associated with uncontrolled hyperglycemia like retinopathy, nephropathy, and neuropathy.

The treatment of choice for type 1 diabetes is insulin, but there is no established guideline for managing patients with LADA.7, 17 Earlier studies18, 19, 20, 21 have demonstrated that early initiation of insulin (within 1 year of diagnosis) slowed the progression of beta cell destruction while achieving normal glycemia. The patients in these studies had higher C-peptide responses, more stable HbA1c values, and reduced antibody levels.

Insulin therapy decreases the need for endogenous insulin and consequently may slow the immune destruction of islet cells.20 In spite of the evidence that LADA patients appear to benefit from insulin due to this effect, there are other studies that fail to show this effect for type 1 diabetics. Insulin may slow the progression of autoimmune destruction for LADA patients because they have a more insidious process. It may seem paradoxical to administer insulin to protect patients from insulin dependency; however, these patients will have better glycemic control, suffer fewer micro and macro complications, and benefit from preserving more beta cell function over time.

Pharmacologic management with oral agents has a role in managing some LADA patients. Because insulin resistance may be a factor for some patients, metformin may be beneficial. Metformin's actions of inhibiting hepatic gluconeogenesis and making the liver more sensitive to insulin will decrease the need for insulin. This theoretically may slow the immune destruction of beta cells.12

Thiazolidinediones reduce insulin resistance in peripheral tissues such as muscle and fat, thereby improving the secretory function of beta cells. Zhou22 found that when given with insulin, rosiglitazone maintained C-peptide levels more effectively than insulin alone. One hypothesis asserts that this class of drugs may exhibit anti-inflammatory effects that may slow the immune destruction of beta cells. This potential of preserving beta cell mass makes these drugs attractive for treating patients with LADA; however, more data are needed before making this a practice recommendation.23 Sulfonylureas may be associated with accelerated beta cell dysfunction. It has been speculated that this class of drugs may promote beta cell apoptosis, thus decreasing the number of insulin-secreting cells of the pancreas. This is one of the mechanisms in which beta cells are destroyed in autoimmune diabetes.7 In a Cochrane Systematic Review in which the evidence for best treatment of LADA was presented, Brophy et al17 recommended against the use of sulfonylureas but did not recommend one pharmacologic agent over another.

In one study,24 GAD 65 immunomodulation was given subcutaneously in a randomized clinical trial compared to placebo. The treatment group experienced a significant improvement in HbA1c and a small increase in C-peptide levels compared to placebo at 6 months. However, the sample sizes were small in this pilot study. The data suggest that GAD 65 may be a promising treatment, and more trials are needed that measure more end points over a longer timeframe.

In summary, the results from treatment studies are difficult to generalize due to study design flaws such as extreme heterogeneity of subjects, small sample sizes, poorly described treatment regimes, wide variations in clinical care systems among the many nations represented, and short term follow-up. There is a need for more carefully conducted studies to develop a sound treatment approach for patients with LADA.

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Complications 

Patients with LADA have the same risk for cardiovascular disease that type 2 diabetics have; however, they have lower prevalence of metabolic syndrome. It is thought that the features of metabolic syndrome may place the type 2 diabetic at greater risk for cardiovascular disease.12 Additionally, patients with LADA suffer microvascular complications such as neuropathy, nephropathy, and retinopathy at the same rate at type 2 diabetics. Because they may have poorer glycemic control initially, patients with LADA still display similar risks of complications as type 2 diabetics. Tight glycemic control becomes increasingly imperative for patients with LADA to avoid acute and chronic complications, as demonstrated in the Diabetes Control and Complications Trial (DCCT).

In Jodi's case, management consisted of discontinuing oral hypoglycemic agents and initiating long-acting insulin. Jodi most likely experienced progressive beta cell loss well before she presented with overt signs and symptoms of diabetes. She was instructed on self-glucose monitoring before meals and was started on rapid-acting insulin on a sliding scale. She attended diabetes management classes and met with the nurse educator and dietician. Eventually, Jodi was well controlled on a regular evening dose of Lantus and pre-meal injections of Novolog based on her calculations of insulin to carbohydrate ratios. Her follow-up HbA1c level 6 months later was 6.2%, demonstrating excellent glucose control. Levels below 7% will help her avoid the typical microvascular complications associated with diabetes.25

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Implications for Practice 

LADA is often misdiagnosed as type 2 diabetes, and patients do not always display the typical features of type 2 diabetes. Patients with LADA are usually lean, are diagnosed under the age of 50, lack a family history, have a poor response to oral agents, and typically lack signs and symptoms of the metabolic syndrome with insulin resistance.

Providers need to maintain vigilance when encountering a patient with an atypical presentation. Because of their natural history, the treatment strategy varies from that of the typical patient with type 2 diabetes. Once identified, health care providers need to institute further serological testing for autoimmune markers to confirm the diagnosis of LADA. As with Jodi in the case study, early oral anti-diabetic agent failure should be anticipated and earlier insulin therapy should be considered. Because early insulin administration is associated with prolonged beta cell functioning, the patient with LADA should be managed aggressively with insulin therapy. With appropriate therapy, effective glycemic control can be maintained and long-term microvascular and macrovascular complications can be prevented.

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References 

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 In compliance with national ethical guidelines, the author reports no relationships with business or industry that would pose a conflict of interest.

PII: S1555-4155(08)00409-1

doi:10.1016/j.nurpra.2008.06.004

The Journal for Nurse Practitioners
Volume 4, Issue 9 , Pages 681-687, October 2008

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