Continuing Education Activity

Latent autoimmune diabetes of adults (LADA) is an autoimmune disease that begins in adulthood and does not require insulin for glycemic control at least in the first 6 months after diagnosis. LADA shares genetic, immunologic, and metabolic features with type 1 and 2 diabetes mellitus (DM) but is often mistakenly diagnosed as type 2 diabetes (T2DM). Since several unknown factors cause LADA, lifestyle is one area that may prevent progression, much like T2DM, and lifestyle interventions are similar.

This activity reviews the management of latent autoimmune diabetes and highlights the role of the interprofessional team in evaluating and treating this condition. Participating clinicians gain insight into a lesser-known subtype of diabetes, the differentiating features, and best practice guidelines for seeking endocrinology consultation. The pathophysiology of LADA and its genetic, immunologic, and metabolic similarities and differences with type 1 and type 2 diabetes are discussed. The clinical presentation of LADA, including diagnostic criteria and potential pitfalls in distinguishing it from other forms of diabetes, is presented. Furthermore, the course reviews current management approaches for LADA, including pharmacological interventions, lifestyle modifications, and the role of insulin therapy. and the importance of early detection and appropriate referral to endocrinology specialists for tailored management plans. Importantly, the role of the interprofessional healthcare team in evaluating and treating LADA is emphasized throughout the activity. By fostering collaboration between primary care providers, endocrinologists, diabetes educators, and other healthcare professionals, participants will gain insights into the multidisciplinary approach required for optimal patient care.

Objectives:

• Differentiate between latent autoimmune diabetes of adults and type 2 diabetes by incorporating autoantibody testing into diagnostic algorithms, enabling tailored treatment strategies.

• Evaluate patients with latent autoimmune diabetes of adults for glycemic control, autoimmune markers, and potential complications to guide therapeutic adjustments and improve long-term outcomes.

• Compare the evaluation and management of latent autoimmune diabetes in adults to guide therapeutic adjustments and improve long-term outcomes.

• Implement care coordination amongst interprofessional team members to improve outcomes for adult patients with latent autoimmune diabetes.

Introduction

Diabetes mellitus (DM) is a disease spectrum ranging from classic insulinopenic type 1 diabetes (T1DM) at one end to classic insulin-resistant type 2 diabetes (T2DM) at the other. Latent autoimmune diabetes of adults (LADA) is a form of DM with features of both T1DM and T2DM and is termed Type 1.5 DM.[1][2] In Japan, the synonym is slowly progressive insulin-dependent type 1 diabetes mellitus. [3] The American Diabetes Association lists LADA as T1DM that evolves more slowly than the classic disease and does not recognize it as a specific type of DM. The World Health Organization defines LADA as slowly evolving immune-related diabetes.

LADA is, by definition, a disease of adults. The Immunology for Diabetes Society has specified 3 criteria for the diagnosis of LADA:

1.  Age greater than 30 years
2.  Positive autoantibodies to islet β cells
3.  Insulin independence for at least the initial 6 months after initial diagnosis [4] 

Although attractive, this set of criteria has been challenged, mainly because the choice of insulin as a treatment is highly clinician-dependent. LADA is immunologically similar to T1DM as antibodies to islet β cells are present, albeit at lower titers, and immune destruction progresses at a much slower rate when compared to classic T1DM. Most of these patients present with hyperglycemia that is not as dramatic as T1DM and is misdiagnosed and managed as T2DM. Only later is it realized that they have poor control with many conventional agents, especially sulfonylureas, and eventually require insulin therapy.

LADA itself is a heterogeneous disease where some patients have high antibody titers, a low body mass index (BMI), and progress to insulin therapy fairly rapidly. Others with low antibody titers and features of insulin resistance, such as a higher BMI, progress more slowly to requiring insulin. Early recognition of LADA is paramount so that appropriate strategies are employed to delay β-cell destruction and reduce complications. This article reviews the advances in the pathophysiology of LADA, how to establish a diagnosis, and the treatment plan.

Etiology

Genetic factors determine LADA. As in T1DM, the risk of acquiring LADA is highest in carriers of certain HLA haplotypes.[5] The HLA genes code for the major histocompatibility antigens with important immunoregulatory functions. Therefore, it is unsurprising that LADA is caused by dysregulated immunity. However, the precise factors that precipitate autoimmunity have not been established.

Unlike T2DM, there is a lack of studies investigating the role of environmental factors like lifestyle in LADA. The reasons for this are:

• The need for autoantibody measurement in every newly diagnosed adult diabetes patient to identify and classify patients as LADA
• The absence of comparable cohort groups
• Unavailability of lifestyle information antecedent to the diagnosis of LADA 
• The inadequate sample size of LADA patients in the studies enhances the power of the study [6]

In some studies, LADA shares several lifestyle risk factors with T2DM: excess body weight, greater waist-hip ratio, low birth weight, intake of 2 or more sweetened beverages daily, and heavy smoking. These risk factors are of greater significance in the subset of LADA with lower titers of autoantibodies and higher BMI. Although the association is less robust, these risk factors are correlated in those with higher antibody titers. Increased physical activity, moderate alcohol use, and the intake of fatty fish have a protective effect on the risk of LADA.[7] Two or more cups of coffee daily increase the risk for LADA, unlike the beneficial effect seen in T2DM, but this observation is sourced from a single study and needs to be validated.[8] 

Epidemiology

Latent autoimmune disease in adults is the most frequent form of adult-onset autoimmune DM.[9] Geographic and ethnic differences are apparent in the incidence. In the multicentric 'Action LADA' study from Europe, 9.6% of 6156 adults with adult-onset DM had islet cell autoantibodies.[10] In the United Kingdom Prospective Diabetes Study, the antibody positivity among those with a presumptive diagnosis of T2DM in adults was 15%.[11] Similarly, studies from Norway showed a 10% incidence, whereas studies from the Middle East, Korea, and China showed between 4% and 9%.[2][12]

Most patients with LADA are positive for a single islet autoantibody; glutamic acid decarboxylase antibody is the most predominant. Some population groups have a varying prevalence of different autoantibodies, and measuring just one may underestimate the prevalence of LADA. Autoantibodies appear and disappear during longitudinal follow-up. In these situations, the role of assay interference from anti-idiotype antibodies should be considered.[12] A form of latent autoimmune diabetes in the young has been described.[13][14]

Pathophysiology

Islet β cell autoimmunity antedates the onset of LADA by several years. This was observed in nearly two-thirds of patients with LADA in a prospective study and substantiated autoimmunity as the first insult. This is followed by insulin resistance that causes overt hyperglycemia and the diagnosis of autoimmune insulin-independent DM. An assessment of insulin resistance using homeostatic model assessment has shown that patients with LADA have insulin resistance similar to T2DM after correction for BMI. Thus, the pathophysiology of LADA involves both autoimmunity and the metabolic derangements of insulin resistance.[15]

Most patients with T2DM (and a lower percentage with LADA and T1DM) present with features of metabolic syndrome (MetS). The prevalence was higher in patients with LADA compared to control subjects. Eliminating glucose as a criterion, MetS remained more frequent in T2DM than in LADA, although the prevalence of those with LADA was comparable to the control subjects.[16]

Pancreatic tissue from humans with LADA and a rat model mimicking LADA were analyzed using immunohistochemistry and PCR. Predominant macrophage (CD68) infiltration was shown in the islet cells as opposed to T1DM, which showed CD8 lymphocytes. Islet groups exist with and without infiltration. The cell type shift translated to greater interleukin-1β cytokine secretion and decreased expression of TNF-α in T lymphocytes. Also, the proliferation marker of nuclear antigen and the anti-inflammatory cytokine interleukin 10 (IL-10) were elevated, while the apoptotic promoters caspase3 and TUNEL were diminished. The result was increased β-cell gene transcription, greater C-peptide levels, slower progression of β-cell destruction, and slower onset of LADA compared to T1DM.[17]

The presence of more than one diabetes-associated autoantibody (DAA) predicts a faster progression of β-cell failure. In older patients with LADA, the sensitivity of glutamic acid decarboxylase antibodies (GADA) in predicting insulin requirement diminishes.

A Chinese study showed that GADA alone was insufficient to identify all cases of LADA, although it was the most dominant. This highlights the geographic and ethnic variability in the distribution of DAAs in LADA.[12] Anti-gliadin antibodies (IgA and IgG) increase in LADA compared to T2DM. A compromised intestinal mucosal barrier may allow environmental antigens to gain access via the oral route and initiate immunological events to induce the disease. Furthermore, unlike T1DM, anti-thyroid peroxidase antibodies are increased in LADA compared to T2DM.[18][19]

Regulatory T lymphocytes produce proteins like transcription factor forkhead box protein 3 (FOXP3), suppressing autoimmunity. Hypermethylation of DNA and decreased expression of FOXP3 diminish protection against immune destruction. FOXP3 and other proteins are lower in the high GADA subtype than the low GADA, indicating higher β-cell destruction in the former.[20][21]

The IgG4 class of GADA is more prevalent in LADA than in T1DM, which yields a T helper 2 lymphocyte immune response, which may be one explanation for the delayed onset of diabetes in LADA compared to T1DM. Another reason may be the binding site on the GAD molecule for the GADA. A greater degree of amino-terminal binding is apparent in LADA, whereas, in T1DM, it is in the carboxy-terminal. In the United Kingdom Prospective Diabetes Study (UKPDS), some patients who were GADA positive after 5 years did not progress to insulin requirement, and the epitope specificity may explain this. Also, a high-affinity subtype of GADA to GAD65 antigen predicts the rate of β-cell failure.[22]

A variant of the IA2A antibody (256-760) is more frequently found in LADA and may prove useful in its detection.[23][24] In the UKPDS and subsequent studies, a subset of T2DM negative for islet autoantibodies had T lymphocytes immunoreactive to islet cell antigens. The autoimmunity in these patients was more intense than in those with autoantibodies alone. They demonstrated a lower stimulated C-peptide response in this cohort, who subsequently went on to require insulin earlier than the group of T2DM without both antibodies and reactive T cells, creating a separate category of T-LADA.[25][26]

LADA shares immunological features with both T1DM and T2DM. A recent study analyzing fresh-blood-derived peripheral blood mononuclear cells showed that LADA was similar to T2DM in antigen-presenting cell characteristics and the number of regulatory B lymphocytes. In contrast, it mimicked T1DM in the number of natural killer cells.[27]

LADA has more genetic similarity to T1DM than T2DM. Studies have shown certain HLA types increase while others decrease the risk for LADA.[5] Fewer 'risk alleles' in LADA explain the later onset of the disease. Genetic loci that are common in T1DM are associated with LADA. These include the major histocompatibility complex region, PTPN22, SH2B3, and INS. In a recently published study, the key T2D risk allele TCF7L2 had a lower occurrence in LADA cases; this locus may not play a role in the etiology of LADA.[28]

The only genetic similarity with T2DM at the HNF1A locus was not reproduced in a subsequent study by the same investigators, who found a strong signal at the PFKFB3 locus during a landmark Genome-wide association study (GWAS).[29] LADA subtypes differ from GADA titers that are inversely related to BMI.[30] The inflammatory biomarkers associated with obesity vary when sera from various types of DM are analyzed. If these results are reproduced in larger populations, their utility to diagnose and differentiate LADA from T1DM and T2DM in conjunction with antibody testing may be enhanced.[31] Furthermore, a positive correlation exists in patients with LADA between BMI and interleukin-17, a pro-inflammatory cytokine from peripheral B lymphocytes implicated in T2DM and obesity.[32]

Serious life events resulting from significant psychological stress can trigger an autoimmune response and have been associated with an increased risk of T1D in children. Similar serious life events were not identified as risk factors for the development of LADA.[33] Modulating the immunoreactivity of T cells may be a viable therapeutic target in LADA, just like T1DM.

History and Physical

Patients with LADA may present with symptoms of polyuria, polydipsia, nocturia, fatigue, visual changes, tingling in the feet, and weight loss or may be asymptomatic. Other factors for risk of LADA include:

• A personal or family history of autoimmune disease should raise suspicion that a patient with hyperglycemia has LADA or T1DM.[2]
• A history of low birth weight is a strong risk factor for both LADA and T2DM.[34] 
• A history of smoking, alcohol consumption, and the number of sweetened beverages are risk factors.[2][35]

The amount and type of physical activity and exercise should be sought and recorded to quantify the risk of LADA. The blood pressure must be accurately measured. Several diagnostic tools have been proposed to identify patients with LADA.

One diagnostic screening tool with 3 criteria was used to identify LADA in diabetic patients older than 50 years of age:

1. A low or normal BMI
2. Despite good compliance, fasting blood glucose of 270 mg/dL or higher, HbA1c 10% or greater
3. Loss of weight after a diet with constant calorie content

This tool was able to detect three-fourths of patients with LADA.[36] 

Foulanos et al developed the following clinical risk score:

1. Age younger than 50
2. Symptomatic hyperglycemia
3. BMI of less than 25 kg/m²
4. A personal history of autoimmune disease
5. A family history of autoimmune disease

Two or more criteria, when positive, yielded a sensitivity of 90% and specificity of 71%, while less than 2 criteria virtually excluded LADA.[37] Although the above algorithms have been described and validated in some studies, it must be mentioned that the phenotypes of LADA may resemble T1DM or T2DM and, therefore, exhibit a normal or high BMI. Patients with LADA have BMI, waist circumference, blood pressure, and triglyceride levels that are midway between those with T1DM and T2DM.[38]

Patients with LADA may have features of the MetS. Two phenotypes have been described based on GADA titers. LADA1 with cytoplasmic islet cell antibodies and high GADA titers manifesting characteristics more typical of a T1DM phenotype with lower BMI and C-peptide levels. LADA2 patients had lower GADA titers, single antibody positivity, and a phenotype more characteristic of T2DM.[39] Patients with LADA are usually ketosis-resistant when first diagnosed.

Evaluation

When an adult patient presents with hyperglycemia with or without symptoms and is controlled without the need for insulin in the first 6 months, LADA should be considered. A positive antibody to one of the islet antigens is the hallmark of LADA. Worldwide, the most prevalent islet autoantibody utilized is GADA. Others include IA-2A, insulin antibodies, and zinc transporter isoform 8 antibody that occurs with varying frequencies.

Patients with LADA have residual C-peptide levels, typically between those with T1DM and T2DM. In T1DM, C-peptide is absent at first clinical presentation, and in T2DM, it is often increased. The levels of C-peptide correlate inversely with GADA titers. A stimulated C-peptide has a greater predictive value than a fasting level. The glucagon stimulation test and mixed meal tolerance test (MMTT) have been validated and useful among the methods studied. The former is shorter in duration but associated with transient nausea, while the latter takes a long time but is free of side effects. C-peptide measurement is preferable to insulin measurement as it has a longer half-life, is not subject to first-pass hepatic metabolism, and has steady-state clearance from the circulation. Insulin undergoes first-pass hepatic metabolism and has a much shorter half-life and variable clearance. Exogenously administered insulin can confound results. The MMTT has also been utilized to choose the treatment modality and predict the time to transition to managing insulin.[40]

C-peptide can be a cost-effective initial test to distinguish LADA from T2DM. Bell and Ovalle reported that C-peptide levels were significantly higher in T2DM compared to patients with LADA. All patients with T2DM had normal or high C-peptide levels, but only 1 of 39 subjects with LADA had a C-peptide above the reference range. However, the diagnosis of LADA must be confirmed with antibody testing.[41]

HLA typing is not routinely utilized in the evaluation of LADA.

All other routine investigations appropriate for evaluating and managing patients with diabetes should be employed in LADA at the recommended intervals and as dictated by the clinical situation.

Recommended tests include:

• Fasting glucose
• Glycosylated hemoglobin (HbA1c)
• Self-monitoring of blood glucose 
• Measures of glycemic variability, best done by continuous glucose monitoring
• Lipid profile
• Estimated glomerular filtration rate 
• Serum creatinine
• Urinalysis for albumin excretion (spot and 24-hour specimen with simultaneous creatinine)
• Test for peripheral neuropathy (Semmes Weinstein monofilament test)
• Retinopathy screening by an ophthalmologist.

Other tests may be indicated if diabetes-related complications develop based on individual circumstances.

Treatment / Management

When the diagnosis of LADA is made, non-pharmacological therapies include individualized medical nutrition and exercise plans similar to those employed in patients with T1DM and T2DM. Since LADA is a heterogeneous condition, pharmacological treatment should be personalized to gain the maximum therapeutic advantage. The 2 goals of pharmacological treatment are (1) to obtain good glycemic control and (2) to prevent or delay complications. Therapies that will preserve β-cell function are a priority. Insulin is required in most patients with LADA, may be required at the time of diagnosis in those with low C-peptide levels, and can be considered at any stage of the disease. Study results have shown preserved β-cell function, a stimulated C-peptide response, normal HbA1C levels, and decreased autoantibody concentrations.[42]

The general agreement suggests that sulfonylureas are a poor choice for treating patients with LADA. Their use results in the depletion of β-cells, more rapid decreases in C-peptide levels, the persistence of antibodies, and earlier progression to insulin therapy.[1][42] Although not officially approved to treat patients with LADA, metformin improves insulin sensitivity, may result in weight loss, and delay the onset of diabetic-related complications. While more studies are needed on the use of metformin, an international expert panel stated inconclusive evidence for or against the use.[1]

Thiazolidinediones improve insulin sensitivity by activating nuclear peroxisome proliferator-activated receptors gamma receptors. Limited data is available on their use in patients with LADA. In one study, rosiglitazone preserved β-cell function.[43] However, in a small trial of only 10 patients, pioglitazone caused a more rapid decline in C-peptide levels than metformin.[44] More long-term studies are warranted, and clinicians need to be aware of potential side effects, including weight gain, edema, congestive heart failure, fractures, and macula edema.

Dipeptidyl peptidase (DPP) 4 inhibitors have shown promise alone or when combined with insulin in preserving β-cell function in LADA. They affect metabolic control by prolonging endogenous glucagon-like peptide-1 (GLP1) and other peptides. Their primary action is to increase levels of GLP1, suppressing glucagon and increasing insulin secretion after a glucose load. DPP4 receptors have also been identified on the surface of T lymphocytes, where they may affect immune regulation. This latter action may be important in slowing the β-cell immune destruction in LADA.[45] Some studies with DPP4 inhibitors have demonstrated improved diabetic control and preservation of β-cell function.[1][46][47][48] There is limited data to assess the use of GLP1 agonists in managing patients with LADA. However, dulaglutide studies have shown reductions in HbA1c levels.

Differential Diagnosis

The main challenge is to distinguish patients with LADA from those with T2DM. By definition, patients with T2DM have absent autoantibodies to islet cell antigens, normal or elevated fasting, and stimulated C-peptide and usually do not require insulin for an extended period. Clinicians should consider screening for LADA in patients with T2DM who do not achieve adequate glycemic control within a reasonable period after compliance with therapy. This is particularly true if they are not obese, lack the features of the MetS, or they, or their first-degree relatives, have other autoimmune disorders, including Hashimoto thyroiditis, Graves disease, celiac disease, rheumatoid arthritis, or pernicious anemia.[2]

Patients with classic T1DM present dramatically with ketoacidosis, need insulin at the time of presentation, and are easily differentiated from LADA. At times, a young adult with maturity-onset diabetes of the young is mistakenly diagnosed as T1DM, T2DM, or LADA. MODY is rare, has a strong family history, residual C-peptide, and absent humoral and cellular immunity to islet cell antigens. It can be distinguished from LADA.

Prognosis

Patients with LADA have mortality as high as T2DM despite having more favorable metabolic parameters. In the Trøndelag Health (HUNT) study, hyperglycemia was the only significant influencing factor, not the other components of the metabolic syndrome, in determining mortality due to cardiovascular disease.[49] Strict glycemic control is the key to improving the prognosis in LADA.

Complications

Compared to those with T2DM, patients with LADA have a lower rate of microvascular complications at the time of diagnosis but an increased risk during long-term follow-up. They have the same risk of cardiovascular disease as those with T2DM.[2] Evidence suggests that small-fiber neuropathy (SFN) occurs early and with increased frequency in LADA when compared to T2DM, which is related to higher HbA1c and poor glycemic control. Patients with LADA have severe SFN more often than those with age and duration-matched T2DM patients. However, the involvement of large nerve fibers is not different from T2DM. During the evaluation of a patient with LADA, tests to detect SFN should be included. Small nerve fibers carry pain and temperature sensations, mediate sweating, regulate vascular tone, and control blood flow. Tests for SFN include cold sensation threshold, warm sensation threshold, intraepidermal nerve fiber density (IENFD), and corneal confocal microscopy. The sensitivity of nerve conduction studies to diagnose SFN is low and not recommended.[50] A window of opportunity exists if detected early, as the treatment of hyperglycemia may reverse SFN and decrease morbidity.[51][52]

Long-term follow-up of patients with LADA reveals a lower risk in the first 9 years but a higher risk for microvascular complications in later years compared to T2DM after adjustment for several factors.[53] Patients with LADA have a similar degree of carotid artery atherosclerosis as T1DM and T2DM, though a better vascular risk profile.[54] Three studies, the Botnia study, the Freemantle diabetes study, and the HUNT study, all concurred on the increased cardiovascular disease and mortality in LADA, similar to T2DM. Therefore, LADA is associated with both microvascular and macrovascular complications, like patients with T1DM and T2DM.

Consultations

The following consultations are recommended:

• Primary care (family medicine, internal medicine)
• Endocrinology
• Laboratory medicine
• Clinical genetics
• Ophthalmology
• Podiatry
• Bariatric surgery

Deterrence and Patient Education

Patients with LADA need insight into the nature of their disease and the importance of strict glycemic control to prevent microvascular and macrovascular complications. They require the same education as those with other types of diabetes, including medical nutrition plans, medication use, glucose self-monitoring, and knowledge of recognizing and managing microvascular complications and cardiovascular disease. If patients are treated with sodium-glucose cotransporter-2 (SGLT2) inhibitors, they should be educated about the risk of ketoacidosis and the need to monitor for ketones.

Pearls and Other Issues

Some important pearls to consider for LADA include:

• LADA is a form of DM with features standard to both T1DM and T2DM.
• Early diagnosis is paramount to initiating appropriate treatment and preventing complications.
• Clinicians should consider screening for LADA in patients with T2DM who do not achieve adequate glycemic control within a reasonable period despite compliance with therapy. This is particularly true if they are not obese, lack the features of the MetS, or they or their first-degree relatives have other autoimmune disorders.
• New insights into LADA's pathophysiology explain β-cell destruction's slow progression.
• A C-peptide test, basal or after a mixed meal, may be used as an initial, cost-effective test to screen patients with LADA to identify which patients need confirmatory testing for islet autoantibodies.
• Sulfonylureas are a poor choice to treat patients with LADA as they result in β-cell failure and a more rapid progression to the time insulin is required to control hyperglycemia.
• Insulin and DPP4 inhibitors alone and combined with insulin, thiazolidinediones, and GLP1 receptor agonists have shown promise in achieving glycemic control and preserving β-cell function.
• If patients are treated with SGLT2 inhibitors, they should be educated about the risk of ketoacidosis and the need to monitor for ketones.

Enhancing Healthcare Team Outcomes

According to the World Health Organization, there are 422 million people with diabetes globally. As the prevalence of LADA in a population of T2DM is between 4% and 12%, depending on the population, approximately 17 to 50 million will have LADA. This number is likely to grow exponentially. The primary care practitioner (PCP) will likely encounter patients with LADA frequently and should be equipped with the knowledge and understanding to recognize and manage this condition promptly.

The endocrinologist sees difficult and complex patients and coordinates care with the PCP, ophthalmologist, podiatrist, and geneticist. Laboratory medicine advises on the appropriateness of tests, performs biochemical and serological tests, and communicates the results to the treating clinician. Bariatric surgeons must have a high index of suspicion for LADA in patients with diabetes and counsel them regarding the less-than-optimal glycemic control post-surgery. Healthcare professionals need coordinated efforts to achieve excellent glycemic control, prevent or delay complications, and substantially reduce morbidity, mortality, and healthcare costs.