Diagnosis of Latent Autoimmune Diabetes in Adults (LADA): Key Considerations for Accurate Identification

Introduction

Diabetes mellitus (DM) encompasses a spectrum of conditions, ranging from insulin-deficient type 1 diabetes (T1DM) to insulin-resistant type 2 diabetes (T2DM). Latent autoimmune diabetes in adults (LADA), sometimes referred to as Type 1.5 DM, represents a distinct form of diabetes that shares characteristics with both T1DM and T2DM.[1, 2] In Japan, it’s known as slowly progressive insulin-dependent type 1 diabetes mellitus.[3] While the American Diabetes Association categorizes LADA as a slowly evolving form of T1DM rather than a separate type, the World Health Organization recognizes it as slowly evolving immune-related diabetes. Accurate Diagnosis Of Lada is crucial because it differs significantly in its progression and management compared to T2DM.

LADA is defined as a condition developing in adulthood. The Immunology for Diabetes Society has established three key criteria for the diagnosis of LADA:

1. Onset at age 30 years or older
2. Presence of autoantibodies against islet β cells
3. Insulin independence for at least the first six months following diagnosis [4]

While these criteria offer a framework for LADA diagnosis, the reliance on insulin treatment as a differentiating factor can be subjective, depending on clinical decisions. Immunologically, LADA resembles T1DM, indicated by the presence of islet β cell autoantibodies, although typically at lower levels, and a slower rate of immune-mediated destruction compared to classic T1DM. Many individuals with LADA initially present with hyperglycemia that is less severe than in T1DM, leading to frequent misdiagnosis and management as T2DM. The realization that conventional treatments, especially sulfonylureas, are ineffective often comes later, eventually necessitating insulin therapy. Therefore, a timely and accurate diagnosis of LADA is essential for appropriate management.

LADA exhibits heterogeneity; some patients present with high autoantibody levels and a low body mass index (BMI), progressing rapidly to insulin dependence. Others, with lower antibody levels and insulin resistance features like higher BMI, progress more slowly. Early and precise diagnosis of LADA is paramount to implement strategies that can potentially delay β-cell destruction and mitigate long-term complications. This article will explore the current understanding of LADA’s pathophysiology, the methods for establishing a definitive diagnosis of LADA, and effective treatment approaches.

Etiology of LADA

Genetic predisposition is a significant factor in LADA development. Similar to T1DM, individuals carrying specific HLA haplotypes have an elevated risk of developing LADA.[5] These HLA genes are responsible for coding major histocompatibility antigens, which play critical roles in immune regulation. Consequently, LADA is considered to be triggered by immune dysregulation. However, the precise environmental triggers that initiate autoimmunity in LADA remain unidentified.

Unlike T2DM, research into lifestyle factors contributing to LADA is limited. This scarcity of data is due to several challenges:

• Infrequent routine autoantibody testing in adults newly diagnosed with diabetes, which is essential for identifying LADA cases.
• Lack of suitable comparison groups in studies.
• Absence of pre-diagnosis lifestyle data for LADA patients.
• Small sample sizes of LADA patients, which can limit the statistical power of studies.[6]

Despite these limitations, some studies suggest that LADA shares lifestyle risk factors with T2DM, including excess body weight, high waist-hip ratio, low birth weight, consumption of two or more sweetened beverages daily, and heavy smoking. These factors appear more strongly associated with LADA cases characterized by lower autoantibody levels and higher BMI. While the link is less pronounced, these risk factors are also observed in individuals with higher antibody titers. Conversely, increased physical activity, moderate alcohol consumption, and diets rich in fatty fish have been associated with a reduced risk of LADA.[7] Interestingly, consuming two or more cups of coffee daily has been linked to an increased risk of LADA, contrasting with the protective effect seen in T2DM, although this finding requires further validation from additional studies.[8]

Epidemiology of LADA

Latent autoimmune diabetes in adults is the most common form of autoimmune diabetes that develops in adulthood.[9] The incidence of LADA varies significantly across different geographic regions and ethnicities. The ‘Action LADA’ study, a multicenter European investigation, reported that 9.6% of 6156 adults with adult-onset diabetes had islet cell autoantibodies.[10] The UK Prospective Diabetes Study found antibody positivity in 15% of adults initially diagnosed with presumptive T2DM.[11] Studies from Norway reported a 10% incidence, while those from the Middle East, Korea, and China showed rates between 4% and 9%.[2, 12] These variations highlight the importance of considering geographic and ethnic factors in the diagnosis of LADA.

Most individuals with LADA test positive for only one islet autoantibody, with glutamic acid decarboxylase antibody (GADA) being the most prevalent. The varying prevalence of different autoantibodies across populations means that relying on a single autoantibody test may underestimate the true prevalence of LADA. Autoantibodies can also appear and disappear over time, necessitating consideration of assay interference from anti-idiotype antibodies in longitudinal assessments.[12] It’s also important to note that a form of latent autoimmune diabetes in young individuals has been documented.[13, 14]

Pathophysiology of LADA

The autoimmune process targeting islet β cells in LADA often begins years before the clinical onset of diabetes. Prospective studies have observed islet β cell autoimmunity preceding LADA diagnosis in nearly two-thirds of patients, confirming autoimmunity as the primary initiating event. This is followed by insulin resistance, eventually leading to overt hyperglycemia and the diagnosis of autoimmune insulin-independent DM. Assessments of insulin resistance, using methods like the homeostatic model assessment, have shown that insulin resistance in LADA patients is comparable to that in T2DM patients when adjusted for BMI. Thus, the pathophysiology of LADA is a complex interplay of both autoimmunity and the metabolic disturbances characteristic of insulin resistance.[15]

Metabolic syndrome (MetS) features are common in patients with T2DM, and to a lesser extent in LADA and T1DM. The prevalence of MetS is higher in LADA patients compared to healthy controls. While MetS remains more prevalent in T2DM compared to LADA when glucose is excluded as a criterion, the prevalence in LADA is still comparable to control subjects.[16]

Histopathological analysis of pancreatic tissue from LADA patients and a rat model mimicking LADA reveals distinct features compared to T1DM. In LADA, macrophage (CD68) infiltration predominates in islet cells, whereas T1DM is characterized by CD8 lymphocyte infiltration. Islets can be found both with and without cellular infiltration in LADA. This cellular difference correlates with increased secretion of interleukin-1β and decreased expression of TNF-α in T lymphocytes. Furthermore, LADA shows elevated levels of the proliferation marker nuclear antigen and the anti-inflammatory cytokine interleukin 10 (IL-10), along with reduced apoptotic promoters caspase3 and TUNEL. These findings suggest a mechanism in LADA leading to increased β-cell gene transcription, higher C-peptide levels, slower β-cell destruction, and a more gradual onset compared to T1DM.[17]

The presence of multiple diabetes-associated autoantibodies (DAAs) is predictive of faster progression to β-cell failure. However, in older LADA patients, the predictive value of glutamic acid decarboxylase antibodies (GADA) for insulin requirement decreases.

Studies in Chinese populations have shown that GADA alone may not be sufficient for identifying all LADA cases, although it remains the most common autoantibody. This underscores the geographic and ethnic variability in DAA profiles in LADA.[12] Elevated levels of anti-gliadin antibodies (IgA and IgG) are also observed in LADA compared to T2DM. This may indicate a compromised intestinal mucosal barrier, potentially allowing environmental antigens to trigger immunological events leading to disease onset. Additionally, anti-thyroid peroxidase antibodies are more frequently elevated in LADA compared to T2DM, unlike in T1DM.[18, 19]

Regulatory T lymphocytes, which produce proteins like transcription factor forkhead box protein 3 (FOXP3), are critical for suppressing autoimmunity. DNA hypermethylation and reduced FOXP3 expression can impair this protective mechanism. FOXP3 and related proteins are found to be lower in the high-GADA subtype of LADA compared to the low-GADA subtype, suggesting more pronounced β-cell destruction in the former.[20, 21]

The IgG4 subclass of GADA is more prevalent in LADA than in T1DM, inducing a T helper 2 lymphocyte immune response, which may contribute to the slower progression of diabetes in LADA compared to T1DM. Another factor may be the GADA binding site on the GAD molecule. LADA exhibits a greater degree of amino-terminal binding, while T1DM is characterized by carboxy-terminal binding. The UK Prospective Diabetes Study (UKPDS) found that some GADA-positive patients did not progress to insulin dependence after 5 years, and epitope specificity might explain this variability. Moreover, a high-affinity subtype of GADA to the GAD65 antigen is associated with a faster rate of β-cell failure.[22]

A variant of the IA2A antibody (256-760) is more frequently detected in LADA and may serve as a useful marker in LADA diagnosis.[23, 24] The UKPDS and subsequent research have identified a subset of T2DM patients without islet autoantibodies but with T lymphocytes immunoreactive to islet cell antigens. These patients exhibited more intense autoimmunity than those with autoantibodies alone and showed lower stimulated C-peptide responses, progressing to insulin dependence earlier than T2DM patients without both antibodies and reactive T cells, thus defining a separate category termed T-LADA.[25, 26]

LADA shares immunological features with both T1DM and T2DM. Recent studies analyzing peripheral blood mononuclear cells indicate that LADA is similar to T2DM in antigen-presenting cell characteristics and regulatory B lymphocyte counts, while resembling T1DM in natural killer cell counts.[27]

Genetically, LADA is more similar to T1DM than T2DM. Studies have identified specific HLA types that increase or decrease LADA risk.[5] The lower number of ‘risk alleles’ in LADA may explain its later onset. Genetic loci common in T1DM, such as the major histocompatibility complex region, PTPN22, SH2B3, and INS, are also associated with LADA. Interestingly, the T2D risk allele TCF7L2 appears less frequently in LADA, suggesting it may not play a significant role in LADA etiology.[28]

While an initial study suggested a genetic overlap with T2DM at the HNF1A locus, subsequent research by the same group did not replicate this finding but identified a strong association at the PFKFB3 locus in a landmark Genome-wide association study (GWAS).[29] LADA subtypes differ based on GADA titers, which are inversely related to BMI.[30] Inflammatory biomarkers associated with obesity also vary when comparing sera from different diabetes types. If these findings are confirmed in larger studies, they may enhance the diagnosis of LADA and its differentiation from T1DM and T2DM, especially when used in conjunction with antibody testing.[31] Furthermore, a positive correlation exists between BMI and interleukin-17 in LADA patients, a pro-inflammatory cytokine from peripheral B lymphocytes implicated in both T2DM and obesity.[32]

While significant psychological stress has been linked to an increased risk of T1D in children, similar life events have not been identified as risk factors for LADA development.[33] Modulating T cell immunoreactivity may be a potential therapeutic target in LADA, mirroring strategies in T1DM.

History and Physical Examination in LADA Diagnosis

Patients with LADA can present with typical diabetes symptoms like polyuria, polydipsia, nocturia, fatigue, visual disturbances, foot paresthesia, and weight loss, or they may be asymptomatic. Risk factors for LADA to consider during history taking include:

• Age of onset (typically over 30 years)
• Personal or family history of autoimmune diseases
• BMI (may be normal or lower than in typical T2DM)
• Symptomatic hyperglycemia

It is also important to document the patient’s level and type of physical activity to assess LADA risk. Accurate blood pressure measurement is essential. Several diagnostic tools have been proposed to aid in identifying LADA patients.

One screening tool for LADA in diabetic patients over 50 years old uses three criteria:

1. Low to normal BMI
2. Persistent high fasting blood glucose (≥270 mg/dL) or HbA1c (≥10%) despite lifestyle modifications
3. Unexplained weight loss despite consistent calorie intake

This tool has been shown to detect approximately three-quarters of LADA cases.[36]

Foulanos et al. developed a clinical risk score for diagnosis of LADA based on five criteria:

1. Age under 50 years
2. Symptomatic hyperglycemia
3. BMI < 25 kg/m2
4. Personal history of autoimmune disease
5. Family history of autoimmune disease

Having two or more positive criteria demonstrated a 90% sensitivity and 71% specificity for LADA diagnosis, while fewer than two criteria effectively ruled out LADA.[37] While these algorithms have been validated in some studies, it’s crucial to remember that LADA phenotypes can resemble either T1DM or T2DM, thus BMI can be normal or even elevated. Typically, LADA patients exhibit intermediate values for BMI, waist circumference, blood pressure, and triglyceride levels when compared to T1DM and T2DM.[38]

Patients with LADA may also exhibit features of metabolic syndrome. Two phenotypes have been identified based on GADA titers. LADA1, characterized by cytoplasmic islet cell antibodies and high GADA titers, tends to present more like T1DM with lower BMI and C-peptide levels. LADA2 patients have lower GADA titers, single antibody positivity, and a phenotype more akin to T2DM.[39] Notably, LADA patients are generally resistant to ketosis at initial diagnosis of LADA.

Evaluation and Diagnosis of LADA

When an adult patient presents with hyperglycemia, with or without classic diabetes symptoms, and achieves initial glycemic control without insulin for the first six months, diagnosis of LADA should be considered. The presence of autoantibodies against islet antigens is a hallmark of LADA. Globally, glutamic acid decarboxylase antibody (GADA) is the most commonly used islet autoantibody for LADA diagnosis. Other relevant autoantibodies include IA-2A, insulin antibodies, and zinc transporter isoform 8 antibody, though their prevalence varies.

Patients with LADA typically have residual C-peptide levels, falling between those seen in T1DM and T2DM. In T1DM, C-peptide is usually absent at initial presentation, whereas in T2DM, it is often normal or elevated. C-peptide levels show an inverse correlation with GADA titers. Stimulated C-peptide measurements have a higher predictive value than fasting levels. Validated methods for stimulated C-peptide testing include the glucagon stimulation test (GST) and the mixed meal tolerance test (MMTT). The GST is shorter but may cause transient nausea, while the MMTT is longer but generally well-tolerated. C-peptide measurement is preferred over insulin measurement due to its longer half-life, lack of first-pass hepatic metabolism, and stable clearance from circulation. Insulin is subject to first-pass hepatic metabolism, has a shorter half-life, and exhibits variable clearance. Exogenous insulin administration can also interfere with insulin level measurements. The MMTT has also been used to guide treatment decisions and predict the time to insulin dependence in LADA.[40]

C-peptide testing can be a cost-effective initial step in differentiating LADA from T2DM. Bell and Ovalle reported significantly higher C-peptide levels in T2DM compared to LADA patients. All T2DM patients in their study had normal or high C-peptide levels, while only one out of 39 LADA subjects had C-peptide levels above the reference range. However, definitive diagnosis of LADA requires confirmation through antibody testing.[41]

HLA typing is not routinely used in the standard evaluation for diagnosis of LADA.

Beyond specific LADA diagnostic tests, all routine investigations appropriate for diabetes management should be conducted at recommended intervals and as clinically indicated.

Recommended tests include:

• Fasting plasma glucose
• Glycated hemoglobin (HbA1c)
• Self-monitoring of blood glucose (SMBG)
• Continuous glucose monitoring (CGM) for glycemic variability assessment
• Lipid profile
• Estimated glomerular filtration rate (eGFR)
• Serum creatinine
• Urinalysis for albuminuria (spot and 24-hour urine with creatinine)
• Peripheral neuropathy assessment (Semmes-Weinstein monofilament test)
• Retinopathy screening by an ophthalmologist

Additional tests may be necessary based on individual patient circumstances and the development of diabetes-related complications.

Image alt text: Diagnostic algorithm for diabetes mellitus illustrating the process for differentiating LADA from Type 1 and Type 2 diabetes, emphasizing autoantibody testing and C-peptide assessment.

Treatment and Management of LADA

Upon diagnosis of LADA, initial non-pharmacological management includes individualized medical nutrition therapy and exercise plans, similar to those used in T1DM and T2DM. Given the heterogeneous nature of LADA, pharmacological treatment should be tailored to maximize therapeutic benefit. The dual goals of pharmacological intervention are: (1) to achieve optimal glycemic control and (2) to prevent or delay diabetes-related complications. Therapies aimed at preserving β-cell function are particularly important. Insulin therapy is often necessary in LADA, and may be required at diagnosis in patients with low C-peptide levels, or at any stage of disease progression. Studies have shown that early insulin therapy can preserve β-cell function, maintain stimulated C-peptide response, normalize HbA1c levels, and reduce autoantibody concentrations.[42]

There is broad consensus that sulfonylureas are not recommended for LADA treatment. Their use has been linked to accelerated β-cell depletion, faster decline in C-peptide levels, persistent autoantibody presence, and earlier progression to insulin therapy.[1, 42] Metformin, while not specifically approved for LADA, can improve insulin sensitivity, potentially aid in weight management, and may delay diabetes complications. While more research is needed, an international expert panel considers the evidence for or against metformin use in LADA to be inconclusive.[1]

Thiazolidinediones enhance insulin sensitivity by activating peroxisome proliferator-activated receptor gamma (PPARγ). Data on their use in LADA is limited. One study suggested that rosiglitazone could preserve β-cell function.[43] However, a small trial with pioglitazone indicated a more rapid decline in C-peptide levels compared to metformin.[44] Further long-term studies are warranted, and clinicians should be aware of potential side effects, including weight gain, edema, heart failure, fractures, and macular edema.

Dipeptidyl peptidase-4 (DPP-4) inhibitors have shown promise, both as monotherapy and in combination with insulin, for preserving β-cell function in LADA. They improve metabolic control by prolonging the action of endogenous glucagon-like peptide-1 (GLP-1) and other peptides, primarily increasing GLP-1 levels, which suppresses glucagon and enhances insulin secretion after glucose intake. DPP-4 receptors are also present on T lymphocytes, where they may modulate immune responses. This immunomodulatory effect may be crucial in slowing β-cell destruction in LADA.[45] Several studies using DPP-4 inhibitors have demonstrated improved glycemic control and β-cell function preservation.[1, 46, 47, 48] Data on GLP-1 receptor agonists in LADA management is limited, but studies with dulaglutide have shown HbA1c reductions.

Differential Diagnosis of LADA

The primary challenge in diagnosis of LADA is distinguishing it from T2DM. By definition, T2DM is characterized by the absence of islet cell autoantibodies, normal to elevated fasting and stimulated C-peptide levels, and typically no need for insulin for an extended period after diagnosis. Clinicians should consider screening for LADA in patients initially diagnosed with T2DM who fail to achieve adequate glycemic control within a reasonable timeframe despite adherence to therapy. This is particularly relevant in non-obese individuals without metabolic syndrome features, or those with personal or family histories of other autoimmune disorders, such as Hashimoto’s thyroiditis, Graves’ disease, celiac disease, rheumatoid arthritis, or pernicious anemia.[2]

Classic T1DM typically presents with diabetic ketoacidosis and requires insulin from the outset, making it easier to differentiate from LADA. Maturity-onset diabetes of the young (MODY) in young adults can sometimes be misdiagnosed as T1DM, T2DM, or LADA. MODY is rare, presents with a strong family history, residual C-peptide, and lacks humoral and cellular autoimmunity to islet cell antigens, distinguishing it from LADA.

Prognosis of LADA

Despite often having more favorable metabolic profiles compared to T2DM, patients with LADA exhibit similarly high mortality rates. The Trøndelag Health (HUNT) study identified hyperglycemia as the main factor influencing cardiovascular mortality in LADA, more so than other components of metabolic syndrome.[49] Strict glycemic control is therefore crucial for improving prognosis in LADA.

Complications of LADA

Compared to T2DM, patients with LADA may have a lower initial rate of microvascular complications at diagnosis but face an increased risk over long-term follow-up. Their risk of cardiovascular disease is comparable to that of T2DM patients.[2] Evidence suggests that small fiber neuropathy (SFN) occurs earlier and more frequently in LADA than in T2DM, linked to higher HbA1c levels and poor glycemic control. LADA patients often experience more severe SFN than age- and duration-matched T2DM patients, although large nerve fiber involvement is similar in both conditions. Evaluation for SFN should be included in the management of LADA patients. Small nerve fibers transmit pain and temperature sensations, regulate sweating, and control vascular tone and blood flow. Diagnostic tests for SFN include cold and warm sensation thresholds, intraepidermal nerve fiber density (IENFD) measurement, and corneal confocal microscopy. Nerve conduction studies have low sensitivity for SFN diagnosis and are not recommended.[50] Early diagnosis of LADA and subsequent glycemic control may offer a window of opportunity to reverse SFN and reduce morbidity.[51, 52]

Long-term follow-up indicates a lower risk of microvascular complications in LADA in the first 9 years compared to T2DM, but a higher risk in later years after adjusting for confounding factors.[53] Patients with LADA have similar levels of carotid artery atherosclerosis to both T1DM and T2DM patients, despite having a better vascular risk profile.[54] The Botnia study, Freemantle diabetes study, and HUNT study all support the finding of increased cardiovascular disease and mortality in LADA, similar to T2DM. Thus, LADA is associated with both microvascular and macrovascular complications, mirroring the risks seen in T1DM and T2DM.

Consultations for LADA Management

The following consultations are recommended for comprehensive LADA management:

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

Deterrence and Patient Education for LADA

Patients with LADA need comprehensive education about their condition, emphasizing the importance of strict glycemic control to prevent both microvascular and macrovascular complications. They require similar diabetes education as patients with T1DM and T2DM, covering medical nutrition plans, medication management, self-monitoring of blood glucose, and awareness of microvascular complications and cardiovascular disease management. Patients treated with sodium-glucose cotransporter-2 (SGLT2) inhibitors should be educated about the risk of ketoacidosis and the need for ketone monitoring.

Key Points for LADA Diagnosis and Management

Important considerations for LADA include:

• LADA is a distinct form of diabetes with features of both T1DM and T2DM.
• Early diagnosis of LADA is essential for initiating appropriate treatment and preventing complications.
• Clinicians should consider screening for LADA in T2DM patients with suboptimal glycemic control despite therapy adherence, especially in non-obese patients without metabolic syndrome or with autoimmune disease histories.
• New insights into LADA pathophysiology clarify the slower progression of β-cell destruction.
• C-peptide testing, basal or post-mixed meal, can be a cost-effective initial screening tool to identify patients needing confirmatory islet autoantibody testing for diagnosis of LADA.
• Sulfonylureas are contraindicated in LADA due to accelerated β-cell failure and faster progression to insulin dependence.
• Insulin and DPP-4 inhibitors, alone or combined, along with thiazolidinediones and GLP-1 receptor agonists, show promise for glycemic control and β-cell function preservation in LADA.
• Patients on SGLT2 inhibitors need education about ketoacidosis risk and ketone monitoring.

Enhancing Healthcare Team Outcomes in LADA Management

The global prevalence of diabetes is estimated at 422 million individuals. Given a LADA prevalence of 4% to 12% within the T2DM population, approximately 17 to 50 million people worldwide may have LADA. This number is likely to increase. Primary care physicians are likely to encounter LADA frequently and require adequate knowledge to recognize and manage this condition effectively.

Endocrinologists play a crucial role in managing complex LADA cases and coordinating care with primary care, ophthalmology, podiatry, and genetics specialists. Laboratory medicine experts provide guidance on appropriate testing, perform biochemical and serological assays, and communicate results to clinicians. Bariatric surgeons should maintain a high index of suspicion for LADA in diabetic patients and counsel them about potentially suboptimal glycemic control post-surgery. Coordinated efforts among healthcare professionals are vital to achieve optimal glycemic control, prevent or delay complications, and minimize morbidity, mortality, and healthcare costs associated with LADA.

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References

(References from the original article – References – to be included here for completeness and proper attribution)

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Disclosures

(Disclosures from the original article – Disclosures – to be included here for completeness)

Disclosure: Venkatraman Rajkumar declares no relevant financial relationships with ineligible companies.

Disclosure: Steven Levine declares no relevant financial relationships with ineligible companies.