Latent Autoimmune Diabetes in Adults (LADA)

LADA, Type 1.5 diabetes, late-onset autoimmune diabetes of adulthood, adult-onset autoimmune diabetes, slowly progressive insulin-dependent type 1 diabetes mellitus, slow-onset diabetes in adults

Latent autoimmune diabetes in adults (LADA) is a form of diabetes that shares features of both Type 1 and Type 2 diabetes, affecting adults over 30 years old. Often called Type 1.5 diabetes, it develops slowly over months to years and is frequently misdiagnosed as Type 2 diabetes, potentially leading to inappropriate treatment and complications.

Table of contents

• What is Latent Autoimmune Diabetes in Adults?
• How Common is LADA?
• What Causes LADA?
• Signs and Symptoms
• Risk Factors
• How LADA is Diagnosed
• Potential Complications
• Treatment Options

What is Latent Autoimmune Diabetes in Adults?

Latent autoimmune diabetes in adults is a type of diabetes that combines characteristics of both Type 1 and Type 2 diabetes. Like Type 1 diabetes, LADA is caused by an autoimmune condition (a condition where the body’s immune system mistakenly attacks its own tissues). The immune system creates antibodies that attack and destroy the cells in the pancreas (an organ in your belly that produces insulin) that make insulin^[1].

However, unlike Type 1 diabetes which typically appears in childhood or teenage years and progresses rapidly, LADA develops much more slowly in adults. The destruction of insulin-producing cells happens gradually over months or even years^[2]. This slow progression means that the pancreas continues to produce some insulin initially, which is why LADA is often mistaken for Type 2 diabetes when doctors first see patients^[1].

Healthcare providers typically diagnose LADA in adults between ages 30 and 50^[1]. Some medical organizations classify LADA as a slowly evolving form of Type 1 diabetes, while others consider it a distinct condition between Type 1 and Type 2 diabetes^[4].

How Common is LADA?

Although many people have not heard of LADA, it is actually fairly common. Research studies suggest that between 4% and 12% of people who initially receive a Type 2 diabetes diagnosis actually have LADA^[1][3]. To put this in perspective, approximately 530 million adults worldwide have Type 2 diabetes, which means several million people potentially have LADA^[1].

The percentage of LADA cases varies by geographic region. Studies show that positive tests for antibodies associated with LADA range from 4% to 12% in European countries and 3.8% to 9% in Asian countries among patients diagnosed with Type 2 diabetes^[4]. In the large UK Prospective Diabetes Study, antibodies related to LADA were found in 10% of the 5,000 patients with Type 2 diabetes, with higher rates in younger patients^[3].

What Causes LADA?

Researchers believe LADA happens when the immune system mistakenly produces antibodies that attack and destroy the cells in your pancreas that make insulin. When your body cannot release enough insulin, sugar (also called glucose) builds up in your bloodstream instead of being used by your cells for energy^[1].

The exact reasons why this autoimmune attack begins are not fully understood. LADA appears to be a polygenic disease (a disease caused by multiple genes working together), involving genetic defects that lead to gradual destruction of insulin-producing cells combined with autoimmune features^[4]. The genetic factors in LADA differ from both Type 1 and Type 2 diabetes. Adults with LADA appear to have a lighter genetic load compared to those with childhood Type 1 diabetes, which may explain why the disease progresses more gradually^[4].

There are no specific triggers for LADA because it is something your immune system does without your conscious control. LADA can go unnoticed for a long time because your pancreas still releases enough insulin initially to prevent obvious symptoms^[1].

Signs and Symptoms

The symptoms of LADA are similar to those of other forms of diabetes. However, compared to childhood Type 1 diabetes where symptoms develop rapidly over weeks, LADA symptoms develop slowly over a period of at least six months^[7]. The symptoms are often more obvious and come on more quickly than expected with Type 2 diabetes^[8].

Common symptoms include:

• Being very thirsty (called polydipsia by doctors)^[1]
• Needing to urinate more often, including during the night^[1][6]
• Losing weight unexpectedly without trying^[1]
• Blurred vision^[1]
• Feeling very tired (fatigue)^[1]
• Itchy, dry skin^[1]
• Increased hunger^[6]

Risk Factors

Several factors can increase the likelihood of developing LADA. Understanding these risk factors can help identify people who may need testing for LADA rather than assuming they have Type 2 diabetes.

LADA has a strong genetic component, meaning you may be more likely to develop it if your biological parents or grandparents have it^[1]. If you have a family history of Type 1 diabetes or other autoimmune diseases, your risk may be higher^[9].

Environmental and lifestyle factors also appear to play a role in developing LADA. Obesity has been shown to increase the risk of LADA in several studies, with particularly high risk when combined with having diabetes in the family^[7]. However, people with LADA often have a normal or only slightly elevated body weight compared to those with Type 2 diabetes^[8][9].

Physical inactivity increases the risk of LADA, while regular physical activity appears protective^[7]. Other factors that may increase risk include consumption of sweetened beverages and processed red meat, while eating fatty fish has been shown to have a protective effect^[7]. Low birth weight has also been linked to increased LADA risk^[7].

A recent study identified specific clinical features that increase the likelihood of LADA. Adults diagnosed with diabetes who have at least two of these characteristics should be considered for LADA testing^[3]:

• Age under 50 at diagnosis
• Having symptoms for less than six months before diagnosis
• Body weight below the overweight range
• Having another autoimmune disease
• Family history of autoimmune disease

How LADA is Diagnosed

Diagnosing LADA can be challenging because it often resembles Type 2 diabetes when people first develop symptoms. Many individuals with LADA are initially diagnosed with Type 2 diabetes by mistake^[1][8]. Healthcare providers may begin to suspect LADA when someone diagnosed with Type 2 diabetes cannot manage their blood sugar with oral medications (such as metformin) and lifestyle changes like eating nutritious foods^[1].

The only way to confirm a LADA diagnosis is through blood tests. The main test is called a GAD Antibodies Test (glutamic acid decarboxylase antibodies test)^[1]. Antibodies against GAD-65 are the most common type found in people with LADA^[5]. While people with childhood Type 1 diabetes typically test positive for multiple types of antibodies, those with LADA usually test positive for only one antibody, most commonly GAD antibodies^[3][5].

Other autoantibodies that may be tested include islet cell antibodies, antibodies to tyrosine phosphatase-related islet antigen 2 (IA-2A), insulin autoantibodies, and zinc transporter 8 antibodies. However, these are less frequently found in LADA^[5].

Healthcare providers also measure C-peptide levels, which is a marker for how much insulin the body produces. The pancreas releases one C-peptide molecule for every insulin molecule it makes^[9]. People with LADA tend to have low C-peptide levels compared to those with Type 2 diabetes who have normal to high levels^[10].

An international expert panel recommended in 2020 that all patients with newly diagnosed Type 2 diabetes should be screened for LADA with a test for GAD antibodies. If financial constraints make universal screening impractical, testing should at least be done for patients who are lean, physically active, have experienced unexplained weight loss, have poor blood sugar control despite treatment, are younger at diagnosis (under 60), or have a family history of Type 1 diabetes or autoimmune disease^[9][10].

Potential Complications

The biggest complication of LADA comes from not receiving the right treatment for the condition. Because LADA often appears similar to Type 2 diabetes, people may not get treatment with insulin as early as they need it. This can increase the risk for health problems such as kidney damage^[1].

People with LADA tend to have more rapid and progressive loss of the cells that produce insulin compared to those with Type 2 diabetes. This means they need intensive insulin treatment sooner^[3]. Studies show that LADA patients generally require insulin therapy about five years after diagnosis, although some may need it within one year^[10][14].

Diabetic ketoacidosis (DKA) is a life-threatening complication that can occur with LADA. It happens when your liver starts breaking down body fat for energy because you don’t have enough glucose in your cells to use for energy. While DKA is usually absent at the time of LADA diagnosis, it may develop later when the person becomes severely deficient in insulin^[1][3].

Like other forms of diabetes, LADA increases the risk of various complications including heart disease, nerve damage, eye problems (retinopathy), kidney disease (nephropathy), and nerve damage (neuropathy)^[3]. Patients with LADA are more likely to experience worse blood sugar control and higher hemoglobin A1C levels compared to those with Type 2 diabetes if not properly treated^[16].

Treatment Options

The goal of LADA treatment is to achieve good blood sugar control and prevent complications. Because the body gradually loses its ability to produce insulin, treatment plans need to be adjusted over time and tailored to each individual^[9].

In the early stages, LADA may be managed with lifestyle changes such as exercising regularly, losing weight if needed, making healthy diet choices, and quitting smoking. Medications taken by mouth to lower blood sugar may also be used initially^[14][19].

Insulin therapy is the primary treatment for LADA. Although insulin is effective and safe, there is debate about whether it should be given early in the disease when the pancreas still produces some insulin, or delayed until absolutely necessary^[9]. Some experts believe that starting insulin therapy early helps preserve the remaining insulin-producing cells and prevents complications. Studies show that starting insulin within one year of diagnosis helps slow the destruction of these cells and improves blood sugar control^[16][22].

The international expert panel developed treatment recommendations based on C-peptide levels. People with C-peptide levels greater than 0.7 nmol per liter can be managed similarly to Type 2 diabetes patients. Those with levels below 0.3 nmol per liter should start insulin therapy. Patients with C-peptide levels between 0.3 and 0.7 nmol per liter (the “gray area”) should start with metformin and other medications appropriate for their situation, with C-peptide levels rechecked every six months to monitor for developing insulin deficiency^[9].

Certain oral medications are not recommended for LADA. Sulfonylureas (medications that stimulate the pancreas to release more insulin) are discouraged because they may accelerate the loss of insulin-producing cells and increase the risk of low blood sugar when combined with insulin therapy^[9][16].

Metformin, a common diabetes medication that improves how the body uses insulin, may be effective in early LADA, particularly for patients who are overweight^[9][16]. Other medication classes that have shown promise in small studies include dipeptidyl peptidase 4 inhibitors, glucagon-like peptide receptor 1 agonists, and sodium-glucose cotransporter 2 inhibitors. However, more research is needed before these can be routinely recommended for LADA^[9][16].

Because LADA is less well-studied than Type 1 or Type 2 diabetes, treatment approaches continue to evolve as researchers learn more about the condition. Close monitoring by healthcare providers is essential to adjust treatment as the disease progresses and to minimize complications^[16].