What is Latent Autoimmune Diabetes?
Diabetes mellitus (DM) is a broad condition that includes different types from Type 1 diabetes, characterized by the lack of insulin, to Type 2 diabetes, characterized by insulin resistance. Within this diabetes spectrum, there’s a condition called Latent Autoimmune Diabetes of Adults (LADA), also known as Type 1.5 DM. LADA shares traits of both Type 1 and Type 2 diabetes. In different regions it goes by different names; for example, in Japan, it’s called slowly progressive insulin-dependent type 1 diabetes. While LADA is listed by the American Diabetes Association as a slow-developing form of Type 1 diabetes, it is not officially recognized as a unique type of diabetes. Contrarily, the World Health Organization regards LADA as a gradually developing form of diabetes linked to the immune system.
LADA, as the name suggests, typically affects adults. There are three key criteria set by the Immunology for Diabetes Society for diagnosing LADA: the patient should be older than 30, tests positive for specific antibodies related to cell destruction in the pancreas, and should not require insulin for the first six months after diagnosis. However, these criteria aren’t universally accepted as insulin usage can rely heavily on individual doctors’ considerations.
People with LADA experience an illness similar to Type 1 diabetes, producing antibodies that gradually destroy cells in the pancreas, but it progresses more slowly and less severely. Often, LADA patients are initially diagnosed and treated as if they have Type 2 diabetes because the high blood sugar levels common in LADA are less extreme than those in typical Type 1 diabetes. However, these patients often struggle to maintain control of their blood sugar levels with conventional medications and ultimately need insulin therapy.
LADA is not a homogeneous disease; it varies from person to person. Some patients quickly need insulin therapy due to higher antibody levels and lower body weight, while others with lower antibody levels and signs of insulin resistance, like a higher body weight, require insulin more gradually. Early diagnosis of LADA is essential for managing the condition and delaying the destruction of cells in the pancreas. This will also help reduce complications related to the disease.
What Causes Latent Autoimmune Diabetes?
Latent Autoimmune Diabetes in Adults (LADA) is influenced by genetic factors. These genetic factors, particularly certain HLA haplotypes, are associated with a higher possibility of developing LADA. HLA genes influence important immune functions so it makes sense that a malfunction in these functions can cause LADA. However, the exact triggers of these malfunctions are still not known.
It’s different from Type 2 diabetes in that there aren’t many studies investigating the potential role that environmental factors, like lifestyle habits, could play in causing LADA. There are a few reasons for this gap in research. One is the necessity to conduct tests for specific antibodies in every new adult diabetes patient to identify and classify them as LADA. Another reason is that there aren’t comparable groups of patients with LADA for study. Furthermore, getting information about lifestyle habits prior to a diagnosis of LADA is difficult, and many studies have based their findings on a small number of LADA patients, creating challenges in the research power.
Even with these research challenges, some studies suggest that LADA shares some lifestyle risk factors with type 2 diabetes. These factors include overweight, higher waist-to-hip ratio, low birth weight, consumption of two or more daily sweetened drinks, and heavy smoking. These risk factors tend to matter more in a subgroup of LADA patients who show less severe symptoms and higher body mass index. The connection is less pronounced but still present among patients with high antibody levels.
In contrast, a more active lifestyle, moderate alcohol consumption, and eating fatty fish may help lower the risk of LADA. In one study, drinking two or more cups of coffee a day increased the risk for LADA, which is surprising since coffee is usually beneficial for Type 2 diabetes patients. But since this finding comes only from one study, further investigation is needed to confirm this.
Risk Factors and Frequency for Latent Autoimmune Diabetes
Latent autoimmune diabetes in adults (LADA) is the most common type of adult-onset autoimmune diabetes. The frequency of this condition can vary depending on geographic location and ethnicity. For example, in a European study involving over 6000 adults with adult-onset diabetes, nearly 10% had islet cell autoantibodies, which are a typical indicator of LADA. In contrast, a UK study found a 15% positivity rate among adults presumed to have Type 2 diabetes. Studies from Norway also recorded a 10% incidence, whereas research from the Middle East, Korea, and China suggested a prevalence between 4% and 9%.
Typically, people with LADA have one type of islet autoantibody, with the glutamic acid decarboxylase antibody being the most common. Depending on the population, the prevalence of different autoantibodies can vary, meaning that only looking for one type may not offer a complete picture of LADA prevalence. It’s also important to remember that the presence of these autoantibodies can change over time. In some cases, there can be interference from other antibodies, called anti-idiotype antibodies, that affect the test results. A version of LADA has also been found in young people.
Signs and Symptoms of Latent Autoimmune Diabetes
Latent Autoimmune Diabetes of Adulthood (LADA) can show up with different symptoms such as excessive urination, feeling very thirsty, urinating at night, tiredness, blurry vision, tingling sensation in the feet, and weight loss. In some cases, people with LADA might not show any symptoms.
Here are some indicators that could increase the risk of having this condition:
- Individuals or their families having a history of autoimmune diseases – this could hint at either LADA or Type 1 Diabetes Mellitus (T1DM).
- Individuals who were born underweight – this increases the risk for both LADA and type 2 Diabetes Mellitus (T2DM).
- Individuals who smoke, consume alcohol, and drink sweetened beverages – these habits are also risk factors for LADA.
Physical activity levels and exercise patterns should also be considered when assessing LADA risk. Accurate blood pressure measurements are important too. There have been several tools proposed to help identify those with LADA. One such tool includes three criteria used to find LADA in individuals over 50 years old who have diabetes:
- A normal or low Body Mass Index (BMI)
- A fasting blood sugar level of 270 mg/dL or more even when following a strict diet, and a Hemoglobin A1c (HbA1c) level of 10% or more
- Weight loss even though they are on a fixed calorie diet
This tool was successful in detecting LADA in about 75% of patients. Another tool, the clinical risk score developed by Foulanos et al, includes:
- Being under 50 years old
- Having symptoms of high blood sugar
- A BMI of less than 25 kg/m2
- Having a personal or family history of autoimmune diseases
If two or more of these criteria are met, there is a high chance of the individual having LADA. However, it is important to remember that LADA can manifest with characteristics common in both T1DM and T2DM, including showing a normal to high BMI. In fact, LADA patients generally have levels of BMI, waist circumference, blood pressure, and triglycerides that fall between those found in individuals with T1DM and T2DM. Some patients with LADA may also have features of Metabolic Syndrome (MetS). It’s also worth noting that LADA patients are usually resistant to ketosis when they are first diagnosed.
Testing for Latent Autoimmune Diabetes
If you show signs of high blood sugar and can control it without the need for insulin within the first six months, you may have a condition called LADA. This condition is typically confirmed by testing for a specific antibody within the body. The most common antibody tested for globally is GADA. However, there are also others such as IA-2A, insulin antibodies, along with zinc transporter isoform 8 antibody, that may be tested.
In LADA patients, a substance known as C-peptide can usually be detected, albeit in levels between those seen in people with Type 1 and Type 2 diabetes. If you have Type 1 diabetes, C-peptide is often absent when you first get diagnosed, and in Type 2 diabetes, the levels are usually elevated. As it turns out, the amount of C-peptide in your body has an inverse relationship with GADA levels. But it’s worth noting that measuring C-peptide after a stimulus gives a more accurate picture than a fasting level. Two tests, the glucagon stimulation test and mixed meal tolerance test (MMTT), have been developed for this purpose. MMTT, particularly, can help doctors determine the right treatment and predict when a patient might have to start on insulin therapy.
Testing for C-peptide can be a cost-effective way to tell LADA apart from Type 2 diabetes. Research suggests that C-peptide levels are generally higher in people with Type 2 diabetes than in those with LADA. Nonetheless, the diagnosis of LADA must be confirmed with antibody testing.
While there are standard tests for determining the type of diabetes such as HLA typing, it is not usually used to diagnose LADA.
Now, if you are a patient with LADA, apart from the aforementioned tests, additional regular checks are recommended to manage the conditions better. These include testing for fasting glucose, glycosylated hemoglobin (HbA1c), self-monitoring of blood sugar levels, and measures of glycemic variability, which are best achieved by continuous glucose monitoring. Furthermore, maintaining regular check-ups on the lipid profile, renal function, creatinine levels, and urinalysis for protein excretion is also important. Additionally, tests for detecting peripheral neuropathy and retina checks conducted by an ophthalmologist are highly recommended. Depending on the individual circumstances, other tests may be necessary to monitor complications arising from diabetes.
Treatment Options for Latent Autoimmune Diabetes
When a person is diagnosed with Latent Autoimmune Diabetes in Adults (LADA), the first steps usually involve a custom diet and exercise plan. These are the same methods used for patients with type 1 and type 2 diabetes. However, since LADA varies from person to person, treatment should be specifically tailored to each individual to achieve the best results. The main aims are to control blood sugar levels and prevent or delay complications. The priority should be to preserve the ability of the pancreas’s beta-cells to function. Many patients with LADA might need insulin treatment, which may be necessary at the time of diagnosis or introduced at any point in the disease progression.
Sulfonylureas, a class of diabetes medications, are generally not recommended for people with LADA because they can deplete beta-cells in the pancreas, lead to more rapid declines in certain proteins, and lead to faster progression to insulin dependency. Instead, metformin, another diabetes medication, is often used as it can improve insulin sensitivity, assist in weight loss, and delay the onset of complications related to diabetes. But more research is needed on metformin’s effectiveness in LADA patients.
Another class of drugs, thiazolidinediones, also enhance insulin sensitivity. However, the data on their use in LADA patients is limited. In one study, a medication called rosiglitazone helped preserve beta-cell function, but another medication, pioglitazone, was found to cause a rapid decline in proteins associated with insulin production in a small trial. Prolonged studies and careful consideration of potential side effects such as weight gain, fluid retention, heart failure, and eye problems are needed before use.
Another promising treatment for LADA are DPP4 inhibitors, either on their own or in combination with insulin. These work by increasing levels of certain substances that help manage blood sugar levels after eating. They also may have a role in immune regulation, which could help slow the immune system’s attack on the pancreas’s beta cells in LADA. Studies have shown improved diabetes control and beta-cell function with DPP4 inhibitors. The use of GLP1 agonists, another class of drugs, in managing LADA is less clear. However, some studies have shown that a medication called dulaglutide can lower blood sugar levels.
What else can Latent Autoimmune Diabetes be?
It can be tricky to tell the difference between people with LADA (Latent Autoimmune Diabetes in Adults) and those with Type 2 diabetes. Usually, people with Type 2 diabetes lack specific antibodies, have normal or higher levels of a substance called C-peptide and they typically don’t need insulin for a long time. Doctors might want to test for LADA in those Type 2 diabetes patients who can’t get their blood sugar under control, even with treatment. This might especially be the case if they aren’t overweight, don’t show signs of the Metabolic Syndrome, or if they or their close family members have other autoimmune disorders. These disorders could include conditions like Hashimoto’s thyroiditis, Graves’ disease, celiac disease, rheumatoid arthritis, or pernicious anemia.
People with classic Type 1 diabetes often show up in hospitals with a serious condition called ketoacidosis. They need insulin straight away and are easy to tell apart from LADA patients. Sometimes a young adult with a rare kind of diabetes, called maturity-onset diabetes of the young (MODY) is wrongly diagnosed as Type 1 diabetes, Type 2 diabetes, or LADA. MODY runs in families and people with it have some amount of C-peptide and no signs of immune reaction against their own pancreas cells. It can be differentiated from LADA.
What to expect with Latent Autoimmune Diabetes
Patients with Latent Autoimmune Diabetes in Adults (LADA) face death rates as high as those with Type 2 Diabetes Mellitus (T2DM), even though they generally exhibit better metabolic health. The Trøndelag Health Study found that high blood sugar levels were the only significant factor affecting the risk of death from heart disease, not other metabolic syndrome components.
Keeping blood sugar levels under strict control is crucial for improving health prospects in individuals with LADA.
Possible Complications When Diagnosed with Latent Autoimmune Diabetes
Patients with LADA (Latent Autoimmune Diabetes in Adults) share some similarities with those suffering from T2DM (Type 2 Diabetes Mellitus), in the pattern of complications they face. When initially diagnosed, these patients have fewer small blood vessel complications compared to T2DM patients. However, their risk for such complications increases during extended periods of follow-up care. They also have an equal risk for cardiovascular diseases, just like T2DM patients.
Studies have indicated that LADA patients may experience small-fiber neuropathy (a form of nerve damage) earlier, and more frequently compared to T2DM patients, which is influenced by higher HbA1c (a measure of long-term blood glucose levels) and poor blood sugar control. LADA patients often have more severe instances of this type of nerve damage than age and duration-matched T2DM patients. The involvement of large nerve fibers, however, is similar to T2DM.
Patients with LADA should be evaluated for small-fiber neuropathy through various tests. These nerves carry pain and temperature sensations, control sweating, regulate the widening and narrowing of blood vessels, and manage blood flow. Some of the tests for detecting this condition include:
- Cold sensation threshold
- Warm sensation threshold
- Intraepidermal nerve fiber density (IENFD), and
- Corneal confocal microscopy
Diagnostic testing that measures nerve conduction speeds may not be very useful for detecting small-fiber neuropathy, and isn’t generally recommended. Importantly, if detected early, treatment of high blood sugar may potentially reverse this condition and also reduce associated health issues.
Longer-term follow-up of LADA patients reveals that while their risk of small blood vessel complications is lower in the first 9 years, it increases in the following years, when compared to T2DM patients. This is after taking several factors into account. LADA patients also have similar levels of carotid artery hardening as those with either T1DM (Type 1 Diabetes Mellitus) or T2DM, though they display a better vascular risk profile. Various studies underline the increased risk of cardiovascular diseases and mortality in LADA, similar to T2DM patients. Therefore, just like T1DM and T2DM patients, those with LADA are at risk for both small blood vessel and large blood vessel complications.
Preventing Latent Autoimmune Diabetes
Patients with LADA, a type of diabetes, need to understand the specifics of their condition. It’s crucial that they control their blood sugar levels tightly to prevent damage to small and large blood vessels, which could lead to serious complications. Their education should be the same as those with other types of diabetes. This means understanding their diet plan, how to use their medication, how to check their own blood sugar levels, and how to recognize and manage complications related to blood vessels and heart disease.
If patients are taking a medication called sodium-glucose cotransporter-2 (SGLT2) inhibitors, it’s important that they’re aware of the risk of a serious condition called ketoacidosis. They should know to check their body for ketones, which, if found, could be a sign of this dangerous condition.
