LADA: latent autoimmune diabetes in adults

Yes. Although type 1 diabetes was long considered a "childhood disease", adults of any age can develop classic type 1 diabetes. All forms of diabetes that arise through autoimmune destruction of the beta cells, regardless of age at onset, are included in the type 1 diabetes category. Your immune system mistakenly identifies the pancreatic beta cells as foreign and progressively destroys them, leading to an absolute insulin deficiency. This autoimmune process can be triggered at 15, 45 or even over 70 years of age. The islet autoantibodies (GAD65, IAA, IA-2, ZnT8) can appear across the entire age range [1].

What changes with age is not the nature of the disease, but its presentation. Adult-onset type 1 diabetes usually evolves more slowly than the classic pediatric form. In adults, polyuria, polydipsia, unintentional weight loss and fatigue can accumulate over weeks or months, and ketoacidosis at diagnosis is rarer. The main form of diabetes in adults is type 2 diabetes. That is why the initial label is often type 2. The diagnosis is later revised to type 1 diabetes, depending on the course and the response to treatment. Diabetes that appears in an adult is not necessarily type 2, not even in the presence of obesity [2].

LADA (Latent Autoimmune Diabetes in Adults) is a slowly progressive form of autoimmune diabetes. It is not a separate subtype but part of the type 1 diabetes spectrum, with a slower loss of beta cells [3]. LADA generally appears after the age of 30 and has at least one islet autoantibody present (most commonly anti-GAD65). One of the proposed definitions also requires that insulin not be needed in the first 6 months after diagnosis [4]. However, there are no universally accepted diagnostic criteria [3]. The LADA label can delay the start of insulin, so treatment is guided by autoantibodies, C-peptide and the course of the disease, not by the name [3].

The unofficial label of "type 1.5 diabetes" reflects its apparently hybrid nature, with features of both type 1 and type 2. Thus, LADA resembles type 1 diabetes through autoimmune destruction of the beta cells and inevitable progression toward insulin dependence (over years). It also resembles type 2 diabetes through its onset in adults, often in overweight people or in people with features of insulin resistance. Initially it responds to lifestyle measures and oral diabetes medications. You usually experience a "honeymoon" period in which residual beta-cell function preserves good insulin secretion, but this window closes at some point. Recognizing this intermediate phenotype is very important. Treating LADA as ordinary type 2 diabetes, especially with sulfonylureas, can accelerate beta-cell exhaustion and delay the timely introduction of insulin treatment, as the figure below shows [5].

The classic epidemiological picture of type 1 diabetes shows an incidence peak in childhood and adolescence, around 10–14 years of age. Across the whole of adult life, however, the absolute number of new cases diagnosed in adulthood is greater than in the pediatric range. The reason is simple — adult life covers many more decades. Incidence remains relatively constant throughout adult life, and some registries describe even a new, smaller peak at older ages [6].

LADA is found specifically in middle-aged adults. Most people with LADA are diagnosed between 30 and 60 years of age. The peak falls in the fourth and fifth decades of life, that is around the ages of 40 and 50. A significant proportion of adults initially labeled with type 2 diabetes are reclassified as LADA when autoantibodies are tested systematically and come back positive. There is no upper age beyond which autoimmune diabetes "no longer occurs". Even if someone is over 70 years old, new-onset diabetes deserves a diagnostic process that does not automatically assume type 2 diabetes [5].

The distinction between LADA and type 2 diabetes is one of the most important clinical decisions in adult diabetes. The two forms can have a similar initial appearance, with adult-onset hyperglycemia and no spontaneous tendency to ketoacidosis. The clinical clues that raise suspicion of LADA are:

• relatively young age within the adult spectrum;
• a normal or slightly elevated body mass index;
• a lean phenotype without features of metabolic syndrome — central obesity, hypertension, dyslipidemia with elevated triglycerides and low HDL, hepatic steatosis;
• a personal history of autoimmune diseases — Hashimoto's thyroiditis, Graves' disease, vitiligo, celiac disease, pernicious anemia, Addison's disease;
• possibly a family history of type 1 diabetes (not type 2).

Unintentional weight loss, rapid symptomatic deterioration or the appearance of ketoacidosis in someone initially considered to have type 2 diabetes are additional warning signals [4]. These signs call for the diagnosis to be reassessed, not for oral treatment to continue as in type 2 diabetes. If vomiting, difficulty breathing or drowsiness appear, go to the emergency room right away.

Laboratory investigations involve the measurement of islet autoantibodies, especially anti-GAD65, considered the most prevalent and most sensitive marker in LADA. A high titer or the presence of several autoantibodies strongly supports the diagnosis [3]. An isolated anti-GAD65 at a low titer, however, is interpreted with caution, because it also occurs in 1–2% of the general adult population [3]. That is why anti-GAD65 is measured only when there is a clinical suspicion of type 1 diabetes [3]. The endogenous insulin reserve is best evaluated through basal and possibly stimulated C-peptide. In LADA, C-peptide values decrease progressively from year to year. Clinically, people with LADA progress more rapidly toward a significant need for insulin than those with type 2 diabetes. The response to oral diabetes medications (especially to sulfonylureas) becomes weaker and weaker as the pancreatic beta cells are exhausted. That is why a patient with LADA is offered insulin treatment, like any patient with suspected type 1 diabetes [3].

When an adult presents with hyperglycemia that does not resemble type 2 diabetes, it is good practice to measure the standardized islet autoantibodies (GAD65/GADA, IAA, IA-2A and ZnT8A). A fifth, older marker is the islet cell antibodies (ICA), detected by indirect immunofluorescence. It is still available, but no longer recommended, because it is less specific and difficult to standardize between laboratories [1]. In practical terms, GAD65 is the first-line test in adults.

It is the most sensitive individual marker for adult-onset autoimmune diabetes, persists for many years after diagnosis and is frequently the only positive autoantibody in LADA. IA-2A is more characteristic of pediatric type 1 diabetes, and when it appears in adults it indicates more aggressive disease. ZnT8A is useful as an arbiter when GAD65 is negative but clinical suspicion persists, and it can reclassify a sizeable subset of cases. IAA (anti-insulin antibodies) is informative especially in young children and must be measured before the initiation of exogenous insulin, otherwise it cannot be differentiated from antibodies induced by treatment. A reasonable sequence is to start with GAD65, and if it is negative add IA-2A and ZnT8A. A single autoantibody at a low titer often indicates a milder autoimmune process, sometimes even a false-positive result [3]. Several positive autoantibodies signal a more aggressive autoimmune attack and faster progression to insulin dependence [5].

Misclassification of adult-onset autoimmune diabetes as type 2 diabetes is one of the most common diagnostic pitfalls. First, the clinical presentation in adults is atypical. In children, type 1 diabetes often begins with significant hyperglycemia and ketoacidosis. Adults with autoimmune diabetes of the LADA form usually have a slow onset, with mild symptoms and initially preserved insulin secretion. Second, there is substantial phenotypic overlap with type 2 diabetes, as patients are often overweight or obese, sedentary, or present with features of metabolic syndrome. Obesity does not exclude autoimmune diabetes, yet in current practice it strongly steers the physician toward a diagnosis of type 2 diabetes [2].

The second group of reasons relates to the organization of the healthcare system. Autoantibody testing is not part of the routine evaluation of newly diagnosed adults with diabetes. The reasons are cost, lack of easy access to testing, or guidelines that have historically restricted this testing to young patients. This perpetuates an age bias, in which type 1 diabetes is assumed to be in children and type 2 diabetes in adults (incorrectly). Another pitfall is the good initial response to oral diabetes medications, sustained by the residual beta-cell function still present in LADA. Metformin and sulfonylureas can achieve apparently satisfactory control for months or years, offering the clinician an apparently easy and cheap solution [5].

The answer differs from one patient to another. To achieve glycemic control, the time until the need for insulin is highly variable, but generally in the range of 1–5 years. The pace is set by the speed at which the autoimmune process exhausts the pancreatic beta cell mass. That is what determines when insulin becomes necessary to keep blood glucose in target. Generally, beta cell mass falls relatively quickly in the first years after diagnosis, and then a slower and more stable phase follows [4].

Insulin treatment is, however, offered right from diagnosis, because LADA is part of the type 1 diabetes spectrum [3]. In some patients, when the course looks more like type 2 diabetes, a treatment without insulin may be tried [3]. In that case the patient needs close follow-up and education, so that insulin treatment starts promptly if blood glucose rises [3]. This offers the greatest possible long-term benefit. If C-peptide has very low values (below 0.3 nmol/L, about 0.9 ng/mL), a multi-dose insulin regimen is required, as in classic type 1 diabetes [4]. The use of modern technologies (continuous glucose monitors, insulin pumps) brings benefits similar to classic type 1 diabetes [3].

In the early phase of adult-onset autoimmune diabetes (LADA), endogenous insulin secretion is partially preserved. Oral diabetes medications can therefore improve glycemic control transiently. This is also why LADA is confused with type 2 diabetes. This response, however, is borrowed time, paid back with very high interest. Autoimmune destruction continues (sometimes accelerated), and as residual insulin secretion decreases, the apparent benefit of oral therapy begins to disappear. The choice of treatment must be guided not by the initial glycemic response, but by the autoimmune nature of the disease. Residual beta-cell function also counts, typically estimated through C-peptide [4].

Sulfonylureas should be avoided because they force already stressed pancreatic beta cells to secrete more insulin. They produce more "noise", which makes it easier for the immune system to "hear" them. Sulfonylureas are considered to accelerate beta-cell exhaustion and shorten the time to insulin dependence. Insulin treatment is offered right from diagnosis [3]. At the latest, it starts when oral antidiabetic drugs no longer keep blood glucose on target, when HbA1c rises despite your efforts, or when C-peptide decreases. The same applies when unintentional weight loss or accumulation of ketone bodies appears [5].

Adult-onset type 1 diabetes, including LADA, has the same fundamental risk pattern as juvenile-onset type 1 diabetes. In the LADA form, the autoimmune process usually evolves more slowly and residual beta-cell function is preserved for longer. The consequence is usually better glycemic control [2]. Adults with type 1 diabetes, however, have an increased risk of cardiovascular events and all-cause mortality compared with the general population [6] [7]. This could improve in the future through modern insulin delivery technologies (smart pumps capable of closed-loop operation).

When LADA is misdiagnosed and inadequately treated as type 2 diabetes, typically with sulfonylureas and without insulin, the trajectory can be much more severe. The dominant determinant of prognosis remains the quality of glycemic control, expressed through time in range, coefficient of variation and glycated hemoglobin. Correct and early classification changes outcomes, because it avoids a delay in insulin treatment and the increased risk of ketoacidosis [3]. Continuous glucose monitoring systems and automated insulin delivery (AID) systems substantially improve metabolic control and quality of life. They are now recommended right from the initiation of insulin therapy. Adult-onset type 1 diabetes is a serious condition. But a correct and early diagnosis, insulin therapy initiated right at diagnosis, modern monitoring and aggressive control of cardiovascular risk factors all help. With them, the long-term prognosis can approach that of the general population.