LADA-type diabetes mellitus

Yes. Although type 1 diabetes was long considered a "childhood disease", current evidence shows unequivocally that adults of any age can develop classic type 1 diabetes. All forms of diabetes that arise through autoimmune destruction of the β 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 reformulated as 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, considered for this reason a subform of type 1 diabetes. LADA generally appears after the age of 30 and has at least one islet autoantibody present (most commonly anti-GAD65). Insulin is not absolutely necessary in the first 6 months after diagnosis [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 β cells and inevitable progression towards 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 antidiabetic drugs. You usually experience a "honeymoon" period in which residual β-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 β-cell exhaustion and delay the timely introduction of insulin treatment, as the figure below shows [4].

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 [5].

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 [4].

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 [3]. 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 straight away.

Laboratory investigations involve the measurement of islet autoantibodies, especially anti-GAD65, considered the most prevalent and most sensitive marker in LADA. A positive result, even at a modest titer, indicates an active autoimmune process and establishes the diagnosis of LADA-type diabetes. 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 towards a significant need for insulin than those with type 2 diabetes. The response to oral antidiabetic drugs (especially to sulfonylureas) becomes increasingly weaker as the pancreatic beta cells are exhausted. In LADA, early initiation of insulin treatment is recommended (initially only basal) [6].

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, being 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, being able to reclassify an important 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. Several positive autoantibodies signal a more aggressive autoimmune attack and a more rapid evolution towards insulin dependence [4].

Misclassification of adult-onset autoimmune diabetes as type 2 diabetes is one of the most frequent 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 orients the physician towards 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 antidiabetic drugs, sustained by the residual β-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 [4].

The answer to how quickly insulin treatment is needed in LADA-type diabetes depends on the goal you are pursuing. 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, there is a relatively rapid decrease in the first years after diagnosis, followed by a slower and more stable phase [3].

If the goal becomes preservation of the pancreatic beta cells, insulin should be initiated immediately, in the form of basal insulin. This offers the greatest possible long-term benefit. If C-peptide has very low values (below 0.3 nmol/L), a multi-dose insulin regimen is required, as in classic type 1 diabetes. The use of modern technologies (continuous glucose monitors, insulin pumps) brings benefits similar to classic type 1 diabetes [6].

In the early phase of adult-onset autoimmune diabetes (LADA), endogenous insulin secretion is partially preserved. Oral antidiabetic drugs 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 (even 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 β-cell function also counts, typically estimated through C-peptide [3].

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 β-cell exhaustion and shorten the time to insulin dependence. Insulin should be initiated right at diagnosis. At the latest, it must start when oral agents no longer maintain targets, when HbA1c rises despite your efforts, when C-peptide decreases, or when unintentional weight loss or accumulation of ketone bodies appears [4].

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 β-cell function is preserved for longer. The consequence is better glycemic control, especially in the first 5 years. Severe hypoglycemic episodes are clearly rarer than in childhood-onset type 1 diabetes. Adults with type 1 diabetes, however, have an increased risk of cardiovascular events and all-cause mortality compared with the general population. This could improve in the future through modern insulin delivery technologies (smart pumps capable of closed-loop operation) [7].

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, allowing timely initiation of insulin and avoidance of regimens toxic to beta cells. 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 with a correct and early diagnosis, insulin therapy initiated right at diagnosis, modern monitoring and aggressive control of cardiovascular risk factors, the long-term prognosis can approach that of the general population.