📘 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 T1D. All forms of diabetes that arise through autoimmune destruction of the β cells, regardless of age at onset, are included in the T1D category. The immune system mistakenly identifies the pancreatic beta cells as foreign bodies 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, and 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. T1D with adult onset usually evolves more slowly than the classic pediatric form. In adults, polyuria, polydipsia, involuntary weight loss and fatigability (tiredness) can accumulate over weeks or months, and ketoacidosis at diagnosis is rarer. The main form of diabetes in adults is T2D, which is why initially the diagnosis of T2D may be made and later reformulated as T1D, depending on evolution and response to treatment. Diabetes that appears in an adult is not necessarily T2D, 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 T1D. LADA generally appears after the age of 30, has at least one islet autoantibody present (most commonly anti-GAD65), and 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 T1D through autoimmune destruction of the β cells and inevitable progression toward insulin dependence (over years), but it also resembles T2D through onset in adults, often in overweight people or with features of insulin resistance, and initially responds to lifestyle measures and oral antidiabetic drugs. Patients usually experience a "honeymoon" period in which residual β-cell function preserves a good insulin secretion, but this window closes at some point. Recognition of this intermediate phenotype is very important, because treating LADA as ordinary T2D, especially with sulfonylureas, can accelerate β-cell exhaustion and delay timely introduction of insulin treatment [4].

The classic epidemiological picture of T1DM shows an incidence peak in childhood and adolescence, around 10–14 years of age. Looking, however, at the entire duration of adult life, the absolute number of new cases diagnosed in adulthood is greater compared to the pediatric range, simply because 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, with a peak in the fourth and fifth decades of life, that is around the ages of 40 and 50. A significant portion of adults initially labeled with T2D 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, a new-onset diabetes deserves a diagnostic process that does not automatically assume T2D [4].

The distinction between LADA and T2D is one of the most important clinical decisions in adult diabetes, because the two forms of diabetes can have a similar initial appearance, with hyperglycemia of adult onset, without spontaneous tendency to ketoacidosis. The clinical clues that raise suspicion of LADA are relatively young age within the adult spectrum, normal or slightly elevated body mass index, lean phenotype without features of metabolic syndrome (central obesity, hypertension, dyslipidemia with elevated triglycerides and low HDL, hepatic steatosis), personal history of autoimmune diseases (Hashimoto thyroiditis, Graves, vitiligo, celiac disease, pernicious anemia, Addison disease) and possibly family history of T1D (not T2D). Unintentional weight loss, rapid symptomatic deterioration or the appearance of ketoacidosis in someone initially considered to have T2D are additional warning signals [3].

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, patients with LADA progress more rapidly toward a significant need for insulin compared to those with T2D, and 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 T2D, it is good to measure the standardized islet autoantibodies (GAD65/GADA, IAA, IA-2A and ZnT8A). A fifth, older marker, the islet cell antibodies (ICA), detected by indirect immunofluorescence, is still available, but is no longer recommended, being less specific and difficult to standardize between laboratories [1].

In practical terms, GAD65 is the first-line test in adults because it is the most sensitive individual marker for autoimmune diabetes with adult onset, persists for many years after diagnosis and is frequently the only positive autoantibody in LADA. IA-2A is more characteristic of pediatric T1DM, and when it appears in adults it indicates a 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, while several positive autoantibodies signal a more aggressive autoimmune attack and a more rapid evolution toward insulin dependence [4].

Misclassification of adult-onset autoimmune diabetes as T2D is one of the most frequent diagnostic pitfalls. This mistake arises in the first place because the clinical presentation in adults is atypical. Unlike children, in whom T1D often begins with significant hyperglycemia and ketoacidosis, adults with autoimmune diabetes of LADA form usually have a slow onset, with mild symptoms and initially preserved insulin secretion. In the second place, there is substantial phenotypic overlap with T2D, patients often being overweight or obese, sedentary, or presenting features of metabolic syndrome. Obesity does not exclude autoimmune diabetes, however in current practice it strongly orients the physician toward a diagnosis of T2D [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, for reasons of cost, lack of easy access to testing or because guidelines have historically restricted this testing to young patients. This fact perpetuates an age bias, where T1D is in children and T2D is 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 the question of how quickly insulin treatment is needed in LADA-type diabetes depends on the goal pursued. To achieve glycemic control, the time interval until the need for insulin is highly variable, but generally in the range of 1-5 years. The rate of progression toward the need for insulin to keep blood glucose in target is determined by the speed at which the autoimmune process exhausts the pancreatic beta cell mass. 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 pancreatic beta cells, so as to obtain the greatest possible long-term benefit, insulin should be initiated immediately, in the form of basal insulin. If C-peptide has very low values (below 0.3 nmol/L), use of a multi-dose insulin regimen is required, as in classic T1D. The use of modern technologies (continuous glucose monitors, insulin pumps) brings benefits similar to classic T1D [6].

In the early phase of adult-onset autoimmune diabetes (LADA), where endogenous insulin secretion is partially preserved, oral antidiabetic drugs can transiently improve glycemic control, which is also why there is confusion with T2D. 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 and possibly by the residual β-cell function, typically estimated through C-peptide [3].

Sulfonylureas should be avoided because they force already stressed pancreatic beta cells to secrete more insulin, producing more "noise", which makes the immune system "hear" them more easily. Sulfonylureas are considered to accelerate β-cell exhaustion and shorten the time to insulin dependence. Insulin should be initiated right at diagnosis, but no later than the moment when oral agents no longer maintain targets, when HbA1c rises despite efforts, when C-peptide decreases, when involuntary weight loss or accumulation of ketone bodies appears [4].

T1D with adult onset, including LADA, has the same fundamental risk pattern as juvenile-onset T1D. In the LADA form, the autoimmune process usually evolves more slowly and residual β-cell function is preserved longer, which has as a consequence better glycemic control, especially in the first 5 years. Severe hypoglycemic episodes are clearly rarer compared to childhood-onset T1D. Adults with T1D, however, have an increased risk of cardiovascular events and all-cause mortality compared to the general population, which could be improved in the future through the use of modern insulin delivery technologies (smart pumps, capable of closed-loop) [7].

When LADA is misdiagnosed and inadequately treated as T2D, typically with sulfonylureas, 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, with 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 and are now recommended right from the initiation of insulin therapy. T1D with adult onset 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 [8].