Adult-onset autoimmune diabetes

Abstract

Diabetes mellitus is a disease characterized by high blood glucose levels. When the disease is associated with severe loss of insulin secretion, it is referred to as insulin dependent, as affected individuals need insulin therapy to survive. Conversely, if the disease is caused by less severe insulin deficiency, affected patients are not dependent on insulin. Disease forms in which certain immune signatures are present, such as peripheral blood islet-specific autoantibodies, are classified as autoimmune diabetes, that is, type 1 diabetes mellitus (T1DM) or, more accurately, type 1A diabetes to distinguish it from idiopathic type 1B diabetes 1 . In broad terms, individuals who present in childhood usually have insulin-dependent T1DM, but may also be affected by monogenic diabetes, known as maturity-onset diabetes of youth (MODY), or even type 2 diabetes (T2DM). Conversely, those who present in adulthood usually have non-insulin-dependent T2DM, but cases of adult-onset autoimmune (AOA) diabetes are also frequent. Adult-onset diabetes has been suggested to encompass five different phenotypic groups in which those phenotypes that present with islet-specific autoantibodies are classified together as severe autoimmune diabetes (SAID) 2 . The distinction between severe insulin deficiency, requiring insulin treatment, and more modest insulin deficiency, treatable by other means, is not always clear, especially in adult-onset diabetes 3 .Many of the issues surrounding adult-onset diabetes relate to the relationship between T1DM and T2DM in the context of age at onset, blood glucose levels and insulin deficiency, with lack of clear boundaries that define these major types of diabetes (Fig. 1). For example, although most cases of childhood-onset diabetes are autoimmune diabetes, most cases of autoimmune diabetes, in actual numbers, develop in adulthood. AOA diabetes is much more heterogeneous than young-onset autoimmune diabetes, as the rate of β-cell destruction is highly variable, probably owing to the differential presence of genetic factors and differing severity of the individual autoimmune process 4,5 .Epidemiological studies have highlighted that most patients with AOA diabetes do not require insulin treatment at diagnosis 6,7 , and these patients are commonly defined as having latent autoimmune diabetes in adults (LADA). In 2022, LADA has been included under the category of T1DM in the diabetes classification proposed by the American Diabetes Association (ADA), although the term retains its own identity, being defined as common and acceptable in everyday clinical practice, raising awareness of individuals at risk of progressing towards requiring insulin therapy 1 . As most studies in AOA diabetes referred to 'people with LADA' , we retain the term LADA in this Primer when appropriate. The inherent conundrum has implications for this interface between the two major types of diabetes, that is T1DM and T2DM, and how they should be treated in clinical practice.In this Primer, we discuss the epidemiology, pathogenesis, c...

GAD65Abs Are Not Associated With Beta-Cell Dysfunction in Patients With T2D in the GRADE Study

“…Emerging data suggest that islet autoimmunity, associated with deficient insulin secretion, may also develop in many patients with T2D, blurring the distinction between T1D and T2D [ 8 ]. One example of a pathophysiologic overlap between T1D and T2D is Latent Autoimmune Diabetes of Adults (LADA), wherein patients with an initial diagnosis of T2D manifest islet autoantibodies typical of T1D, associated with an earlier requirement for insulin therapy [ 9 ]. We recently showed, in a cohort of T2D patients in the Glycemia Reduction Approaches in Diabetes—a Comparative Effectiveness (GRADE) Study, that 13.5% of patients had one or more T1D-associated islet cell autoantibodies (7.8% with autoantibodies directed against the 65 kDa glutamate decarboxylase [GAD65Ab]) while 41.3% had islet autoimmunity defined by T-cell autoreactivity to islet antigens [ 10 ].…”

Exploration of Immune Targets for Type 1 Diabetes and Latent Autoimmune Disease Immunotherapy

“…It is characterized by genetic, phenotypic, and humoral variability, encompassing varying degrees of insulin resistance and autoimmunity. 42 , 43 Although these patients did not require insulin at the time of diagnosis, they are believed to have a slowly progressing form of autoimmune diabetes with serum immunological markers of T1D.…”

“…The primary current diagnostic criteria for LADA include adult-onset diabetes (>30 years at diagnosis), the presence of diabetes-associated autoantibodies, and the lack of insulin demand for at least 6 months following diagnosis. 43–45 …”

Semaglutide Treatment in Adult-Onset Autoimmune Diabetes: A Case Study With Long-Term Follow-Up and Periodic Evaluation of Beta-Cell Function

“…LADA is often challenging to diagnose and treat due to its atypical age of onset and its heterogeneous clinical presentations. To date, no clear guidelines are available for the management of LADA and the most accepted therapeutic approaches include treatments aimed to preserve residual beta-cell function a mass beyond glycemic control [ 2 ].…”