LADA: A Little Known Type of Diabetes

Dr. Nguyen is a clinical pharmacy writer based in San Jose, California. Dr. Muzyk is a freelance clinical pharmacy writer based in Tampa, Florida.

In recent years, researchers have discovered another form of diabetes, referred to as latent autoimmune diabetes in adults (LADA). Some other names for LADA include diabetes type 1.5, slow-progressing type 1 diabetes, and late-onset autoimmune diabetes.^1-4 Although different names have caused confusion, they all refer to a subset of patients with type 2 diabetes who have antibodies and genetic factors commonly found in those with type 1 diabetes.

LADA is often misdiagnosed as type 2 diabetes because its onset occurs during adulthood.3,4 In addition, patients may still have some healthy b-cell function and thus do not require insulin therapy initially. Patients with LADA can adequately control their blood glucose by making lifestyle changes and taking oral hypoglycemic agents at early stages. Unlike patients with type 2 diabetes who may never need insulin, however, those with LADA will continue to experience a decline in b-cell function and will eventually progress toward insulin dependency.

One factor that is central to the pathophysiology of diabetes is insulin resistance. Many studies agree that insulin resistance in LADA is higher than in recent-onset type 1 diabetes and is similar to long-term type 1 diabetes.^1,5-7 Some studies showed that patients with LADA have less insulin resistance, compared with those with type 2 diabetes; however, others did not find a difference between the 2 groups.^1,5-7

Besides having a similar clinical presentation as that of type 2 diabetes, LADA carries many immunologic and genetic features of type 1 diabetes. In classic type 1 diabetes, the 4 common islet autoantibodies responsible for attacking the b-cells include glutamic acid decarboxylase antibodies (GADAs), islet cell antibodies (ICAs), islet antigen 2 (IA-2) antibodies, and insulin autoantibodies.¹ Two or more types of autoantibodies are often present in type 1 diabetes, whereas a single type of autoantibody is common in LADA. Many studies have shown that patients with LADA are more likely to test positive for GADAs and/or ICA than IA-2 or insulin autoantibodies.^8-11

Genetic controls, such as the frequency of immune-regulating genes in the major histocompatibility complex— human leukocyte antigen (HLA)—region and non-HLA region, play an important role in susceptibility of diseases.¹ Certain allelic variations in the HLA region and non-HLA loci that contribute to the risk of type 1 diabetes are also found in patients with LADA.^1,10-13 At the same time, some differences exist in the degree of immune regulation between LADA and type 1 diabetes. These differences possibly account for a more gradual progression to b-cell destruction in LADA. Some potential contributors include a less marked HLA genetic predisposition to type 1 diabetes, immune tolerance to b-cell antigens, partial regeneration of b-cells, possible protection toward b-cell destruction from certain genes, and less exposure to environmental factors that cause damage to b-cells.^12-14 The actual pathogenesis of LADA remains unknown, however.

At this time, no specific treatment guidelines for LADA are available. In general, treatment should aim to provide metabolic control and prevent chronic complications. Current treatment options for LADA consist of therapeutic lifestyle changes, oral hypoglycemic agents, and insulin. Additionally, ongoing trials that study experimental agents to prevent the progression toward b-cell destruction may lead to a new approach in treating LADA.^15-18

First, making therapeutic lifestyle changes is crucial in the management of diabetes. A healthy diet and an active lifestyle can significantly improve therapeutic outcomes. They increase insulin sensitivity, improve blood sugar control, and reduce the risk of developing long-term complications.19 Because most likely some healthy b-cell function remains at diagnosis, many LADA patients are initiated on oral medication(s). Although commonly used hypoglycemic agents, such as sulfonylureas (SUs), metformin, or thiazolidinediones (TZDs), are beneficial in providing blood glucose control, they are used for only short-term treatment of LADA. Eventually, insulin therapy will be required.

Furthermore, the use of oral hypoglycemic agents to treat LADA may have some drawbacks. Many studies do not recommend SUs in the management of LADA. By stimulating insulin secretion, SUs may also release the granules with antigenic properties.²⁰ This in turn amplifies the immune response toward b-cell antigens, which may lead to early exhaustion of b-cell function and can expedite the need for insulin therapy.²¹ Although metformin is commonly used as a first-line oral agent, it has not been shown to affect the pathogenic process that leads to b-cell destruction when tested in an experimental model of autoimmune diabetes.²² TZDs are often used to control blood glucose by improving insulin sensitivity, but they may not be as effective in treating LADA because there may be less insulin resistance in these patients compared with patients with type 2 diabetes. The comparison of insulin resistance in these 2 groups is still controversial.^1,5-7

Even though the benefit of insulin therapy to the remaining b-cells is unclear, many reports are in favor of early initiation of insulin in patients with LADA. To determine when to begin insulin treatment, residual b-cell function is often evaluated based on C-peptide values, which are directly proportional to levels of insulin production. ^23,24 One study compared the effects of insulin therapy versus treatment with SUs on C-peptide secretion in patients with LADA.²⁵ The results of the study revealed that patients treated with insulin had sustained C-peptide response and maintained better b-cell function. The results also indicated that early initiation with insulin may protect b-cell mass. Another study evaluated the rate of progression to an insulin-dependent state in patients with LADA who were on insulin treatment, compared with those on SUs.²⁶ The results of this study showed that the progression to an insulin-dependent state was slower in the group receiving insulin therapy. Nonetheless, initiation with insulin therapy in patients with LADA may be deterred due to a moderate increase of blood glucose at early stages and reluctance toward insulin injections.

Another future approach to treating LADA is the use of vaccine-based therapy with Diapep277, an immunogenic peptide from the 60kDa heat shock protein. ^15-17 During a phase 2 clinical trial, it has been found to preserve endogenous insulin production in patients newly diagnosed with type 1 diabetes. At this time, Diapep277 also is being explored in another phase 2 trial involving LADA patients, and a phase 3 trial is being conducted to investigate its long-term effects.

Numerous studies are ongoing to explore the distinguishable factors contributing to LADA and focus on potential treatments that can arrest b-cell destruction. Currently, many questions regarding the pathogenesis of and the best treatment for LADA remain unanswered. Nonetheless, it is crucial to accurately diagnose LADA as significant differences in its pathogenesis and treatment approach emerge.