Latent Autoimmune Diabetes In Adults Lada Biology Essay


Latent autoimmune diabetes in adults (LADA) is a slowly progressive form of type 1 diabetes mellitus. Patients are often diagnosed as type 2 diabetes but have anti islet antibodies like glutamic acid decarboxylase (GAD). They do not require insulin in the start but progress to type 1 diabetes depending on the rate of beta cell destruction [1]. Unlike type 2 diabetes they are not over weight and have little or no insulin resistance. The pathogenesis is of the form of classical type 1 diabetes except the rate of destruction of beta cells is variable and slow hence diagnosis is missed, delayed or inappropriate ineffective treatment is given to the patients. Hence better diagnostic methods are required. Although destruction of beta cells cannot be prevented but hyperglycemic states and further complications can be avoided and newer treatments for LADA like immunomodulation are being investigated.


Diabetes mellitus is a disorder of carbohydrate fat and protein metabolism characterized by an elevated blood glucose level and glycosuria associated with defective or deficient insulin [2]. There are 2 typical forms of diabetes type 1 insulin-dependent diabetes mellitus (IDDM) and type 2 insulin independent diabetes mellitus or non insulin dependent diabetes mellitus (NIDDM) [3]. Type 1 diabetes occur when the body’s immune system attacks its own cells. Producing islet antibodies and type 2 diabetes occurs when the body is no longer responding to the insulin produced.


LADA - stands for Latent Autoimmune Diabetes in Adults. It is a type 1 diabetes, the usual features of LADA patients reported are onset of diabetes at ≥25 years of age, where the body’s immune system attacks its own insulin producing cells but is phenotypically similar to non obese type 2 diabetes and hence also called type 1.5 diabetes, unlikely to have a family history of type 2 diabetes, initial control of hyperglycemia with diet and oral antidiabetic agents. People with LADA can be diagnosed by having a blood test for GAD antibodies. People with LADA have a slowly progressing form of type 1 diabetes. This means they do not need insulin when they are diagnosed but will probably need insulin in the future. How soon they will be insulin dependent depends on the level of antibody they have in their blood. Higher levels of antibodies suggest a faster progression to insulin. People with low levels of antibodies are very similar to type 2 diabetes patients. This means they are more likely to be overweight and have some insulin resistance. They are likely to benefit from tablets that act on insulin resistance. People with very high antibody levels are similar to type 1 diabetes. This means they are likely to have acute symptoms (thirst, unexplained weight loss, frequent urination, dry mouth) and are less likely to be overweight. They are likely to need insulin treatment soon after diagnosis. About 20% of the patients diagnosed with type 2 diabetes may have LADA [4].

Beta cell function in LADA

In a study LADA patients soon after diagnosis of LADA were observed for 12 years and the outcome were as follows adult onset diabetic patient with 2 or 3 antibodies like ICAs GADAs had deemed beta cells function within 5 year whereas subjects having only ICAs or only GADAs seemed to have severe beta cell dysfunction later. In contrast beta cell function without islet antibodies and individuals only with IA-2As was unaffected and preserved 12 years after diagnosis.[5]

Diagnosing LADA

Circulating autoantibodies, such as autoantibodies to islet-cell cytoplasms (ICAs) and /or to GAD 65 (GADAs) and/or to the intra-cytoplasmic domain of the tyrosine phosphatase-like protein IA-2 (IA-2As), are markers of destruction of beta cells of Langerhans. ICAs and GADAs are also common in LADA, but both IA-2 antibodies and insulin autoantibodies are much less common in LADA than in type 1 diabetes [6]. As mentioned previously type 1 diabetic patients are very often positive for two or more autoantibodies, whereas single autoantibodies are common in LADA patients

In the attempt to standardize the diagnosis of LADA, three criteria are currently recommended, but all of them have some drawbacks.

Criterion 1: Adult age at onset various cut-off ages have arbitrarily been used (between 25 and 45 years), but the proposed lower limit is now 30 years of age. Nevertheless, since adulthood starts earlier in life, this limit might not be all inclusive.

Criterion 2: Presence of circulating islet autoantibodies (at least one). Because autoantibodies to insulin (IAA) and tyrosine phosphatase-like insulinoma- associated protein 2 (IA2) have been reported to be rather infrequent, the diagnosis basically relies on identifying glutamic acid decarboxylase autoantibodies (GADAs), which is the best single marker for screening. Epitope specificity, antibody levels, and concomitant presence of ICAs discriminate two subcategories of LADA with a different risk toward insulin dependency . Obviously, to ascertain an accurate immune profile of LADA, further investigations should be performed.

Criterion 3: lack of insulin requirement for at least 6 months after diagnosis. This criterion is however variable.[7]

C-peptide (also known as insulin C-peptide, connecting peptide)-

C peptide is the peptide connecting the A and B chain of insulin. This test measures residual beta cell function by determining the level of insulin secretion (C-peptide). Persons with LADA typically have low, although sometimes moderate, levels of C-peptide as the disease progresses. Patients with insulin resistance or type 2 diabetes are more likely to, but will not always, have high levels of C-peptide due to an over production of insulin. [8]

Islet cell antibodies (ICA) tests

Islet Cell IgG4 Cytoplasmic Autoantibodies, IFA; Islet Cell Complement Fixing Autoantibodies, Indirect Fluorescent Antibody (IFA); Islet Cell Autoantibodies Evaluation; Islet Cell Complement Fixing Autoantibodies – Aids in a differential diagnosis between LADA and type 2 diabetes. Persons with LADA often test positive for ICA, whereas type 2 diabetics only seldom do.

Glutamic acid decarboxylase (GAD) antibodies tests

L-Glutamic acid decarboxylase is the major enzyme in the synthesis of g-amino butyric acid (GABA) which is a potent inhibitory neurotransmitter and a critical component of neurophysiologic function. GAD/GABA are also detected in certain non-neural cells and organs such as the pancreas, where GABA is stored in synaptic-like vesicles in islet beta cells.[9] Autoantibodies against GAD are a valuable diagnostic biomarkers of risk and progression to overt autoimmune diabetes. Glutamic acid decarboxylase antibodies (GADA) are commonly found in diabetes mellitus type 1. GADA is measured by a radio ligand assay using human recombinant GAD 65 as antigen In addition to being useful in making an early diagnosis for type 1 diabetes mellitus, GAD antibodies tests are used for differential diagnosis between LADA and type 2 diabetes and may also be used as well as a tool to monitor prognosis of the clinical progression of type 1 diabetes.[10]

Insulin antibodies (IAA) tests

RIA: Anti-GAD, Anti-IA2, Anti-Insulin; Insulin Antibodies - These tests are also used in early diagnosis for type 1 diabetes mellitus, and for differential diagnosis between LADA and type 2 diabetes, as well as for differential diagnosis of gestational diabetes, risk prediction in immediate family members for type 1, and to monitor prognosis of the clinical progression of type 1 diabetes. Persons with LADA may test positive for insulin antibodies; persons with type 2, however, rarely do

Pathogenesis of LADA

LADA is characterized by the presence of circulatory islet cell autoantibodies, glutamic acid decarboxylase autoantibodies (GADA), insulin autoantibodies (IAA) and/or anti phosphatase autoantibodies (IA2A), indicating the beta cells damage produced by cytotoxic T lymphocyte.

It is also established that anti GAD and ICA are much more common than IAA IA-2A and ZnT8 autoantibodies in LADA patients. GAD and IA- 2 could block a number ICA staining in approximately 60% of sera from type 1 diabetes but only in 37% subjects with LADA suggesting autoantibodies other than GAD and IA-2 in LADA [6] The IgG4 subclass of anti- GAD has been demonstrated to be more frequent in LADA than in type 1 diabetes (a dominant TH2 immune response) in LADA. T cells responding to multiple islet proteins have been found in LADA patients with and without autoantibodies in type 1 diabetes patients.[]

In normal cells immunological tolerance is maintained by multiple central and peripheral mechanisms including the action of a specialized set of regulatory T cells characterized by expression of CD4 and CD25 (CD4 CD25 FOXP3 Treg). A defect in this cell population, either numerically or functionally, could contribute to the development of autoimmune diseases, such as type 1 diabetes. Yang et al. in their study of lymphocyte subsets showed that CD4 regulatory T cells are reduced and the expression of FOXP3 mRNA in CD4 T cell was decreased in LADA patients.

It is also becoming increasingly evident that many factors that are involved in the type 1 diabetes-specific process are also integral to the beta cell lesion in type 2 diabetes, including IL-1, Fas, nuclear factor-B, and increased expression of c-Myc .recent studies have also shown macrophage infiltration in islets of type 2 diabetes subjects . The mechanisms leading to cytokine- inducedbeta cell dysfunction in type 1 diabetes and to nutrient induced beta-cell dysfunction in type 2 diabetes may share common pathways.


There is abundant evidence that suggests, cytokines are involved in the pathogenesis of latent autoimmune diabetes of adults (LADA). A study suggest that the G/A mutation at position −1082 of IL-10 promoter gene region might be one of the factors participating to the pathogenesis of LADA diabetes and that identification of cytokine gene polymorphisms might contribute to the characterization of the different types of diabetes mellitus (TNF-α, TGF-β1, IL-10, IL-6, Gene Polymorphisms in Latent Autoimmune Diabetes of Adults (LADA) and Type 2 Diabetes Mellitus.


The treatment used for LADA is similar to that of type 1 diabetics. Sulfonylurea and Metformin is given as a drug of choice. Sulfonylurea stimulates insulin secretion. The insulin secretion is triggered by binding of sulfonylureas to a specific site on the ATP sensitive K channels at the level of plasma membrane, which leads to their closure and subsequent opening of the calcium channels and activation of an effector system of insulin released in Gluconeogenesis is suppressed, and stimulation of peripheral glucose uptake is increased Insulin therapy is also the treatment of choice. Though there not complete beta cell destruction but at the time of diagnosis 80% of the beta cells are destroyed. Hence insulin therapy is the treatment of choice.

Potential treatments

Assuming the disease process in LADA is similar to that of type 1 diabetes, though less destructive, prevention of b-cells from complete destruction should be attempted. A large number of attractive therapeutic possibilities are available for preventing progression toward insulin dependency in LADA patients, ranging from antigen based therapies to monoclonal antibody– and cytokine-based therapies; such approaches are under consideration for preventing the development of type 1 diabetes in the young.

Glitazones - commonly used for the treatment of type 2 diabetes can also be used for management of LADA. The glitazones have the potential to preserve endogenous insulin secretory reserve, improvement in glucose metabolism is accompanied by a reduction in circulating insulin concentration. There is also an interesting evidence that glitazones increase insulin synthesis and the insulin content of islet cells as well as improve the secretory response of islets.


Insulin might help in progression of LADA by helping the beta cells to rest and to reduce the antigenic exposure.

In A study they treated patients with a small dose of insulin rather than sulfonylurea which gave them a steady plasma C-peptide level and unlike their counterparts who were given sulfonylurea had insulin dependence. This was not found to be true for type 2 diabetes patients without islet antibodies hence disapproving the immune-modulating effect of insulin. Insulin improves beta cell function because of its unspecific effect on glucose toxicity.

Heat shock protein peptide was found to preserve endogenous insulin production in a phase 2 clinical trial, perhaps through induction of a shift from TH 1 subset to a TH 2


Incretin mimetics are a new class of pharmacologic agents developed to improve metabolic control in patients with type 2 diabetes. The most advanced drug of this class is exendin-4, which acts as a full agonist at the glucagon-like peptide (GLP)-1 receptor and has glucoregulatory actions similar to the incretin hormones (glucose-dependent enhancement of insulin secretion and inhibition of glucagon secretion), as well as slows gastric emptying and reduces food intake . In addition, exendin-4 has been shown in vitro and in animal models to have trophic effects on the pancreas, since it modifies the susceptibility to apoptotic injury and stimulates beta-cell proliferation and islet neogenesis from precursor cells. Like the TZDs, exendin-4 has islet growth-promoting effects through regulation of genes controlling proliferation, growth, and differentiation, apparently by targeting different components of the epigenetic machinery. It induces multiple signalling pathways intrinsic to beta-cells (including expression of Pdx-1), which results in expansion of beta-cell mass through promoting differentiation of precursor into mature beta-cells and stimulation of mature -cell proliferation. Therefore, the reports of exenatide increasing the mass of beta-cells, in addition to its glucose-lowering effects, provide encouragement for its use in the treatment of LADA. There are a few studies evaluating GLP-1 (and exendin-4) in subjects with type 1 diabetes, and they showed reduction of fasting hyperglycemia and glycemic excursions after a meal, accompanied by inhibition of abnormal rises of blood levels of glucagon (40). Additionally, in islet transplant recipients, exendin-4 has stimulated insulin secretion and demonstrated an ability to reduce exogenous insulin requirements. Current clinical trials test the hypothesis that its use at the time.

Immune modulation

Since LADA is an autoimmune disease caused by failure to maintain tolerance to auto antigens, targeting them through administration of auto antigen in a tolerogenic regimen should provide an effective means of controlling the autoimmune process by inducing tolerance by shifting Th1 phenotype of the antigen-reactive cells toward a Th2 phenotype. The beneficial effect of an immune intervention in LADA in protecting residual beta-cell function may not be possible due to several factors such as age at diagnosis, metabolic control, and extension of beta-cell destruction. The latter is influenced by HLA genotypes. Recent data seem to indicate that patients possessing a moderate or low-risk HLA genotype, as is the case in LADA, have a higher residual beta-cell function. LADA patients with such genotypes might benefit more in terms of beta-cell protection after immune intervention. The antigens that have been used so far as tolerogens in LADA have included the following: insulin, GAD, heat shock protein (HSP), and their constituent peptides.