Latent autoimmune diabetes in adults 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 . 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.
A disorder in the metabolism of carbohydrates, fats and proteins leads to Diabetes Mellitus. It is characterized by an elevated blood glucose level. Another characteristic of Diabetes Mellitus is glycosuria, which is associated with the absence of insulin . 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) . A situation in which the host's immune system attacks its own "self" cells by producing islet antibodies is characteristic of Type I Diabetes, whereas, if the body stops responding to the insulin produced, it indicates that Type II Diabetes has set in.
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FEATURES OF LADA
LADA- stands for Latent Autoimmune Diabetes in Adults. It is type 1 diabetes. It is seen in individuals above the age of 25 years. In this type, cells are produced which are phenotypically similar to non obese type 2 diabetes and hence also called type 1.5 diabetes. These individuals do not have a history of the disease. This type of Diabetes can be treated with proper diet and oral antidiabetic agents. People with LADA can be diagnosed by having a blood test for GAD antibodies. The individuals suffering from this type of diabetes also have a slowly progressing form of Type I 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. Type I diabetes show a very high level of antibodies. Symptoms like thirst, frequent urination, dry mouth, unexplained weight loss indicate that people suffering from Type I diabetes are less likely to be overweight. 20% of the patients diagnosed with Type II diabetes suffer from LADA.
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.
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 . 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 order to facilitate the diagnosis of LADA, the following three criterias are laid down. However, all of them have some drawbacks.
Criterion 1: It occurs in adults in the age group of 25-40 years, with 30 years being the lower level cut off.. 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) are not present frequently, 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. In order to establish a concrete profile of LADA, further tests and investigations needs to be carried out.
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Criterion 3: There is an absence of insulin requirement 6 months after diagnosis. However, this criterion is however variable.
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 is based on the residual beta cell function. This function can be determined by estimating the level of insulin secretion (C peptide). Low levels of C- peptide is seen in patients suffering from LADA as the disease progresses. Type II diabetes patients are more likely to have high levels of C peptide due to an elevated production of insulin .
Islet cell antibodies (ICA) tests and Insulin Antibody (IAA)Tests
There are different tests that differentiate between LADA and type II diabetes like - Islet Cell IgG4 Cytoplasmic Autoantibodies, IFA; Islet Cell Complement Fixing Autoantibodies. LADA patients test positive for ICA. However, the opposite is seen in case of Type II diabetic patients. These tests are also used in early diagnosis for type 1 diabetes mellitus, and for differential diagnosis between LADA and type 2 diabetes. It can also test whether the family members are prone to acquire this disease.
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. It also plays an important role in neurophysiology. GAD/GABA is found in the pancreas, whereas GABA is found in the synaptic-like vesicles of the islet cells. Autoantibodies against GAD can act as a biomarker that helps to track the risk and progression of autoimmune diabetes. Diabetes mellitus type 1 patients show the presence of GADA residues. 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. It can also be used to trace the progression of Type I diabetes .
Pathogenesis of LADA
Circulatory islet cell autoantibodies, glutamic acid decarboxylase autoantibodies (GADA), insulin autoantibodies (IAA) and/or anti phosphatase autoantibodies (IA2A) are present in LADA patients. This indicates that the beta cells damage is 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 LADA patients are shown to have high levels of the IgG4 subclass of anti-GAD than type I diabetes patients.. 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 that prevents the immune system from distinguishing between self and nonself, is maintained by 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, can contribute to the development of autoimmune diseases, such as type 1 diabetes. Though the entire mechanism is not understood one possible explanation for autoimmunity is that beta cells are first destroyed by an environmental factor such as a virus. The dying or dead beta cell is next phagocytozed by local dendritic cells (DC) The DC is activated and migrates through the lymphatics presenting The autoantigen to a CD4+ T lymphocytes causing its activation which in turn activates CD8+ T lymphocytes specific for islet autoantigen and perhaps also of B-lymphocytes that would produce autoantibodies against either insulin, GAD65, IA-2 or ZnT8. The islet autoantigen-specific CD8+ T lymphocytes return to the blood circulation and lead to infiltration of the islets. The beta-cell killing will generate a new cycle of DC and B-lymphocyte mediated islet autoantigen presentations in the draining lymph nodes of the pancreas resulting in the recruitment of T and B lymphocytes recognizing another epitope on the initial autoantigen or perhaps additional autoantigens. This phenomenon is known as epitope spreading CD4+ CD25+ T reg lymphocytes may be important to as they may inhibit islet autoantigen specific CD4+ T lymphocytes. These cells express FOXp3 from the X chromosome and are important to maintain peripheral tolerance . 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 [11, 6]. In addition to these cell types, antigen-presenting cells (APCs) such as dendritic cells (DCs) and B cells are responsible for the direct activation of T cells in response to specific antigens .
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T helper (Th) cells are one of these populations and are divided into 3 groups based on their cytokine production profiles: proinflammatory Th1 and Th17 and anti-inflammatory Th2. The balance of Th cell populations is an important regulator of the immune system . 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 âˆ’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 
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. Metformin suppresses Gluconeogenesis and stimulates the peripheral glucose uptake. Sulfonylurea though effiecient they do not prevent beta cell exhaustion [7, 8].
Insulin therapy is also the treatment of choice. It is not immodulator, 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. Also the idea is to prevent further damage of the beta cells by minimizing antigenic exposure .
As the disease process in LADAis similar to type I diabetes, the incidence of the disease can be prevented by avoiding the complete destruction of beta cells. 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.
Glitazones are commonly used for the treatment of type 2 diabetes. However, they can also be used for management of LADA. The endogenous insulin secretory reserves can be protected by glitazones. Thus, it helps in the improvement of glucose metabolism and a reduction in the circulating insulin concentration. Studies have shown that glitazones increase insulin synthesis and the insulin content of islet cells. It also helps to 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 [14, 15].
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. 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.
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.
ANTI-CD3 ANTIBODIES: More specific immunotherapy is in understanding when antigen is presented to the T cells, one of the important receptors is the CD3 receptor. Monoclonal antibodies against this receptor can be expected to block or at least modulate the immune process . using monoclonal anti-CD3 antibodies have shown that it is possible to block the destructive autoimmune process and thereby at least postpone the decline of beta-cell function[16,7,17]
Peptide of HSP60 (DiaPep277). HSP60 is a ubiquitous protein. It is chaperones, present in the mitochondria and mature insulin-secretory granules of pancreatic beta-cells and is one of the important autoantigen in diabetes. The dominant epitope of HSP60 was found to be peptide HSP277 , and its modified form, Dia- Pep277, has been used in patients with recent-onset type 1 diabetes for prevention of further beta -cell loss and has been to preserve C-peptide, as at the end of the follow-up period, the subjects had improved mean C-peptide levels and required significantly less exogenous insulin to obtain Similar A1C as the placebo group. Interestingly, the drug treated group had a shift of the T-cell response to HSP60 from a proinflammatory Th1 to a predominant Th2 phenotype (with interleukin [IL]-10 and IL-13) (18, 19)
GAD65 (Diamyd). The 65-kDa isoform of GAD (GAD65) is found in beta-cells (and other tissues) and considered a major autoantigen in autoimmune diabetes (20). A large body of evidence has indicated that antibodies to GAD65 may be found in 70-75% of type 1 diabetic patients and that GADA is the most sensitive autoantibody marker for LADA.(16,17,7).Studies of nonobese mice with diabetes show that administration of the GAD65 isoform can prevent autoimmune destruction of beta cells.These findings suggest that GAD65 administration couldbe used as a preventive treatment.No study-related adverse effects were reported
A variety of novel therapeutic agents and therapies like transplantation, DNA vaccines are being tried to treat LADA. Because the autoimmune process in LADA is thought to be slower than in childhood type 1 diabetes, there is a larger window of opportunities for intervention. Prevention of destruction of beta cells in LADA can also prove useful model for treatment of IDDM. Hence a lot of research is required in this area to define the best strategy to combat LADA.