Latent autoimmune diabetes in adults (LADA) is a term to describe adults who have a slowly progressive form of autoimmune or Type 1 Diabetes (T1DM). The term “LADA” has been used since the 1990s to describe patients who develop a phenotypic Type 2 Diabetes (T2DM), but with the presence of GADA (glutamic acid decarboxylase usually GADA -65) , IA-2A (protein tyrosine phosphatase), IAA (insulin), islet cell antibodies (ICA) and a slower progression to beta cell failure compared to classical type 1 diabetes. 11 LADA is considered to be synonymous with SPIDDM (slowly progressive insulin dependent diabetes mellitus). 12, 13
The onset is usually late in life, and is often initially diagnosed as Type 2 Diabetes (T2DM). However, because of the presence of antibodies that destroy the beta cells of the pancreas, LADA patients usually progress to insulin dependence as the beta cells are destroyed The progression to insulin usually occurs within a few years after the diagnosis, 14 – 20 and there is an increased risk for development of other organ specific autoimmune disease. 14,
LADA patients have clinical and metabolic features intermediate between type 1 and Type 2 Diabetes and are sometimes referred to as diabetes 1.5. They may
or may not have insulin resistance. 21-26 While the metabolic syndrome is not characteristic of LADA. 27 It does occur in LADA 28 with a prevalence similar to that in non diabetic controls. 27
Typically LADA or GAD positive patients present with lower BMI, 26, 29-32 lower waist to hip ratio, 31 lower blood pressure, 26, 31 lower triglyceride levels 26, 31, 32 lower cholesterol 31, 32 and higher HDL levels 31, 32 than type 2 diabetics. Type 1 Diabetes and LADA show no di erences in cholesterol, HDL, triglyceride levels, BMI, waist to hip ratios. 32 Many of these patients initially present with a clinical picture of T2DM with an adult onset. Initially they are insulin independent, but many progress to insulin dependence. 14 – 20
The hallmarks of LADA and criteria for diagnosis are:
33-35
.
None of these three traits are exclusive to LADA. 34
1 these patients are initially diagnosed with non- insulin
dependent diabetes and progress to insulin dependency
as their pancreatic insulin secretion fails.
2. the presence of beta cell specific autoantibodies to
glutamic acid decarboxylase 65 (GAD 65), IA-2A or islet
cell antibodies (ICA).
3 These patients typically lead to Type 1Diabetes (T1DM) and insulin dependence due to the ultimate destruction of their beta cells. However, the destruction of their Beta cells occurs over a longer time period than in T1D patients.
The prevalence of LADA varies according to ethnic group and antibodies analyzed. Prevalence is estimated to range from 1% – 12 % among patients with Type 2 Diabetes. 20, 33, 36-53
Classification of LADA
Some researchers believed that LADA is a form of the diabetes type 1 of autoimmune origin. 32, 54 Others believe LADA is a mixture of Type 1 Diabetes and Type 2 Diabetes as it shares genetic features with both types 37 and appears to be at the genetic intersection of T1DM and T2DM. 55, 56
Yet, others believe that believed that LADA was a partially distinct process from Type 1 Diabetes because of autoantibody di erences, di erences in islet proteins recognized by the T cells and di erences in insulin 57-59 and partly distinct from type 2 diabetes. It is phenotypically and genetically di erent from T1DM and T2DM depending on the GADA levels. 58
Like LADA, Type 1 Diabetes, LADA is an autoimmune disease that results in antibody destruction of the insulin producing beta cells in the pancreas of genetically predisposed individuals. 60 – 63 Mechanisms of susceptibility include epigenetic and transcriptional e ects that regulate transmission and expression of the inherited genes. 64
Type 2 Diabetes is a multi factorial disease usually including insulin resistance and subsequent insulin deficiency. Beta cell function is lost through other mechanisms including glucotoxicity, 65-69 lipotoxicity, 65, 66, 69 – 71 basal hyperproinsulinemia, 72 reduced ability of glucose to suppress glucagon release, 73 and oxidative stress and ER stress. 66, 71 Hyperglycemia alters intracellular energy metabolism and oxidative stress changing the activity of beta cell specific transcription factors. 67, 68 Contributing factors to Type 2 Diabetes are insulin resistance and beta cell defects that impair insulin secretion including islet amyloid depositions, 65, 72 early intrauterine malnutrition,
65 changes in insulin secretogogues such as amyloid polypeptide (IAPP) or amylin, 65, 72 GLP-1, GIP, and gatanin, 65 Neither glucolipotoxicity 68 nor insulin deficiency 65 alone cause meaningful beta cell toxicity or Type 2 Diabetes.
The aggressiveness of the course of LADA is determined by genetic predisposition, age, metabolic control and may vary within individuals over the course of their disease. 74
Two distinct types of LADA were identified by GADA titers.
LADA patient with high GAD 65 Ab titer; 14, 21, 75 – 78
the epitope (target of the autoimmune response) towards the middle or COOH terminal of the auto antigen GAD 65; 15 – 17, 79 GAD Ab with ICA; 80 ICA alone; 75, multiple antibodies; 21, 81 – 84 or TPO antibodies 82 resemble type 1 diabetic patients and are referred to a LADA 1.
These patients tended to have a lower C-peptide levels. 14
and have a higher risk of premature beta cell failure with a need for future insulin and have a higher prevalence of other autoantibodies (anti TPO, anti 21 hydroxylase and celiac disease associated antibodies). 21, 83, 85 They tend to have a low prevalence of the markers of the metabolic syndrome. 83, 86
LADA patients with a single autoantibody; 80 a low level of GAD 65 Ab in the absence of other antibodies; or the epitope of GAD 65 Ab directed to the middle epitope of auto antigen characterizes a subgroup of LADA patients with clinical characteristics almost indistinguishable from those of GAD65 Ab negative Type 2 Diabetes. 15, 16, 87 This group is referred to as LADA 2. The patients with these configurations have a less aggressive form of autoimmune diabetes that could result in a longer non-insulin requirement phase. 26, 88
Low GADA in old do not predict a progressive or rapid loss of beta cell failure, and beta cell destruction will develop more slowly. 26, 88 Diabetic patients with lower levels of or no GAD antibodies tended to have higher BMIs, more hypertension more dyslipidemia and higher levels of c-peptide. Insulin resistance was highest in the GAD negative group followed by patients with a low GADA. There was little di erence in the BMI, blood pressure, lipid profiles, between the GADA negative and the low GAD patients. 85
Diabetic continuum
Hence, there seems to be a continuum with increasing antibodies as one goes from Type 2 Diabetes, to LADA 2 to LADA 1 to Type 1 Diabetes. People with Type 1 Diabetes have higher level and more type of these antibodies 89 than do those with LADA which is the reason beta cells are destroyed more quickly in T1DM. LADA and diabetic patients on insulin have high levels of GAD Ab C whereas LADA patients not on insulin have higher levels of GADAb M 87
Type 2 Diabetes, tends not to have antibodies against the beta cells so the subsequent decline in beta cell is slower and may be due to other mechanisms. Hence, T2DM, LADA 2, LADA 1 and T1DM can be viewed as a continuum. The antibody activity and chronic inflammation of the pancreatic beta cells increases as one progresses from T2DM to LADA 2 to LADA 1 to T1DM. The c-peptide is high in T2DM and decreases
in LADA. 31, 32, 90 – 92 LADA 1 patients tend to be slim and without metabolic syndrome
The symptoms related to insulin resistance, the metabolic syndrome, and systemic inflammation tend to decrease as on goes from T2DM to T1DM although insulin resistance can occur in any of these states. Type 2 Diabetes has a higher concentration of the cytokines IL-1RA,IL-6and TNFa 93
and adhesion molecules 94 than T1DM and LADA independent of BMI. 95 These findings are summarized in Figure 1
Role of Antibodies
Islet autoantibodies in diabetes, are strong predictors of later development of T1DM. 96 The antigens that are seen in the autoimmune process of diabetes in are also seen in LADA. The GAD antibody is the most prevalent and is found in 10 – 20 % of diabetic patients who are not on insulin. 19, 20, 39, 50, 53, 88, 97
IAA and IA-2A are less often reported. 20, 50, 97
There are other potential antigens targeted by T cells. 98 These include the zinc transporter antibody that is common in childhood Type 1 Diabetes. 98 – 100 Reduced ZnT-8 production in the pancreas can impair beta cell function, contribute to inflammatory cytokine induced alterations in the beta cell 101 and advance defects in insulin secretion. 102
IA-2 is a useful diagnostic tool for LADA. 103 IA-2A may be more specific marker of beta-cell damage, whereas GADA might reflect a propensity to autoimmunity in general. 104, 105
GAD antibodies indicate an underlying autoimmune process and have a high positive predictive value on LADA patients for T1DM and future insulin dependency in adults. 14, 17, 38, 50, 53, 85, 86, 89, 106 – 108 GAD antibodies indicate an underlying autoimmune process and have a high positive predictive value on LADA patients for T1DM and future insulin dependency in adults 14, 17 38, 50, 53, 85, 86, 106 – 109
IgG 4 frequently occurs in LADA changing the balance between Th1 and TH2 cytokine profile in the pancreatic beta cells. This di erence could contribute to the slower rate of beta cell destruction in LADA patients as reflected by a higher C-peptide. 110
There is a debate on the usefulness of the di erent antibodies in screening T2DM patients for LADA. Some researchers believe that GAD 65 are not useful in screening for LADA. 110-114 Other researchers believe IA2 is not useful in screening for LADA 15, 113, 115 except in a population of diabetics from Eastern India. 116 IAA is generally considered the least useful in predicting LADA 117 except IAA was found to be a useful screen in a population of diabetics in China. 118
After the diagnosis of diabetes, the GAD antibodies persist, 81, 119 but change over time. Perhaps the
varying results with GAD antibodies can be explained by the fact that the GAD antibodies change as a person progresses towards diabetes. The early GAD 65 epitope (target of the autoimmune response) is the middle region of the GAD 65 antibody. As the immune progresses towards diabetes, the epitope moves to the carboxy-region of the GAD 65 antibody. 111, 120 – 122
Epitopes in the carobxy-region (COOH) region of the GADA are similar to Type 1 Diabetes. 15 – 17, 79 and have a diagnostic specificity for insulin requirement as high as 99.4 %. 87 ICA changes over time as well and can develop for patient who were initially ICA negative indicating decreasing beta cell function. 81
However, it is not a question of which autoantibodies or which combinations of autoantiobodies are available, but it is the total number of autoantibodies that predict insulin dependence in LADA. 82, 83, 88, 117 Multiple autoantibodies in circulation or high titres correspond to rapid Beta cell destruction just as GADA or low titres have a much slower development of beta cell failure 86 – 88
Other researchers found that GADA with IAA (insulin auto antibodies) or IA-2A provides 100 % predictability in predicting insulin dependence. 123, 124. This could possibly be related to the killing e cacy of the CD 8 and / or CD4T cells. 124 IAA or IA-2 are useful second line tests 123 although the IAA is less predictive of type I diabetes than other antibodies. 117 Those with multiple islet ell antibodies (ICA) mostly develop beta cell failure after 5 years. 83 Verge et al
found that having no autoantibodies predicts a risk of type 1 diabetes in 5 years as zero, if only one antibody is present, the risk rises to 44 % and the risk is 100 % if all three pancreatic enzymes were positive. 88.
If a single marker is chosen, GADA is predictive and a practical alternative to ICA. 125 High GAD65Ab titers per se not risk factor for disease progression in LADA. 82 The presence of a single autoantibody mainly GADA which is commonest in LADA or a low titre can have a much slower development of beta cell failure. 88
C-peptide levels
C-peptide levels decreased in antibody positive LADA patients who progressed rapidly to need insulin. The c-peptide levels remained stable in those who were not insulin dependent. 38
Low fasting C-peptide values as a marker of reduced pancreatic Beta cell function. 86 C-peptide levels also fall as a patient progresses towards diabetes 31, 38, 91, 96, 124, 126
C-peptide falls rapidly during the last six month before diagnosis. 127 Before that, the decline was gradual. At end C-peptide may rise slightly probably in response to the small rise in fasting glucose. 128
This decline in c-peptide persists even after insulin is started. 38
Glucose levels fluctuate as a patient progresses towards T1DM. As the glucose levels increase, the early c-peptide response declines. In contrast, glucose fluctuations are not related to early c-peptide response. 128 and islet anti bodies with low C- peptide at diagnosis of diabetes mellitus are useful markers to predict insulin dependence. 86, 107, 125, 129, 130
Other autoimmune diseases
Patients with one autoimmune endocrine disease (e.g, autoimmune diabetes), have a high risk of development for another autoimmune endocrine disorder. 131 LADA patients have higher prevalence of other autoantibodies including thyroid, 21, 132 casein antibodies, 133 gluten antibodies, 21, 133, 134 TPO antibodies, 21, 133 and anti -21- hydroxylase antibodies. 21 Persons with GAD65Ab 79, 106 and GAD65-M and C Ab 15, 79, 87 are at risk for TPO antibodies, thyroid and adrenal autoimmune diseases. 15 These findings are consistent with the fact that higher level of antibodies with the COOH epitome is a form of LADA 1 that is more similar to diabetes I. 15 – 17, 79
Genetics
LADA shares genetic features with both type 1 diabetes (HLA, INS VNTR, and PTPN22) 37, 55, 136 and type 2 diabetes (TCF7L2). 37, 55 , 137 (INS-VNTR is responsible for insulin gene expression in the pancreas and thymus. It modulates the selection of autoreacitve T lymphocytes acting towards insulin. ) Some view
LADA as the genetic intersection of T1DM and T2DM 55 Some researchers found that the strongly associated HLA-haplotypes for diabetes 1 were significantly associated with LADA but mainly with high anti GAD LADA patients. 58, 59 LADA patients with low GADA shared the CC/CT genotypes of (FTO) with type 2 diabetes. 58
Patterns of susceptibility at the HLA-DRB1 and HLA- DQB1 loci in LADA are similar to those reported for Type 1 Diabetes.
31, 82, 86, 138-140 Yet LADA has many HLAA types with confers protection against T1DM. 45 LADA pts di ered genetically and pheontypically from T2DM and T1DM depending on GADA 58 DNA methylation levels are altered in CD4+ cells from LADA which may contribute to disease onset and progression by a ecting the expression of autoimmune related genes. 141
Family History
First degree relatives of patients with LADA tended to have increased rate of insulin resistance, insulin secretion defects, 142 and defects in the processing of insulin precursors. 143 The concordance rate for beta cell autoimmunity in identical twin of a Type I Diabetes is about 2/3 – higher than that for overt diabetes. 144 It has been reported that first degree relatives of patients with multiple autoantibodies have a higher risk of irregular glucose tolerance test, 142 Type 1 Diabetes , 84, 108, 124
Diagnosis
LADA is under diagnosed in patients 145 and is diagnosed by the co occurrence of the three traits mentioned above. None of these traits is not which is exclusive to LADA. 34
BMI, 97, 146 – 148 clinical presentation, 147 c- peptide levels, 97 and adiponectin levels 149 are of limited use in identifying LADA. Routine screening for islet antibodies. 14, 23, 39, 107, 113, 150 – 153 mainly GAD and is recommended, 154- 156 especially in thin adults with new onset diabetes should have routine testing for GADA. 11, 26, 39, 50, 109, 147, 150, 155 Screening for other autoimmune diseases is recommended as well. 15 C-peptide is recommended in equivocal situations. 107, 148 A high c-peptide which often occurs in Type 2 Diabetes rules out LADA. 128
Genetic factors such as HLA-DQ and INS VNTR need to be combined with islet autoantibody markers when evaluating the risk for type 1 diabetes development. 157
Adiponectin and intact proinsulin may facilitate treatment decisions and monitoring in patients with type 2 diabetes. 150
Adiponectin tends to be higher in LADA than in type 2 diabetes and are equivalent to those found in non diabetic controls. 158 Adiponectin is correlated
positively with GADA titre and negatively with hs CRP. 159 High levels of adiponectin are associated with a lower risk of T2DM. 160
Treatment
LADA patients tend to have better lipid profiles that patients with T2DM, yet the risks for cardiovascular complications is similar to those of T 2 DM patients. Glycemic control is a stronger risk factor for cardiovascular disease in LADA patients than in type 2 diabetes. 161
Optimal treatment is not known. 156 Approaches are similar for prevention and treatment of LADA. Treatment includes both specific and nonspecific immunomodulation in order to limit the loss of endogenous insulin secretion. 13, 162
Specific modulation focuses on DiaPep277(an immunomudulatory peptide that arrests beta cell destruction), GAD and insulin while nonspecific immumodulation includes 1,25 dehydroxy- vitamin D 3 (calcitriol) and thiazolidinediones 13
Research suggests importance of early and strict glycemic control in these patients. 29 Insulin is the treatment of choice 21, 83, 162 as it provides good glycemic control 163
as evidenced by preservation of Hba1c early in insulin treatment. 163 While the best treatment not clear , early
insulin treatment may prevent pancreatic beta cell failure
38, 90, 164 – 168 and reduces the occurrence of ketosis and prevent diabetic complications in the eyes, nerves and kidneys. 165 and to reduce diabetic complications of eye, kidney and nerve-damage. 166
The benefits of insulin in LADA is linked to degree of autoimmunity, 168 high levels of GAD antibodies, 85, 97, 169 and the degree of beta cell failure. 168 Studies did not show a preservation of c-peptide with treatment. 164, 170 While insulin maintained c peptide levels better than sulphonlurea drugs, 170 the decline in c-peptide is progressive independent of age, gender, BMI, HbA1c level and antibody titer. Baseline c-peptide is an independent predictor of the ability to preserve adequate c-peptide. 164 In one study insulin was found to reduce ICA antibodies with no a ect on GAD antibodies. 163
Sulfonyhlurea drugs are not recommended 97, 163 as they can cause early insulin dependence. 170 – 172 Rosiglitazone combined with insulin may preserve islet beta cell function in LADA better than insulin alone. 173, 174 Meformin has not been shown to a ect the course of LADA or of beta cell destruction. Yet, it is possible that metformin may slow the immune destruction of beta cells by inhibiting insulin. 175
Alpha (OH)D3 plus can preserve pancreatic beta cell function in patients with LADA 13, 170, 175, 177 The combination of vitamin D with insulin showed steady fasting C peptide levels. 170, 178
Phase II trials were completed using alum formulated GAD as a modifier of the immune process. The researches felt positive about the ability of this formulation to prevent the deterioration of c-peptide 179-186 although no studies show improvement in glycemic control or changes in beta cell function. 187, 188 More studies are needed to prove the e cacy of this treatment. 170
Deltaran (delta sleep induced peptide ) an antioxidant, immunomodulator, antistressor helped reduce insulin resistance in LADA, an increase insulin secretion and decrease in dose of daily insulin requirement. 189 Immunomodulatory agents may be of benefit but clinical studies need to demonstrated the benefit. 163
Chinese medicine for LADA helped preserve beta cell function and did best synergistically with insulin. 190 Tangyikang (TYK) could improves he function of islet beta-cell, its possible mechanism is related with the regulation on cell immunity and the correction of T lymphocyte subsets (Th1/Th2) ratio imbalance. 191
Summary
LADA is underdiagnosed and should be suspected with an adult unset of diabetes in an individual who is thin
or who otherwise does not have the symptoms of metabolic syndrome. In these patients, antibody tests should be performed for GADA, IAA, IA-2 as well as autoimmunity markers for thyroid and other diseases. If the number of antibodies is not high, additional support for the LADA diagnosis can be obtained from a low c-peptide value and normal adiponectin levels.
The earliest signs of a progression towards diabetes are irregular glucose tolerance tests with the immediate post prandial hyperglycemia being the first sign. It is unfortunate that the HMO in question placed little value on post prandial glucose values because glucose swings trigger more oxidative stress than a pattern of hyperglycemia. 192 Post prandial hyperglycemia is from the loss of the first phase glucose-induced insulin release is defective. This occurs before the development of fasting hyperglycemia in the development of Type 2 Diabetes. It is a risk factor for diabetes. It is one of the first signs of beta cell dysfunction. 193, 194
An abnormal glucose tolerance test can identify unsymptomatic diabetic patients with normal fasting glucose. and normal A1C levels. Screening with HbA1C will miss many newly diagnosed diabetic patients. 195
72, 193 Post prandial hyperglycemia, itself, is also a high risk for future cardiovascular damage. 196 Early awareness is important to preserve glycemic control with diet, exercise and if necessary insulin. The
sulfaurea drugs could make the situation worse.
Also, as in this case early identification of the irregular glucose tolerance, allowed Sally to reverse the contribution of insulin resistance to her dysglycemia.
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