Diabetes mellitus (DM) is a disease spectrum ranging from the classic insulinopenic type 1 diabetes (T1DM) at one end to the classic insulin-resistant type 2 diabetes (T2DM) at the other. Latent autoimmune diabetes of adults (LADA) is a form of DM with features of both T1DM and T2DM and has therefore been termed Type 1.5 DM. In Japan, the synonym used is slowly progressive insulin-dependent type 1 diabetes mellitus (SPIDDM). The American Diabetes Association (ADA) lists LADA as T1DM that evolves more slowly than the classic disease and does not recognize it as a specific type of DM. The World Health Organization's term for LADA is 'slowly evolving immune-related diabetes.'
LADA is, by definition, a disease of adults. The Immunology for Diabetes Society (IDS) has specified three criteria for the diagnosis of LADA:
Although attractive, this set of criteria has been challenged, especially because the choice of insulin as a treatment is highly physician dependent. It is immunologically similar to T1DM as antibodies to islet beta cells are present, albeit at lower titers, and immune destruction progresses at a much slower rate when compared to classic T1DM. The majority of these patients present with hyperglycemia that is not dramatic like T1DM and is misdiagnosed and managed as T2DM. Only later is it realized that they have poor control with many conventional agents, especially sulfonylureas, and eventually require insulin therapy.
LADA itself is a heterogeneous disease where some patients have high antibody titers, a low BMI, and progress to insulin therapy faster and others who have low antibody titers, features of insulin resistance like higher BMI, and progress more slowly to requiring insulin.
Early recognition of LADA is paramount so that appropriate strategies are employed to delay beta-cell destruction and reduce complications. This article reviews the advances in the pathophysiology of LADA and its implications in the evaluation and treatment.
LADA is determined by genetic factors. As in T1DM, the risk for acquiring LADA is highest in carriers of certain HLA haplotypes. The HLA genes code for the major histocompatibility antigens (MHC) which have important immunoregulatory functions, and therefore it is not surprising that LADA is caused by dysregulated immunity. However, the factors that precipitate the autoimmunity have not been established.
Unlike T2DM, there is a paucity of studies investigating the role of environmental factors like lifestyle in LADA. The reasons for this are:
In the few studies in this regard, it is evident that LADA shares several lifestyle risk factors with T2DM, namely, excess body weight, greater waist-hip ratio, low birth weight, intake of two or more sweetened beverages daily, and heavy smoking. These risk factors are of greater significance in the subset of LADA with lower titers of autoantibodies and higher BMI. Although weaker, they hold even for those with higher antibody titers. Increased physical activity, moderate alcohol use, and the intake of fatty fish have a protective effect on the risk of LADA. Two or more cups of coffee daily increase the risk for LADA, unlike the beneficial effect seen in T2DM, but this observation is sourced from a single study and needs to be validated.
LADA is the most frequent form of adult-onset autoimmune DM. It is also the most prevalent form of autoimmune diabetes as a whole. There are geographic and ethnic differences in its incidence. In the multicentric 'Action LADA' study from Europe, almost 10 percent of 6000 adults with adult-onset DM had islet cell autoantibodies. In the United Kingdom Prospective Diabetes Study (UKPDS), the antibody positivity among those with a presumptive diagnosis of T2DM in adults was 12 percent. Similarly, studies from Norway showed a 10 percent incidence, whereas studies from the middle-east, Korea, and China showed between 4 and 6 percent. Even within individual studies involving multiple centers, there were variations in the incidence between northern and southern latitudes both in Europe and Asia.
Most patients with LADA are positive for a single islet autoantibody, and glutamic acid decarboxylase antibody (GADA) is the most predominant. Some population groups have a varying prevalence of different autoantibodies, and measuring just one may underestimate the prevalence of LADA. Autoantibodies have been observed to appear and disappear during longitudinal follow-up. In these situations, the role of assay interference from anti-idiotype antibodies should be considered.
Islet beta cell autoimmunity antedates the onset of LADA by several years. This was observed in nearly two-thirds of patients with LADA in a prospective study and substantiated autoimmunity as the first insult. This is followed by insulin resistance that causes overt hyperglycemia and the diagnosis of autoimmune insulin-independent DM. An assessment of insulin resistance (IR) using HOMA-IR has shown patients with LADA have IR similar to T2DM even after correction for BMI. Thus, the pathophysiology of LADA involves both autoimmunity and the metabolic derangements of IR.
Most patients with T2DM and some with LADA and T1DM present with features of the metabolic syndrome (MetS). Irrespective of glucose as a criterion, MetS was more frequent in T2DM than in LADA. When glucose levels were included, MetS was higher in LADA than in T1DM.
Pancreatic tissue from humans with LADA and from a rat model mimicking LADA were analyzed using immunohistochemistry and PCR. Predominant macrophage (CD68) infiltration was shown in the islet cells as opposed to T1DM, which showed CD8T lymphocytes. There were islet groups with and without infiltration. The cell type shift translated to greater expression of Interleukin 1 beta cytokine secretion and decreased expression of TNF alfa in T lymphocytes. Also, the proliferation marker of nuclear antigen (PCNA) and the anti-inflammatory cytokine interleukin 10 (IL10) were elevated while the apoptotic promoters caspase3 and TUNEL were diminished. The result was increased beta-cell gene transcription, greater C-peptide levels, slower progression of beta-cell destruction, and slower onset of LADA compared to T1DM.
The presence of more than one diabetes-associated autoantibody (DAA) predicts a faster progression of beta-cell failure. In patients with LADA, the sensitivity of GADA in predicting insulin requirement diminishes in older patients.
In a Chinese study, it was shown that GADA alone was insufficient to identify all cases of LADA, although it was the most dominant. This highlights the geographic and ethnic variability in the distribution of DAAs in LADA.
Anti-gliadin antibodies (both IgA and IgG) are increased in LADA compared to T2DM and compromised intestinal mucosal barrier may allow environmental antigens to gain access via the oral route and initiate immunological events to induce the disease. Furthermore, similar to T1DM, anti-TPO antibodies are increased in LADA when compared to T2DM.
LADA subtypes differ with GADA titers that are inversely related to BMI.
Regulatory T lymphocytes produce proteins like transcription factor forkhead box protein 3 (FOXP3), which suppresses autoimmunity. Hypermethylation of DNA and decreased expression of FOXP3 diminish protection against immune destruction. It has been shown that FOXP3 and other proteins are lower in high GADA subtype compared to low GADA, indicating higher beta-cell destruction in the former.
The IgG4 class of GADA is more prevalent in LADA than T1DM, and this yields a T helper 2 lymphocyte (TH2) immune response, which may be one explanation for delayed onset of diabetes in LADA compared to T1DM. Another reason may be the binding site on the GAD molecule for the GADA. In LADA, there is more amino-terminal binding, whereas, in T1DM, it is in the carboxy-terminal. In the UKPDS, some patients who were GADA positive even after 5 years did not progress to insulin requirement, and the epitope specificity may explain this. Also, a high-affinity subtype of GADA to GAD65 antigen predicts the rate of beta-cell failure.
In the UKPDS and subsequent studies, a subset of T2DM negative for islet autoantibodies had T lymphocytes that were immunoreactive to islet cell antigens. The autoimmunity in these patients was more severe than in those with autoantibodies alone. They demonstrated a lower stimulated C-peptide response and subsequently went on to require insulin earlier than the group of T2DM without both antibodies and reactive T cells, thus creating a separate category of T-LADA.
The inflammatory biomarkers which are associated with obesity vary when sera from various types of DM are analyzed. If these results are reproduced in larger populations, their utility to diagnose and differentiate LADA from T1DM and T2 DM in conjunction with antibody testing may be enhanced.
LADA shares immunological features with both T1DM and T2DM. In a recent study analyzing fresh-blood derived peripheral blood mononuclear cells, it was shown that LADA was similar to T2DM in antigen-presenting cell characteristics and the number of regulatory B lymphocytes, whereas it mimicked T1DM in the number of Natural killer cells.
In patients with LADA, there is a positive correlation between BMI and interleukin 17, a pro-inflammatory cytokine from peripheral B lymphocytes implicated in T2DM and obesity.
LADA has more genetic similarity to T1DM than T2DM. Studies have shown certain HLA types increase while others decrease the risk for LADA. The number of 'risk alleles' is lesser in LADA, explaining the later onset of the disease. Genetic loci that are common in T1DM are associated with LADA. These include the major histocompatibility complex (MHC) region, PTPN22, SH2B3, and INS. In a recently published study, the key T2D risk allele TCF7L2 had a lower occurrence in LADA cases; it appears that this locus may not play a role in the etiology of LADA.
The only genetic similarity with T2DM at the HNF1A locus was not reproduced in a subsequent study by the same investigators who instead found a strong signal at the PFKFB3 locus during a landmark Genome-wide association study (GWAS).
Recent data do not support the independent effects of class I MHC in LADA, unlike in T1DM.
Modulating immunoreactivity of T cells may be a viable therapeutic target in LADA, just like T1DM.
Serious life events did not seem to precipitate LADA, unlike childhood T1DM.
Patients with LADA may present with symptoms of polyuria, polydipsia, nocturia, fatigue, visual changes, tingling in the feet, and weight loss or may be asymptomatic.
A personal or family history of autoimmune disease should raise suspicion that a patient with hyperglycemia has LADA or T1DM.
A history of low-birth-weight is a strong risk factor for both LADA and T2DM.
A history of smoking, alcohol consumption, the number of sweetened beverages are risk factors.
The amount and type of physical activity and exercise should be sought and recorded to quantitate the risk of LADA.
The blood pressure must be accurately measured.
Several diagnostic tools have been proposed to identify patients with LADA.
A diagnostic screening tool with three criteria was used to identify LADA in diabetic patients older than 50 years of age:
This tool is said to detect three-fourths of patients with LADA.
Another investigator developed a clinical risk score:
Two or more criteria when positive yielded a sensitivity of 90 percent and specificity of 71 percent while less than 2 criteria virtually excluded LADA.
Although the above algorithms have been described and validated in some studies, it must be mentioned that the phenotypes of LADA may resemble T1DM or T2DM and therefore exhibit a normal or high BMI, respectively, with the latter having higher blood pressure and triglycerides albeit midway between T1DM and T2DM.
Some patients with LADA may have features of the MetS. Two phenotypes have been described based on GADA titers. LADA1 with ICA and high GADA titers and a T1DM phenotype and LADA2 with lower GADA titers, single antibody, and a T2DM phenotype.
Patients with LADA are usually ketosis resistant at first diagnosis.
When an adult patient presents with hyperglycemia with or without symptoms and is controlled without the need for insulin in the first six months, LADA should be considered. A positive antibody to one of the islet antigens is the hallmark of LADA. Worldwide, the most prevalent islet autoantibody utilized is GADA. Others include IA-2A, which is associated increasingly with the LADA2 phenotype, insulin antibodies, and zinc transporter isoform 8 (ZnT8) antibody that occurs with varying frequencies. LADA has more of the other DAAs apart from GADA and IA2A than T1DM.
Patients with LADA have residual C-peptide levels typically between those with T1DM and T2DM. In T1DM, C-peptide is absent at first clinical presentation, and in T2DM, it is often increased. The levels of C-peptide correlate inversely with GADA titers. A stimulated C-peptide has a greater predictive value than a fasting level. Among the methods studied, the glucagon stimulation test (GST) and Mixed Meal Tolerance Test (MMTT) have been validated and found to be useful. The former is shorter in duration but associated with transient nausea while the latter takes a long time but is free of side-effects. Measurement of C-peptide is preferable than measurement of insulin as it has a longer half-life, not subjected to the first-pass hepatic metabolism, and a steady-state clearance from the circulation. Insulin undergoes first-pass hepatic metabolism, has variable clearance, a much shorter half-life, and exogenously administered insulin can confound results. C-peptide is cost-effective when used as the initial test to distinguish LADA from T2DM but has to be later confirmed with antibody testing. In LADA, the MMTT has also been utilized for choosing the treatment modality and predicting the time to transition to managing with insulin.
HLA typing is not routinely utilized in the evaluation of LADA.
All other routine investigations for other DM patients should be employed in LADA at recommended intervals and as dictated by the clinical situation.
If diabetes-related complications set in, other tests may be indicated.
Once the diagnosis of LADA is made, non-pharmacological therapies including a diet with carbohydrate and calorie counting, exercise, and precautions to prevent complications similar to those employed in patients with T1DM and T2DM. Since LADA is a heterogeneous condition, pharmacological treatment has to be personalized to gain the maximum therapeutic advantage.
The two goals of pharmacological treatment are (1) to obtain good glycemic control and (2) to prevent or delay complications. Therapies that will preserve beta-cell function are a priority. Insulin has been the treatment of choice for LADA. Studies have shown preserved beta-cell function as evidenced by a maintained stimulated C-peptide response, normal HbA1C levels, and a decrease in autoantibody concentrations.
Sulfonylureas are a poor choice for LADA. They deplete beta-cells of insulin as depicted by falling C-peptide levels, the persistence of antibodies, and the earlier progression to insulin.
Although metformin may help initially in glycemic control in patients with LADA with higher BMI, it alone cannot achieve the second and more important goal of preserving beta-cell function or delaying its destruction.
Thiazolidinediones have antiinflammatory effects on beta-cells and can prolong their survival and can be useful if used in the earlier stage in LADA. They can also be combined with insulin. Rosiglitazone is the only drug studied in LADA. Unfortunately, the cardiovascular risks associated with this drug have extremely limited its use in the past decade. More long-term studies are warranted with other compounds in this class, like pioglitazone.
DPP4 inhibitors have shown promise alone or when combined with insulin in preserving beta-cell function in LADA. They affect metabolic control by prolonging levels of GLP1 and other peptides. Their primary action is to increase levels of GLP1, thereby suppressing glucagon and increasing insulin secretion after a glucose load by activating DPP4 receptors in the GI tract and brain. DPP4 receptors have also been identified on the surface of T lymphocytes, where they may affect immune regulation. This latter action may be of importance in slowing the beta-cell immune destruction in LADA. Thus far, these studies with DPP4 inhibitors have been either underpowered or not long-term. While this drug category has potential value, additional studies are needed before routinely recommending them for patients with LADA.
A study using the GLP1 receptor agonist dulaglutide has shown reductions in HbA1C levels and improvement in beta-cell function in patients with LADA with results comparable to T2DM.
Similarly, a Chinese herbal decoction combined with insulin has yielded positive results.
SGLT2 inhibitors have not been well-studied in LADA. However, some case reports of euglycemic ketoacidosis have appeared. Therefore this category is not recommended.
There are no studies with metformin alone in LADA, and with understandings of both the pathogenesis of LADA and the pharmacological profile of metformin, the latter has no role as a single agent for this condition.
The novel immunomodulating treatment with alum formulated recombinant human GAD65 by administering 3 injections of 4 mcg each into a lymph node in the groin along with daily oral vitamin D is in phase II of the GADinLADA trial. The study will evaluate the effects of the drug on the parameters of the beta-cell function for one year. This is based on the encouraging results from the DIAGNODE2 T1DM trial and the Diamyd LADA trial, which involved the injection of the GAD 65 formulation subcutaneously 20 mcg per dose for 2 doses one month apart. Several beneficial changes were noted in the immunological system. These included a shift of the GADA isotypes to IgG3/igG4, increased beneficial cytokines, increased FOXP3, and TGF beta, all favoring a Th2 lymphocyte response, more regulatory T lymphocytes and downplay of activated T lymphocytes thereby promoting a state of immune tolerance. These beneficial effects were persistent even after four years.
In some patients with obesity and DM, bariatric surgery (BS) is undertaken for weight loss and glycemic control. Some cases with presumed T2DM and obesity, in reality, have LADA. In such patients, BS causes successful weight loss, but inadequate glycemic control post-surgery and the remission of diabetes often seen in T2DM are absent in LADA confirming a progressive beta-cell failure. Patients with LADA have an increased post-operative risk of ketoacidosis and should be diligently watched. Some experts have even suggested screening for beta-cell function before BS to avoid disappointment with glycemic control in all obese patients with DM.
The main challenge is to distinguish patients with LADA from those with T2DM, with which it is often confused. By definition, T2DM has absent autoantibodies to islet cell components, a high normal or often elevated fasting and stimulated C-peptide, and does not need insulin for an extended period. If the risk factors of T2DM are reduced, there is a good chance of control with non-pharmacological measures with or without minimal medications. Physicians should consider screening for LADA in patients with T2DM who do not achieve adequate glycemic control within a reasonable period despite compliance to therapy. This is particularly true if they are not obese, lack the features of the MetS, or they, or their first degree relatives, have other autoimmune disorders, including Hashimoto thyroiditis, Graves disease, celiac disease, rheumatoid arthritis, or pernicious anemia.
T1DM presents dramatically, often with ketoacidosis, needs insulin on detection, and has more than one autoantibody and is easily differentiated from LADA.
Sometimes, a young adult with maturity-onset diabetes of the young (MODY) is mistakenly diagnosed as T1DM, T2DM, or LADA. MODY is rare, has a strong family history, has residual C-peptide, and absent humoral and cellular immunity to islet cell antigens and can thereby be distinguished from LADA.
Patients with LADA have mortality as high as T2DM despite having more favorable metabolic parameters. In the HUNT study, which is to date the largest population-based data on mortality in autoimmune diabetes (LADA), it was shown that hyperglycemia was the only significant influencing factor, and not the components of the metabolic syndrome, in determining mortality that was chiefly due to cardiovascular disease.
It, therefore, goes without saying that strict glycemic control is the key to improving the prognosis in LADA.
There is evidence that small-fiber neuropathy (SFN) occurs early and with increased frequency in LADA when compared to T2DM, which is related to higher HbA1C and poor glycemic control. Patients with LADA have severe SFN more often than those with age and duration-matched T2DM patients. However, the affliction of large nerve fibers is not different from T2DM. It is recommended that during the evaluation of a patient with LADA, tests to detect SFN should be included. Small nerve fibers carry pain and temperature sensations, mediate sweating and regulate vascular tone, thereby controlling blood flow. Tests for SFN include cold sensation threshold (CST), warm sensation threshold (WST), intraepidermal nerve fiber density (IENFD), and corneal confocal microscopy. The sensitivity of nerve conduction studies (NCS) to diagnose SFN is low and not recommended.
Long-term follow up of patients with LADA reveals a lower risk in the first nine years but a higher risk in later years for microvascular complications when compared to T2DM even after adjustment for several factors.
patients with LADA have as much carotid artery atherosclerosis as T1DM and T2DM despite a better vascular risk profile.
Three studies, the Botnia study, the Freemantle diabetes study, and the HUNT study all concurred on the increased cardiovascular disease and mortality in LADA, similar to T2DM.
It is clear, therefore, that LADA is associated with both microvascular and macrovascular complications like T1DM and T2DM.
Bone resorption is reduced in LADA, but the mechanisms are different from those in T2DM.
Patients with LADA need insight into the nature of their disease and the importance of strict glycemic control to prevent microvascular and macrovascular complications.
According to the World Health Organization (WHO), there were 422 million people with DM globally. As the prevalence of LADA in a population of T2 DM is between 4 and 12 percent depending on the population, between 17 to 50 million will have LADA. This number is likely to grow exponentially in the coming years.
The primary care practitioner (PCP) is very likely to encounter patients with LADA frequently and should be equipped with the knowledge and understanding to recognize and manage this condition promptly.
The endocrinologist sees difficult and complex patients and coordinates care with the PCP, ophthalmologist, podiatrist, and geneticist.
Laboratory medicine advises on the appropriateness of tests, performs biochemical and serological tests, and communicates them to the treating physician on time.
Bariatric surgeons must have a high index of suspicion for LADA in the obese with diabetes and counsel them regarding the less than optimal glycemic control post-surgery.
A coordinated effort by all the above health care providers is needed to achieve good glycemic control, prevent or delay complications, and substantially reduce morbidity, mortality, and health care costs. [Level 3]
|||Carlsson S, Etiology and Pathogenesis of Latent Autoimmune Diabetes in Adults (LADA) Compared to Type 2 Diabetes. Frontiers in physiology. 2019; [PubMed PMID: 30971952]|
|||Löfvenborg JE,Andersson T,Carlsson PO,Dorkhan M,Groop L,Martinell M,Tuomi T,Wolk A,Carlsson S, Fatty fish consumption and risk of latent autoimmune diabetes in adults. Nutrition [PubMed PMID: 25329601]|
|||Laugesen E,Østergaard JA,Leslie RD, Latent autoimmune diabetes of the adult: current knowledge and uncertainty. Diabetic medicine : a journal of the British Diabetic Association. 2015 Jul; [PubMed PMID: 25601320]|
|||Xiang Y,Huang G,Shan Z,Pan L,Luo S,Yang L,Shi L,Li Q,Leslie RD,Zhou Z, Glutamic acid decarboxylase autoantibodies are dominant but insufficient to identify most Chinese with adult-onset non-insulin requiring autoimmune diabetes: LADA China study 5. Acta diabetologica. 2015 Dec; [PubMed PMID: 26239144]|
|||Zachariah S,Sharfi MO,Nussey SS,Bano G, Latent autoimmune diabetes in the young. Clinical medicine (London, England). 2008 Oct; [PubMed PMID: 18975494]|
|||McDonald TJ,Colclough K,Brown R,Shields B,Shepherd M,Bingley P,Williams A,Hattersley AT,Ellard S, Islet autoantibodies can discriminate maturity-onset diabetes of the young (MODY) from Type 1 diabetes. Diabetic medicine : a journal of the British Diabetic Association. 2011 Sep; [PubMed PMID: 21395678]|
|||Chiu HK,Tsai EC,Juneja R,Stoever J,Brooks-Worrell B,Goel A,Palmer JP, Equivalent insulin resistance in latent autoimmune diabetes in adults (LADA) and type 2 diabetic patients. Diabetes research and clinical practice. 2007 Aug; [PubMed PMID: 17234296]|
|||Hawa MI,Thivolet C,Mauricio D,Alemanno I,Cipponeri E,Collier D,Hunter S,Buzzetti R,de Leiva A,Pozzilli P,Leslie RD, Metabolic syndrome and autoimmune diabetes: action LADA 3. Diabetes care. 2009 Jan; [PubMed PMID: 18945926]|
|||Jörns A,Wedekind D,Jähne J,Lenzen S, Pancreas Pathology of Latent Autoimmune Diabetes in Adults (LADA) in Patients and in a LADA Rat Model Compared With Type 1 Diabetes. Diabetes. 2020 Apr; [PubMed PMID: 31974139]|
|||Kucera P,Nováková D,Behanová M,Novak J,Tlaskalová-Hogenová H,Andel M, Gliadin, endomysial and thyroid antibodies in patients with latent autoimmune diabetes of adults (LADA). Clinical and experimental immunology. 2003 Jul; [PubMed PMID: 12823288]|
|||Jin P,Huang G,Lin J,Yang L,Xiang B,Zhou W,Zhou Z, High titre of antiglutamic acid decarboxylase autoantibody is a strong predictor of the development of thyroid autoimmunity in patients with type 1 diabetes and latent autoimmune diabetes in adults. Clinical endocrinology. 2011 May; [PubMed PMID: 21470281]|
|||Maruyama T,Nakagawa T,Kasuga A,Murata M, Heterogeneity among patients with latent autoimmune diabetes in adults. Diabetes/metabolism research and reviews. 2011 Nov; [PubMed PMID: 22069295]|
|||Wang X,Yang L,Cheng Y,Liang H,Hu J,Zheng P,Huang G,Zhou Z, Downregulation of T-Cell Transcription Factors in Adult Latent Autoimmune Diabetes with High-Titer Glutamic Acid Decaroxylase Antibody. Diabetes therapy : research, treatment and education of diabetes and related disorders. 2019 Jun; [PubMed PMID: 30895467]|
|||Li Y,Zhao M,Hou C,Liang G,Yang L,Tan Y,Wang Z,Yin H,Zhou Z,Lu Q, Abnormal DNA methylation in CD4 T cells from people with latent autoimmune diabetes in adults. Diabetes research and clinical practice. 2011 Nov; [PubMed PMID: 21864931]|
|||Krause S,Landherr U,Agardh CD,Hausmann S,Link K,Hansen JM,Lynch KF,Powell M,Furmaniak J,Rees-Smith B,Bonifacio E,Ziegler AG,Lernmark A,Achenbach P, GAD autoantibody affinity in adult patients with latent autoimmune diabetes, the study participants of a GAD65 vaccination trial. Diabetes care. 2014 Jun; [PubMed PMID: 24598244]|
|||Naik RG,Brooks-Worrell BM,Palmer JP, Latent autoimmune diabetes in adults. The Journal of clinical endocrinology and metabolism. 2009 Dec; [PubMed PMID: 19837918]|
|||Tiberti C,Giordano C,Locatelli M,Bosi E,Bottazzo GF,Buzzetti R,Cucinotta D,Galluzzo A,Falorni A,Dotta F, Identification of tyrosine phosphatase 2(256-760) construct as a new, sensitive marker for the detection of islet autoimmunity in type 2 diabetic patients: the non-insulin requiring autoimmune diabetes (NIRAD) study 2. Diabetes. 2008 May; [PubMed PMID: 18332100]|
|||Liang H,Cheng Y,Tang W,Cui Q,Yuan J,Huang G,Yang L,Zhou Z, Clinical manifestation and islet β-cell function of a subtype of latent autoimmune diabetes in adults (LADA): positive for T cell responses in phenotypic type 2 diabetes. Acta diabetologica. 2019 Nov; [PubMed PMID: 31367990]|
|||Goel A,Chiu H,Felton J,Palmer JP,Brooks-Worrell B, T-cell responses to islet antigens improves detection of autoimmune diabetes and identifies patients with more severe beta-cell lesions in phenotypic type 2 diabetes. Diabetes. 2007 Aug; [PubMed PMID: 17473222]|
|||Castelblanco E,Hernández M,Castelblanco A,Gratacòs M,Esquerda A,Molló À,Ramírez-Morros A,Real J,Franch-Nadal J,Fernández-Real JM,Mauricio D, Low-grade Inflammatory Marker Profile May Help to Differentiate Patients With LADA, Classic Adult-Onset Type 1 Diabetes, and Type 2 Diabetes. Diabetes care. 2018 Apr; [PubMed PMID: 29358494]|
|||Singh K,Martinell M,Luo Z,Espes D,Stålhammar J,Sandler S,Carlsson PO, Cellular immunological changes in patients with LADA are a mixture of those seen in patients with type 1 and type 2 diabetes. Clinical and experimental immunology. 2019 Jul; [PubMed PMID: 30843600]|
|||Badal D,Kumar R,Paul M,Dayal D,Bhansali A,Bhadada SK,Kumar R,Sachdeva N, Peripheral blood mononuclear cells of patients with latent autoimmune diabetes secrete higher levels of pro- [PubMed PMID: 29067979]|
|||Zhang M,Lin S,Yuan X,Lin Z,Huang Z, HLA-DQB1 and HLA-DRB1 Variants Confer Susceptibility to Latent Autoimmune Diabetes in Adults: Relative Predispositional Effects among Allele Groups. Genes. 2019 Sep 13; [PubMed PMID: 31540313]|
|||Mishra R,Chesi A,Cousminer DL,Hawa MI,Bradfield JP,Hodge KM,Guy VC,Hakonarson H,Mauricio D,Schloot NC,Yderstræde KB,Voight BF,Schwartz S,Boehm BO,Leslie RD,Grant SFA, Relative contribution of type 1 and type 2 diabetes loci to the genetic etiology of adult-onset, non-insulin-requiring autoimmune diabetes. BMC medicine. 2017 Apr 25; [PubMed PMID: 28438156]|
|||Cousminer DL,Ahlqvist E,Mishra R,Andersen MK,Chesi A,Hawa MI,Davis A,Hodge KM,Bradfield JP,Zhou K,Guy VC,Åkerlund M,Wod M,Fritsche LG,Vestergaard H,Snyder J,Højlund K,Linneberg A,Käräjämäki A,Brandslund I,Kim CE,Witte D,Sørgjerd EP,Brillon DJ,Pedersen O,Beck-Nielsen H,Grarup N,Pratley RE,Rickels MR,Vella A,Ovalle F,Melander O,Harris RI,Varvel S,Grill VER,Hakonarson H,Froguel P,Lonsdale JT,Mauricio D,Schloot NC,Khunti K,Greenbaum CJ,Åsvold BO,Yderstræde KB,Pearson ER,Schwartz S,Voight BF,Hansen T,Tuomi T,Boehm BO,Groop L,Leslie RD,Grant SFA, First Genome-Wide Association Study of Latent Autoimmune Diabetes in Adults Reveals Novel Insights Linking Immune and Metabolic Diabetes. Diabetes care. 2018 Nov; [PubMed PMID: 30254083]|
|||Mishra R,Åkerlund M,Cousminer DL,Ahlqvist E,Bradfield JP,Chesi A,Hodge KM,Guy VC,Brillon DJ,Pratley RE,Rickels MR,Vella A,Ovalle F,Harris RI,Melander O,Varvel S,Hakonarson H,Froguel P,Lonsdale JT,Mauricio D,Schloot NC,Khunti K,Greenbaum CJ,Yderstræde KB,Tuomi T,Voight BF,Schwartz S,Boehm BO,Groop L,Leslie RD,Grant SFA, Genetic Discrimination Between LADA and Childhood-Onset Type 1 Diabetes Within the MHC. Diabetes care. 2020 Feb; [PubMed PMID: 31843946]|
|||Rasouli B,Andersson T,Carlsson PO,Hjort R,Löfvenborg JE,Martinell M,Groop L,Tuomi T,Carlsson S, Serious life events and the risk of latent autoimmune diabetes in adults (LADA) and Type 2 diabetes. Diabetic medicine : a journal of the British Diabetic Association. 2017 Sep; [PubMed PMID: 28632336]|
|||Hjort R,Alfredsson L,Andersson T,Carlsson PO,Grill V,Groop L,Martinell M,Rasouli B,Storm P,Tuomi T,Carlsson S, Family history of type 1 and type 2 diabetes and risk of latent autoimmune diabetes in adults (LADA). Diabetes [PubMed PMID: 28669512]|
|||Hjort R,Alfredsson L,Carlsson PO,Groop L,Martinell M,Storm P,Tuomi T,Carlsson S, Low birthweight is associated with an increased risk of LADA and type 2 diabetes: results from a Swedish case-control study. Diabetologia. 2015 Nov; [PubMed PMID: 26208603]|
|||Löfvenborg JE,Andersson T,Carlsson PO,Dorkhan M,Groop L,Martinell M,Tuomi T,Wolk A,Carlsson S, Sweetened beverage intake and risk of latent autoimmune diabetes in adults (LADA) and type 2 diabetes. European journal of endocrinology. 2016 Dec; [PubMed PMID: 27926472]|
|||Monge L,Bruno G,Pinach S,Grassi G,Maghenzani G,Dani F,Pagano G, A clinically orientated approach increases the efficiency of screening for latent autoimmune diabetes in adults (LADA) in a large clinic-based cohort of patients with diabetes onset over 50 years. Diabetic medicine : a journal of the British Diabetic Association. 2004 May; [PubMed PMID: 15089790]|
|||Fourlanos S,Perry C,Stein MS,Stankovich J,Harrison LC,Colman PG, A clinical screening tool identifies autoimmune diabetes in adults. Diabetes care. 2006 May; [PubMed PMID: 16644622]|
|||Mollo A,Hernandez M,Marsal JR,Esquerda A,Rius F,Blanco-Vaca F,Verdaguer J,Pozzilli P,de Leiva A,Mauricio D, Latent autoimmune diabetes in adults is perched between type 1 and type 2: evidence from adults in one region of Spain. Diabetes/metabolism research and reviews. 2013 Sep; [PubMed PMID: 23483713]|
|||Lohmann T,Kellner K,Verlohren HJ,Krug J,Steindorf J,Scherbaum WA,Seissler J, Titre and combination of ICA and autoantibodies to glutamic acid decarboxylase discriminate two clinically distinct types of latent autoimmune diabetes in adults (LADA). Diabetologia. 2001 Aug; [PubMed PMID: 11484077]|
|||Leighton E,Sainsbury CA,Jones GC, A Practical Review of C-Peptide Testing in Diabetes. Diabetes therapy : research, treatment and education of diabetes and related disorders. 2017 Jun; [PubMed PMID: 28484968]|
|||Brophy S,Davies H,Mannan S,Brunt H,Williams R, Interventions for latent autoimmune diabetes (LADA) in adults. The Cochrane database of systematic reviews. 2011 Sep 7; [PubMed PMID: 21901702]|
|||Zhou Z,Li X,Huang G,Peng J,Yang L,Yan X,Wang J, Rosiglitazone combined with insulin preserves islet beta cell function in adult-onset latent autoimmune diabetes (LADA). Diabetes/metabolism research and reviews. 2005 Mar-Apr; [PubMed PMID: 15386806]|
|||Pieralice S,Pozzilli P, Latent Autoimmune Diabetes in Adults: A Review on Clinical Implications and Management. Diabetes & metabolism journal. 2018 Dec [PubMed PMID: 30565440]|
|||O'Neal KS,Johnson JL,Panak RL, Recognizing and Appropriately Treating Latent Autoimmune Diabetes in Adults. Diabetes spectrum : a publication of the American Diabetes Association. 2016 Nov [PubMed PMID: 27899877]|
|||Awata T,Shimada A,Maruyama T,Oikawa Y,Yasukawa N,Kurihara S,Miyashita Y,Hatano M,Ikegami Y,Matsuda M,Niwa M,Kazama Y,Tanaka S,Kobayashi T, Possible Long-Term Efficacy of Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor, for Slowly Progressive Type 1 Diabetes (SPIDDM) in the Stage of Non-Insulin-Dependency: An Open-Label Randomized Controlled Pilot Trial (SPAN-S). Diabetes therapy : research, treatment and education of diabetes and related disorders. 2017 Oct; [PubMed PMID: 28929327]|
|||Zhu LQ,Liu YH,Huang M,Wei H,Liu Z, [Study on improvement of islet beta cell function in patients with latent autoimmune diabetes mellitus in adults by integrative Chinese and Western medicine]. Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine. 2004 Jul; [PubMed PMID: 15307692]|
|||D'Alessio DA,Denney AM,Hermiller LM,Prigeon RL,Martin JM,Tharp WG,Saylan ML,He Y,Dunning BE,Foley JE,Pratley RE, Treatment with the dipeptidyl peptidase-4 inhibitor vildagliptin improves fasting islet-cell function in subjects with type 2 diabetes. The Journal of clinical endocrinology and metabolism. 2009 Jan; [PubMed PMID: 18957505]|
|||Pozzilli P,Leslie RD,Peters AL,Buzzetti R,Shankar SS,Milicevic Z,Pavo I,Lebrec J,Martin S,Schloot NC, Dulaglutide treatment results in effective glycaemic control in latent autoimmune diabetes in adults (LADA): A post-hoc analysis of the AWARD-2, -4 and -5 Trials. Diabetes, obesity [PubMed PMID: 29377522]|
|||Rapti E,Karras S,Grammatiki M,Mousiolis A,Tsekmekidou X,Potolidis E,Zebekakis P,Daniilidis M,Kotsa K, Combined treatment with sitagliptin and vitamin D in a patient with latent autoimmune diabetes in adults. Endocrinology, diabetes [PubMed PMID: 27252860]|
|||Li X,Liao L,Yan X,Huang G,Lin J,Lei M,Wang X,Zhou Z, Protective effects of 1-alpha-hydroxyvitamin D3 on residual beta-cell function in patients with adult-onset latent autoimmune diabetes (LADA). Diabetes/metabolism research and reviews. 2009 Jul; [PubMed PMID: 19488999]|
|||Patoulias D,Manafis A,Mitas C,Avranas K,Lales G,Zografou I,Sambanis C,Karagiannis A, Sodium-glucose Cotransporter 2 Inhibitors and the Risk of Diabetic Ketoacidosis; from Pathophysiology to Clinical Practice. Cardiovascular [PubMed PMID: 29412120]|
|||Larsson HE,Lernmark Å, Vaccination against type 1 diabetes. Journal of internal medicine. 2011 Jun; [PubMed PMID: 21481019]|
|||Manning SB,Pucci A,Batterham RL,Finer N, Latent autoimmune diabetes in adults presenting as diabetes [PubMed PMID: 23881974]|
|||Olsson L,Grill V,Midthjell K,Ahlbom A,Andersson T,Carlsson S, Mortality in adult-onset autoimmune diabetes is associated with poor glycemic control: results from the HUNT Study. Diabetes care. 2013 Dec; [PubMed PMID: 24130367]|
|||Perkins BA,Bril V, Diabetic neuropathy: a review emphasizing diagnostic methods. Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology. 2003 Jul; [PubMed PMID: 12842711]|
|||Alam U,Jeziorska M,Petropoulos IN,Pritchard N,Edwards K,Dehghani C,Srinivasan S,Asghar O,Ferdousi M,Ponirakis G,Marshall A,Boulton AJM,Efron N,Malik RA, Latent autoimmune diabetes of adulthood (LADA) is associated with small fibre neuropathy. Diabetic medicine : a journal of the British Diabetic Association. 2019 Sep; [PubMed PMID: 30575096]|
|||Alam U,Asghar O,Petropoulos IN,Jeziorska M,Fadavi H,Ponirakis G,Marshall A,Tavakoli M,Boulton AJ,Efron N,Malik RA, Small Fiber Neuropathy in Patients With Latent Autoimmune Diabetes in Adults. Diabetes care. 2015 Jul; [PubMed PMID: 26106229]|
|||Maddaloni E,Coleman RL,Agbaje O,Buzzetti R,Holman RR, Time-varying risk of microvascular complications in latent autoimmune diabetes of adulthood compared with type 2 diabetes in adults: a post-hoc analysis of the UK Prospective Diabetes Study 30-year follow-up data (UKPDS 86). The lancet. Diabetes [PubMed PMID: 32032540]|
|||Hernández M,López C,Real J,Valls J,Ortega-Martinez de Victoria E,Vázquez F,Rubinat E,Granado-Casas M,Alonso N,Molí T,Betriu A,Lecube A,Fernández E,Leslie RD,Mauricio D, Preclinical carotid atherosclerosis in patients with latent autoimmune diabetes in adults (LADA), type 2 diabetes and classical type 1 diabetes. Cardiovascular diabetology. 2017 Jul 28; [PubMed PMID: 28750634]|
|||Napoli N,Strollo R,Defeudis G,Leto G,Moretti C,Zampetti S,D'Onofrio L,Campagna G,Palermo A,Greto V,Manfrini S,Hawa MI,Leslie RD,Pozzilli P,Buzzetti R, Serum Sclerostin and Bone Turnover in Latent Autoimmune Diabetes in Adults. The Journal of clinical endocrinology and metabolism. 2018 May 1; [PubMed PMID: 29506222]|