Neuro-ophthalmologic Considerations in Latent Autoimmune Diabetes of Adults

From EyeWiki

Disease Entity

Latent autoimmune diabetes in adults (LADA) was first introduced by Zimmet to describe the subcategory of adult phenotypic type 2 diabetes patients with autoantibodies against glutamic acid decarboxylase 65 (GAD 65). Patients with LADA often failed sulfonylurea treatment and required insulin therapy earlier in the course of the disease. In 1974, the discovery of islet cell antibodies completely changed the classification of diabetes. When adults were found to have the same autoantibodies against pancreatic islet cells as those diagnosed with type 1 diabetes (T1D), it necessitated the creation of a new subtype of disease, type 1.5. This blended the previously known versions of diabetes because LADA has both an autoimmune component and delayed onset. Similar to those with T1D and type 2 diabetes (T2D), LADA can cause chronic hyperglycemia leading to microvascular damage. The microvessels that supply the retina are a common target for the deleterious effects of hyperglycemia leading to diabetic retinopathy. [1] This EyeWiki describes the neuro-ophthalmic considerations in LADA.


The Immunology of Diabetes Society has defined strict criteria to classify LADA including:

  • An age of onset of at least 30 years of age
  • Seropositivity of at least one related autoantibody
  • Lack of dependence on insulin within the first six months after diagnosis

The most common autoantibodies implicated in both T1D and LADA are GAD65 and islet-cell antibodies (ICA); however, in T1D alone, both the intracytoplasmic domain of the tyrosine phosphatase-like protein IA-2 (IA-2A) and insulin autoantibodies (IAA) are more prevalent. It has been demonstrated that LADA shares genetic features of both T1D and T2D. The autoimmune inflammation induced by autoantibodies promotes destruction of the beta cells in the pancreas; therefore, eliminating their ability to create insulin. Without exogenous insulin therapy, these patients may still enter into a state of ketoacidosis resulting in serious complications including seizure, coma, and even death.[1]


Several studies have shown that LADA may account for 2-12% of all cases of diabetes. The typical LADA patient is nonobese, older than 35 years, with diabetes initially controlled with lifestyle modifications that eventually progresses to the point of full insulin dependence. Another multicenter study carried out in Europe, Asia, and North America demonstrated that 4% to 14% of patients diagnosed with T2D were positive for diabetes-related autoantibodies.[2] Interestingly, some studies have shown the prevalence of diabetic retinopathy in those with LADA is significantly lower compared to those with T2D (20.3 vs 26.4%, P < 0.001).[3]

Risk Factors

LADA shares risk factors with T1D such as personal or familial history of autoimmune diseases. LADA also shares environmental risk factors including obesity, lack of exercise, smoking, low birth weight, drinking sweetened beverages, and alcohol overconsumption associated with T2D. Common risk factor characteristics suggest LADA is a hybrid of T1D and T2D. The interaction of physiologic stressors may exacerbate the ongoing autoimmune processes in LADA patients, contributing to disease onset.[4][5]

General Pathology


LADA shares characteristics of both T1D and T2D therefore there are two separate pathophysiologic processes at work. In patients who are genetically susceptible to developing T1D, certain immunological factors can spark an autoimmune process causing islet cell destruction in the pancreas by autoantibodies. This leads to insulin deficiency as beta cells go through apoptosis. In contrast, obese individuals who share genetic susceptibility to T2D develop low grade inflammation from visceral adiposity. This can trigger an autoimmune process specifically marked by IA-2 antibody positivity. This causes beta cell dysfunction and decreased insulin production as well.[2]

Primary prevention

Primary prevention strategies typically employed by those with T2D can be utilized for those with LADA as well. This includes diet and lifestyle modifications. However, on November 17, 2022, the US Food and Drug Administration approved Teplizumab as an immunotherapy injection to delay the onset of T1D. Teplizumab is a monoclonal antibody that binds CD3, a cell surface antigen present on T cells. This causes deactivation of pancreatic beta cell autoreactive T cells. This is not yet approved or studied in patients with LADA; however, because LADA is also caused by an autoimmune process Teplizumab may delay its onset as well. More studies need to be conducted regarding immunosuppression and its impact on those with LADA.[6]


LADA shares many characteristics of both T1D and T2D. Patients often test positive for at least one autoantibody at presentation with relatively fewer metabolic comorbidities as compared to T2D (elevated blood pressure, hyperlipidemia, increased waist-hip ratio).[7] However, LADA has relatively more components of metabolic syndrome compared to those with T1D.[8] Patients might present with ketoacidosis or symptoms of hyperglycemia. Age of onset is between 30-50 years with subclinical symptoms of hyperglycemia. Insulin requirements generally begin at least six months after diagnosis with an average patient BMI of 25. Biochemical features include islet-cell antibodies of either high or low titer and detectable yet decreased C-peptide levels.[2]

For diabetic retinopathy, see reference below:


Physical examination

Signs and symptoms

Patients with LADA present with symptoms of hyperglycemia including but not limited to polyuria, polyphagia, polydipsia, and dehydration. Within the phenotypic variability of LADA, patients will present with either diabetic ketoacidosis or worsening hyperglycemia despite the use of hypoglycemic agents.

Patients with diabetes including LADA can develop visual loss from diabetic retinopathy, non-arteritic anterior ischemic optic neuropathy (NAION), and cortical stroke (e.g., homonymous hemianopsia). Efferent problems including anisocoria, ocular motor cranial neuropathies, and nystagmus can occur depending on the location of an ischemic infarct. GAD antibodies can also produce other GAD related neurologic disorders that may occur with LADA including stiff person syndrome, cerebellar ataxia, or nystagmus.

Clinical diagnosis

Diagnostic procedures

Diabetic retinopathy at diagnosis of LADA occurs in approximately 12% of cases. As a result, a slit lamp examination and dilated fundus examination should be performed. Observation of microaneurysms, hemorrhages, exudates, and swelling should be noted around the macula. Signs of retinal neovascularization, vitreous cells, and retinal detachment should be noted for more progressive DR. See diabetic retinopathy for more details on positive signs.[9]

Laboratory test

Autoantibody tests that show seropositivity for GAD65 and/or, less commonly, ICA, IA-2A, zinc transporter 8 (ZnT8A), and tetraspanin 7 help diagnose LADA. C-peptide blood tests can be used as a marker of insulin-secreting pancreatic beta-cell function. C-peptides determine the level of insulin dependency for patients with LADA. All other routine testing for T1D and T2D should also be employed such as repeated glycosylated hemoglobin (HbA1C), continuous glucose monitoring (CGM) for glycemic variability, lipid profiles, estimated glomerular filtration rate (eGFR), serum creatinine and cystatin C.[10][11]

Differential diagnosis

  • T2D – Presents >35 years old, normal to high C-peptide, negative for islet cell antibodies (ICA, GAD65, IA-2, IAA), high serum insulin, none-to-low insulin dependency for many years. Treated mainly with lifestyle modifications.
  • T1D – Present <35 years old, low C-peptide, often positive for islet cell antibodies (ICA, GAD65, IA-2, IAA), deficient serum insulin, immediate onset insulin dependency
  • Maturity-onset diabetes of the young (MODY) – MODY has a strong family history and is negative for antibodies to islet cell antigens listed above.
  • Latent autoimmune diabetes in the young (LADY)



General treatment

No evidence suggests a unique approach to treating diabetic complications (e.g., optic neuropathy, retinopathy) associated with LADA. Treatment for DR includes use of focal lasers and injection of drugs such as anti-VEGF therapies to reduce retinal swelling and edema. In proliferative diabetic retinopathy, primary treatment is panretinal photocoagulation (PRP) with some evidence to support anti-VEGF injection therapy as alternative treatment (see diabetic retinopathy for more information).[13]

Medical therapy

For systemic treatment, the goal of medical therapy is to preserve beta-cell (B-cell) function, and maintain strict glycemic control. These goals are achieved through a personalized approach to therapeutics given that LADA can present with different metabolic phenotypes, particularly the pre-existing level of insulin secretion.

Patients with extremely low C-peptide (<0.3 nmol/L), a measure of insulin secretion, are considered equivalent to T1D and should follow insulin-based therapies. Recent guidelines by an international panel of experts suggest that in patients with higher C-peptide levels, insulin-based therapy in combination with other hypoglycemic agents are recommended. These agents include metformin, glucagon-like peptide-1 receptor agonists (GLP-1RAs), dipeptidyl peptidase IV (DPP4) inhibitors. Sulfonylureas are not indicated in treatment of LADA due to their effect of deteriorating B-cell function and maintaining poor glycemic control. Evidence is limited, however, and will require more large-scale trials to replicate results of combination therapies. Sodium-glucose cotransporter-2 inhibitors (SGLT2) have not been studied in LADA yet to define their benefits. [10] Lifestyle modifications such as weight loss and physical exercise, though indicated in treatment of T2D, are not sufficiently clear to improve outcomes in LADA yet.[10]


Patients with LADA can present with microvascular complications such as diabetic retinopathy similar to those commonly present in T1/T2D. The risk of microvascular complication is smaller for LADA patients in the short-term when compared to T1/T2D counterparts, but increases as the disease duration continues. These complications are likely due to earlier worsening of glycemic control in patients with LADA, thus signifying the importance of maintaining glycemic levels. Patients with LADA may also experience microvascular and macrovascular neurologic afferent and efferent complications related to atherosclerosis and cardiovascular disease similar to the rates found in T1 and T2D. A recent study has also found LADA can present with small fiber neuropathy (SFN), a condition where in particular A-delta fibers and C fibers atrophy due to metabolic-related damage, resulting in pain, burning, and stinging beginning in the feet.[4][14]


The prognosis of LADA is similar to that of Type 2 Diabetes Mellitus. Poor glycemic control adversely affects the prognosis of LADA. The excess risk of mortality is associated with cardiovascular disease, specifically ischemic heart disease. Strict glycemic control improves prognosis.[15]


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