Occult autoimmune diabetes in adults



Overview of the disease

Definition

Latent autoimmune diabetes in adults (LADA) is a type of diabetes characterized by slow autoimmune damage to pancreatic β-cells that is not dependent on insulin therapy in the early clinical phase.

The American Diabetes Association (ADA) classifies LADA as a subtype of type 1 diabetes.

Typing

Classification according to glutamic acid decarboxylase antibody (GADA) titers

LADA type 1

A GADA titer of ≥180 U/ml, i.e., high-titer LADA, has clinical features similar to classic type 1 diabetes, with a more rapid decline in pancreatic islet function and less often with metabolic syndrome.

LADA type 2

GADA titer <180U/ml, i.e. low titer LADA, similar to type 2 diabetes.

Classified according to the type of LADA antibody

GADA positive LADA

It has the most typical clinical phenotype, with patients who are younger, thinner, have poorer β-cell function, and have more rapid islet attenuation.

Transmembrane protein 7 autoantibody (Tspan7A positive) LADA

LADA with transmembrane protein 7 autoantibody (Tspan7A) also has a more rapid decline in islet function than those who are negative for Tspan7A.

Other

Less commonly, LADA patients are positive for autoantibodies to the single protein tyrosine phosphatase (IA-2A), zinc transporter 8 autoantibodies (ZnT8A), or insulin autoantibodies (IAA).

LADA is categorized according to the age of onset of the disease.

Adult LADA

Adult LADA has an age of onset of 18-59 years. Adult LADA patients have poorer β-cell function, less insulin resistance, and less comorbid metabolic syndrome.

Elderly LADA

Older adults with LADA have an age of onset of ≥60 years. Compared with older adults with type 2 diabetes mellitus, older adults with LADA have similar islet function, level of insulin resistance, metabolic syndrome, and human leukocyte antigen (HLA) genetic features.

Incidence

LADA is prevalent worldwide, and the prevalence of LADA in China is at a high level, with the highest number of cases in the world.

The 2016 multicenter flow data showed that LADA patients accounted for 65% of the new-onset type 1 diabetes patients in China, and according to the 2018 diabetes flow data, it is speculated that there are more than 10 million existing LADA patients in China [1-3].

Our multicenter LADA study, which screened for a single GADA antibody, found that the prevalence of LADA was 6.1% among Chinese patients with first-ever type 2 diabetes aged 18 years or older, and the prevalence of LADA among Chinese patients with first-ever type 2 diabetes aged 30 years and older was 5.9% [1,4].

Etiology

Pathogenesis

The pathogenesis of LADA has a significant genetic background, and susceptibility genes for both type 1 and type 2 diabetes are involved in the pathogenesis of LADA, such as the human leukocyte antigen (HLA) genes, especially the HLA ⁃ class II genes.

LADA is a T-cell-mediated autoimmune disease, which belongs to the autoimmune-mediated diabetes, and the immunologic features include pancreatic islet inflammation and humoral immune alterations.

The histoimmunopathological feature of LADA is pancreatic islet inflammation, in which there are multiple immune cells infiltrating the pancreatic islets, including CD4+ T cells, CD8+ T cells, CD20+ B cells, CD68+ macrophages, etc. At the same time, the levels of many inflammatory factors, such as interleukin ⁃ 1β (IL ⁃ 1β), tumor necrosis factor ⁃ α (TNF ⁃ α), and IL ⁃ 10, were elevated in the pancreatic islets of the patients.

Humoral immune abnormalities in LADA are mainly manifested by the presence of islet autoantibodies in the patient’s serum, and common islet autoantibodies include glutamic acid decarboxylase antibody (GADA), insulin autoantibody (IAA), protein tyrosine phosphatase autoantibody (IA ⁃2A), and zinc transporter 8 autoantibody (ZnT8A).

Symptoms

Main Symptoms

LADA presents early as autoimmune insulitis and can be clinically asymptomatic.

In the non-insulin-dependent phase, which is in the early clinical stage, the manifestations are similar to those of type 2 diabetes mellitus, with no tendency to spontaneous ketosis, and as the disease progresses, patients may have typical symptoms such as polydipsia, polyphagia, polyuria, and weight loss.

In the insulin-dependent period, patients are prone to diabetic ketosis or acidosis, may have polydrinking, polyphagia, polyuria symptoms aggravated, but also nausea, vomiting, loss of appetite, exhaling rotten-apple flavor and other symptoms.

Accompanying symptoms

LADA may be associated with other autoimmune diseases or autoimmune-related antibody abnormalities. Common autoimmune diseases include autoimmune thyroid disease, celiac disease, Addison’s disease and autoimmune gastritis.

Symptoms in patients with autoimmune thyroid disease are related to the type of disease.

Patients with Hashimoto’s thyroiditis may have goiter, neck pain, pressure, dyspnea, dysphagia, etc. As the disease progresses, patients may have symptoms of hypothyroidism, such as bradycardia, chills, mucous edema, and constipation.

Patients with toxic diffuse goiter may have symptoms such as irritability, palpitations, fear of heat, excessive sweating, diarrhea, fatigue, and insomnia.

Patients with celiac disease may have diarrhea, abdominal distension, abdominal pain, pale eyelids, and edema.

Patients with Addison’s disease may have symptoms such as fatigue, loss of appetite, nausea, vomiting, and deepening of skin color.

Patients with autoimmune gastritis may have abdominal pain, loss of appetite, abdominal distension, nausea, vomiting, black stools, vomiting blood, diarrhea, belching and other symptoms.

Complications

Patients with LADA are prone to diabetes-related complications, including acute complications (diabetic ketoacidosis, hyperosmolar hyperglycemic syndrome) and chronic complications (diabetic nephropathy, diabetic retinopathy, diabetic foot, etc.), as well as infectious lesions. For more information, check the diabetes entry Diabetes Mellitus.

Medical Care

Department of Medicine

Endocrinology

When an examination reveals elevated blood glucose, or symptoms such as excessive drinking, excessive eating, excessive urination, or weight loss, it is recommended that you seek prompt medical attention.

Emergency Department

When symptoms such as deep and rapid breathing, rotten apple odor of exhaled breath, drowsiness, coma, etc. appear, it is recommended to seek medical treatment immediately.

Preparation for medical treatment

Preparation for medical consultation: registration, preparation of documents, frequently asked questions

Tips for the doctor

It is recommended to record the time of blood glucose measurement and blood glucose value for the doctor’s reference.

Preparation Checklist

Symptom list

Pay special attention to the time of onset of symptoms, special manifestations, etc.

When was the abnormal blood glucose value detected? What is the specific blood glucose value?

Is there excessive drinking, eating or urinating?

Has there been any recent weight loss? How much did you lose?

How long have the above symptoms lasted?

Medical History Checklist

Is there a family history of diabetes?

Any autoimmune thyroid disease?

Is there a history of autoimmune gastritis?

Any history of drug or food allergies?

Checklist

Test results for the last six months, which can be brought to the doctor’s office

General examination: body mass index, etc.

Laboratory tests: e.g. blood glucose, glycosylated hemoglobin, serum C-peptide, islet autoantibodies, glucose tolerance test (OGTT), etc.

Medication list

Medication used in the last 3 months, if available in boxes or packages, carry with you to the doctor’s office

Dipeptidyl peptidase IV inhibitors (DPP-4i): selegiline, saxagliptin, etc.

Glucagon-like peptide-1 receptor agonists (GLP-1RA): liraglutide, dulaglutide, etc.

Sodium-glucose cotransporter protein 2 inhibitors (SGLT2i): dagliflozin, empagliflozin, etc.

Thiazolidinediones (TZD) drugs: pioglitazone, rosiglitazone, etc.

Metformin drugs: metformin, etc.

Glucosidase inhibitors: acarbose, etc.

Insulin injections: glycemic insulin, menthol insulin, etc.

Immunomodulators: vitamin D, tretinoin, etc.

Diagnosis

Diagnosis is based on

Medical history

Patients with this disease may have the following medical history.

Family history of diabetes mellitus.

History of autoimmune thyroid disease.

History of autoimmune gastritis.

Clinical manifestations

Early in the course of the disease, there may be no obvious symptoms, but as the disease progresses, there may be symptoms such as polydipsia, polyphagia, polyuria, and weight loss.

There may be other symptoms associated with autoimmune disease, such as goiter, abdominal pain, nausea, and vomiting.

General Examination

Body Mass Index (BMI)

Based on the patient’s height and weight, BMI can be calculated by using the formula BMI = weight (kg)/height2 (m2), and the BMI of LADA patients is usually <25kg/m2.

Laboratory Tests

Blood glucose

Patients with LADA may have elevated fasting blood glucose and postprandial blood glucose.

Glycated hemoglobin

Glycated hemoglobin reflects the average level of blood glucose in the last 3 months. Patients with LADA may have elevated glycated hemoglobin.

Islet autoantibodies

Autoimmune antibodies to pancreatic islets are of interest in the diagnosis of LADA, including glutamic acid decarboxylase antibody (GADA), protein tyrosine phosphatase autoantibody (IA-2A), insulin autoantibody (IAA), islet cell antibody (ICA), and zinc transporter 8 autoantibody (ZnT8A).

C-peptide levels

Patients with LADA may have decreased C-peptide levels.

Oral glucose tolerance test (OGTT test)

For the diagnosis of diabetes mellitus, the following matters need to be noted.

Fasting for 8 to 10 hours before the test, and fasting after 12:00 p.m. the night before the test.

Fasting blood is drawn first on the day of the test.

Dissolve 75 grams of glucose in 250 to 300 ml of warm boiled water and drink it within 5 minutes after it melts.

Start timing from the first sip and measure the blood glucose after 2 hours, or take blood at half an hour, 1 hour, 2 hours and 3 hours to measure the blood glucose level.

Smoking, alcohol, coffee and tea were prohibited during the test and no strenuous exercise was done [11].

Diagnostic criteria

The diagnostic criteria for LADA are described below, and the diagnosis is made when 3 of the following are present.

Age of onset ≥ 18 years;

Positive islet autoantibodies, or islet autoimmune T-cells;

Not dependent on insulin therapy for at least six months after diagnosis of diabetes mellitus [1].

Differential diagnosis

Type 1 diabetes of adult onset

Type 1 diabetes of adult onset is late-onset type 1 diabetes with a propensity for spontaneous ketosis, without a long non-insulin dependent phase, and often requiring insulin therapy at onset.LADA has no propensity for spontaneous ketosis, usually has a non-insulin dependent phase, and often requires insulin therapy when it develops into an insulin dependent phase.

Type 2 diabetes with poor islet function

Type 2 diabetes mellitus with poor pancreatic islet function often presents late in the course of type 2 diabetes mellitus and requires insulin therapy, but negative serum autoantibodies can be used to make a differential diagnosis with LADA.

Juvenile onset adult-onset diabetes mellitus

Adolescent-onset adult-onset diabetes mellitus is an autosomal dominant disease, with a family history of more than two generations. The age of onset of the disease is usually less than 25 years old, and the disease is mild, most of which does not require insulin therapy, and autoantibody negativity can be differentiated from LADA.

Treatment

Aim of treatment: control blood glucose, regulate autoimmunity, protect pancreatic islet function, prevent and control complications and concomitant diseases.

Principle of treatment: choose glucose-lowering drugs that may have immune regulation, pancreatic islet protection, and improvement of cardiac and renal outcomes to achieve individualized control of blood glucose to reach the target.

Lifestyle intervention

Dietary treatment

Maintain a healthy lifestyle, eat a well-balanced diet, and recommend a low-salt, low-fat, low-sugar diet.

Diet needs to be regular, small and frequent.

Exercise therapy

Appropriate exercise can improve the body’s sensitivity to insulin, which is conducive to blood glucose control.

The way and amount of exercise should vary from person to person, and attention should be paid to gradual progress and persistence.

It is recommended to maintain 60 minutes of moderate-intensity exercise every day.

Glucose-lowering drugs

HbA1c levels in patients with LADA are recommended to be usually controlled below 7%. For most patients with LADA, fasting blood glucose control is recommended to be 4.4~ 7.2 mmol/L and postprandial <10 mmol/L.

The goal during pregnancy is to control fasting glucose at 3.9 to 5.3 mmol/L, 1 h postprandial 6.1 to 7.8 mmol/L, and 2 h postprandial 5.6 to 6.7 mmol/L [1].

Insulin

Insulin therapy can protect pancreatic β-cell function in patients with LADA by promoting islet rest and inducing immune tolerance.

In LADA patients with high titers of GADA, multiple islet autoantibodies, low C-peptide levels, or poor glycemic control, insulin therapy needs to be initiated as early as possible.

For patients with low titers of GADA, low C-peptide levels, or good glycemic control, appropriate oral hypoglycemic agents may be chosen.

Dipeptidyl peptidase IV inhibitors (DPP-4i)

DPP⁃4i can inactivate DPP⁃4 enzyme, increase GLP⁃1 level, and promote insulin secretion from pancreatic β-cells to lower blood glucose.

Without contraindications, patients with LADA can choose DPP⁃4i treatment, either alone or in combination with these drugs, such as selegiline and saxagliptin treatment.

Thiazolidinediones (TZD) drugs

TZD drugs (e.g., pioglitazone, rosiglitazone) activate the intracellular peroxisome proliferator-activated receptor (PPAR), which enhances insulin sensitivity and has anti-inflammatory and immunomodulatory effects.

TZD drugs (e.g., rosiglitazone) can be used to treat LADA in the absence of contraindications to use and to protect pancreatic β-cell function in patients with LADA.

Glucagon-like peptide-1 receptor agonists (GLP-1RA)

GLP-1RA can promote insulin synthesis and secretion, inhibit glucagon release, suppress appetite, slow gastric emptying and lower blood glucose .

GLP⁃1RA (e.g. liraglutide, dulaglutide) can be used in LADA patients who still have some islet function.

Sodium-glucose cotransporter protein 2 inhibitors (SGLT2i)

SGLT2i (e.g., dagliflozin, empagliflozin) reduces blood glucose by inhibiting proximal renal tubular sodium⁃glucose cotransporter and promoting urinary glucose excretion.

SGLT2i can be considered for LADA patients with high C-peptide levels and combined cardiac and renal complications or overweight.

Biguanides

In the absence of contraindications to the use of metformin, metformin can be used in combination with other appropriate drugs to treat LADA.

Glucosidase inhibitors

For LADA patients with good islet function, glucosidase inhibitors (e.g., acarbose) may be considered as a triple drug of choice, depending on complications and level of glycemic control.

Immunomodulators

Vitamin D

May exert anti-inflammatory and immunomodulatory effects through the vitamin D receptor (VDR).

It has been shown that the use of 1α⁃hydroxyvitamin D3 in combination with insulin in the treatment of patients with LADA improved fasting C-peptide levels better than in the insulin-alone group.

Radix Polypeptide

Lei Gong Teng Polyglucoside is a traditional Chinese medicine with anti-inflammatory and immunomodulatory effects.

Small doses of Radix Rehmanniae Polyglucoside can protect the function of the residual pancreatic islet β-cells in LADA patients.

The consensus suggests that a combination of low-dose tretinoin can be tried for the treatment of LADA [1].

GAD Vaccine

The islet-specific antigen GAD65 vaccine helps protect pancreatic β-cell function in patients with LADA.

However, the vaccine is still in the research stage, and its effectiveness and safety have yet to be further verified.

Monoclonal Antibodies and Cell Therapy

Immunotherapy such as anti-CD3 monoclonal antibody, anti-CD20 monoclonal antibody, stem cells or regulatory T cells are still in the research stage.

Prognosis

Cure

There is no cure for LADA, but active treatment can control the progression of the disease and delay the emergence of related complications.

When blood glucose control is poor, the disease can continue to progress and acute or chronic complications of diabetes mellitus may occur, even leading to death.

Hazards

Patients with poor glycemic control may develop acute or chronic complications of diabetes, such as diabetic ketoacidosis, diabetic retinopathy, diabetic nephropathy, etc., which may even cause death.

Daily

Daily management

Maintain a balanced and light diet, ensure the supply of protein, avoid high-sugar and high-fat foods, and choose more high-fiber foods.

Pay attention to the order of meals and eat in the order of vegetables-meat-main food.

Pay attention to cooking with less oil and salt, and keep the amount of cooking oil used to less than 30g per day, and the daily salt intake should not be more than 6g.

Alcohol is not recommended.

Appropriate sports exercise can be performed to increase the sensitivity of the body to insulin [5-11].

Disease monitoring

Poor glycemic control requires daily monitoring of blood glucose as directed by the physician until the blood glucose is under control.

The use of diet and exercise interventions requires purposeful blood glucose measurement to adjust diet and exercise.

Oral medications should be monitored regularly for fasting and postprandial glucose.

For those using insulin, blood glucose monitoring should be conducted accordingly to exercise and diet.

Follow-up

Regular follow-ups can help patients adjust their glucose-lowering regimen and avoid or delay the emergence of complications.

Blood glucose, glycosylated hemoglobin, C-peptide level and other tests can be performed during the review, and the specific review time and tests should be in accordance with the doctor’s instructions.

For patients with a disease duration of more than 5 years, comprehensive screening for complications, including diabetic retinopathy and diabetic foot, is required at least once a year [1].

Prevention

Adopt good living habits, such as paying attention to rest, avoiding staying up late.

Pay attention to diet and avoid overeating.

Control blood pressure and blood lipids to prevent cardiovascular disease and diabetic microangiopathy.