LADA type diabetes mellitus

What is LADA diabetes? The abbreviation LADA stands for: L – Latent, A – Autoimmune, D – Diabetes, A – in Adults.

That is, it is latent diabetes in adults, caused by an inadequate immune response of the body. Some researchers consider it a slowly developing subtype of type I diabetes, others call it type 1.5 or intermediate (mixed, hybrid) diabetes.

Both the type of disease itself and the name latent autoimmune diabetes of adults are the result of many years of research conducted by two groups of medical scientists, headed by Tiinamaija Tuomi, Doctor of Medical Sciences at the University of Helsinki (Finland), Head of the Diabetes Center at Lund University (Sweden), and Australian endocrinologist, Professor Paul Zimmet from the Baker Heart and Diabetes Institute in Melbourne.

Clinical practice will show how justified it is to single out another type of diabetes, but the problems associated with this pathology are constantly discussed by specialists in the field of endocrinology.

[ 1 ], [ 2 ], [ 3 ]

Epidemiology

Today, almost 250 million people are diagnosed with diabetes, and this figure is estimated to rise to 400 million by 2025.

According to various estimates, 4-14% of people with type 2 diabetes may have autoantibodies to β-cells. Chinese endocrinologists have found that antibodies specific to autoimmune diabetes in adult patients are found in almost 6% of cases, and according to British experts – in 8-10%.

[ 4 ], [ 5 ], [ 6 ], [ 7 ], [ 8 ]

Causes LADA diabetes mellitus

We should start with type 1 diabetes, which is caused by a disorder of the endocrine function of the pancreas, specifically the β-cells localized in the nuclei of the islets of Langerhans, which produce the hormone insulin, which is necessary for the absorption of glucose.

Of decisive importance in the etiology of type 2 diabetes is the increased need for insulin due to resistance to it (insensitivity), that is, the cells of target organs use this hormone ineffectively (which is why hyperglycemia occurs).

And the causes of diabetes type LADA, as in cases of diabetes type 1, are rooted in the initial immune attacks on the β-cells of the pancreas, causing their partial destruction and dysfunction. But with diabetes type 1, the destructive consequences occur quite quickly, and with the latent version of LADA in adults - as with diabetes type 2 - this process is very slow (especially in adolescence), although, as endocrinologists note, the rate of destruction of β-cells varies over a fairly wide range.

[ 9 ], [ 10 ]

Risk factors

Although latent autoimmune diabetes mellitus (LADA) appears to be quite common in adults, risk factors for its development have only been generally characterized.

Research in this area has led to the conclusion that – as with type 2 diabetes – prerequisites for the disease may include advanced age, limited physical activity, smoking, and alcohol.

However, the special significance of having a family history of an autoimmune disease (usually type 1 diabetes or hyperthyroidism) is emphasized. But extra pounds on the waist and stomach do not play such an important role: in most cases, the disease develops with normal body weight.

According to the researchers, these factors support the hybridity version of LADA-type diabetes mellitus.

[ 11 ], [ 12 ], [ 13 ], [ 14 ], [ 15 ]

Pathogenesis

Several processes are involved in the pathogenesis of diabetes, but in the case of LADA type diabetes, the mechanism of pathology is triggered by immune system-mediated (activation of autoreactive T cells) disruption of pancreatic β-cell function under the influence of specific antibodies to antigens of the islets of Langerhans: proinsulin, an insulin precursor protein; GAD65, an enzyme of β-cell membranes of L-glutamic acid decarboxylase (glutamate decarboxylase); ZnT8 or zinc transporter, a dimeric membrane protein of insulin secretory granules; IA2 and IAA or tyrosine phosphatases, regulators of phosphorylation and the cell cycle; ICA69, a cytosolic protein of the membranes of the Golgi apparatus of islet cells 69 kDa.

Presumably, the formation of antibodies may be associated with a special secretory biology of β-cells, which is programmed to react in an infinitely repeatable manner in response to the breakdown of food carbohydrates and other stimuli, which creates opportunities and even some prerequisites for the formation and circulation of various autoantibodies.

As β-cell destruction progresses, insulin synthesis very slowly but steadily decreases, and at some point their secretory potential decreases to a minimum (or is completely depleted), which ultimately leads to severe hyperglycemia.

[ 16 ], [ 17 ], [ 18 ]

Symptoms LADA diabetes mellitus

Symptoms of latent autoimmune diabetes in adults are similar to those of other types of diabetes, with the first signs likely to include sudden weight loss, as well as a feeling of constant fatigue, weakness, and drowsiness after eating, and a feeling of hunger shortly after eating.

As the disease progresses, the pancreas' ability to produce insulin will gradually decrease, which can lead to more typical diabetes symptoms, which include:

• increased thirst at any time of the year (polydipsia);
• abnormal increase in the formation and excretion of urine (polyuria);
• dizziness;
• blurred vision;
• paresthesia (tingling, numbness of the skin and a sensation of crawling “goosebumps”).

[ 19 ], [ 20 ]

Complications and consequences

The long-term consequences and complications of LADA diabetes are the same as those of type 1 and 2 diabetes. The prevalence and incidence of complications such as diabetic retinopathy, cardiovascular disease, diabetic nephropathy, and diabetic neuropathy (diabetic foot with risk of skin ulcers and subcutaneous tissue necrosis) in adult patients with latent autoimmune diabetes are comparable to their occurrence in other types of diabetes.

Diabetic ketoacidosis and diabetic ketoacidotic coma are acute and life-threatening complications of this chronic disease, especially after pancreatic β-cells have largely lost the ability to produce insulin.

[ 21 ], [ 22 ]

Diagnostics LADA diabetes mellitus

It is estimated that more than a third of people with diabetes who are not obese may have LADA diabetes. Because the condition develops over several years, people are often first diagnosed with type 2 diabetes, which is associated with insulin resistance.

Today, the diagnosis of latent autoimmune diabetes in adults is based – in addition to the detection of hyperglycemia – on such non-specific criteria (defined by experts from the Immunology of Diabetes Society) as:

• age 30 years and older;
• positive titer for at least one of the four autoantibodies;
• The patient did not use insulin during the first 6 months after diagnosis.

To diagnose type LADA diabetes, blood tests are taken to determine:

• sugar level (on an empty stomach);
• Serum C-peptide (CPR);
• antibodies GAD65, ZnT8, IA2, ICA69;
• serum proinsulin concentration;
• HbA1c (glycated hemoglobin) content.

Urine is also tested for glucose, amylase and acetone.

[ 23 ], [ 24 ]

Differential diagnosis

Correct diagnosis of latent autoimmune diabetes in adults and its differentiation from types 1 and 2 diabetes is necessary to select the correct treatment regimen that will achieve and maintain glycemic control.

Type of diabetes	Type 1	Type LADA	Type 2
Typical age of onset	Youth or adults	Adults	Adults
Presence of autoantibodies	Yes	Yes	No
Insulin dependence in diagnosis	Marked at the time of diagnosis	Absent, develops 6-10 years after diagnosis	As a rule, there is no dependence
Insulin resistance	No	Some	Yes
Progression of insulin dependence	Up to several weeks	From months to several years	For many years

[ 25 ], [ 26 ], [ 27 ], [ 28 ]

Treatment LADA diabetes mellitus

Although the pathophysiological characteristics of LADA diabetes mellitus are comparable to type 1 diabetes, its treatment – in cases of misdiagnosis – is carried out according to the treatment regimen of type 2 diabetes, which negatively affects the condition of patients and does not ensure adequate control of blood glucose levels.

A unified strategy for treating latent autoimmune diabetes in adults has not yet been developed, but endocrinologists at leading clinics believe that oral drugs like Metformin are unlikely to help, and drugs containing sulfonyl and propyl urea may even enhance the autoimmune process. A possible reason for this is the acceleration of oxidative stress and β-cell apoptosis due to long-term exposure to sulfonylurea, which depletes secretory pancreatic cells.

Accumulated clinical experience confirms the ability of some hypoglycemic agents to maintain endogenous insulin production by β-cells, reducing blood glucose levels. In particular, these are drugs such as:

Pioglitazone (Pioglar, Pioglit, Diaglitazone, Amalvia, Diab-norm) - taken 15-45 mg (once a day). Possible side effects include headaches and muscle pain, inflammation in the nasopharynx, a decrease in the number of red blood cells;

Sitagliptin (Januvia) in tablets - also taken only once every 24 hours, on average 0.1 g). Possible side effects include headache and dizziness, allergic reaction, pain in the pancreas;

Albiglutide (Tandeum, Eperzan) is administered subcutaneously (30-50 mg once a week), and Lixisenatide (Lyxumia) is also used.

A feature of latent autoimmune diabetes in adults is the absence of the need for insulin treatment for a fairly long time after diagnosis. However, the need for insulin therapy in LADA type diabetes occurs earlier and more often than in patients with type 2 diabetes.

Many experts argue that it is better not to delay the use of insulin in this type of diabetes, because, as some studies have shown, injections of insulin drugs protect the β-cells of the pancreas from damage.

In addition, with this type of disease, doctors recommend checking blood glucose levels regularly, on an ongoing basis, ideally before each meal and before bed.

[ 29 ], [ 30 ], [ 31 ]

Prevention

While research into various aspects of this form of autoimmune endocrine disease is still ongoing, and experts are trying to determine the optimal strategy for its treatment, the only preventive measure that can be used is following a diet for elevated blood glucose.

[ 32 ], [ 33 ]

Forecast

The destruction of pancreatic β-cells by the immune system eventually leads to absolute dependence on exogenous insulin. This is the prognosis for both type 1 diabetes patients and those diagnosed with LADA diabetes.

[ 34 ], [ 35 ], [ 36 ]