Diabetes mellitus type LADA

What is diabetes mellitus type LADA? The abbreviation LADA stands for L: Latent (latent), A - Autoimmune (autoimmune), D - Diabetes (A), A - in Adults (in adults).

That is, it is hidden diabetes in adults, due to inadequate immune response of the body. Some researchers consider it a slowly developing subtype of type I diabetes, others are called type 1.5 diabetes or intermediate (mixed, hybrid).

Both the type of disease itself and the name latent autoimmune adult diabetes are the result of many years of research conducted by two groups of medical scientists headed by a doctor of medical sciences at the University of Helsinki (Finland), the head of the Center for Diabetes at the University of Lund (Sweden), Tiinamaija Tuomi and Australian endocrinologist, professor Paul Zimmet of the Baker Heart and Diabetes Institute in Melbourne.

How justified the allocation of another type of diabetes, clinical practice will show, but the problems associated with this pathology are constantly discussed by experts in the field of endocrinology.

[1], [2], [3]

Epidemiology

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

According to various estimates, autoantibodies to β-cells can be detected in 4-14% of people with type 2 diabetes. Chinese endocrinologists have found out that antibodies specific for 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 of the diabetes mellitus LADA

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

Crucial in the etiology  of type 2 diabetes  is the increased need for insulin due to its resistance (immunity), that is, the cells of target organs use this hormone ineffectively (which is why hyperglycemia occurs).

And the causes of LADA type diabetes, as in cases of type 1 diabetes, lie in the initial immune attacks on the β-cells of the pancreas, causing their partial destruction and dysfunction. But with type 1 diabetes, the devastating effects occur fairly quickly, and with the hidden version of LADA in adults — like with type 2 diabetes — this process proceeds very slowly (especially during adolescence), although, as endocrinologists note, the rate of β-cell destruction varies fairly wide range.

[9], [10]

Risk factors

Although, as it turned out, latent autoimmune diabetes (LADA) is very common in adults, but the risk factors for its development are characterized only in general terms.

Studies in this direction led to the conclusion that, as for type 2 diabetes, prerequisites for the disease can be mature age, limited physical activity, smoking, and alcohol.

But it emphasizes the particular importance of having a family history of an autoimmune disease (usually type 1 diabetes or hyperthyroidism). But those extra pounds in the waist and abdomen do not play such an important role: in most cases, the disease develops with normal body weight.

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

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

Pathogenesis

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

Presumably, the formation of antibodies may be associated with the special secretory biology of β-cells, which is programmed to react infinitely in response to the splitting of carbohydrates, write 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 declines, 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 of the diabetes mellitus LADA

The symptoms of latent autoimmune diabetes in adults are similar to  those of  other types of diabetes, with early signs showing sudden weight loss, as well as a feeling of constant fatigue, weakness and drowsiness after eating and a feeling of hunger soon after eating.

As the disease progresses, the ability of the pancreas to produce insulin will gradually decrease, which can lead to more characteristic symptoms of diabetes, which manifest themselves:

• increased thirst at any time of the year (polydipsia);
• an abnormal increase in the formation and excretion of urine (polyuria);
• dizziness;
• blurred vision;
• paresthesias (tingling, numbness of the skin and the feeling of tingling running).

[19], [20]

Complications and consequences

The long-term effects and complications of LADA diabetes are the same as in Type 1 and Type 2 diabetes. The prevalence and incidence of complications such as  diabetic retinopathy, cardiovascular diseases,  diabetic nephropathy,  and  diabetic neuropathy  (diabetic foot with the risk of skin ulcers and subcutaneous necrosis cellulose) in adult patients with latent diabetes of autoimmune genesis comparable to their appearance in other types of diabetes.

Diabetic ketoacidosis and diabetic ketoacid coma  are an acute and life-threatening complication of this chronic disease, especially after pancreatic β-cells lose their ability to produce insulin to a significant extent.

[21], [22]

Diagnostics of the diabetes mellitus LADA

It is estimated that more than a third of people with diabetes who are not obese can have diabetes mellitus type LADA. As pathology develops over several years, people are often diagnosed with type 2 diabetes 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 (as determined by experts from the Immunology of Diabetes Society), such as:

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

For the  diagnosis of diabetes mellitus  type LADA blood tests are performed to determine:

• sugar levels (on a thin stomach);
• Serum C-peptide  (CPR);
• antibodies GAD65, ZnT8, IA2, ICA69;
• serum concentration of proinsulin;
• HbA1c (glycohemoglobin) content.

A urine test for glucose, amylase and acetone is also conducted.

[23], [24]

Differential diagnosis

Proper diagnosis of latent autoimmune diabetes in adults and its differentiation from types of diabetes 1 and 2 is necessary for choosing the right treatment regimen that will ensure and maintain glycemic control.

Type of diabetes	Type 1	LADA type	Type 2
Typical age of onset	Youth or adults	Adults	Adults
The presence of autoantibodies	Yes	Yes	Not
Insulin Dependence in Diagnosis	Celebrated at the time of diagnosis	Absent, develops in 6-10 years after diagnosis	As a rule, there is no dependence
Insulin resistance	Not	Some	Yes
Progression of insulin dependence	Up to several weeks	From months to years	For many years

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

Treatment of the diabetes mellitus LADA

Although the pathophysiological characteristics of diabetes mellitus type LADA are comparable to type 1 diabetes, its treatment — in cases of an erroneous diagnosis — is carried out according to the type 2 diabetes therapy regimen, which adversely affects the patient's condition and does not provide adequate control of blood glucose levels.

A single strategy for treating latent autoimmune diabetes in adults has not yet been developed, but endocrinologists at leading clinics believe that oral medications like Metformin are unlikely to help, and products containing sulfonyl and propyl urea can even enhance the autoimmune process. A possible reason for this is the acceleration of oxidative stress and apoptosis of β-cells due to prolonged 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 the level of glucose in the blood. In particular, these are drugs such as:

Pioglitazon (Pyoglar, Pioglit, Diaglitazon, Amalvia, Diab-norm) - 15-45 mg is taken (once a day). Possible side effects include headache and muscle pain, inflammation in the nasopharynx, reduction in the number of red blood cells in the blood;

Sitagliptin (Januvia) tablets - also take only once per 24 hours on average 0.1 g). Side effects such as headache and dizziness, allergic reaction, pain in the pancreas;

Albiglutid (Tandeum, Eperzan) is injected subcutaneously (once a week, 30-50 mg), Lixisenatide (Lixumia) is also used.

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

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

In addition, with this type of disease, doctors recommend regularly, on an ongoing basis, to check the level of glucose in the blood, ideally - before each meal and before bedtime.

[29], [30], [31]

Prevention

If various aspects of this form of autoimmune endocrine disease are still being researched, and specialists are trying to determine the optimal strategy for its treatment, then the only preventive measure can be  dieting with elevated blood glucose.

[32], [33]

Forecast

The destruction of pancreatic β-cells by the immune over time leads to an absolute dependence on exogenous insulin. This is the prognosis for patients with type 1 diabetes and for those who have diabetes mellitus type LADA.

[34], [35], [36]