MODY Diabetes

MODY diabetes is a group of clinically similar forms of diabetes mellitus with an autosomal dominant inheritance pathway. The disease manifests itself in childhood and adolescence. The main symptoms are frequent urge to urinate and an increase in urine volume, increased thirst and appetite, weight loss, redness of the skin, an increase in body temperature. The diagnosis is complex, it includes a clinical examination, a set of laboratory tests: fasting and post-meal glucose, hormonal and genetic blood test. The treatment program involves taking hypoglycemic drugs, nutrition correction and systematic sports.

ICD 10

E13 Other specified forms of diabetes mellitus

Meaning

MODY diabetes is called adult-type diabetes mellitus in young people. The term was first used in 1974-75. They indicated the forms of the disease that are detected in childhood or in youth, but proceed relatively easily, like type 2 diabetes, characteristic of people over 45 years old, and without reducing the sensitivity of cells to the effects of insulin. The prevalence of the disease has not been determined, but among different types of diabetes in young people and children, it occurs in 2-5% of cases. Epidemiology and symptoms are most fully described for populations in Europe and North America, data for Asian countries remain very limited.

Causes

This form of endocrine pathology is caused by mutational changes in genes that are responsible for the activity of pancreatic islet cells (pancreas). The causes of structural changes in chromosome sites remain unclear, but studies of the epidemiology of the disease can identify groups of patients at increased risk. Presumably, the development of MODY diabetes is associated with the following factors:

• Age. The vast majority of cases are children, adolescents and young people aged 18-25. These age periods are considered the most dangerous in relation to the manifestation of the disease.
• Gestational diabetes. About half of the cases of MODY diabetes are diagnosed in pregnant girls. Pathology proceeds according to the type of gestational diabetes, but persists after childbirth.
• Glycemia in relatives. One of the diagnostic criteria is the presence of close relatives with an increased concentration of glucose in the blood. The mother, father, grandfather or grandmother was found to have Diabetes mellitus, suffered gestational diabetes, hyperglycemia is determined before and / or two hours after eating.
• Diseases during pregnancy. A genetic mutation in the fetus can be triggered by diseases of the mother during pregnancy. The most likely causes include bronchial asthma, cardiac ischemia, arterial hypertension.

Pathogenesis

Pathology is formed on the basis of mutations of genes affecting the functionality of the cells of the islets of Langerhans, is transmitted by an autosomal dominant type, which causes non-gender-linked inheritance and the identification of close relatives suffering from one form or another of hyperglycemia. MODY is based on a mutation of only one gene. Diabetes is manifested by a decrease in the activity of pancreatic cells – a lack of insulin production.

As a result, glucose entering the blood from the stomach is not absorbed by the body’s cells. A state of hyperglycemia develops. Excess sugar is excreted by the kidneys, glucosuria (glucose in urine) and polyuria (increased urine volume) are formed. Due to the resulting dehydration, the feeling of thirst increases. Ketone bodies become a source of energy for tissues instead of glucose. Their excess in plasma provokes the development of ketoacidosis – metabolic disorders with a shift in blood pH to the acidic side.

Classification

MODY diabetes is represented by several forms with genetic, metabolic and clinical heterogeneity. Classification is based on distinguishing the types of disease, taking into account the site of the mutated gene. 13 genes have been identified whose changes provoke diabetes:

1. MODY-1. The factor involved in the control of glucose metabolism and distribution is damaged. Pathology is characteristic of newborns, young children.
2. MODY-2 is determined by a mutation of the gene of a glycolytic enzyme that controls glucose-mediated insulin excretion from glandular cells. It is considered a favorable form, does not cause complications.
3. MODY-3. Gene mutations are manifested by progressive dysfunction of insulin-producing cells, which provokes the manifestation of the disease at a young age. The course is progressive, the condition of patients gradually worsens.
4. MODY-4. The factor that ensures the normal development of the pancreas, the production of insulin, changes. The mutation can lead to persistent diabetes in newborns against the background of underdevelopment of the endocrine organ or to dysfunction of beta cells.
5. MODY-5. This factor affects the embryonic development and coding of the genes of the pancreas and some other organs. Progressive nondiabetic nephropathy is characteristic.
6. MODY-6. The differentiation of insulin-producing cells, nerve cells of individual parts of the brain is disrupted. Mutations are manifested by diabetes in children and adults, neonatal diabetes with neurological pathology.
7. MODY-7. The factor regulates the formation and activity of the pancreas. The disease is typical for adults, but 3 cases were detected with the onset at an early age.
8. MODY-8. Mutations contribute to the development of atrophy, fibrosis and lipomatosis of the pancreas. Hormonal insufficiency and diabetes are formed.
9. MODY-9. The factor participates in the differentiation of insulin-producing cells. The course of the disease with ketoacidosis is typical.
10. MODY-10. Genetic changes in the factor become a common cause of neonatal diabetes. Proinsulin production is disrupted, programmed death of pancreatic cells is possible.
11. MODY-11. The factor is responsible for stimulating the synthesis and secretion of the hormone insulin. Diabetes with obesity is characteristic. An extremely rare variant of the disease.
12. MODY-12. It is based on a change in the sensitivity of sulfonylurea receptors and potassium channels of the pancreas. It is manifested by neonatal, childhood and adult diabetes.
13. MODY-13. The receptor susceptibility of K+ channels decreases. The clinical picture has not been investigated.

Symptoms

Among all types of MODY diabetes, 50-70% of clinical cases occur in MODY 3. MODY 2 is in second place by prevalence, MODY 1 is in third (1%). Other variants of the disease are less common, insufficiently studied, and do not represent clinical significance. The second type of disease often manifests in childhood. It proceeds asymptomatically or with mild manifestations, is extremely rarely accompanied by complications, therefore it is diagnosed during screening examinations and during pregnancy when the gestational form of diabetes develops.

The third type has a progressive course, most patients begin at the age of 20 to 40 years. The manifestations are similar to the symptoms of classic type 1 diabetes: the amount of urine increases, thirst increases, appetite increases, body weight decreases, insomnia, convulsions are possible at night, hot flashes, agitation, increased blood pressure and temperature during the day.

Without treatment, symptoms progressively increase, and there is a high risk of micro- and macrovascular complications. A long “honeymoon” is typical – 3 years or more. This phrase refers to the period after the start of insulin therapy, when the doses of the drug initially selected by the doctor lower the blood sugar level more than expected, and treatment adjustment is required until the complete withdrawal of insulin.

The first type of diabetes MODY is similar in clinical picture to the third, but manifests more often in newborns and young children. Macrosomia and neonatal hypoglycemia are determined.

Complications

With MODY diabetes of the third type, there is a gradual progressive increase in symptoms. Therapy with insulin and hypoglycemic drugs gives a good result, but patients remain at risk of developing angiopathy. The defeat of capillary networks in the retina of the eye leads to diabetic retinopathy (decreased vision), in the renal glomeruli – to nephropathy (impaired urine filtration).

Atherosclerosis of large vessels is manifested by neuropathies – numbness, pain, tingling in the legs, impaired nutrition of the lower extremities (“diabetic foot”), malfunctions of internal organs. In expectant mothers, the disease of the second and first type can provoke fetal macrosomia.

Diagnostics

Due to the similarity of symptoms of various forms of diabetes and the rarity of MODY, diagnosis is quite complex, voluminous and lengthy. From the moment of the patient’s first treatment to the confirmation of the diagnosis, at least a month passes. The examination is supervised by an endocrinologist, and consultations of a geneticist, an ophthalmologist, and a neurologist are additionally prescribed. The main stages are the detection of hyperglycemia, differentiation of MODY diabetes with normal type 1 and type 2 diabetes. The complex of diagnostic procedures includes the following methods:

• Clinical survey, examination. MODY is characterized by an early start, the absence of obesity. It is distinguished from type I diabetes by the high hereditary nature of transmission (about 100%) – the patient has at least one close relative with some form of diabetes, prediabetes, mild fasting hyperglycemia. Another differential sign is the absence of symptoms of ketoacidosis (vomiting, abdominal pain, acetone smell from the mouth). Long-term remissions are characteristic.
• Standard laboratory tests. The level of glucose, insulin, C-peptide, antibodies (blood) is determined, a glucose tolerance test is performed. With MODY 2, prolonged, but mild or moderate fasting hyperglycemia is detected (on average 5.5-8.5 mmol / l). For type 3 and 1, the fasting sugar index is normal, but after a carbohydrate load it remains elevated for more than 2 hours (from 11.1 mmol/ l). Antibodies to insulin and pancreatic cells are absent, there is no correlation with the HLA system. The level of C-peptide is relatively normal.
• Genetic tests. It is possible to reliably diagnose the type of disease with the help of a molecular genetic study that detects mutations in genes. The procedure is lengthy, all sections of the isolated chromosome are studied in detail, but first of all those changes in which are associated with the development of MODY type 1, 2, 3.

Treatment

The principles of therapy for diabetes MODY are the same as in the treatment of common variants of the disease. They are aimed at eliminating hyperglycemia, normalizing metabolic processes in the body. The methods depend on the type of disease and on the presence of pregnancy – when carrying a child, hyperglycemia can negatively affect not only the woman, but also the fetus, so insulin therapy is used. The general scheme of therapeutic effects includes:

• Medical correction. These types of diabetes are sensitive to hypoglycemic tablet drugs. Hypoglycemic agents are prescribed to most patients, with a disease of the second type, it is enough to change the diet. Pregnant women, adolescents at puberty, as well as patients with a long-term current third type of disease may require the use of insulin to prevent complications.
• Compliance with the diet. A diet with a reduced carbohydrate content is shown – products containing refined sugar are excluded, sources of complex carbohydrates (cereals, cereals) are acceptable in moderation. The basis of the diet consists of vegetables, dairy and meat products, fish, eggs. Fractional food intake avoids pronounced fluctuations in glucose levels.
• Regular physical activity. Most cases of the disease are mild, patients can organize sports on their own. Aerobic exercise is recommended – walking, jogging, team games, gymnastics. It is undesirable to perform weightlifting exercises.

Prognosis and prevention

The course of MODY diabetes is considered more favorable than other types of diabetes – the symptoms are less pronounced, the disease is well amenable to correction with the help of diet, exercise and taking hypoglycemic medications. With strict adherence to the doctor’s prescriptions and recommendations, the prognosis is positive. Since the decrease in insulin production is caused by genetic factors, prevention is ineffective. Patients from risk groups should periodically undergo blood tests for early detection of hyperglycemia and prevention of complications.

Literature

1. Approach to the Patient with MODY-Monogenic Diabetes. / Broome DT, Pantalone KM, Kashyap SR, Philipson LH. / J Clin Endocrinol Metab. 2021 Jan 1;106(1):237-250. link
2. MODY diabetes and screening of gestational diabetes./ Urbanová J, Brunerová L, Nunes MA, Brož J./ Ceska Gynekol. 2020 124-130. link
3. Precision diabetes: Lessons learned from maturity-onset diabetes of the young (MODY)./ Tosur M, Philipson LH./ J Diabetes Investig. 2022 Sep;13(9):1465-1471.
4. Introduction to diabetes mellitus./ Kaul K, Tarr JM, Ahmad SI, Kohner EM, Chibber R. / Adv Exp Med Biol. 2012;771:1-11. 
5. Genetic Factors of Diabetes./ Antosik K, Borowiec M./ Arch Immunol Ther Exp (Warsz). 2016 Dec;64(Suppl 1):157-160. link