MODY-diabetes

What is MODY-diabetes? This is a hereditary form of diabetes associated with the pathology of insulin production and the violation of glucose metabolism in the body at a young age (up to 25 years). The disease has code E11.8 for ICD-10.

At present, the term MODY-diabetes (Maturity Onset Diabetes of the Young) is used in endocrinology to determine monogenic juvenile diabetes - the inherited defects of the secretion of pancreatic hormone insulin, which can occur between the ages of 10 and 40 years.

[1], [2], [3], [4]

Epidemiology

According to WHO, 1-2% of young patients with insulin-independent type 2 diabetes actually have juvenile monogenic diabetes. According to rough estimates, on the world scale MODY-diabetes suffer from 70 to 110 people per million.

According to the American Diabetes Association, in the United States, MODY-diabetes accounts for up to 5% of all diagnosed cases of diabetes mellitus.

British endocrinologists estimate the prevalence of monogenic diabetes in young people at 2% of the total number of diabetics in the country (that is, about 40 thousand patients). However, experts note that these data are not accurate, and, in addition, more than 80% of cases of MODY are currently being diagnosed as more common types of the disease. In one of the reports of the UK Diagnostic testing center there is a figure - 68-108 cases per million. Among the British, diabetes MODY 3 (52% of cases) and MODY 2 (32%) are most common.

Studies conducted in Germany led to the conclusion that up to 5% of the cases of type 2 diabetes mellitus are likely to be MODY-type phenotypes, and in patients younger than 15 years this figure is 2.4%.

According to some reports, significantly higher prevalence of MODY-diabetes is observed in patients in Asian countries.

According to the clinical statistics, MODY-diabetes 1, 2 and 3 are most often diagnosed. And such varieties as MODY 8 (or syndrome of diabetes-pancreatic exocrine dysfunction), MODY 9,10, 11, 13 and 14, are extremely rare.

[5], [6], [7],

Causes of the mODY-diabetes

Studies have identified the key causes of MODY diabetes, and this is a genetically determined violation of the insulin secretion function of endocrine beta cells in the pancreas concentrated in pancreatic islets (islets of Langerhans). Pathology is inherited by autosomal dominant principle, that is, in the presence of a mutant allele in one of the parents. The main risk factors for the development of MODY diabetes are the history of family diabetes in two or more generations. This increases the likelihood of transmission of a genetic disorder to a child - regardless of body weight, lifestyle, ethnicity, etc.

For each type of MODY-diabetes, specific pathological changes have been identified, including various amino acid substitutions that affect the clinical signs of the disease and the age of its manifestation. And depending on the gene in which the inherited mutations have occurred, phenotypes or types of MODY diabetes are distinguished. To date, mutations have been established in thirteen different genes: GCK, HNF1A, HNF4A, IPF1, HNF1B, NEUROD1, CEL, ABCC8, KCNJ11, INS, Pax4, KLF11, BLK.

So, the causes of MODY-diabetes1 are mutations of the gene HNF4A (nuclear factor 4-alpha liver cells of hepatocytes). And MODY 2 diabetes develops because of the anomaly of the gene for the enzyme glucokinase (GCK), necessary for the conversion of glucose into glycogen. The HNF4A gene regulates the amount of insulin produced by the pancreas in response to the glucose level in the blood. In patients with this type of monogenic diabetes (manifested from the neonatal period to 16-18 years), the blood glucose level can rise to 6-8 mmol / l, since the sensitivity of pancreatic beta cells to glucose is reduced.

[8], [9], [10],

Pathogenesis

The pathogenesis of diabetes MODY 3 is associated with a mutation in the homeobox gene HNF1A, which encodes the nuclear factor of 1-alpha hepatocytes. Diabetes occurs during adolescence, shows a low renal threshold for glucose (glucosuria), but with age, the blood sugar level rises.

Diabetes MODY 4 occurs with the mutation of the gene IPF1 (encoding the factor promoter of insulin 1 in the pancreas) and is accompanied by significant functional impairment in the work of this organ. Diabetes MODY 5 occurs with the mutation of the gene HNF1B (hepatocyte nuclear factor 1-beta); MODY 6 - with mutation of the gene of the factor of neurogenic differentiation 1 (Neurod1); MODY 7 - gene KLF11 (regulating levels of insulin expression in pancreatic beta cells).

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

Symptoms of the mODY-diabetes

The clinical symptoms of MODY-diabetes depend on its genetic subtype. Some forms of the disease - for example, MODY 1 - manifest a typical picture of hyperglycemia: polyuria (increased urination), polydipsia (increased thirst) and laboratory confirmed levels of elevated blood sugar.

Due to a lack of insulin in MODY 1 diabetes, a progressive form is possible, which is fraught with carbohydrate starvation of cells - diabetic ketoacidosis, in which the pH balance is violated and the acidity of blood and interstitial fluids is increased, a generalized metabolic disorder with a comatose state threat.

At the same time, in many cases, monogenic juvenile diabetes can be asymptomatic - as in the phenotypes MODY 2 and MODY 3 - and is diagnosed accidentally, when a slightly elevated glucose level is detected when the analysis is given for another reason.

Thus, the course of diabetes MODY 2 is accompanied by a moderate increase in blood glucose levels (not more than 8 mmol / l) in the absence of other symptoms.

And with diabetes MODY 3, the first signs in the form of a violation of the metabolism of carbohydrates and hyperglycemia occur in adolescents during puberty or a little later. And the tendency to glucosuria is tracked at a completely normal level of sugar in the blood, and before the diagnosis of diabetes, nephropathy can develop. With age, the dysfunction of the pancreatic beta cells and insulin resistance of the liver become more evident, and at a certain stage, patients need endogenous insulin.

Symptoms of MODY-diabetes 4 can appear at any age (more often - after 18 years up to the advanced age) and are expressed in severe hyperglycemia, pancreatic insufficiency (partial agenesis), and in malabsorption syndrome (with weight loss, dehydration, anemia, diarrhea, muscle weakness, convulsions, etc.).

Among the most typical clinical manifestations of diabetes MODY 5 (in patients older than 10 years of age), experts identify the presence of kidney cysts; high levels of uric acid in the blood; liver dysfunction; anatomical defects of the genitals.

Complications and consequences

Most MODY-type phenotypes - in addition to MODY 2 - can cause the same short-term and chronic effects and complications as in type 1 and 2 diabetes mellitus:

• ketoacidosis and diabetic coma;
• damage to the retina of the eye with hemorrhage and retinal detachment leading to blindness;
• diabetic angiopathy (fragility of blood vessels, tendency to block them);
• loss of sensitivity in the extremities (polyneuropathy);
• diabetic foot;
• impaired kidney function;
• poorly healing trophic skin ulcers and subcutaneous soft tissue;
• a high risk of developing cardiovascular pathologies.

[16], [17], [18], [19], [20], [21]

Diagnostics of the mODY-diabetes

To date, the diagnosis of MODY diabetes is complicated by the fact that an accurate diagnosis can be made only on the basis of genetic testing. The family history of diabetes can be an indirect indication that this type of diabetes affects a particular patient.

And the usual tests include (see more details - Diagnosis of diabetes mellitus ):

• blood test for sugar content (surrendered on an empty stomach);
• OTTG test for glucose tolerance (after glucose load);
• a blood test for HbA1c (glycosylated hemoglobin) and C-peptide;
• a blood test for autoantibodies to insulin-producing beta cells;
• urine analysis for sugar content;
• urine analysis for microalbumin, amylase, acetone;
• analysis of feces for trypsin.

For the diagnosis of MODY, instrumental diagnostics, ultrasound of the pancreas, may be required.

[22], [23], [24]

Differential diagnosis

Differential diagnosis is intended to detect the presence of either MODY-diabetes, or type 1 or type 2 diabetes, autoimmune forms of the disease, mitochondrial mitochondria of the beta cells of the Langerhans islets, and pathologies of carbohydrate metabolism of another etiology.

Treatment of the mODY-diabetes

All kinds of monogenic juvenile diabetes are life-long, and MODY-diabetes treatment is aimed at maintaining blood sugar levels as close as possible to normal.

In principle, the therapeutic effect on diabetes MODY 2 can be limited to changes in the diet, read more - Diet for type 2 diabetes, also effective physiotherapy treatment, which consists of metered exercise. Together, this helps maintain physiologically tolerable levels of glucose and cholesterol in the blood, which in turn reduces the risk of complications, and also contributes to oxygen saturation and the burning of excess calories (in the presence of obesity).

Some progress in the treatment of MODY-diabetes (varieties MODY 1, MODY 3 and MODY 4) is the replacement of insulin injections with oral hypoglycemic agents based on sulfonylureas. Although with diabetes MODY 1, MODY 5, MODY 6, etc. Insulin therapy can not be avoided.

Derivatives of sulfonylureas - Gliklazid (other trade names - Diamikron, Glimicron, Diabeton, Medoclaside), Glibenclamide (Antibes, Hylemal, Glybamide, Glucobene), Glikvidon (Gljurenorm), Glimepiride (Amaryl, Glimeaz, Glumex, Diamerid) - activate beta cells pancreas and promote the secretion of insulin. In MODY-diabetes therapy, these drugs remain hypoglycemic drugs of the first line.

For example, the drug Gliklazid (in tablets of 80 mg) endocrinologists appoint one tablet twice a day. Do not exclude the appearance of allergies to the drug. Among the contraindications are: acute infections, severe liver and / or kidney failure, age under 18, pregnancy and lactation.

Dimethylbiguanide is the active substance of the drug Metformin (other trade names - Metformin hydrochloride, Methaspanine, Formethine, Gliiformin, Glicon, Gliket, Gliminfor, Siofor) - inhibits the formation of glucose and reduces glycogen stores in the liver. Metformin is taken after a meal - one tablet (0.5-0.85 g) twice a day.

This drug is contraindicated in infectious diseases, liver and kidney pathologies, acute heart failure, as well as children under 15 years of age and pregnant women. The use of dimethyl biguanide can cause nausea, vomiting, diarrhea, abdominal pain; with prolonged admission there is a threat of development of megaloblastic anemia.

Hypoglycemic agent Pioglitazone (Pioglit, Diab-norm, Diaglitazone, Amalvia) belongs to the class of glitazones and, acting on the liver, helps to reduce its insulin resistance. It is prescribed one tablet (15-30 mg) once a day. In the list of contraindications for this drug appear: type 1 diabetes, severe heart failure, pregnancy and lactation. It is not recommended to use Pioglitazone in patients younger than 18 years of age. And among the side effects are hypoklikemia, anemia, headaches and muscle pains, swelling, increased bilirubin and a decrease in the calcium content.

Prevention

Warnings MODY-diabetes, like most genetically determined pathologies, is impossible. If the patient has the prerequisites for the development of this disease, then doctors recommend to avoid obesity: of course, this can not prevent the disease, but to delay the development of symptoms will help.

[25], [26], [27], [28], [29]

Forecast

Patients with MODY 2 have the best prognosis, as it causes an easier hyperglycemia. Other types of MODY-diabetes tend to progress with time.

[30], [31], [32]