MODY-diabetes

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

Currently, the term MODY diabetes (Maturity Onset Diabetes of the Young) is used in endocrinology to define monogenic juvenile diabetes – Monogenic Diabetes in the Young – inherited defects in the secretion of the pancreatic hormone insulin, which can manifest between the ages of 10 and 40 years.

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Epidemiology

According to WHO, 1-2% of young patients with non-insulin-dependent diabetes mellitus type 2 actually have juvenile monogenic diabetes. According to rough estimates, MODY diabetes affects 70 to 110 people per million worldwide.

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

British endocrinologists estimate the prevalence of monogenic diabetes of the young at 2% of all diabetics in the country (i.e. about 40 thousand patients). However, experts note that this data is not accurate, and, in addition, more than 80% of MODY cases are currently diagnosed as more common types of the disease. One of the reports of the UK Diagnostic testing centre includes the figure of 68-108 cases per million. Among the British, the most common diabetes types are MODY 3 (52% of cases) and MODY 2 (32%).

Research conducted in Germany has concluded that up to 5% of identified cases of type 2 diabetes are likely to be MODY diabetes phenotypes, and in patients under 15 years of age this figure is 2.4%.

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

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

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Causes MODY-diabetes

Research has identified the key causes of MODY diabetes, and this is a genetically determined disorder of the insulin-secreting function of the endocrine beta cells of the pancreas, concentrated in the pancreatic islets (islets of Langerhans). The pathology is inherited in an autosomal dominant manner, that is, if one of the parents has a mutant allele. The main risk factors for the development of MODY diabetes are a family history of diabetes in two or more generations. This increases the likelihood of passing on the 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 occurred, phenotypes or types of MODY diabetes are distinguished. To date, mutations have been identified in thirteen different genes: GCK, HNF1A, HNF4A, IPF1, HNF1B, NEUROD1, CEL, ABCC8, KCNJ11, INS, Pax4, KLF11, BLK.

Thus, the causes of MODY diabetes 1 are mutations in the HNF4A gene (hepatocyte nuclear factor 4-alpha). And MODY diabetes 2 develops due to an abnormality in the gene of the glucokinase enzyme (GCK), which is necessary for converting glucose into glycogen. The HNF4A gene regulates the amount of insulin produced by the pancreas in response to blood glucose levels. In patients with this type of monogenic diabetes (manifested from the neonatal period to 16-18 years), blood glucose levels can rise to 6-8 mmol/l, since the sensitivity of pancreatic beta cells to glucose is reduced.

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Pathogenesis

The pathogenesis of diabetes MODY 3 is associated with a mutation in the homeobox gene HNF1A, which encodes the hepatocyte nuclear factor 1-alpha. Diabetes manifests itself in adolescence, demonstrates a low renal threshold for glucose (glycosuria), but with age, blood sugar levels increase.

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

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Symptoms MODY-diabetes

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

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

At the same time, in many cases, monogenic juvenile diabetes can be asymptomatic – as with the MODY 2 and MODY 3 phenotypes – and is diagnosed by chance when slightly elevated glucose levels are detected during a test for another reason.

Thus, the course of MODY 2 diabetes is accompanied by a moderate increase in blood glucose levels (no more than 8 mmol/l) in the absence of other signs.

And with diabetes MODY 3, the first signs in the form of carbohydrate metabolism disorder and hyperglycemia appear in adolescents during puberty or a little later. Moreover, a tendency towards glucosuria with a completely normal blood sugar level is tracked, and before diabetes is detected, nephropathy may develop. With age, dysfunction of beta cells of the pancreas and insulin resistance of the liver become more obvious, and at a certain stage, patients require endogenous insulin.

Symptoms of MODY diabetes 4 can appear at any age (most often after 18 years up to old age) and are expressed in severe hyperglycemia, insufficiency (partial agenesis) of the pancreas, as well as malabsorption syndrome (with weight loss, dehydration, anemia, diarrhea, muscle weakness, cramps, etc.).

Among the most characteristic clinical manifestations of MODY 5 diabetes (in patients over 10 years of age), specialists highlight the presence of cystic formations in the kidneys; high levels of uric acid in the blood; liver dysfunction; and anatomical defects of the genitals.

Complications and consequences

Most MODY diabetes phenotypes – except for the MODY 2 variety – can cause the same short-term and chronic consequences and complications as those seen in types 1 and 2 diabetes:

• 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 their blockage);
• loss of sensation in the limbs (polyneuropathy);
• diabetic foot;
• impaired renal function;
• poorly healing trophic ulcers of the skin and subcutaneous soft tissues;
• high risk of developing cardiovascular pathologies.

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Diagnostics MODY-diabetes

Currently, MODY diabetes diagnosis is complicated by the fact that an accurate diagnosis can only be made based on genetic testing. A family history of diabetes may be an indirect sign that this type of diabetes is affecting a particular patient.

And routine tests include (see more details – Diagnosis of diabetes ):

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

To diagnose MODY, instrumental diagnostics may be required – ultrasound of the pancreas.

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Differential diagnosis

Differential diagnostics are designed to identify the presence of either MODY diabetes or diabetes mellitus type 1 or 2, autoimmune forms of the disease, mitochondrial dysfunction of the mitochondria of the beta cells of the islets of Langerhans, as well as carbohydrate metabolism pathologies of other etiologies.

Treatment MODY-diabetes

All types of monogenic juvenile diabetes are lifelong diseases, and treatment for MODY diabetes is aimed at maintaining blood sugar levels as close to normal as possible.

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

A certain 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 sulfonylurea. Although with diabetes MODY 1, MODY 5, MODY 6 and others, insulin therapy cannot be avoided.

Sulfonylurea derivatives – Gliclazide (other trade names – Diamicron, Glimicron, Diabeton, Medoclazide), Glibenclamide (Antibet, Gilemal, Glibamide, Glucobene), Glicvidone (Glurenorm), Glimepiride (Amaryl, Glemaz, Glumedex, Diamerid) – activate beta cells of the pancreas and promote insulin secretion. In the treatment of MODY diabetes, these drugs remain first-line hypoglycemic agents.

For example, endocrinologists prescribe the drug Gliclazide (in tablets of 80 mg) one tablet twice a day. The development of an allergy to the drug is not excluded. Contraindications include: 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 are Metformin hydrochloride, Metospanin, Formetin, Gliformin, Glykon, Glycomet, Glyminfor, Siofor) - it inhibits the formation of glucose and reduces glycogen stores in the liver. Metformin is taken after meals - one tablet (0.5-0.85 g) twice a day.

This medicine is contraindicated in infectious diseases, liver and kidney pathologies, acute heart failure, as well as in children under 15 and pregnant women. The use of dimethylbiguanide can cause nausea, vomiting, diarrhea, abdominal pain; with prolonged use, there is a risk of developing megaloblastic anemia.

The 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. The list of contraindications for this drug includes: type 1 diabetes, severe heart failure, pregnancy and lactation. It is not recommended to use Pioglitazone for patients under 18 years of age. And the side effects include hypoglycemia, anemia, headaches and muscle pain, edema, increased bilirubin and decreased calcium levels.

Prevention

It is impossible to prevent MODY diabetes, like most genetic pathologies. If a patient has predispositions for developing this disease, doctors recommend avoiding obesity: of course, this will not prevent the disease, but it will help delay the development of symptoms.

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Forecast

Patients with MODY 2 have the best prognosis because it causes milder hyperglycemia. Other types of MODY diabetes tend to progress over time.

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