Physiological regulation of glycemia and metabolic disorders
Normally, blood glucose levels are strictly controlled by hormones and the nervous system (sympathetic and parasympathetic divisions). A key role is played by insulin, which is secreted by $\beta$-cells of the pancreas. Its task is to lower blood sugar levels by ensuring the transport of glucose into cells.
The action of insulin is counteracted by counter-regulatory factors. For example, glucagon stimulates lipolysis and glycogenolysis (glycogen breakdown), thereby increasing glucose levels. In turn, somatostatin acts as a universal brake, suppressing the secretion of both insulin and glucagon. Sex hormones (estrogens, progesterone) and glucocorticoids also affect carbohydrate metabolism, which is extremely important to consider when prescribing oral contraceptives to female patients.
The pathogenesis of Diabetes mellitus comes down to two fundamental disorders:
- Insufficient secretion of insulin itself.
- Impaired binding of the hormone to cellular receptors (tissue resistance).
As a result, hyperglycemia triggers a cascade of pathological changes in all types of metabolism:
- Carbohydrate: chronic excess of glucose in the blood.
- Lipid: development of dyslipidemia and hyperlipidemia.
- Protein: appearance of dysproteinemia.
- Mineral: electrolyte balance disruption, particularly often manifesting as hypokalemia.
Primary diabetes mellitus: types I and II
The classification distinguishes two main primary forms of the disease, which differ cardinally in etiology, pathogenesis, and clinical course.
Type I diabetes mellitus (insulin-dependent) Manifests predominantly at a young age (under 40 years). Patients usually have a normal or even reduced body weight.
- Etiology: The disease has an autoimmune nature—antibodies against the antigens of the islets of Langerhans are produced in the body. Viral infections (measles, mumps, Coxsackie viruses) often act as triggers. There is also a clear genetic link with the HLA system.
- Pathogenesis: Physical destruction of $\beta$-cells occurs. This leads to absolute insulin deficiency against the background of increased activity of its antagonists (glucagon, somatostatin). Plasma insulin levels are sharply reduced. Without replacement therapy with an exogenous hormone, ketoacidosis and diabetic coma inevitably develop.
Type II diabetes mellitus (non-insulin-dependent) Characteristic of patients older than 40 years and in most cases occurs against the background of obesity.
- Etiology: The autoimmune component and the link to the HLA system are absent. The main proven risk factor is overeating and obesity.
- Pathogenesis: The pathogenesis is based on insulin resistance—a decrease in the sensitivity of tissue receptors to insulin. Meanwhile, the pancreas may produce the hormone in normal or even excessive amounts (hyperinsulinemia). Ketoacidosis is untypical for this form, but the risk of hyperosmolar coma persists. Treatment includes not only exogenous insulin, but also sulfonylureas, which stimulate endogenous secretion.
Secondary diabetes mellitus
In addition to primary forms, carbohydrate metabolism can be disrupted due to other diseases or external influences. Secondary diabetes occurs in:
- Endocrinopathies: acromegaly, pheochromocytoma, Cushing's disease.
- Drug exposure: prolonged or incorrect use of hormonal drugs, diuretics, and $\beta$-adrenoceptor blockers.
Risk factors and prevention
Type II diabetes mellitus is widespread, so screening high-risk groups is crucial. Impaired glucose tolerance and diabetes itself are regarded as critical cardiovascular risk factors requiring just as strict correction as arterial hypertension.
Key risk factors:
- Anamnestic: age over 45 years, presence of type II DM in close relatives.
- Anthropometric and metabolic: body mass index (BMI) over 27, blood pressure above 140/90 mm Hg, and dyslipidemia (decreased HDL, increased LDL, and hypertriglyceridemia).
- Obstetric and gynecological: presence of polycystic ovary syndrome or giving birth to a large baby in the past (weighing more than 4 kg).
Briefly: answers to topical questions
What are the exact biochemical mechanisms for the development of diabetic ketoacidosis in absolute insulin deficiency?
The development of diabetic ketoacidosis is caused by impaired fat metabolism and enhanced lipolysis, which is not suppressed due to insulin deficiency.
A key role is played by a decrease in the activity of acetylation processes in the liver, which leads to accelerated synthesis of ketone bodies. As a result of a cascade of pathological reactions, the following manifestations are observed:
- Ketonemia — accumulation of ketone bodies in the blood.
- Ketonuria — excretion of ketone bodies in the urine.
- Acidosis — metabolic acidosis due to the accumulation of acidic products (ketone bodies).
Against the background of starvation or acute illnesses, enhanced lipolysis and hypoglycemia contribute to the progression of metabolic acidosis with the subsequent development of coma.
What changes in the immunogram (specific antibodies) are determined in the diagnosis of type I diabetes mellitus?
In the diagnosis of type I diabetes mellitus, specific autoantibodies are detected, serving as markers of autoimmune $\beta$-cell destruction. The presence of two or more autoantibodies is characteristic of the development of the disease.
The following spectrum of antibodies is determined:
- ICA (Islet cell autoantibody) — autoantibodies to islet cell proteins;
- GADA — autoantibodies to glutamate decarboxylase;
- IAA — autoantibodies to the insulin molecule itself;
- IA-2 (or IA-2A) — autoantibodies to tyrosine phosphatase;
- ZnT8A (or Zn-T8A) — autoantibodies to zinc transporter 8.
Antibodies to a protein with a molecular weight of 64 kDa can also be detected. In children under 10 years of age, IAA and GADA are more often detected, while IA-2 and ZnT8A predominate at an older age.
The classical triad of diabetes symptoms is easy to remember as "GPP": Glucosuria, Polyuria, Polydipsia.
Class and exam questions
Why are sulfonylureas not used in type 1 diabetes?
Sulfonylureas act as stimulators of insulin secretion. In type I diabetes, the $\beta$-cells of the pancreas are destroyed, so it is impossible to stimulate the production of the hormone—only exogenous insulin is effective.
How does the plasma hormonal profile differ between types of DM?
Glucagon levels remain stably high in both types. However, the concentration of insulin in type I is critically reduced, while in type II it is normal or elevated (compensatory hyperinsulinemia).
Is type 2 diabetes mellitus associated with viral infections?
No, viral infections (Coxsackie, measles, mumps viruses) are a trigger only for the autoimmune process in type I DM. The development of type II is not associated with viruses or the HLA system.
What else to study on this topic
- Mechanisms for the development of diabetic ketoacidosis in absolute insulin deficiency.
- Features of the pathogenesis of hyperosmolar coma in type II DM.
- The link of the HLA system with the development of autoimmune diabetes mellitus.
- Pathogenesis of dyslipidemia and dysproteinemia against the background of chronic hyperglycemia.
- Effect of oral contraceptives on carbohydrate metabolism.
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