An Overview of T2DM: A Model of Diabetes Mellitus

A large part of the population suffers from a disorder in the metabolism of energy-rich substances (glucose, fats or proteins), diabetes mellitus (DM). A simple model allows us to understand the aetiology, pathophysiology and basic methods of modern treatment of the disease.

In many cases, the disease is caused by a malfunction of hormones, especially insulin. More than 10% of cases of DM are caused by an absolute or relative lack of insulin, mainly due to an autoimmune process that destroyed insulin-producing cells - type 1 diabetes (DM1) or in the final stages of other types of diabetes due to terminal failure of regulatory mechanisms. In rare cases, DM is due to a decrease in all the effects of insulin - real insulin resistance or due to a real lack of insulin (Mody 2 for example). Metabolism takes place in cells. Hundreds of different enzymes affect the metabolism of energy-rich substances. Each of them can be damaged. However, it seems that the main cause of the disease is an inappropriate lifestyle, which secondarily damages the regulatory systems. This is the cause of type 2 diabetes (DM2). A high energy input/low energy expenditure (HEILEE) lifestyle is not compatible with a human genetic background. Deviations in glucose metabolism initially arise as a feedback, cellular defence against energy-rich substances overload, and are therefore reversible. If energy surplus persists for a long time, irreversible malfunctions occur. Untreated DM1 is characterized by intracellular starvation and lack of ATP. DM2 is characterized by “cellular overeating”. There gradually develop serious collision between intracellular regulatory mechanisms (AMPK, CD36-SR-B2, controlled by the amount of ATP, glycogen, lipid and other energy-rich substances), and cascades of hormone second messengers. Insulin deficiency and insulin resistance in DM2 are emphasized above all today. The question, of which of these disorders (or obesity) is the first, provoking the development of DM2, is discussed in the literature. Neither of them – both are the consequence of a chronic energy surplus. Chronic hyperinsulinemia is present in the early stages of the disease. Insulin ensures a high transfer of glucose from the blood to the tissues in obese people, but it is unable to maintain an adequate level of glucose in the blood. The disease is characterized by a special disorder - “Insulin uncoupling", a defect when there is a simultaneous increase in some effects and a decrease in other effects of the hormone. The ability of insulin to ensure anabolic processes is preserved. The ability to form visceral fat stores or the ability to retain sodium is increased. Hormone synthesis in DM2 gradually decreases, and the patients may become fully dependent on external insulin administration.

What therapy results from the above-mentioned principles? The goal of our efforts should be the complete restoration of the metabolism of energy-rich substances, carbohydrates, fats and other substances. Patients who are unable to synthesize insulin need this hormone (its analogues), in adequate amounts depending on needs. Patients who produce insulin but are unable to release it sufficiently will be optimally treated with sulfonylurea derivatives (MODY 2, MODY 12). Patients who are unable to release insulin depending on food intake will be optimally treated with GLP1 analogues, and incretins. The basic medical treatment for patients suffering from DM 2 reduces energy intake. The anorexic effect of GLP1 agonists is beneficial. Metformin reduces the metabolism efficiency. This drug increases the amount of glucose processed anaerobically. Subsequently, metabolism in the Cori cycle causes significant energy losses. Currently, there are even drugs available that allow the removal of unnecessarily received energy by removing glucose from the body via urine-gliflozins. Insulin administration is appropriate to restore adequate blood glucose levels. Long-term administration of high doses of insulin is nevertheless not the optimal therapy for early-stage DM2. A return to a lifestyle that corresponds to the conditions under which the human organism evolved - with limited food intake and relatively high energy expenditure through physical exercise- could prevent the population from developing diabetes mellitus.