Type 2 Diabetes: What Do We Know up to Today? Glurenorm Opportunities in Clinical Practice

The paper presents an overview on type 2 diabetes pathophysiology, clinical pattern, diagnostics, and the treatment. It underlines that the drug called gliquidone (Glurenorm) has benefits in type 2 diabetes treatment, including possibility of its use in patients with reduced glomerular filtration rate. Glurenorm is associated with a low risk of side effects such as hypoglycemic condition and weight gain.

Diabetes mellitus (DM) is a serious medical and social problem of the XI century, almost 90% of cases occur in type 2 diabetes (DM 2). The prevalence of the disease around the world is continuously increasing; in particular, as of 01.01.2013, 3 million 700 thousand people were registered in Russia. Despite advances in the diagnosis and treatment of the disease, chronic complications of DM 2 remain a major problem for most patients [1, 2, 9, 20].

Etiology, pathogenesis of the disease

DM 2 is the most common form of the disease, which is a group of heterogeneous disorders of carbohydrate metabolism. In the latest etiological classification of glycemic disorders (WHO, 1999), it is indicated that DM 2 can be with predominant insulin resistance (IR) and relative insulin deficiency or with a predominant disturbance of insulin secretion with or without IR [1]. Great importance in the development of diabetes 2 has the so-called risk factors (FF); conditionally, they can be divided into two groups: variable (presence of excessive body weight, hypodynamia) and unchanged (age, heredity, etc.) [2, 19]. Overweight increases the risk of developing the disease at any age, with more than 80% of cases of the disease associated with it. Among obese patients, 2 and 3 develops diabetes 2, and about 90% of patients with diabetes 2 have excessive weight or obesity [8]. However, the degree of MI and the incidence of DM 2 are most pronounced in individuals with abdominal obesity. Low level of physical activity independently affects the incidence of diabetes. Physical loads increase the sensitivity of target tissues to the action of insulin.

Age is one of the strongest FR. The prevalence of DM 2 increases with age. However, recently in connection with the obesity epidemic, diabetes 2 began to appear not only in young people, but even in children and adolescents. DM 2 is distinguished by genetic predisposition [8]. Concordance in monozygotic twins is 60-90%. The presence of gestational diabetes mellitus (HSD) in a woman's history increases the risk of its development in subsequent pregnancies and diabetes mellitus 2 in the future (by 7.5 times). There is a definite relationship between the body weight of a child at birth and the risk of developing it with DM 2. Individuals with both high and low molecular weight at birth have an increased risk of developing the disease. The relative risk of DM 2 in adulthood is increased with a body weight> 4.0 kg and <2.5 kg.

Treatment of any disease can be successful only with a clear understanding of its pathogenesis. In the development of DM 2, two fundamental pathophysiological mechanisms are important: a progressive impairment of the function of pancreatic pancreatic cells and a different degree of severity of the IR (a disturbed biological response of the peripheral tissues of the body to the effect of insulin), which is much faster than the clinical manifestation of diabetes 2 [2, 6, 13] . With diabetes 2, the greatest clinical significance is the loss of sensitivity to liver insulin, muscle and adipose tissue. There are many different states in which an IR is formed of one degree or another; it accompanies stresses, infections, pregnancy, old age, alcohol intake, obesity and many other conditions. At the same time, insulin secretion is found only in diabetes mellitus [6, 13]. For a long time, IR is compensated by non-physiological hyperinsulinemia (GI), which helps maintain normoglycemia at this stage of the disease. GI is commonly considered a marker of MI and precursors of the development of diabetes 2 [12]. So, the initial disturbances of carbohydrate metabolism occur 6-8 years before the diagnosis of diabetes 2, so it is not surprising that by this time half of the patients already have complications associated with the illness that lead to a deterioration in the quality of life, rapid disability and high mortality [20].

Over time, the mechanism of compensatory GI is lost, and insulin secretion becomes insufficient with respect to IR. Increasing hyperglycemia, as well as an increase in the level of free fatty acids (FFA) entering the bloodstream from abdominal fat depots, exacerbate MI, reduce the ability of b-cells to secrete the necessary amount of insulin in response to various stimuli. In addition, excess SFA stimulates hepatic gluconeogenesis, suppresses the transport of glucose to the muscles. The greatest disproportion between the secretion of insulin and the need for it occurs just after eating. The first indicator of the disruption of the secretory function of the b cells is the loss of the early phase of insulin secretion, which plays an important role in the metabolism of glucose in the body [26]. The early phase of the prandial response of insulin causes suppression of endogenous production of glucose by the liver, secretion of glucagon and lipolysis, increases the sensitivity of peripheral tissues to the action of insulin, facilitating the utilization of glucose by them. Making up about 10% of all the days of secreted insulin, it limits the rise in glycemia in the post-food period [4, 13].

At the present time, the concept of a reduced "incretin effect" in diabetes mellitus 2 has been formulated. These are hormones of the gastrointestinal tract (GIT) stimulating the secretion of insulin and suppressing the secretion of glucagon in response to food intake, such as glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. In patients with DM 2, the effectiveness of endogenous incretins is reduced, which is one of the mechanisms of development of hyperglycemia [22].

Clinical symptoms of the disease, diagnosis

The disease usually affects people of middle or advanced age (> 40-50 years) and develops not immediately, but for many years. The process of losing mass of b-cells is not clinically manifested for a long time and takes about 6-12 years before the diagnosis of DM 2. By this time, more than half of the cells do not work and do not secrete insulin. The early latent disorders of carbohydrate metabolism include impaired fasting glycemia and impaired glucose tolerance, diagnosis during an oral glucose tolerance test.

Almost all patients with diabetes 2 suffer from excessive body weight or obesity. Symptoms of hyperglycemia are often absent or increase gradually (polyuria, especially at night, polydipsia, polyphagia, pruritus and genital itching).

Typical are recurrent skin infections (candidiasis, pyoderma), xanthamatosis (yellowish plaques on the flexor surfaces of the extremities, on the chest, face, neck), xanthelasm in the eyelid region developing against a background of hyperlipidemia. Sign of IR are villous hyperpigmented growths, mainly in the folds of the neck and axilla (Acanthosis nigricans). Sometimes on the skin of one or both shins, less often other parts of the body, lipoid necrobiosis (dense red-brown spots) is observed. Cuts, splinters and injections often go unnoticed due to a decrease in sensitivity, easily become infected. Insufficient blood supply to the background of angiopathy contributes to the formation of ulcerative shin and foot defects. Periodontal disease, gingitis, stomatitis are observed. In some patients, the motor function of the stomach decreases, dyskinesia of the gallbladder, non-alcoholic fatty liver disease are characteristic.

Chronic hyperglycemia combines with damage, dysfunction of various organs, especially the kidneys, cardiovascular, nervous system, organs of vision. By the time of diagnosis of DM 2 complications, which are observed in almost half, sometimes are one manifestation of the disease. Chronic (vascular) complications of diabetes are divided into microangiopathies and macroangiopathies. Diabetic retinal lesions (proliferative retinopathy and macular edema) are the main cause of blindness among persons of working age. In addition, with CD 2, the risk of cataracts increases. Diabetic nephropathy can develop asymptomatically for a life of 10-12 years, and its manifestations (general weakness, decreased appetite, edema, headaches) are characteristic only for the clinically pronounced stage. The first sign of this complication of diabetes is the presence of microalbuminuria, with the development of proteinuria, the function of the kidneys is steadily decreasing. Diabetic neuropathy is a lesion of the nervous system in DM 2 and is characterized by a wide variety of manifestations depending on the form (peripheral, autonomous). Trophic disturbances of the feet and other parts of the legs, numbness, hypo- and areflexia, motor disorders are a consequence of peripheral neuropathy; defeat usually bilateral. Manifestations of autonomic neuropathy are a violation of sweating orthostatic hypotension, delayed evacuation of gastric contents, diarrhea or constipation, urinary incontinence.

Atherosclerosis in patients with diabetes 2 begins earlier and is more severe; its manifestations are diverse. For DM 2 characterized by hypertriglyceridemia, a decrease in the concentration of HDL cholesterol and the hyperproduction of small dense LDL, which is already observed with NTG. At the heart of diabetic dyslipidemia is IR. The likelihood of developing a myocardial infarction is increased by a factor of two in diabetes, six times in the risk of stroke, or three times. In occlusive lesions of peripheral vessels, intermittent claudication is observed, and in men - erectile dysfunction. Often there is "mute ischemia" and painless myocardial infarction, which is a consequence of autonomic cardiac neuropathy.

DM 2 promotes the development of various infectious and inflammatory diseases, in particular pulmonary pathology, urinary tract infections, which often occur without pronounced subjective disorders, with scant symptoms. Adherence to glycemic quality disorders, and often ketosis. The final diagnosis of DM 2 is specified by a number of laboratory studies based on WHO diagnostic criteria (1999-2006) (Table 1). Since 2011, for the diagnosis of diabetes 2, the use of the HbA1c level has been approved - an integral indicator that reflects the average level of glycemia over the previous 2-3 months (Table 2).

Treatment of diabetes 2

Hyperglycemia is not only an integral metabolic sign of the disease and a leading factor in the development of diabetic complications, but the main violation against which is directed to its treatment. The choice of individual treatment goals depends on the patient's age, expected life expectancy, the presence of severe complications and the risk of severe hypoglycemia [1, 12] (Table 3).

Non-medicamentous methods of treatment of DM 2 are an important component of the complex therapy of DM 2. Modern nutrition recommendations for diabetes 2 include the following basic principles: the energy value of food that maintains body weight close to ideal, and in case of excessive weight, low-calorie meals. Decrease in body weight is achieved by reducing the caloric content of the diet by 500-600 kcal / day; the total daily calorific value should not be less than 1200 kcal for women and 1500 kcal for men. According to modern recommendations, clinically significant weight loss is 5-10% of the initial body weight. Optimum weight loss from 0.5 to 1 kg per week; all this is feasible for the majority of patients with diabetes mellitus 2. The recommended carbohydrate content is 50-55%, proteins 15-20% of the total calorie content of the daily ration; the maximum restriction or elimination of easily assimilated and preferential intake of complex carbohydrates is provided. Fats, as the most energy-intensive of all nutrients (1 g = 9 kcal), are the main cause of accumulation of excess mass. The proportion of fats in the daily diet should not exceed 30%, saturated fat should not exceed 10% of total fat intake. The inclusion of polyunsaturated fats as an anti-atherogenic agent is also envisaged, it is also necessary to reduce consumption of cholesterol (less than 300 mg per day) and increase the intake of foods high in dietary fiber, fiber (20 to 40 g per day).

Physical loads reduce the severity of TS and stimulate the utilization of glucose by insulin-independent tissues. A good physical effect is provided by a rational physical load, safe and effective, taking into account the individual characteristics of each patient, for example, walking, swimming for 30-45 minutes 3-5 times a week, or any feasible exercise program.

Modern hypoglycemic agents, depending on the mechanism of pharmacological action, include several main groups (Table 5):

• Drugs that reduce IR: biguanides (metformin), thiazolidinediones (TZD).
• Drugs that stimulate the secretion of insulin: derivatives of sulfonylureas (PSM), clay.
• Ingredins of the incretin series: glucagon-like peptide type 1 receptor agonists, dipeptidyl peptidase inhibitors 4.
• Drugs that block the absorption of glucose in the digestive tract: a-glucosidase inhibitors.
• Insulins.

One of the most well-known and widely used in the treatment of DM 2 is PSM [9, 10]. The expediency of their use is beyond doubt, since the most important pathogenetic link in the disease is the secretory defect of pancreatic pancreatic cells and, above all, the loss of the early phase of insulin secretion [6, 17, 22, 26]. PSM can quickly reduce the level of glycemia, on monotherapy, the level of HbA1c is reduced by an average of 1-2% [8, 9]. Studies of recent years have made it possible to obtain an accurate characterization of the interaction of various PSM with pancreatic receptors. PSM binds to specific receptor proteins on the cell membrane of b cells - SUR-1, which are proteins of ATP-dependent K + -channels. Preparations of this group directly stimulate the secretion of insulin by b-cells, especially in the presence of glucose. The interaction of PSM with specific sulfonylurea receptors (SUR1) on the surface of b cells, which are a subunit in ATP-dependent potassium channels, leads to closure of the latter, cell membrane depolarization, calcium channel opening, calcium entry into the cell, and secretion of insulin into the bloodstream by exocytosis [ 8, 21].

A principled approach to the choice of a particular MS is based on an assessment of the balance of hypoglycemic efficacy, drug safety, metabolic pathways, and withdrawal and accessibility for the patient [6, 10, 17]. In addition, drugs within the group (in our case, PSM) may be more or less preferable in certain clinical situations because of their additional benefits, which are of great benefit to the patient. It is necessary to evaluate the functional state of the liver and kidneys, because if there is a violation of the function of these organs, there is a regular restriction in the use of certain drugs depending on the metabolic pathways and characteristics of their metabolites [9, 11, 13, 18].

Features of glycidone (glenororm)

Among the PSM of the second generation, the preparation gljurenorm (fig. 1) is distinguished due to a number of pharmacological features, such as short-term action and minimal excretion through the kidneys (see Table 1). According to the results of clinical studies (CI), the effectiveness of therapy with gljurorormom is comparable with some other PSM. Studies pharmacokinetics of the drug testify that after a single ingestion of glenororm (15 mg or 30 mg) quickly and almost completely (80-95%) is absorbed from the digestive tract (9, 15-17).

Gljurororm is completely metabolized by the liver, while its metabolites do not have or have poorly expressed pharmacological activity in comparison with the initial preparation. A distinctive feature of glenororm is that it is excreted by 95% from the body through the digestive tract, practically bypassing the kidneys (only about 5% in the urine), which favorably distinguishes it from other PSM. Clinical observations indicate that in patients with impaired renal function the drug does not accumulate. It is important that in elderly patients and middle-aged patients the pharmacokinetic parameters of the glenororm are similar [3, 4, 14, 23].

For gljurenorma the clear stimulation of secretion of insulin in reply to food intake is characteristic. Due to this the drug effectively affects postprandial hyperglycemia, which is now considered as an independent independent risk factor for the development of cardiovascular diseases in diabetes 2 [2, 5].

Hypoglycemia is the main and most frequent side effect of PSM. Hypoglycemia can cause any PPS, although with varying probability [6, 5]. Fear of hypoglycemia, both from the doctor and the patient, is an additional obstacle to achieving targeted control. In other words, fear of hypoglycemia leads to unwillingness to initiate or intensify therapy at the right time for patients who do not achieve therapeutic goals and who need to enhance treatment [7, 19]. In comparison with other representatives of the PSM class, glenororm has a low risk of hypoglycemic conditions (1%). In comparative CI, it was demonstrated that therapy with gljurenorm was associated with a lower incidence of mild hypoglycemia (5% on gljurenorma, 34% on glibenclamide). Moreover, severe hypoglycemia was not observed against the background of therapy with glenororm, glibenclamide therapy was fixed in 1.5% of cases, gliclazide - 0.5% [14].

It should be added that, along with the efficacy that is not inferior to most PSM, the low risk of hypoglycemic conditions, the drug does not cause significant weight gain [16, 25].

Glenororm use in special clinical cases

It is well known that diabetic nephropathy is one of the most serious and disabling effects of diabetes 2 [3, 15]. Approximately one third of patients with DM 2 may eventually develop chronic kidney disease (CKD) (Fig. 2), the risk of which is 2.6 times higher with diabetes [11]. Violation of the renal function imposes serious limitations on the choice of a hypoglycemic agent [9, 17]. It should be borne in mind that Glenororm is PSM, the use of which is safe in case of impaired renal function, correction of its dose is not required [3, 7, 16, 17]. A serious problem for patients with DM 2 and CKD is an increased risk of developing hypoglycemia (Figure 3). Patients with impaired renal function have a higher risk of hypoglycemic conditions due to reduced clearance of creatinine and some oral hypoglycemic agents, as well as impaired renal gluconeogenesis [16, 25]. Therefore among MSP, preference in this clinical situation should be given to glycvidone also because it is characterized by a low incidence of hypoglycemic reactions.

In this regard, the results of CI are interesting, which showed that treatment with glenororm for 24 weeks led to an improvement not only in glycemic parameters but also in kidney function: normoalbuminuria was achieved in 19% of patients with DM 2 with microalbuminuria [4]. In the group of patients with proteinuria, improvement in glycemic control was also accompanied by a significant decrease in urinary protein excretion. Treatment with glenororm was not associated with impaired renal function, which confirms the safety of prolonged use of the drug in patients with diabetes 2 even at the initial stage of chronic renal failure. Experimental studies Jian-Ting Ke et al. (2013) on model organisms (Goto-Kakizaki rats) with diabetic nephropathy showed a significant decrease in proteinuria, an improvement in tubular reabsorption after 4 weeks of therapy with glenororm [15]. Based on the results of CI Tuerk T.R. et al. Glenorhm is an effective and safe treatment for people who have diabetes after kidney transplantation. Thus, there was a significant decrease in glycemia from 154 ± 62 to 120 ± 30 mg /% (p = 0.002) in patients after kidney transplantation [22].

There is evidence that glucurorm metabolism does not change in patients with hepatic insufficiency. In CI in patients with diabetes and liver function disorders of varying severity (including acute liver cirrhosis with portal hypertension), glenororm did not cause further impairment of liver function, the incidence of side effects did not increase, hypoglycemic reactions were not detected [16, 25]. R.Yanardag et al. in an experiment on rats with streptozotsin-induced diabetes showed that against the background of administration of glenororm (10 mg / kg), damage to liver cells decreased [24].

Thus, glenorhom is characterized by a short duration of action, excretion from the body, bypassing the kidneys, low risk of hypoglycemia, which allows active and safe use of the drug in the treatment of patients with diabetes 2 of any age, including the elderly, with diabetic nephropathy, with an initial stage of CRF, without fear its progression, with the concomitant pathology of the kidneys and patients at high risk of hypoglycemia. The drug can be used as a monotherapy or combination with other hypoglycemic drugs. In combination therapy, glucrenorm is prescribed with metformin, meglitinides, thiazolidinediones and insulin, which increases the overall therapeutic effectiveness and significantly improves glycemic control [9, 16, 17].

Treatment with glenororm begins with a dose of 15-30 mg, if necessary gradually increasing it: a single dose of up to 30 mg, and a daily dose of up to 120 mg; The average therapeutic dose is 120-180 mg / day. Gljurororm should be taken 30 minutes before the start of food intake, the frequency of reception 2-3 times a day.

In conclusion, it should be noted that gljurenorm has a valid place in the pharmacotherapy of diabetes 2 and has a number of undoubted advantages: the possibility of using glomerular filtration in patients with a reduced rate, a low risk of side effects such as hypoglycemic conditions and weight gain. All this allows in practice to solve the problem of choosing a hypoglycemic therapy in patients of different categories, including the elderly.