Metformin in the treatment of type 2 diabetes mellitus: a bestseller not fully read

Metformin[edit | edit code]

Glucophage
Metformin hydrochloride

is a tablet drug for the treatment of diabetes mellitus of the biguanide class, which has the ability to reduce weight, therefore it is often used for weight loss.
Available on the market under the brand names: Metformin, Glucophage, Siofor, Bagomet, Metfogamma, Glycon, Metospanin, Gliformin, Gliminfor, Sophamet, Formetin, Langerin, Metadiene, Formin Pliva, NovoFormin, Diaformin
. Metformin has virtually no side effects when used correctly and is not hazardous to health, unlike most other fat burners. Metformin reduces levels of bad cholesterol and glucose, which are often elevated with excess weight.

A new study from Cardiff University, UK, 2014, which involved 180,000 people, showed that Metformin increases life expectancy not only in people with diabetes, but also in people without this disease.[1] Evidence has also been obtained of a slowdown in the aging process during treatment.[2]

Mechanism of action for weight loss[edit | edit code]

Mechanism of action (detailed)
Glucophage is used for weight loss due to its ability to accelerate the oxidation of fatty acids and inhibit fat synthesis [3] [4], although in various tissues it affects several points of application at once, which is expressed in diverse changes in cellular metabolism. It has also been proven that the absorption of carbohydrates from the digestive tract is reduced.

Glucophage activates AMP kinase, thereby reducing glucose levels as a result of suppressing its synthesis in the liver (suppression of gluconeogenesis). [5] Metformin also increases the sensitivity of insulin receptors to insulin, improves glucose uptake by muscles. [6] Reducing insulin when losing weight is necessary because this hormone promotes the deposition of consumed nutrients into fat, especially if the main problem area is the stomach. Immediately after eating, the level of glucose in the blood rises sharply, to which the pancreas reacts and produces insulin, which in turn forces the tissues to consume glucose, storing it in fats. That is why almost all weight loss diets recommend consuming less foods that cause a rise in blood sugar.

Finally, insulin causes hunger, so metformin helps suppress hunger when losing weight.[7]

The effectiveness of metformin decreases with increasing blood acidity, so some authors recommend eliminating exercise during the course of glucophage, since physical activity leads to the formation of lactic acid. However, recent studies have shown that exercise does not affect the overall acidity of the blood, so while taking metformin you can exercise without restrictions, thereby only increasing the effectiveness of the course.[8]

Application in bodybuilding[edit | edit code]

The mechanism of action of metformin has been established: inhibition of the mitochondrial respiratory chain, activation of AMP-dependent protein kinases, suppression of glucagon-induced cAMP formation, activation of protein kinase A, and suppression of the key anabolic mechanism mTOR through the RPS6 protein. [9][10][11]

The anabolic mechanism mTOR is very important for muscle growth, and it can be triggered by growth hormone, insulin, glucose, fatty acids, amino acids, etc. As a result, protein is synthesized in the muscles and cells begin to divide.

Thus, metformin and its analogues (glucophage) cause conditions in the body close to starvation or exhausting training, while muscle hypertrophy is almost impossible. Therefore, these drugs can only be used for weight loss, when muscle volume is of secondary importance. In addition, training is much more difficult and has little effect on the results, so these drugs are often taken without background physical activity.

Metabolic syndrome: possibilities of using metformin

RGMU named after N.I.
Pirogov M
metabolic syndrome X is a complex of interrelated disorders of carbohydrate and fat metabolism, as well as mechanisms of regulation of blood pressure (BP) and endothelial function, the development of which is based on a decrease in tissue sensitivity to insulin - insulin resistance (IR). Patients with metabolic syndrome, as a rule, seek medical help for arterial hypertension, type 2 diabetes mellitus or coronary heart disease, and therefore find themselves in the field of view of doctors of various specialties: therapists, cardiologists, endocrinologists.

Modern ideas about the pathogenesis of metabolic syndrome

In the development of IR, both the factor of genetic predisposition (impairment of receptor and post-receptor mechanisms of insulin signal transmission) and certain lifestyle features are important: excess nutrition, decreased physical activity.

As a result of a decrease in the sensitivity of target cells to the action of insulin, the absorption of glucose by insulin-dependent tissues (liver, muscles and adipose tissue) is disrupted and the preconditions are created for the development of hyperglycemia. However, due to a compensatory increase in insulin secretion by pancreatic b-cells, the concentration of glucose in the blood serum can remain normal for a long time. Thus, hyperinsulinemia

(GI) is the earliest and most constant marker of IR.

Having a powerful lipotropic effect, GI promotes an increase in body weight due to the accumulation of adipose tissue mainly in the upper half of the body and in the abdominal cavity (in the omentum and mesentery). Abdominal obesity

is one of the key points in the development of metabolic syndrome.
Free fatty acids (FFA), released in large quantities from abdominal adipose tissue, enter the portal vein into the liver, and then into the systemic circulation. In the liver, FFAs activate the processes of gluconeogenesis, which leads to an increase in glucose production by the liver
and the development of fasting hyperglycemia.
FFAs entering the systemic circulation disrupt the function of insulin receptors and aggravate IR (lipotoxicity effect)
.
Under these conditions, the amount of insulin secreted by b-cells may be insufficient to overcome the IR barrier and a relative insulin deficiency
.

The inability of b-cells to provide the required level of insulin hypersecretion leads to the development of carbohydrate metabolism disorders:

from a moderate increase in plasma glucose concentration, first on an empty stomach, then after a food load, and finally to type 2 diabetes mellitus.
In turn, hyperglycemia causes a deterioration in pancreatic b-cell function ( glucotoxicity effect
), completing a vicious circle.

Excessive intake of FFAs into the liver, which are substrates for the synthesis of triglycerides, leads to an increase in the production of very low density lipoproteins (VLDL). At the same time, the elimination of VLDL and low-density lipoproteins (LDL) in IR is reduced due to a decrease in lipoprotein lipase activity. The level of high-density lipoproteins (HDL), on the contrary, decreases, since their formation requires apoproteins and phospholipids released from VLDL and LDL during their lipolysis. In addition, with IR, changes occur in the composition of LDL, in which the protein content increases and the amount of cholesterol esters decreases. As a result, smaller and denser LDL are formed, characterized by a high degree of atherogenicity.

Thus, the main characteristics of dyslipidemia in metabolic syndrome are:

hypertriglyceridemia, increased levels of VLDL and LDL, changes in the structure of LDL and decreased levels of HDL.

It has been established that IR and compensatory HI affect a number of mechanisms of blood pressure regulation. GI has a prohypertensive effect by increasing the reabsorption of sodium and water by the kidneys, stimulating the centers of the sympathetic nervous system and activating Na+/H+ metabolism in vascular smooth muscle cells, which promotes the accumulation of Na+ and Ca2+ ions in them and increases sensitivity to the pressor effects of catecholamines and angiotensin II . Through the local renin-angiotensin vascular system, insulin stimulates the growth and proliferation of smooth muscle cells and promotes the development of remodeling processes (hypertrophy of the muscular lining of blood vessels, reduction in internal diameter), which is a factor in stabilizing elevated blood pressure levels.

In addition, with IR, the synthesis and secretion of nitric oxide (NO) by the vascular wall is disrupted. Considering that NO, in addition to its vasodilating effect, also has antiatherogenic properties, disruption of this mechanism can contribute to the development of not only hypertension, but also atherosclerosis.

Diagnostics

To diagnose metabolic syndrome, the presence of two of its three main manifestations is sufficient: abdominal obesity (the earliest clinical marker of IR), dyslipidemia, and impaired carbohydrate metabolism (Table 1).

Arterial hypertension is not an obligatory component of the metabolic syndrome, but is often detected in patients with IR. Thus, in type 2 diabetes mellitus, hypertension is registered in 50% of cases.

On the other hand, in patients with hypertension (HTN), manifestations of metabolic syndrome are present in more than 80% of cases. Elevated insulin concentrations have also been found to predispose to the development of hypertension. The results of long-term observation of people with hyperthyroidism showed that they are more likely than people with normal levels of insulin in the blood plasma to subsequently develop hypertension. At the same time, other manifestations of IR (dyslipidemia, impaired glucose tolerance or type 2 diabetes mellitus) also developed in parallel. Whether IR is an independent cause of the development of hypertension or contributes to the implementation of a genetic predisposition has not yet been definitively established.

In the future, the importance of IR in the pathogenesis of hypertension may recede into the background. Activation of the renin-angiotensin system, development of vascular remodeling processes, restructuring of kidney function and baroreceptor apparatus contribute to the “fixation” of elevated blood pressure levels. However, IR may contribute during headache and at later stages of its development. Activation of the sympatho-adrenal system under the influence of GI and increased levels of FFA leads to a disruption of the circadian rhythm of blood pressure with its insufficient decrease at night, i.e. to the development of nocturnal hypertension. In addition, IR contributes to the formation of a complex of additional risk factors (hyperglycemia, dyslipidemia, disorders of the fibrinolysis system), which significantly increase the total risk of developing cardiovascular complications.

Even when the only manifestation of IR is compensatory GI, the risk of developing cardiovascular complications is already significantly increased. The appearance of IGT is accompanied by a sharp jump in the frequency of macrovascular complications, and by the time chronic hyperglycemia develops, which meets the diagnostic criteria for diabetes, many patients already have clinical manifestations of coronary artery disease, including a previous myocardial infarction. This circumstance emphasizes the need for timely diagnosis of metabolic syndrome X and correction of associated metabolic disorders.

Treatment

A prerequisite for successful treatment of patients with MS is lifestyle changes aimed at reducing body weight (Table 2). Considering that non-drug approaches are not feasible for most patients, the use of drugs that promote weight loss and drugs that restore tissue sensitivity to insulin in the treatment of these patients is of particular interest.

Thiazolidinediones are a relatively new class of antidiabetic drugs, the main mechanism of action of which is to reduce tissue IR, mainly myocytes and adipocytes. However, the widespread use of drugs in this group is currently limited by the presence of a hepatotoxic effect.

Another group of drugs that can increase tissue sensitivity to insulin are biguanides (phenformin, buformin and metformin). Due to the high risk of developing lactic acidosis with the use of phenformin and buformin, the only biguanide currently used is metformin (Siofor®, Berlin-Chemie).

Metformin

The effect of metformin on glucose metabolism is mediated by three main mechanisms: improving the utilization of glucose by tissues, reducing glucose production by the liver and inhibiting glucose absorption in the small intestine. As a result, metformin effectively reduces blood glucose levels both on an empty stomach and after a meal.

Unlike sulfonylurea derivatives, metformin does not have a stimulating effect on insulin secretion, therefore treatment with metformin is not accompanied by the risk of developing hypoglycemic conditions and weight gain. On the contrary, metformin promotes stabilization and even some weight loss in obese patients (Table 3).

Information about the effect of metformin on blood pressure levels is quite contradictory. Giugliano D. et al. (1993) noted a significant hypotensive effect of metformin in hypertensive patients with obesity and type 2 diabetes mellitus. However, Snorgaard O. et al. (1997) found no effect of metformin on blood pressure in patients with both normal and overweight.

We studied the effect of metformin on the 24-hour blood pressure profile in overweight hypertensive patients. 11 patients had abdominal obesity combined with impaired glucose tolerance, 15 patients had abdominal obesity and normal glucose tolerance, and 12 patients had peripheral obesity without signs of impaired carbohydrate metabolism. After 6 weeks of treatment with metformin at a daily dose of 1500–1700 mg, a decrease in blood pressure levels according to the results of daily monitoring was noted only in patients with impaired glucose tolerance. In this group of patients, a decrease in systolic blood pressure (SBP) by 8.4 (1.1–13.6) mmHg was noted. Art. during the day and by 10.7 (2.2–15.5) mm Hg. Art. at night, as well as a decrease in load indicators of both blood pressure and diastolic blood pressure (BPd) at night. The ADS time index decreased by 16.7 (4.0–54.6)%, the ADD time index – by 68.2 (42.3–92.3)%, the ADS area index – by 66.2 (49.1 –71.1)%, area index ADD – by 88.6 (1.3–100.0)%. Changes in the daily blood pressure profile during treatment with metformin occurred in parallel with the dynamics of other manifestations of IR (body weight, glycemic levels, concentrations of insulin and uric acid in the blood plasma).

Metformin is contraindicated in patients with chronic renal failure, hypoxic conditions of various etiologies (anemia, cardiac or respiratory failure, infectious conditions), as well as alcohol abuse and liver dysfunction (increased ALT and AST by more than 2 times). The incidence of lactic acidosis in patients taking metformin is 5–9 cases per 100 thousand people per year, which is almost 20 times less than when treating with buformin and phenformin.

The results of a multicenter prospective study on the primary prevention of diabetes complications (United Kingdom Prospective Diabetes Study, UKPDS) completed in 1998 demonstrated the effectiveness and safety of long-term treatment with metformin.
In patients with type 2 diabetes with obesity, there was a 36% reduction in all-cause mortality, a 32% reduction in the incidence of all diabetes complications, and a 30% reduction in the incidence of macrovascular complications of diabetes, including a 39% reduction in the risk of myocardial infarction. Moreover, among 342 patients who took metformin at a daily dose of 1700–2550 mg/day for an average of 10.7 years, not a single case of lactic acidosis was recorded. The results of this study proved the feasibility of using metformin for the treatment of patients with type 2 diabetes with obesity. According to our data and the results of a number of other studies, it seems promising to prescribe metformin (Siofor) at earlier stages of the development of metabolic syndrome: in patients with impaired glucose tolerance and in patients with mild hypertension with manifestations of IR (in combination with measures to change lifestyle ). References:
1. Reaven GM Role of Insulin Resistance in Human Disease. Diabetes 1988; 37(12): 1595–1600.

2. Almazov V.A., Blagosklonnaya Ya.B., Shlyakhto E.V., Krasilnikova E.I. The role of abdominal obesity in the pathogenesis of insulin resistance syndrome. Therapeutic Archive 1999; 10: 18–22.

3. Moiseev V.S., Ivleva A.Ya., Kobalava Zh.D. Hypertension, diabetes mellitus, atherosclerosis are clinical manifestations of metabolic syndrome X. Bulletin of the Russian Academy of Medical Sciences 1995; 5:15–8.

4. Kobalava Zh.D., Kotovskaya Yu.V. Features of the daily blood pressure profile in hypertensive patients with metabolic disorders. Clinical Pharmacology and Therapy 1995; 4(3): 50–1.

5. Crofford OB Metformin. N Engl J Med 1995; 333(9): 588–9.

Metformin –

Siofor (trade name)

(Berlin-Chemie AG)

Glucophage course for weight loss[edit | edit code]

Glucophage (metformin) is a safe drug and is approved by official medicine for use by healthy people for weight loss.

• Follow a diet to lose weight
• Eliminate fast carbohydrates
• Metformin for weight loss is taken immediately before meals or during meals
  , the dose is selected individually. Most often, 500-850 mg is prescribed, 2-3 times a day (maximum dose no more than 3000 mg/day).
• If you have diarrhea, it means you are overindulging in carbohydrates.
• If you experience nausea after taking metformin, reduce your dose. Slowly increasing the dose may improve gastrointestinal tolerability.
• Perform systematic aerobic training for maximum effectiveness of the course
• If, after reducing the dosage, the symptoms of side effects do not disappear, stop taking the drug and immediately consult a doctor, as there is a possible risk of developing lactic acidosis, which can be fatal!!! If signs of lactic acidosis appear, the patient should be urgently hospitalized and, by determining the lactate concentration, confirm the diagnosis. The most effective measure for removing lactate and metformin from the body is hemodialysis. Symptomatic treatment is also carried out.

The duration of use of the drug should not exceed 18-22 days, after which a break of 1-2 months is required. A shorter break leads to adaptation of the body, and metformin is not able to fully exhibit the properties of a fat burner. The course must be agreed with a medical specialist.

Metformin in bodybuilding

The use of Metformin by bodybuilders as a sports drug is based on its beneficial effects on the body, expressed in:

1. Suppressing hunger.
2. Increased receptor sensations.
3. Increasing muscle glucose consumption.
4. Increased life expectancy.
5. Slow aging.
6. Reducing the level of glucose and cholesterol.

Scientists manage to prove the fat-burning effects of the drug on a citizen even in everyday life, without taking into account the constant training process, with the elimination of the carbohydrate window.

Side effects and harm to health[edit | edit code]

Do not take Glucophage for weight loss if you have:

• Kidney diseases accompanied by insufficiency
• Heart failure
• Another disease in which the acidity of the blood is increased
• Do not take Glucophage with other glucose-lowering agents or other medications without consulting a doctor.

Possible side effects of glucophage (rare):

• Diarrhea (need to reduce carbohydrate intake)
• Headache (usually goes away quickly)
• Abdominal cramps
• Nausea (need to reduce metformin dose)
• Increased gas formation (it is necessary to reduce the amount of carbohydrates consumed)
• Lactic acidosis (in the presence of predisposing diseases), (do not combine with alcohol!!! risk of developing lactic acidosis)

As a rule, side effects of metformin occur at the beginning of the course, and then quickly pass.[12]

Notes[edit | edit code]

1. https://www.medicalnewstoday.com/articles/280725.php
2. https://www.medicalnewstoday.com/articles/277679.php
3. Bailey CJ, Turner RC. Metformin. N Engl J Med. 1996;334(9):574–9. doi:10.1056/NEJM199602293340906.
4. Diamanti-Kandarakis E, Christakou CD, Kandaraki E, Economou FN. Metformin: an old medication of new fashion: evolving new molecular mechanisms and clinical implications in polycystic ovary syndrome. Eur J Endocrinol. 2010 Feb;162(2):193-212. doi: 10.1530/EJE-09-0733. Epub 2009 Oct 19.
5. Kirpichnikov D, McFarlane SI, Sowers JR. Metformin: an update. Ann Intern Med. 2002;137(1):25–33. PMID 12093242
6. Musi N, Hirshman MF, Nygren J, et al. Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Diabetes. 2002;51(7):2074–81. doi:10.2337/diabetes.51.7.2074
7. G Paolisso, L Amato, R Eccellente, A Gambardella, MR Tagliamonte, G Varricchio, C Carella, D Giugliano, F Donofrio. Effect of metformin on food intake in obese subjects. European Journal of Clinical Investigation 28: 6(JUN 1998):441-446
8. U Gudat, G Convent, L Heinemann. Metformin and exercise: No additive effect on blood lactate levels in healthy volunteers. Diabetic Medicine 14:2 (FEB 1997):138-142.
9. Rena G, Pearson ER, Sakamoto K (September 2013). "Molecular mechanism of action of metformin: old or new insights?". Diabetologia 56(9):1898–906.
10. Burcelin R (July 2013). "The antidiabetic gutsy role of metformin uncovered?". Gut 63(5):706–707.
11. Madiraju, Anila K.; Erion, Derek M.; Rahimi, Yasmeen; Zhang, Xian-Man; Braddock, Demetrios T.; Albright, Ronald A.; Prigaro, Brett J.; Wood, John L.; Bhanot, Sanjay; MacDonald, Michael J.; Jurczak, Michael J.; Camporez, Joao-Paulo; Lee, Hui-Young; Cline, Gary W.; Samuel, Varman T.; Kibbey, Richard G.; Shulman, Gerald I. (21 May 2014). "Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase." Nature 510(7506):542–546.
12. Drug Facts and Comparisons 2005. St. Louis, Mo: Facts and Comparisons; 2004. ISBN 1574391933