The Role of Metformin in the Treatment of Type 2 Diabetes and

Topic: Mutual association and connection study between the obesity, visceral obesity, insulin desensitation (with the conesquential hyperinsulinemia), type 2 diabetes, dyslipoproteinemia and anthropometric characteristics of the patients with the metabolic syndrom are the subject of many epidemiological studies. However, it is noticed that there are certain disagreements and contradictions in defi ning the anthropometric and metabolic risk factors for the occurance of the cardiovascular, cerebrovascular and other vascular diseases, especially in population of the obese patients with type 2 diabetes. Topic position in medical public: Theoretically, metformin achieves a good glicoregulation preciselyinthe visceral obese patients. This is explained by a higher glucometabolic activity of the visceral adipose tissue in regard to the subcutenaus tissue. Futher action: More effi cient reduction of the visceral adipose tissue inpatients with achieved better glucoregulation, under the aff ection of the metformin is a result of its complex eff ect mechanism. Metformin plays a signifi cant role in the reduction of the cardiovascular risk that comes from a higher visceral obesity, parallel to the achievement of the good glicoregulation in obese, type 2 diabetes patients.


TOPIC
For the obesity development, as well as for the development of the mentioned metabolic deseases, answering how or in which way does it come to the increasement of the body adipose tissue has a great clinical signifi cance.Th ere are two ways of increasing body adipose tissue in obesity -proliferation or adipose hypertrophy.

TOPIC POSITION IN MEDICAL PUBLIC
Th ere are reports that say that the adipose in type 2 diabetes persons and with positive calory balance, compared to the obese persons without the diabetes, have lower chance for fat storage with cellular proliferation because of the decreased genes expression responsible for the adipogenesis [1,2].However, clinical significance in the obesity patogenesis does not reffl ect only in the fact how, but also where does the body adipose accumulate and store [1,3,4].According to the place -region where the adipose accumulates, the adipose tissue is divided to the visceral and subcutenaus adipose tissue.Th e visceral adipose tissue is adipose more doi:10.5937/hpimj1602409Vmetabolically active compared to the subcotenaus adipose tissue.Bigger metabolic activity of the visceral adipose tissue, compared to the subcutaneous, is refl ected in the schedule and the amount of the receptors in the adipocytes, disballance between the lipogenesis and lipolysis, diff erence in the secretion of the adipokines, cytokines and other mediators of infl ammation, as well as the diff erence in the hormone and protein release [3].
Th e appearance of the visceral adipose tissue in the omentum, mesentery, liver, muscles, pericardially and other organs is marked as ectopic and oft en combines with the high insulin concetration in blood and insulin resistence that is measured by hyperinsulinemic euglycemic clamp or other techincs that measure fast responses of the aimed organs, primarily muscels, to the insulin action [5,6].It is also shown that the acummulation of the visceral adipose tissue in abdomen is combined with the accelerated aterosclerosis development [7].
Th e connection od the insulin resistence and excess accumulation od the visceral adipose tissue still has not been clarifi ed.Th ere are few theories about the connection between the insulin resistence and overaccummulation of the visceral adipose tissue, one of which is "portal" or "lipolitic" theory.Th is theory implies that the intra-abdominal visceral adipose tissue has anatomic and metabolic charachteristics that are unique compared to the adipose tissue of other localization, and, which is very interesting, it is especially regarded to the regions that are drained via the portal circulation (omental and mesenteric adipose tissue) [8].
According to this theory, the connection between the insulin resistence and visceral adipose tissue is in the fact that the visceral adipose tissue has a bigger activation of the β3 adrenergic receptor with polymorphism of the gene allele responsible for the expression of β3 receptors [9].Bigger β3 receptors activity leads to the increasement of the lipolitic activity, circulating non-esterfi ed adipose acids increase, dislipoproteinemia (increased levels of triglycerides with reduced levels of high-density cholesterol) and insulin resistance with a consequent reduction in glucose tolerance.
Alternative to the "portal theory" is "hormone-infl ammatory theory" in whose base is that the visceral adipose tissue is rich in macrophages that increasingly produce pro-infl ammatory cytokines, such as tumor necrosis factor alpha (TNF-α) and interleukin-6, while leading to the decreased protective adipokines secretion, among which adiponectin should be noted [10].
Also, it was demonstrated in animal models that visceral fat aff ects hormone production higher resistin, which got its name based on being established that it causes resistance to insulin [11].For mentioned abdominal visceral fat it has been presented, both in humans and in animal models, that these tissues compared to the subcutaneous adipose tissue produce signifi cantly more interleukin-6, [12] while the excessive secretion of TNF-α could be produced only in animals, but not in the human population [13].It has been shown that interleukin-6 possess great induction potential of C-reactive protein (CRP) in the liver, so the interleukin-6 and CRP have become important predictors of visceral obesity, insulin resistance syndrome and type 2 diabetes [14].Studies that have pointed to the importance of the links between genetic factors, excessive food intake, reduced physical activity, insulin resistance, visceral obesity, infl ammation and endothelial dysfunction of blood vessels in the development of atherosclerosis in patients with type 2 diabetes are especially important [15].Also in animal models has been shown that by specifi c inhibitors of tyrosine kinases (substances among which there are also some drugs that are mainly used in certain leucosis treatment, but are also being tested the treatment of type 2 diabetes resistant to other forms of treatment) reduces insulin resistance and insulinemia [16].It was found that their use increases the takeover and use of glucose, associated with the reduction of proinfl ammatory cytokines and proliferation of macrophages in the mesenteric adipose tissue.All of this was accompanied by a reduction of the insulin receptor substrate 1, which has be proven, next to the tyrosine kinase of the insulin, that can be phosphorylated and serine / threonine kinases, activated by mediators of chronic infl ammation or stress.
Certain newly discovered substances with hormonal action, such as visfatin, which is largely secreted in visceral adipose tissue, has been shown to act like insulin via a tyrosine kinase, and that visfatin and insulin have equal insulin eff ect [17].It has also been suggested that there is no competition between visfatin and insulin, so it was concluded that they bind to diff erent subunits of the insulin receptor.
Great advance in the research of the pathogenetic link between insulin resistance, central type obesity, intra-abdominal obesity, chronical infl ammation, atherosclerosis, dyslipoproteinemia and type 2 diabetes, has an increasing clinical importance, for at least two reasons.Th e fi rst reason certainly is awareness of the role of intra-abdominal visceral adipose tissue in insulin resistance and type 2 diabetes, which led to the improvement and development of new anthropometric measurement methods and visceral obesity diagnosis in the general human population of diff erent age, gender, ethnicity and race [18,19 ].While some authors emphasize the importance of the morphological measurement of visceral adipose in patients with type 2 diabetes with nuclear magnetic resonance imaging, computed tomography or ultrasound, [19] others emphasize the ease of measurement of waist circumference as a measure of abdominal obesity, but also the most important predictor of vascular events in these patients [20].Th e latter authors showed that in patients with type 2 diabetes and waist circumference > 90 cm (for men) or > 85 cm (for women), as well as with the level of serum triglycerides ≥ 2 mmol/L (hypertriglyceridemic waist), multiply increases the risk of a cardiovascular disease.
Second, but not less important reason to clarify the role of increased visceral obesity in type 2 diabetes is that these fi ndings started to apply critically in monitoring the eff ects of pharmacotherapy drugs in type 2 diabetes and its prevention, but also in control of its nonpharmacological treatment, which primarily involves the implementation of strict dietary measures with the programmed physical activity increase [21][22][23].
In newly diagnosed type 2 diabetes patients fi rst step in the treatment is a change of lifestyle that is refl ected in the reduction of patient body weight (if overweight) and increasing physical activity.However, such therapeutic measure, even if it leads to a reduction in glycated hemoglobin (HbA1c) by 1-2%, it becomes insuffi cient to maintain the achieved glucometabolical eff ect already in the fi rst year of non-pharmacological intervention [24].
Th e next step in the type 2 diabetes treatment is conducting therapy with metformin, which is only contraindicated in patients with renal insuffi ciency (creatinine conwww.hophonline.orgcentrations > 132 mmol/L for men and > 124 mmol/ L for women) [25].Th e expected reduction in the level of HbA1c in patients with type 2 diabetes on metformin monotherapy is 1% -2% [26,27].Metformin is an oral anti-diabetic agent from the group of biguanides.Th e bioavailability of metformin is 50% -60%.It is absorbed mainly from the small intestine, and estimated time of resorption him 0.9 hours to 2.6 hours.Aft er 1-2 hours from the oral dose taken from 500 mg -1000 mg, maximum drug concentrations in plasma are 1-2μg/mL.About 90% of metformin is eliminated in the urine within 12 hours.Is evenly distributed in all tissues, in concentrations close to those in the peripheral plasma, while it achieves high concentrations in the liver and kidneys.Metformin achieves the highest concentrations in the salivary glands and in the intestine wall.
Th e metformin treatment increases insulin sensitivity, which is refl ected by reducing fast glucose and insulin circulating concentrations.Metformin has no eff ect in the absence of insulin [28].In patients with type 2 diabetes, the eff ect in reducing the glycemia by metformin is mainly explained by the mechanism of reducing hepatic production and increasing peripheral glucose uptake.Several other mechanisms of metformin action also contribute to the reduction of blood glucose, such as increasing intestinal glucose utilization and reducing adipose acid oxidation.Metformin decreases glucose production in the liver in patients with type 2 diabetes, in which it must be borne in mind that this is a very important mechanism of action on reducing fast glucose [29].
In isolated liver cells metformin increases suppressing gluconeogenesis by insulin and lowers glucagon-stimulated gluconeogenesis [30].In most studies, metformin also increases the availability of glucose which was confi rmed by hyperinsulinemic, euinsulinemic clamp or hyperglycemic clamp procedures in patients with type 2 diabetes, where the muscles were central site of metformin action [27].In animals, metformin increases muscle glucose takeover stimulated by insuline, resulting in a glycogen synthesis increase and the glucose oxidation in peripheral tissues, but not in increasing the production of lactate [31].
Metformin also increases the takeover and oxidation of glucose in adipose tissue, and equally well encourages lipogenesis [32].However, the metformin in vitro eff ect in the peripheral tissues depends on the amount of its concentration, so it's very slow at the beginning.Metformin increases insulin binding to its receptors by increasing the phosphorylation and the tyrosine kinase activity on the insulin receptors in vivo, so this could lead to a reduction in plasma glucose, which could not be reproduced in vitro [33].It also increases the possibility of translocation of the GLUT-1 and GLUT-2 glucose transporter isoforms in various types of cells [34] and thus prevents the occurrence of the insulin resistance in hepatocytes and adipocytes cultures, which are exposed to high concentrations of insulin for a longer period of time [35].
In the case of long-term use, metformin reduces the concentration of plasma lipoproteins (particularly triglycerides, and, to a lesser degree, cholesterol) in patients with hyperlipoproteinemia, especially Type IV, and II-B [36].It is considered to be the drug of choice in obese patients with type 2 diabetes, primarily because it does not increase the body weight of patients, but on the contrary, it can reduce adipose tissue [29].
A signifi cant contribution to the elucidation of the mechanism of the metformin action was given by Zhou et al 2001 [37].Th ey showed that metformin activates the hepatic and muscle adenosine monophosphate-activated protein kinase (AMPK), an enzyme that normally resides adenosine monophosphate-activated, being result of the adenosine triphosphate decomposition.AMPK also gets triggered by the cell signaling for increased energy requirements.Hepatic AMPK activation results in phosphorylation and inhibition of acetyl coenzyme A carboxylase, which catalyzes lipogenesis.Since furthermore there is a blockage in the synthesis of adipose acids, their oxidation is being stimulated.In addition, the activation of hepatic AMPK reduces the expression of a sterol-regulatory elementbinding-protein-1 (SREBP-1), normally an important transcription factor that participates in the pathogenesis of insulin resistance, dyslipidemia, and type 2 diabetes.Reduction of SREBP-1 expression leads to a decrease of gene expression of the lipogenic enzymes that later contribute to the reduction of synthesis of triglycerides and hepatic steatosis occurence.
However, it must be noted that although there is a common view that metformin reduces obesity, with special emphasis on visceral obesity in patients with type 2 diabe-tes, there is a lack of studies that could confi rm this and / or possibly show the correlation of the reduction of abdominal visceral obesity with a parallel increase in insulin sensitivity, glikoregulation recovery or dislipoproteinemia correction in type 2 diabetes patients.
In our earlier work, we showed that in obese type 2 diabetes patients, metformin reduces unproductive fast insulin secretion and increases its productive postprandial secretion [38].It also increases the suppression of gluconeogenesis by insulin and lowers glucagonstimulated gluconeogenesis [30].Metformin increases takeover and oxidation of glucose inadipose tissue [32].Under the action of metformin in omental adipocytes, the expression of SREBP-1 inhibits with an increase in AMPK [39].
All these mechanisms of metformin action, showed that it has a great potential in reducing visceral obesity that combines with insulin resistance.Th e metformin impact on AMPK increase and SREBP-1 inhibition in visceral adipose tissue, is particularly highlighted in the review reports as a potentially important mechanism in the prevention and reduction of cardiovascular risk in patients with type 2 diabetes and insulin resistance [40].
On the other hand, there are few and contradictory reports about the impact of other oral antidiabetics on the visceral obesity in patients with type 2 diabetes.Th ere are only individual detailed reports that certain drugs called insulin sensitizers, such as thiazolidinediones, aft er the fi rst three months of application in patients with type 2 diabetes, although leading to a reduction in HbA1c levels, lead to an increase in overall obesity, increase of subcutaneous adipose tissue, with no changes in visceral obesity [23].Our previous results indicate that the three-month application of metformin in obese patients with type 2 diabetes, and patients with impaired glucose tolerance more oft en led to normalization of HbA1c levels in patients with pretherapy level of HbA1c < 8% compared to patients with HbA1c ≥ 8% [41,42].

FURTHER ACTION
In spite of the clear implications that metformin is the drug of choice in the treatment of obese patients with type 2 diabetes, there is a lack of the pharmacoepidemiological and clinical studies that document the eff ects of metformin on the redistribution of body adipose as well as its impact on the reduction of abdominal and / or visceral obesity.Generally speaking, the eff ects of oral antidiabetic agents in diff erent forms of obesity are imperative for further research, as the current good clinical practice reduced to monitoring of metabolic and anthropometric variables that defi ne obesity, including abdominal obesity, without the actual insight into the visceral obesity.