Tight glycaemic control may prevent neuropathy in type 1 but not type 2

glycaemic control

The importance of glycemic control in the prevention of diabetic nephropathy in type 2 diabetes
Issue of the magazine: may 2013

L. V. Nedosugova
Department of endocrinology FPPOV Sechenov Moscow state medical UNIVERSITY

The article discusses the modern approach to the diagnosis, treatment and prevention of diabetic nephropathy (DN), which develops against the background of type 2 diabetes. It is emphasized that glycemic control is a key factor in preventing the development of DN and aggravating existing symptoms. As a means of glycemic control, especially in the case of severe DN, gliquidone (Glurenorm ® ) can be used – a preparation of sulfonylureas of the 2nd generation. The advantages of the drug include a fast half-life, metabolism in the liver and excretion through the hepatobiliary system.

The value of glycemic control for the prevention of diabetic nephropathy in type 2 diabetes mellitus
Endocrinology Department, PPED Faculty of I.M.Sechenov FMSMU

The paper discusses current approaches to diagnostics, treatment and prevention of diabetic nephropathy (DN) due to type 2 diabetes mellitus. It underlines that glycemic control is considered to be the key factor of DN prevention, as well as stopping of already acquired DN symptoms to become worse. For the proper glycemic control, especially in severe DN, gliquidonum (Glurenorm ® ) might be prescribed. This drug belongs to the 2nd generation of sulfonylureas presenting such benefits as fast elimination half-life, hepatic metabolism, and elimination via hepatobiliary system.
Keywords: diabetic nephropathy, type 2 diabetes mellitus, glycemic control, gliquidonum, Glurenorm.

Information about the author:
Lyudmila nedosugova-MD, Professor of the Department of endocrinology of the FIRST Sechenov Moscow state medical UNIVERSITY

Diabetic nephropathy (DN) is a specific kidney lesion in diabetes mellitus, accompanied by the development of nodular or diffuse glomerulosclerosis, the end stage of which is characterized by the development of chronic renal failure (CRF). Diabetic nephropathy – the most common cause of chronic kidney failure in chronic kidney disease (CKD) requiring hemodialysis-accounts for more than 50% of all new cases of CRF [1]. In the modern world, there is a progressive increase in the prevalence of CRF among patients with type 2 diabetes mellitus (DM), which may be due to both the high prevalence of this type of diabetes, and the fact that due to more intensive treatment of arterial hypertension (AH) and coronary heart disease (CHD), patients with type 2 diabetes live longer and “live” to develop DN and CRF [2]. It is well known that patients with type 2 diabetes have a 4-5-fold risk of cardiovascular mortality compared to the General population, even before the development of CKD, but the survival rate of these patients falls catastrophically when DN progresses to the end stage. The five-year survival rate of patients with type 2 diabetes with CRF is no more than 6% in Germany and is comparable to the survival rate of patients with metastatic carcinoma of the gastrointestinal tract [1]. These data explain the need for early detection of patients at high risk of developing nephropathy, and intensive measures aimed at preventing the progression of CRF.
Data from epidemiological studies show that the risk of developing DN increases in individuals with inadequate glycemic control [3]. 20-40% of patients with type 2 diabetes develop diabetic nephropathy. The risk of developing nephropathy is definitely determined by genetic factors. According to a study of the development of DN in two successive generations of Pima Indian offspring (a natural model of genetically determined type 2 diabetes), the risk of proteinuria increased from 14% if none of the parents had proteinuria, to 23% if one of the parents had proteinuria, and to 46% if both parents who suffered from type 2 diabetes had proteinuria [4]. Genetic factors can directly affect the development of DN and/or can be grouped with genes that affect the development and course of cardiovascular diseases.
However, as mentioned above, diseases of the cardiovascular system are the main cause of death in patients with type 2 diabetes. At the same time, in 80% of cases, the cause of death is atherosclerosis of the coronary, cerebral and peripheral vessels. Ischemic nephropathy, which develops as a result of atherosclerotic lesions of the renal arteries, is currently recognized as one of the most common causes of renal failure in elderly patients with type 2 diabetes. The high prevalence of ischemic nephropathy in type 2 diabetes can be considered as a result of involvement of the renal arteries in accelerated generalized atherosclerosis, which is based on metabolic, rheological and hemodynamic disorders, largely provoked by hyperglycemia [5].
The key role of hyperglycemia in the Genesis of progression of micro-and macroangiopathies in diabetes mellitus is generally recognized. This is proved by numerous randomized studies that have demonstrated the effectiveness of intensive glycemic control for the prevention of diabetic vascular complications [6-8]. Most researchers are inclined to the initiating role of hyperglycemia in the development of initial structural changes in the renal glomeruli, which primarily concern the development of intra-glomerular hypertension, which occurs as a result of relaxation of the afferent (bringing) and narrowing of the efferent (carrying) arterioles. The oxidative stress that develops as a result of hyperglycemia, characterized by excessive production of free oxygen radicals (or reactive oxygen species – ROS) and a decrease in the activity of the antioxidant system, contributes to glucose self-oxidation. The end product of glucose self-oxidation is diacylglycerol – DAG), a powerful stimulator of protein kinase C activity.Activation of protein kinase C (PKS) stimulates the secretion of vasoactive prostanoids, which contribute to intra-glomerular hyperfiltration, exacerbating hemodynamic disorders in the glomerulus. Reduced endothelial barrier function is an early manifestation of diabetic angiopathy. In normoglycemia, the endothelium performs an important function of preventing macromolecules, such as albumin, from penetrating the endothelial barrier. Activation of PKS in hyperglycemia conditions causes a reduction of cytoskeletal proteins, which leads to a change in the shape and organization of endothelial cells and macromolecule leakage, which is manifested, in particular, by macular edema on the fundus and proteinuria [9].
Protein kinase C (PKS) also plays an important role in activating the expression of the vascular endothelial growth factor (VEGF) gene, also known as vascular permeability factor. Sefr is a homodimeric glycoprotein secreted by vascular wall smooth muscle cells (HMCS), which has a potential effect on vascular permeability and angiogenesis. Expression of the sefr gene in vascular wall smooth muscle cells (GMCSS) increases in the presence of high glucose concentrations through PKC-dependent mechanisms, including activation of nuclear transcription factor kB (NF-kB), protein kinase activated by mitogens p38, and stress-activated protein kinases [10]. The level of EGFR in the blood serum is significantly increased in patients with diabetes mellitus complicated by diabetic retinopathy and nephropathy compared to healthy volunteers and patients with diabetes mellitus without retinopathy and albuminuria [11]. PKS plays a major role in the contraction of vascular wall smooth muscle cells (HMCS), as well as in the growth and differentiation of HMCS and cardiomyocytes [12, 13]. Apoptosis of smooth muscle cells of the vascular wall induced by oxygen free radicals is also a process dependent on the activity of PKS [14].
As mentioned above, activation of protein kinase C releases nuclear transcription factor kB (NF-kB), which regulates the expression of a large number of genes, including growth factors and Pro-inflammatory cytokines. Therefore, patients with DN have increased levels of transforming growth factor b1, Pro-inflammatory cytokines, especially interleukins 1, 6 and 8 (IL-1, IL-6, IL-8) and tumor necrosis factor a. Transforming growth factor b1 contributes to cellular hypertrophy and increased collagen synthesis. IL-1 changes intraclubular hemodynamics, increases the expression of adhesive molecules, vascular endothelial permeability, and the production of hyaluronic acid [15]. IL-6 leads to thickening of the glomerular basement membrane, increased endothelial vascular permeability, and proliferation of mesangial cells. IL-8 is associated with cellular apoptosis and the production of tumor necrosis factor a (TNF-a). In turn, TNF-a acts as a direct damaging renal factor affecting both renal hemodynamics, endothelial permeability, and apoptosis. TNF-a has also been shown to play an important role in the development of early kidney hypertrophy and hyperfunction in diabetic nephropathy [16, 17].

Hyperglycemia also causes non-enzymatic glycation of proteins with the formation of end products of irreversible glycation (CPNG), which leads to a violation of the configuration of structural proteins of the glomerular basement membrane in the kidneys, inhibition of the metabolism of the main protein components of renal structures, which is accompanied by an increase in the volume of the mesangial matrix and thickening of the glomerular vascular basement membranes [5]. The end products of irreversible glycation (CNG) and excessive production of oxygen free radicals in hyperglycemia also contribute to glycation and increased oxidability of LDL, as a result of which the latter cause infiltration of the mesangium by monocytes and macrophages that produce cytokines and growth factors. Oxidized LDL is captured by macrophages, forming lipid inclusions in the glomerular mesangium, which reduces the negative charge of the basement membrane and increases its permeability to protein.
The development of DN occurs in several stages, and from the manifestation of DM to the clinical manifestations of CRF takes an average of 15 to 25 years. The most detailed stages of DN development are presented in the Mogensen C. E. classification (table 1) [18].
Functional changes are noted in the nephron at the level of the renal glomerulus even before the development of clinical manifestations already in the debut of type 2 diabetes and are manifested by hyperfiltration, hyperperfusion and glomerular hypertrophy, leading to renal hypertrophy. These functional changes are caused by hemodynamic disorders in the glomerulus, which are manifested in the development of intra-glomerular hypertension. As mentioned above, the starting point for the development of intravascular hypertension is hyperglycemia and the oxidative stress caused by it.
Subsequent initial structural changes, manifested in thickening of the glomerular basement membrane, expansion of the mesangium against the background of increased intra-glomerular pressure and increased glomerular filtration rate (GFR), also do not have clinical manifestations and develop gradually within 2-5 years from the onset of DM. The role of hyperglycemia and the oxidative stress caused by it at this stage also remains key, since an increase in the activity of protein kinase C leads to the expression of transforming growth factor b1 and IL-6, which cause the development of these morphological changes.
Initial clinical manifestations of DN are characterized by the appearance of permanent microalbuminuria (from 30 to 300 mg / s) against the background of normal or slightly elevated GFR. Microalbuminuria (MAU) is the result of developing endothelial dysfunction, the pathogenesis of which in DM is associated with activation of vascular endothelial growth factor (VEGF) and interleukin 1 (IL-1), which increase vascular permeability, which promotes the penetration of plasma proteins and lipids through the glomerular basement membrane. As mentioned above, the main role in increasing the expression of these factors belongs to protein kinase C, activated by diacylglycerol in hyperglycemia.
However, the appearance of microalbuminuria is not yet a predictor of the development of proteinuria as the next stage of DN. In the study of O. R. Wirta [19], it was shown that after 6 years of observation of patients with type 2 diabetes who had microalbuminuria, 35% had a decrease in albuminuria to normal, 46% had albumin excretion in the urine remained at the same level, and only 19% of patients developed proteinuria. Based on functional and morphological studies of kidney tissue in type 2 diabetes at the stage of microalbuminuria, it is concluded that microalbuminuria reflects not so much structural changes in the glomeruli, but rather is a marker of increased cell permeability to albumin and a manifestation of systemic damage to the microvascular bed [20].
In 30-40% of patients with type 2 diabetes mellitus, microalbuminuria (MAU) is detected at diagnosis. Microalbuminuria is not only a predictor of renal pathology (as in the case of type 1 diabetes), but also an important marker of developing atherosclerosis and premature death [21]. Increased cardiovascular mortality may be a consequence of endothelial dysfunction, a sign of which is MAU. 55-60% of patients with type 2 diabetes with MAU die from heart attacks and strokes, and only 3-5% – from uremia. The development of MAU in patients with type 2 diabetes is closely associated with disorders in the system of hemostasis, coagulation, and glucose and lipid metabolism.
We should not forget that in 90% of patients with type 2 diabetes, arterial hypertension (AH) is present even before the disease manifests and often precedes kidney pathology. However, hypertension is one of the most important factors contributing to the development and progression of DN. This is due to the fact that the expansion of the afferent glomerular arterioles ensures unhindered transmission of high systemic blood pressure to the glomerular vessels, which increases the already high gradient of intra-glomerular pressure. This leads to an increase in the activity of the renin-angiotensin system and the concentration of the most powerful vasoconstrictor factor – angiotensin II (ATII), which aggravates intravascular hypertension. Obviously, it is at this stage that the interaction of metabolic and hemodynamic disorders occurs. It is assumed that a prolonged increase in blood pressure in the glomerular vessels may contribute to the hyperproduction of collagen and its accumulation in the mesangium region, which leads to an increase in the mesangial matrix and initial sclerotic processes [22]. On the other hand, increasing the level of transforming growth factor b1 (TGF-b1) also contributes to cellular hypertrophy and increased collagen synthesis. The result is a violation of the architectonics and permeability of the glomerular basement membrane, which causes the penetration of proteins, lipids and other plasma components through it, which, being deposited in the mesangium, also contribute to the processes of sclerosis. The clinical manifestation of progressive nephropathy is the appearance of permanent proteinuria, indicating that 50-75% of the glomeruli are sclerosed, and the process in the kidneys has become irreversible. From this point on, the glomerular filtration rate steadily decreases (10 ml / min / year).
The increase in the process of sclerosis in the glomeruli leads to a progressive decrease in the filtration function of the kidneys, which ultimately leads to the development of terminal renal failure. Hyperglycemia-induced activation of the renin-angiotensin system and an increase in the level of ATII lead to a decrease in the number and function of podocytes and a decrease in the expression of the specific filtration barrier protein produced by them – nephrin [23]. The protein filtration that increases as a result of these injuries, in turn, can lead to excessive secretion by the epithelium of the proximal tubules of a specific renal fibrosis factor – protein 1 of the monocyte chemoattractant [24]. Monocyte chemmoattractant protein 1 (MCP-1) causes aggravation of inflammation and fibrosis in the renal tubules and interstitium. Thus, the progression of CRF in DN can be considered as a result of damage to the entire nephron, the key initiating factor of which is hyperglycemia and associated intravascular hemodynamic disorders.
Modern principles of diagnosis and classification of DN are based on determining the stage of chronic kidney disease (CKD), classified by glomerular filtration rate and the presence or absence of signs of kidney damage (table. 2) [25].
The diagnosis of DN when a patient with DM has microalbuminuria or proteinuria is made in accordance with the classification of CKD depending on GFR:
* DN, microalbuminuria stage, CKD 1, 2, 3 or 4;
* DN, proteinuria stage, CKD 1, 2, 3 or 4;
* DN, CKD 5 (treatment with renal replacement therapy).

When detecting a decrease in GFR in a patient with DM
<60 ml / min and the absence of other signs of kidney damage (microalbuminuria, proteinuria) is diagnosed:
• CKD 3;
• Renal failure 4;
* CKD 5 (treatment with renal replacement therapy).

It should be noted that in patients with type 2 diabetes, the course of DN at the stage of proteinuria is more stable than in patients with type 1 diabetes. Filtration function of the kidneys does not decrease for a long time, despite the presence of proteinuria. In a study by L. L. Humphrey et al. [26], it was shown that only 4% of patients with type 2 diabetes develop chronic renal failure 5 years after the onset of proteinuria, 10% of patients-after 10 years, and
17% – 15 years after the beginning of proteinuria. However, this fact does not mean that patients with type 2 diabetes need less hemodialysis in comparison with patients with type 1 diabetes, on the contrary, due to the fact that the prevalence of type 2 diabetes is almost 10 times higher, the number of patients requiring hemodialysis has been progressively increasing in recent years.
Thus, there is no doubt that hyperglycemia is not only a trigger factor for the development of initial diabetic lesions in the renal glomeruli, but also contributes to their progression and, ultimately, plays an important role in determining the outcome of the disease. The positive effect of compensation of carbohydrate metabolism on the progression of days proven by numerous clinical studies demonstrating that the reduction of glycated hemoglobin (HbA1C) below 7% is accompanied by a reliable and significant reduction in the risk of development of proteinuria and contributes to the reduction of proteinuria at the stage of microalbuminuria [6-8]. Today, there is no doubt about the need to achieve optimal glycemic control for the prevention of DN in patients with type 2 diabetes. Compensation of carbohydrate metabolism is important even in the advanced stages of DN. It was found that patients with type 2 diabetes with unsatisfactory glycemic control during the 6 months preceding the start of dialysis had a worse prognosis than patients with adequate blood glucose control.

The current strategy for the treatment of type 2 diabetes involves individual selection of hypoglycemic agents depending on the patient’s age, the presence or absence of vascular complications and the risk of hypoglycemic conditions in order to prevent the progression of micro – and macroangiopathies (table 3) [25].
What hypoglycemic agents can be used in patients with type 2 diabetes with kidney pathology? At the initial (preclinical) stages of DN, any hypoglycemic agents can be used, including Metformin as the first-choice drug, sulfonylmochines (PSM), new groups of glinides, thiazolidinediones, glucagon-like peptide 1 (GLP-1) receptor agonists, and dipeptidyl peptidase-4 (DPP-4) inhibitors. However, as DN progresses and CRF develops, the Arsenal of hypoglycemic agents falls catastrophically. It is obvious that patients with DN need strict control of glycemia in order to prevent the progression of renal pathology and the development of CRF. In this situation, an effective and safe drug is needed, the use of which would not affect either the increase in the risk of hypoglycemic conditions or the progression of DN.
These conditions are fully met by the 2nd generation sulfonylurea preparation – Glurenorm ® (INN-gliquidone, Boehringer Ingelheim International GmbH, Germany). First, it is a fast-acting drug with a half-life of 1.2 hours, which is practically not accompanied by the risk of hypoglycemic conditions in elderly patients with concomitant cardiovascular pathology. Secondly, the drug is metabolized in the liver and 95% of its inactive metabolites are excreted through the hepatobiliary system, thus not having a negative effect on the kidneys. That is why Glurenorm ® is the only sulfonylurea drug, which can be applied even in the presence of the patient the initial manifestations of chronic renal failure. According to E. Bonora et al. [27], Glurenorm ® has a hypoglycemic effect not only due to stimulation of insulin secretion in response to increased glycemia, but also due to increased sensitivity of peripheral tissues to insulin at the receptor and post-receptor levels. A number of studies have shown that, along with a low risk of hypoglycemic conditions, the drug is nevertheless as effective as most psms, without causing significant weight gain [28].
In a study by K. Strojek et al. [29], it was shown that Glyrenorm ® was not inferior to gliclazide in its antiaggregational effects.
With the development of CRF, the transfer of patients with type 2 diabetes to insulin therapy is indicated, but there are known difficulties in controlling carbohydrate metabolism associated with changes in the need for insulin. On the one hand, nephrosclerosis reduces the need for exogenous administration of insulin due to a violation of its metabolism. On the other hand, CKD increases insulin resistance. As a result, the risk of developing hypoglycemic conditions increases many times against the background of inadequate hypoglycemic therapy. Under these conditions, the combination of small doses of intermediate-acting insulin with Glyrenorm ® is considered the most optimal for maintaining proper control of blood glucose levels [32] without the risk of hypoglycemic conditions.
Thus, the use of the drug Glurenorm ® in type 2 diabetes mellitus complicated by DN allows not only to achieve optimal control of blood glucose levels without the concomitant risk of hypoglycemic conditions, but also helps prevent the progression of such a formidable complication of diabetes mellitus as DN. More than 20 years of clinical experience with glyrenorm ® convincingly proves the effectiveness and safety of Its use in a wide range of therapeutic doses (from 15 to 120 mg/day) both in monotherapy and in combination with background insulin therapy in patients with various stages of DN development, up to CRF.

Douglas Badenoch
I am an information scientist with an interest in making knowledge from systematic research more accessible to people who need it. This means you. I've been attempting this in the area of Evidence-Based Health Care since 1995. So far the results have been mixed. For some reason we expected busy clinicians to search databases and appraise papers instead of seeing patients. We also expected publishers to make the research freely available to the people who paid for it.. Ha! Hence The National Elf service.

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