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Aim: To assess the time course of changes in the level of glycated hemoglobin (HbA1c) for 20 years after the onset of type 1 diabetes mellitus (T1DM) and to compare its correlation with the development of microvascular complications, such as diabetic retinopathy (DR) and diabetic nephropathy (DN)., Subjects and Methods: A total of 187 children with new-onset T1DM were registered in Moscow in 1994. During the 20-year follow-up study, these patients underwent regular check-ups at the Endocrinology Research Center, Ministry of Health of the Russian Federation, which included assessment of physical data, HbA1c 2-4 times a year, biochemical blood and albuminuria tests (once per year), and ophthalmologic examination (twice a year). A total of 155 people fully completed the 20-years follow-up study., Results: During the 20-year follow-up period after the onset of T1DM, 86 of the 155 patients developed microvascular complications: DR and DN in 86 (55.5%) and 24 (15.5%) cases, respectively; while DR concurrent with DN were noted in 20 patients. By the time of their last visit, 69 (44.5%) patients had no evidence suggesting the presence of microvascular complications. The level of HbA1c at the onset of the disease in patients who later developed the complications was higher than in those without complications (10.2±0.6 and 8.5±0.2%, respectively (p = 0.003). The statistically significant differences in HbA1c levels between the groups persisted during subsequent 15 years of follow-up, averaging 9.2±1.5, 9.7±0.9, and 8.1±0.7% after 5, 10, and 15 years, respectively, in the complication group and 7.1±0.3, 8.1±0.4, and 7.2±0.2% in the non-complication group (p < 0.01). Over the last 5 years of the follow-up, the mean HbA1c level between the groups was not significantly different, which at the end of the 20-year follow-up period was 7.8±0.3 and 7.4±0.6%, respectively (p > 0.05). The mean duration of T1DM, in which DR developed, was 9.6±6.2, 11.0±2.0, and 13.6±4.6 years for the non-proliferative, pre-proliferative, and proliferative stages, respectively. That of T1DM, in which DN developed, was 11.8±0.6 years for microalbuminuria and 16.1±1.3 years for macroalbuminuria., Conclusion: The 20-year clinical follow-up of patients who had fallen ill with T1DM in childhood showed that diabetic microangiopathies developed with the long-term preservation of poor blood glucose control (BGC) starting at the onset of the disease. At the same time, the complications progressed to more severe stages, despite a clear trend toward better BGC. This may be suggestive of the negative metabolic memory phenomenon, which necessitates stable BGC, starting at the onset of the disease, for the prevention of microvascular complications.

This original article contains the authors own data on homeostasis of angiogenic growth factors (vascular endothelial growth factor - VEGF, angiopoietin 1 and 2 - Ang-1, Ang-2) in diabetic kidney disease. The aims of study were evaluation of alteration on serum concentration of circulating VEGF, Ang-l and Ang-2, and of their association with markers of renal damage (albuminuria, glomerular filtration rate) and anemia in patients with diabetes mellitus. We studied 78 patients type I diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Among this group 37patients had chronic kidney disease. The serum level of VEGF was elevated in T1DM patients and was associated with degree of proteinuria. The serum concentration of Ang-2 was higher in patients with chronic kidney disease (T1DM and T2DM), renal failure (T1DM), proteinuria and anemia (T2DM). Ang-2 strongly associated with albuminuria (T1DM and T2DM), glomerular filtration rate (T1DM) and hemoglobin (T2DM). Obtained results demonstrate that levels of VEGF and Ang-2 (but not Ang-1) are raised in patients with diabetic kidney disease and associated with markers of renal damage and anemia. These data indicate the presence of the disturbance of angiogenic growth factors (VEGF, Ang-2) homeostasis and activity in diabetic patients with chronic kidney disease.

Aim: To evaluate the kidney status from osmotic urine concentration in different stages of diabetes mellitus (DM) to define whether not only glomeruli and proximal tubules, but also renal medullary substance structures are involved into the pathological process, as well as their reaction to endogenous vasopressin production., Subjects and Methods: Forty patients with a 1-to-28-year history of DM, including 18 with diabetic nephropathy, 10 with chronic renal failure, and 22 without diabetic nephropathy, were examined. Urine and blood osmolality were determined and renal osmoregulating function was estimated., Results: Decreased glomerular filtration rate was found in relation to the duration of DM. The osmolality of nocturnal urine samples tended to diminish during short-term deprivation depending on the duration of DM. Increased diuresis in DM was shown to correlate with the higher reabsorption of osmotically free water., Conclusion: Diminished renal concentrating capacity in DM appears to depend on evolving renal failure rather than vasopressin resistance. The application of a new approach, by calculating the clearance of sodium-free water, suggests that its increased reabsorption favors normalization of serum osmolality in hyperglycemia.

Aim: To ascertain prognostic factors defining the risk of progression of diabetic nephropathy (DN) in patients with diabetes mellitus (DM) type 1 and 2 suffering from DM over 20 years., Material and Methods: A one-stage comparative trial studied 141 patients with DM type 1 and 149 patients with DM type 2 with DN of different severity and 20 year history of the disease. The follow-up study covered 34 CD-1 patients and 45 CD-2 patients with normo-, micro- and macroalbuminuria. The groups were made by the principle case-control. The control group consisted of 24 patients with DM-1 and 19 patients with DM-2 having stable renal function, the case group consisted of 10 and 26 patients, respectively, with DN progression. A total duration of the follow-up was 6 years. The end point of the analysis was chronic renal failure (CRF)., Results: Multivariate regression analysis has shown that the following risk factors of microalbuminuria in DM-1 and DM-2 are independent: the level of HbA1c (RR 3,1 and 2.7, respectively) and duration of arterial hypertension (RR 2.1 and 2.0, respectively); proteinuria - HbA1c (RR 4.4 and 3.4, respectively), systolic blood pressure (RR 3.4 and 3.1, respectively), CRF - systolic blood pressure (RR 5.0 and 4.5, respectively), triglycerides (RR 2.8 and 4.9, respectively) and hemoglobin (RR 3.3 and 5.3, respectively). IN DM-2 other risk factors of CRF were male sex (RR 2.0), family history of hypertension (RR 3.8) and 24-h proteinuria > 2 g (RR 6.7)., Conclusion: Inadequate compensation of carbohydrate metabolism (HbA1c), arterial hypertension and dyslipidemia are main risk factors of MAU and its progression to proteinuria in DM patients. In progression of DN to CRF main risk factors are hypertension, dyslipidemia and severity of anemia.

In groups of type 1 diabetes mellitus patients with and without clinical signs of diabetic nephropathy (n = 62 and n = 68, respectively), a search was made for associations between diabetic nephropathy and the polymorphic marker epsilon2/epsilon3/epsilon4 of apolipoprotein E gene (APOE), I/D marker of apolipoprotein B gene (APOB), and Ser447Ter marker of lipoprotein lipase-encoding gene (LPL). The risk of diabetic nephropathy was higher in the carriers of allele epsilon3 and genotype epsilon3/epsilon3 of the polymorphic marker epsilon2/epsilon3/epsilon4 of APOE gene as well as in the carriers of allele 1 and APOB genotype/gene (OR = 2.08 and 2.16; 1.91 and 2.11, respectively). Conversely, the carriers of allele D showed a reduced risk of this complication (OR = 0.52). No significant differences in distribution of alleles and genotypes of the polymorphic marker Ser447Ter of LPL gene were found between the groups. Our results indicate that the genes encoding two major components of lipid metabolism are involved in the development of diabetic nephropathy in patients with type 1 diabetes mellitus.

Aim: To elucidate the role of endothelial dysfunction in formation of cardiorenal syndrome in patients with type 1 diabetes and diabetic nephropathy., Material and Methods: Sixty patients with type 1 diabetes were divided according to severity of nephropathy into the following groups: with normal albuminuria (n=15), microalbuminuria (n=15), proteinuria (n=15), and chronic renal failure (n=15). Control group consisted of 15 healthy subjects of similar age and sex. Methods of investigation included assessment of brachial artery endothelium dependent dilation by duplex scanning during test with reactive hyperemia, measurement of levels of serum markers of endothelial dysfunction (endothelin-1, von-Willebrand factor), and inflammation (C-reactive protein), analysis of parameters of 24-hour blood pressure monitoring and echocardiography data., Results: More severe diabetic nephropathy was associated with higher prevalence of cardiac pathology. Frequency of ischemic heart disease was 13 (2/15), 33 (5/15) and 53% (8/15), frequency of left ventricular concentric hypertrophy and remodeling - 33 (5/15), 40 (6/15) and 60% (9/15) among patients with microalbuminuria, proteinuria and chronic renal failure, respectively. Abnormalities of 24-hour blood pressure rhythm as well as signs of endothelial dysfunction were more pronounced in patients with more severe nephropathy. Correlation analysis revealed significant relationships between markers of endothelial dysfunction, parameters of renal function, blood pressure level and mass of left ventricular myocardium., Conclusion: In patients with type 1 diabetes: endothelial dysfunction represents a link integrating processes of progression of nephropathy and development of cardiovascular pathology; close relationship between these processes constitutes a basis of cardiorenal syndrome; active search for cardiac pathology should be initiated on the stage of microalbuminuria.

Aim: To elicit the role of endothelial dysfunction in development of cardiorenal syndrome in patients with diabetes mellitus type 1 (DM1) with diabetic nephropathy (DN) and to evaluate the efficacy of endotheliotropic drugs: nebivolol (a selective beta-blocker) and enalapril (ACE inhibitor)., Material and Methods: The trial enrolled 60 patients with DM1: 15 patients with normoalbuminuria (NAU), 15 patients with microalbuminuria (MAU), 15 patients with proteinuria (PU) and 15 with chronic renal failure (CRF). The control group consisted of 15 healthy volunteers matched by sex and age. All the patients were examined for endothelium-dependent dilation of the brachial artery (by duplex scanning in the test with reactive hyperemia), serum markers of endothelial dysfunction (endothelin-1--ET-1), Willebrand factor (WF), inflammation markers (C-reactive protein-CRP), incidence rate of ischemic heart disease (IHD). 24-h arterial pressure monitoring and echocardiography were also made. For 12 weeks the patients were given nebivolol monotherapy in a dose 5 mg/day or enalapril monotherapy in a dose 10 mg/day. The effects of these drugs on urinary excretion of albumin and protein, arterial pressure, circadial rhythm of arterial pressure and endothelial dysfunction were studied., Results: In DM1 patients DN advances with an increase in development of IHD: in MAU--by 13%, PU--by 33%, CRF--53%. Concentric hypertrophy and left ventricular remodeling were registered in 33, 40 and 60% of cases, respectively. A circadian rhythm disturbance correlated with DN severity. DN progression was associated with increasing endothelial dysfunction. It is shown that nebivolol and enalapril correct endothelial dysfunction, have comparable antiproteinuric and antihypertensive actions at different stages of nephropathy., Conclusion: A close correlation was found between DN progression and development of cardiovascular pathology in DM1 patients. This serves the basis of cardiorenal syndrome. These two pathologies are associated with vascular endothelial dysfunction which leads to disorders in vascular tonicity regulation.

Aim: To study a vasomotor endothelial function in patients with diabetes mellitus (DM) type 1 at different stages of diabetic nephropathy (DN)., Material and Methods: Twenty six patients with DM type 1 (11 males and 15 females, mean age 25.9 +/- 4.3 years, mean history of DM 12.9 +/- 3.4 years) entered the study. They were divided into 4 groups: group 1--without renal affection, group 2--with microalbuminuria (MAU), group 3--with proteinuria (PU), group 4--with chronic renal failure (CRF). The control group consisted of 7 healthy volunteers. Endothelium-dependent vasodilation (EDVD) was studied in the test with reactive hyperemia provoked by 4-5 min occlusion of the brachial artery by pneumocollar and subsequent assessment of arterial diameter changes after decompression using high-resolution ultrasound dopplerography., Results: Reactive hyperemia resulted in dilation of the artery in all the examinees. This dilation was maximal on second 30 after removal of the collar in the controls, group 2, 3 and 4 and reached 9.2 +/- 2.9, 9.63 +/- 3.62, 7.25 +/- 5.23 and 4.42 +/- 4.05%, respectively. Resting blood flow velocity was similar in all the groups and rose maximally by 95-150%. To estimate EDVD of the brachial artery more precisely, the coefficient of endothelial sensitivity to shift tension was calculated. It made up 0.084 +/- 0.04 (control group), 0.0825 +/- 0.08 (group 1), 0.138 +/- 0.07 (group 2), 0.067 +/- 0.05 (group 3) and 0.052 +/- 0.04 (group 4)., Conclusion: At the earliest stage of DN (stage MAU), EDVD is not affected as maximal vasodilation of the brachial artery and endothelial sensitivity to shift tension do not differ from the control values. This means that the stage of MAU is reversible in early treatment, but PU and CRF are not reversible stages associated with depletion of endothelial cells and loss of sensitivity to changing hemodynamic conditions.

Polymorphic tetranucleotide microsatellites D3S1512, D3S1744, D3S1550, and D3S232 were used to study the association of chromosome region 3q21-q25 neighboring the angiotensin II receptor type 1 gene (AT2R1) with diabetic nephropathy (DN) in diabetes mellitus type 1 (DM1). Allele and genotype frequencies were compared for DM1 patients with (N = 39) or without (N = 62) DN. Fisher's exact test with Bonferroni's correction revealed significant differences in frequencies of two D3S2326 alleles, one D3S1512 allele, and one allele and one genotype of D3S1550. No significant difference was observed with D3S1744. Thus, region 3q21-q25 proved tightly associated with DN in ethnic Russians with DM1 from Moscow.

Aim: To study allele polymorphism of two variable regions [C1167T substitution in the catalase (CAT) gene D6S392 microsatellite near the Mn-dependent superoxide dismutase (SOD2) gene] was studied in insulin-dependent diabetic (IDDM) patients with (n = 36) or without (n = 56) diabetic nephropathy, and with (n = 30) or without (n = 44) diabetic retinopathy., Material and Methods: Both polymorphic regions were amplified using polymerase chain reaction (PCR). PCR products were separated using polyacrylamide (D6S366) or agarose (C1167T) gel electrophoresis. In a case of C1167, PCR-amplified products were digested with BstXI restriction endonuclease before electrophoresis. A significance of the difference between allele distributions in complicated and uncomplicated IDDM patients was estimated using the exact Fisher's test., Results: No significant difference was observed in allele and genotype frequencies in complicated and uncomplicated IDDM subjects., Conclusion: C1167 polymorphism in the CAT gene and D6S366 near the SOD2 gene are not associated with the development of diabetic nephropathy and diabetic retinopathy in IDDM.

Aim: To examine the expression of the intercellular adhesion molecule-1 (ICAM-1, CD54) on the surface of leukocytes and a soluble E-selectin (CD62) level in patients with diabetes mellitus type 1 (DM1) at various stages of diabetic nephropathy and retinopathy., Material and Methods: 42 patients with newly diagnosed and long-standing DM1 with presence or absence of microangiopathy (diabetic nephropathy and retinopathy) were examined. Routine laboratory, ophthalmologic tests, a special immunological test with ICAM-1 expression and soluble E-selectin (sES) examination were performed., Results: The tests show increased ICAM-1 expression and sES level in all the patients vs controls. In newly diagnosed DM1 a high sES level was observed. In long-standing DM1 and absence of microangiopathy a sES level was also high. In patients with neovascularisation and proteinuria the sES level was two times higher than that in other subgroups. We also found an increased percentage of ICAM-1, CD54-positive lymphocytes and granulocytes in patients with microalbuminuria and especially with proteinuria and neovascularization. There were no correlations of ICAM-1 and sES levels with sex, DM duration, cholesterol and triglycerides., Conclusion: The findings show endothelium and leukocytes activation at early disease stages. Enhanced endothelium and leukocytes activation is associated with late complications.

Patients with type 1 diabetes, aged 18 to 42 years, were compared to those aged 11 to 22 years. Activities of endothelial vasoactive factors and endothelial and leukocyte adhesion molecules were studied at different stages of development diabetes complications: nephropathy and retinopathy. The findings reveal role of the vasoactive factors in microangiopathy course.

Aim: To reveal factors accelerating development of chronic renal failure (CRF) in patients with insulin-dependent diabetes mellitus type I (DM-I)., Materials and Methods: A retrospective analysis of case histories was made for 40 patients with DM-I exhibiting progression of proteinuric stage of diabetic nephropathy prior to CRF stage. Clinical-laboratory indices were compared for patients with slow (group 1, n = 17) and fast (group 2, n = 23) development of CRF., Results: Patients of group 2 had significantly higher levels of glycosylated hemoglobin, total cholesterol, triglycerides in the blood, urine protein excretion, systolic and diastolic blood pressure than patients of group 1. Also, patients of group 2 had not taken antihypertensive drugs regularly., Conclusion: Factors of risk of CRF early development of DM-I patients comprise unsatisfactory compensation of carbohydrate metabolism, hyperlipidemia, high proteinuria, arterial hypertension and inadequate antihypertensive therapy.

A novel pathogenetic approach to treatment of diabetic nephropathy (DN) as a severe complication of diabetes mellitus is aimed at inhibiting DN progression or its involution by means of reestablishment of heparan sulfate synthesis by glycosaminoglycane drug. In the study of 9 patients with microalbuminuria and 9 with proteinuria this drug was low-molecular heparin-sulodexide (Alfa-Wasserman, Italy). The treatment course of 3 weeks resulted in albuminuria fall in 89% of patients. In patients with microalbuminuria protein excretion returned to normal values in a week of treatment. This effect was persistent after the drug discontinuation. This was not so for protein excretion in proteinuria patients which became low after 3 weeks of treatment, but the effect was not long-lasting. The authors believe that glycosaminoglycanes hold great promise in DN, especially at early stages of renal diabetic affection.

To evaluate the secretion of vasoactive factors in vascular endothelium of patients with non-insulin-dependent diabetes mellitus (NIDDM) the authors examined 31 NIDDM patients. Of them, 18 had no signs of renal involvement, 13 patients showed apparent diabetic nephropathy (DN). In the former patients the blood contained much greater content of vasodilating factor prostacyclin than of vasoconstricting factor endothelin-1 (ET-1) and thromboxan A2 (TxA2). In diabetic nephropathy the balance of vasoactive factors shifted to predominance of vasoconstrictors ET-1 and TxA2. Such rearrangement of vasoactive factors to higher quantities of vasoconstrictors in diabetes mellitus may initiate or promote progression of diabetic nephropathy with resultant spasm of afferent glomerular vessels, reduced glomerular filtration and renal blood flow rates, arterial hypertension, increased thrombogenesis. Thus, elevated levels of ET-1 and TxA2 in diabetics and their rise with progression of diabetic nephropathy are likely to act as pathogenetic factors underlying onset and progression of nephroangiopathy.

Progression of diabetic nephropathy is now associated with intrarenal hemodynamic disorders (renal hyperperfusion, hyperfiltration, intraglomerular hypertension). The cause of these disorders is unclear. It is supposed that the relaxation factor which is produced by the vascular endothelium (endothelial relaxation factor-ERF) and an endogenous nitrogen oxide (NO) can cause the above intrarenal hemodynamic alterations in diabetes mellitus. The production of ERF/NO in 35 patients with insulin-dependent diabetes mellitus who had varying severities of diabetic nephropathies were examined. These included the following groups: 1) patients without diabetic nephropathy (n = 9); 2) those with incipient diabetes mellitus (n = 12), 3) those with severe diabetes mellitus (n = 14). From groups 1 and 2, 5 patients with hyperfiltration were identified, their glomerular filtration rate were more than 140 ml/ml. The ability of the cells to produce ERF/NO was indirectly estimated, by determining the levels of human platelet guanylate cyclase in the presence of L-arginine, a NO precursor, the accumulation of cGMP in the cells and plasma. When L-arginine was present, the activity of guanylate cyclase was virtually unchanged in Group 1, but it was substantially increased in Groups 2 and 3, by reaching its peak in patients with hyperfiltration (Group 4). The platelet and plasma levels of cGMP corresponded to the enhancement of guanylate cyclase activity in the presence of L-arginine and increased as diabetic nephropathy progressed. Thus, it is suggested that there is ERF/NO hyperproduction in patients at a high risk for diabetic nephropathy (those having hyperfiltration). ERF/NO is likely to promote the dilation of glomerular arterioles, which results in the development of hyperfiltration and intraglomerular hypertension, causing diabetic nephropathy progression.

Twenty-nine patients with insulin-dependent diabetes mellitus with similarly manifest renal involvement were examined to elucidate the role of dyslipidemia in diabetic nephropathy progress. Clinico-laboratory parameters (urinary albumin excretion, blood serum levels of total cholesterol, triglycerides, low, very low, and high density lipoprotein cholesterol) and morphologic changes in renal tissue biopsy specimens were analyzed. An increment of the number of large lipid incorporations was observed in various cells of renal glomeruli and interstitium, as well as a high prevalence of low density lipoprotein deposition in glomerular basal membranes and canaliculi as the renal process augmented in severity. Since lipids accumulating in glomerular structures may stimulate mesangial cell proliferation and mesangial matrix hyperproduction, the authors believe that dyslipidemia in diabetes mellitus may be conducive to a more rapid progress of renal disease.

To determine the mechanisms underlying diabetic nephropathy (DN) onset, a clinical and morphological study was initiated of 14 diabetics with insulin-dependent disease free of clinical renal manifestations. The patients were examined for intraglomerular hypertension, blood lipid spectrum and renal tissue morphology. In high intraglomerular hypertension, i. e. in renal functional reserve depletion, there is dyslipidemia with a characteristic significant rise in the levels of very low density lipoprotein cholesterol and low density lipoprotein cholesterol, in the value of atherogenic index. Morphologically, renal tissue of the hypertensive and dyslipidemic patients experienced hyperperfusion and massive lipid infiltration in glomerular cells. In contrast, renal tissue underwent only minimal nonspecific changes when intraglomerular hemodynamics and lipidemia were normal. The findings suggest that associated effects of intraglomerular hypertension and dyslipidemia may promote DN onset.

The acute effects of protein loading (1.5 g kg-1) on glomerular filtration rate (GFR) and urinary albumin excretion (UAE) were investigated in 23 type-I diabetic patients with no clinical nephropathy, and in 7 healthy subjects (controls). The results were compared with renal morphology data. In controls and in 14 diabetic patients (group 1) GFR increased by 27 and 37%, respectively, corresponding to normal renal reserve, but in 9 patients (group 2) GFR decreased by 20%, indicating the absence of a renal reserve. Microalbuminuria was found in none of the patients in group 1 and in 50% of patients in group 2. Two hours after the load UAE increased in all groups, but the increase was most marked in group 2, despite the fall in GFR. The two groups of patients did not differ with regard to the duration and control of diabetes, but differed markedly in terms of baseline GFR (131 vs. 195 ml min-1, P less than 0.01, in groups 1 and 2, respectively). Renal morphology showed minimal non-specific glomerular injury in group 1, and signs of glomerulosclerosis in group 2. We conclude that the impaired renal response to protein load precedes other subclinical manifestations of diabetic renal injury, and may be useful in the diagnosis of latent diabetic nephropathy.

Overall 42 normotensive patients suffering from type I diabetes mellitus without proteinuria were examined for the effect of hyperfiltration on renal glomerular function and for changes in glomerular function seen during medicamentous treatment of hyperfiltration. Glomerular function was evaluated from the basal level of glomerular filtration (GF), the status of filtration reserves (i. e. according to the dynamics of the GF level in response to oral protein administration), and from the magnitude of albuminuria. Three groups of diabetes mellitus patients were distinguished: with filtration reserves, with decreased filtration reserves, and with no reserves. All the three groups did not differ in the age, diabetes standing or the degree of carbohydrate disorders compensation (HBA1c). Still, the patients with no filtration reserves significantly differ from the other groups with a high level of GF and albuminuria. In 9 patients, a study was made of the effect produced by captopril (an inhibitor of the angiotensin-transforming enzyme) on filtration reserves and albuminuria. After 3 to 6 months of the treatment five patients with no filtration reserves manifested a fall of the basal level of GF down to normal, the recovery of filtration reserves, and a decline of albuminuria. It is assumed that elimination of hyperfiltration due to the treatment with the inhibitors of the angiotensin-transforming enzyme may be an effective means of diabetic nephropathy prevention.

To identify early markers of the preclinical stage of diabetic nephropathy, a study was made of the activity of the specific canalicular enzymes in urine: N-acetyl-beta-D-glucosaminidase (NAG), beta-glucuronidase (beta-G1), gamma-glutamyl transferase (GGT), alkaline phosphatase (AP) and lactate dehydrogenase (LDH) in patients with diabetes mellitus without (26) and with (15) proteinuria. Patients without the clinical signs of diabetic nephropathy manifested a significant rise of excretion of lysosomal enzymes of the proximal canaliculi (NAG and beta-G1). Concomitant elevation of the excretion of several enzymes (NAG, beta-Gl, GGT and AP) was observed in 50% of cases. Patients with diabetic nephropathy demonstrated an increase of the excretion of all enzymes under study. Puncture biopsy of the kidneys was made in 4 patients without proteinuria with insignificant duration of diabetes mellitus and concomitant elevation of the excretion of a number of enzymes. Light microscopy revealed minimal changes in the glomeruli, whereas electron microscopy changes both in the glomeruli and in the canaliculi. The morphological changes in renal tissue confirm the diagnostic importance of high concomitant excretion of canalicular enzymes (NAG, beta-Gl, AP) as a marker of the preclinical stage of diabetic nephropathy.

In groups of type 1 diabetes mellitus patients with and without clinical signs of diabetic nephropathy ( n = 62 and 68, respectively), a search was made for associations between diabetic nephropathy and the polymorphic marker ε2/ε3/ε4 of apolipoprotein E gene ( APOE), I/D marker of apolipoprotein B gene ( APOB), and Ser447Ter marker of lipoprotein lipase-encoding gene ( LPL). The risk of diabetic nephropathy was higher in the carriers of allele ε3 and genotype ε3/ε3 of the polymorphic marker ε2/ε 3/ε4 of APOE gene as well as in the carriers of allele I and APOB genotype I/I gene ( OR = 2.08 and 2.16; 1.91 and 2.11, respectively). Conversely, the carriers of allele D showed a reduced risk of this complication ( OR = 0.52). No significant differences in distribution of alleles and genotypes of the polymorphic marker Ser447Ter of LPL gene were found between the groups. Our results indicate that the genes encoding two major components of lipid metabolism are involved in the development of diabetic nephropathy in patients with type 1 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Alleles and genotypes of polymorphic markers of paraoxonase 1 and paraoxonase 2 genes ( PON1 and PON2) encoding enzymes of the organism antioxidant defense were compared in type 1 diabetes mellitus patients with or without diabetic nephropathy. The patients with nonoverlapping (“polar”) phenotypes constituted different groups. The first group contained patients with diabetic nephropathy (DN+, n = 62), clinical proteinuria (albuminuria above 300 mg per day), and at least 15-year disease duration. In control group, the patients had no diabetic nephropathy (DN−, n = 68), their albuminuria was below 200 mg per day, and disease duration was at least 20 years. Comparative analysis with exact Fisher’s test revealed no significant differences in frequencies of alleles and genotypes of the PON1 gene polymorphic marker Gln192Arg and of PON2 gene polymorphic markers Ala148Gly and Cys311Ser. Our results suggest that the polymorphic markers studied are not associated with diabetic nephropathy among Russian patients in Moscow. [ABSTRACT FROM AUTHOR]

Polymorphic tetranucleotide microsatellites D3S1512, D3S1744, D3S1550, and D3S2326 were used to study the association of chromosome region 3q21–q25 neighboring the angiotensin II receptor type 1 gene (AT2R1) with diabetic nephropathy (DN) in diabetes mellitus type 1 (DM1). Allele and genotype frequencies were compared for DM1 patients with (N = 39) or without (N = 62) DN. Fisher's exact test with Bonferroni's correction revealed significant differences in frequencies of two D3S2326 alleles, one D3S1512 allele, and one allele and one genotype of D3S1550. No significant difference was observed with D3S1744. Thus, region 3q21–q25 proved tightly associated with DN in ethnic Russians with DM1 from Moscow. [ABSTRACT FROM AUTHOR]