[Damage to the kidneys in diabetes mellitus type 2].
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Biomedical subjects
Publications and source records attributed to M Sh Shamkhalova.
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Alleles and genotypes of polymorphic markers of paraoxonase 1 and paraoxonase 2 genes (PON1 and PON2) encoding enzymes of the body antioxidative 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.
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 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 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.
Polymorphism A1166C of the AT1R gene encoding angiotensin vascular receptor [replacement of C (cytosine) for A (adenine)) at position 1166] was compared in patients with insulin-dependent diabetes mellitus (IDDM) complicated by diabetic nephropathy (DN) and in noncomplicated patients (n = 27 and n = 41, respectively) and also in patients with IDDM complicated by diabetic retinopathy (DR) and in correspondent noncomplicated individuals (n = 30 and n = 44, respectively). The frequency of AT1R gene alleles and genotypes in patients with IDDM complicated by DN did not differ significantly from that observed in patients with noncomplicated IDDM. In contrast, in patients with IDDM complicated by retinopathy, a significant decrease in the content of A allele (68.3% against 82.6%) and a significant increase in the content of C allele (31.7% against 17.4%) was found as compared with the control group. Thus, in the Moscow population, A1166C polymorphism of the AT1R gene is not associated with diabetic renal complications but indeed associated with diabetic retinal complications. C allele is a risk factor of DR (the relative risk, RR, is equal to 2.17), and A allele is, in contrast, a protective factor against early retinopathy development (RR is equal to 0.49).
Complement system was comparatively evaluated in 68 patients with diabetes mellitus and 104 healthy subjects. Hemolytic activity was examined for components C1, C2, C3, C4 and C5, and overall activity of the classic pathways was defined. The complement status appeared different for men and women. Females demonstrated hypofunction of the majority of the complement components, subcompensation in the absence of angiopathies, in decompensation complicated by angiopathies the activity was enhanced. In uneventful course of diabetes mellitus in males component C4 was activated remaining above normal though reduced in decompensation with angiopathies. High complement level in females could serve an aggravating factor, it depends on the dose of exogenic insulin.
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.
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Intensified insulin therapy in patients with type I diabetes mellitus is accompanied by a decrease in a total daily dose of insulin and the activity of the first 5 components of the classical pathway and CH50. A decrease in function of the first 5 components of the complement against a background of intensified insulin therapy can serve as a positive prognostic criterion of stabilization of development of diabetic angiopathies.
A total of 40 patients with type I diabetes mellitus, in whom the disease was diagnosed 1 to 12 months previously, were examined. An imbalance between the T and B cellular components of the immunity was found in the patients with the early stages of the disease, as was an elevated titer of the complement C1 component as against the reference group. The degree of the immunologic shifts was in direct correlation with the HLA A9 antigen expression, this relationship being the most marked in cases with the HLA DR3 and DR4. The incidence of these antigens expression was significantly higher in the patients with marked immunity shifts, than in those with negligible immunity changes. Therapy with an immunosuppressant azathioprine was associated with a noticeable reduction of the initially elevated cellular immunity parameters (total T and B lymphocyte counts, T helpers-inductors, DR carriers) and a trend towards a reduction of all the components and total activity of the classical route of the complement activation predominantly at the expense of the C1 and C5 components. The efficacy of this drug in therapy of new cases of insulin-dependent diabetes mellitus was confirmed, and the indisputable relationship between the efficacy of immunity suppression, that helped achieve a clinical remission, and the disease duration, was demonstrated. Monitoring of the cellular and humoral immunity parameters, of the activity of the classical route of the complement activation permitted an indirect judgement on the usefulness of immunity suppression for the correction of immunity disorders as factors contributing to the development of microvascular disturbances in insulin-dependent diabetes mellitus.
The authors have studied the preventive and therapeutic effects of high doses of nicotinamide on diabetes course in rats with streptozotocin-induced condition. Plasma glucose, glucosuria, C-peptide were assessed at the beginning of experiment and on day 40. Histologic studies were carried out over the course of experiment. On day 40 all rats administered nicotinamide showed almost normal glucose tolerance, and histologic examination showed just slight insulitis. In four of the six rats administered nicotinamide starting from the day when marked glucosuria first manifested glucosuria completely disappeared and their glucose tolerance improved over the course of therapy, though urinary sugar levels normalized in only one of the six rats administered nicotinamide for two weeks after the onset of marked glucosuria. These data evidence a preventive and therapeutic effect of nicotinamide on streptozotocin-induced diabetes in rats and suggest a reversible nature of beta-cell damage as early as at the initial stages of the disease.
Azathioprine immunosuppressive therapy prolongs remissions and stimulates residual beta-cell function, suppresses insulin antibody production, reduces the activity of the complement and CH50 components, reduces initially increased cellular immunity parameters (total T and B cell counts, T helper to T inductor ratio, and the count of DR carrier cells) in patients with newly detected insulin-dependent diabetes mellitus; this makes this drug effective at the first stages of the disease. When selecting patients for immunosuppressive therapy the following immunity parameters should be examined: complement status, total counts of T and B lymphocytes, T-helper-inductor/T-suppressor-cytotoxic immunoregulation index, DR carrier cell counts. Reduced levels thereof are a contraindication against immunosuppressant therapy. Male patients with insulin-dependent diabetes mellitus debut at the age of over 25 are particularly susceptible to immunosuppressive therapy with azathioprine.
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