Angiotensinogen M235T and chymase gene CMA/B polymorphisms are not associated with nephropathy in type II diabetes.

BACKGROUND: Several studies have suggested that the same genetic factors may be involved in the predisposition to both essential hypertension and diabetic nephropathy, but the molecular mechanism underlying this predisposition still remains unclear. In particular, the role of genes involved in blood-pressure regulation and angiotensin II action is still controversial. This study examines a possible association between angiotensinogen M235T and chymase gene CMA/B polymorphisms with the presence of nephropathy in type II diabetic Caucasians. METHODS: For the purposes of the study, 323 microalbuminuric and 127 overt proteinuric cases, together with 243 normoalbuminuric controls with long-duration diabetes were selected from a group of 941 type II diabetic patients with established renal status. RESULTS: No differences in the genotype distributions or allele frequencies of the examined polymorphisms between the study groups were observed. The study groups were also stratified by gender, diabetes duration, level of glycaemic control, body mass index, hypertension, and retinopathy status, but still no distortion in the distributions of genotypes of any of the examined polymorphisms in any of the strata was shown. CONCLUSIONS: Our study provided evidence against an association between angiotensinogen M235T or chymase gene CMA/B polymorphisms and the presence of incipient or overt nephropathy in Caucasian patients with type II diabetes.

Angiotensin II type 1 receptor gene A1166C polymorphism is associated with the increased risk of pregnancy-induced hypertension.

OBJECTIVE: The aim of our study was to evaluate the relation of parental history of hypertension to the development of PIH, and to assess the potential role of plausible candidate loci in the susceptibility to PIH. STUDY DESIGN: Five polymorphisms: ACE gene I/D and Pst1 RFLP polymorphism, AGT gene M235T polymorphism, AGTR1 gene A1166C polymorphism, and chymase gene CMA/B polymorphism were studied in 126 women suffering from PIH in comparison with 150 healthy pregnant women. Genotyping was performed using methods based on polymerase chain reaction. RESULTS: Among the PIH patients, positive parental history of hypertension (hypertension in both parents, in mother alone or in father alone) was significantly more frequent than in healthy pregnant women. Having a hypertensive father or mother statistically significantly increased the risk of PIH (odds ratio 4.34, 95% CI, 1.86-10.13, and 2.33, 95% CI, 1.29-4.12 respectively). CC genotype was significantly more frequent in women with PIH as compared with healthy controls and the C allele frequency was also significantly higher among the cases compared to controls. Having a CC genotype increased the risk of development of PIH 2.74 times (95% CI, 1.08-6.97). We observed no significant differences in genotype distributions or the allele frequencies of other examined polymorphisms. CONCLUSION: On the basis of the results of our study, we may suggest that AGTR1 gene A1166C polymorphism may predispose women to the development of PIH. It seems that ACE gene I/D and Pst1 RFLP polymorphism, AGT gene M235T polymorphism, and finally chymase gene CMA/B polymorphism do not play any significant role in the pathogenesis of PIH in Caucasian women.

[Evaluation of the relationship between the occurrence of headache, use of analgesics and realizing a therapeutic effect among patients with hypertension]. / Ocena zaleznosci pomiedzy wystepowaniem bólów glowy i stosowaniem leków przeciwbólowych a realizacja zalecen terapeutycznych wsród chorych na nadcisnienie tetnicze.

The aim of the study was to assess the prevalence of headaches and analgesic use in hypertensive patients and to evaluate the relationship between taking analgesic drugs and adherence to antihypertensive therapy. 754 consecutive hypertensive patients (446 women and 308 men, aged 18-89 years, median age--58 years) from 7 out-patient centres participated in the study. Anonymous questionnaires consisted of 13 simple questions concerning demographic parameters (age, gender), clinical data (the duration of hypertension and antihypertensive therapy), the history of headache and use of analgesics were distributed among the participants. Among the hypertensives participating in the study, 82.9% (625) reported headaches. Analgesics were used by 65.3% (408) of hypertensive patients with headaches. There was significant, positive linear correlation between the history of headaches and the duration of analgesic use in hypertensive patients. The rate of non-compliance was significantly higher among patients with headaches who reported regular use of analgesics when compared to non-users of analgesics. There were statistically more non-compliants among patients taking more than 1 type of analgesics than in hypertensives reporting use of only 1 analgesic drug. The prevalence of headaches and the rate of analgesic use is considerably significant among hypertensive patients. Analgesic consumption seems to be a risk factor for non-adherence to antihypertensive medication.

[The evaluation of hypertensive patients' adherence to the pharmacological treatment of hypertension]. / Ocena realizacji zalecen terapeutycznych przez chorych na nadcisnienie tetnicze.

Evaluation of patients' compliance is very important considering possible influence on the effectiveness of antihypertensive treatment. The adherence to the rules of pharmacological therapy was assessed by anonymous questionnaires. 414 patients with hypertension participated in the study. Non-compliance is one of the commonest therapeutic problems. Forgetting is the most frequent reason of irregular administration of medicine.

[Some aspects of non-pharmacologic treatment of hypertension]. / Niektóre aspekty niefarmakologicznego leczenia nadcisnienia tetniczego.

Non-pharmacological methods of intervention are often used as individual or complementary forms of antihypertensive therapy. The aim of the study was to assess the level of compliance and acceptance of some life-style modifications in patients with hypertension. 432 hypertensive patients participated in the study. The study consisted of filling in anonymous questionnaires, taking blood pressure, height and weight measurements. Different approaches of nonpharmacological treatment of hypertension are accepted in differing degree. Life-style modifications and blood pressure self-monitoring should be an integral part of antihypertensive-treatment-programme.

Angiotensin I-converting enzyme gene polymorphisms: relationship to nephropathy in patients with non-insulin dependent diabetes mellitus.

Nephropathy is a frequent complication of long-term diabetes. Strong evidence exists that genetic predisposition plays a major role in the development of diabetic nephropathy. The role of the angiotensin I-converting enzyme gene (ACE) in the susceptibility to nephropathy in diabetes, especially in non-insulin dependent diabetes mellitus (NIDDM), remains unclear. This study examines the association of two ACE polymorphisms: a 287-bp insertion/deletion (I/D) in intron 16 and PstI (A/G substitution in intron 7; alleles P/M) with renal complications in 941 NIDDM patients. From this group, for further analysis 127 patients were selected with overt proteinuria or chronic renal failure, 335 patients with microalbuminuria, and a control group of 254 normoalbuminuric patients with a diabetes duration of at least 10 yr. No significant differences in the distribution of ACE I/D and PstI genotypes or allele frequencies were observed between the examined groups. The results of this study strongly suggest that there is no association between the ACE gene I/D and PstI polymorphisms and nephropathy in NIDDM.

[Genetic aspects of diabetic retinopathy]. / Genetyczne aspekty retinopatii cukrzycowej.

Poor metabolic control, hemodynamic factors and long duration of diabetes may predispose to the development of diabetic retinopathy. Recently the hypothesis that genetic factors may play certain role in the pathogenesis of diabetic retinopathy has been also proposed. The angiotensin I converting enzyme (ACE) gene has been the main candidate gene predisposing to the development of diabetic retinopathy. One of its polymorphisms--insertion/deletion seems to be particularly associated with long-term diabetic complications. The HLA system genes, TNF-beta gene, IGF-1 gene and PAI-1 gene are the other candidate genes. If there would be strong evidence that genetic factors play certain role in the pathogenesis and progression of diabetic retinopathy, the high risk diabetics could be selected and the adequate prevention could be applied.

[The role of oxidative stress in development of diabetic angiopathies]. / Rola stresu oksydacyjnego w rozwoju powiklan naczyniowych w cukrzycy.

Oxidative stress is an imbalance between free radicals production and lipid peroxidation on the one hand, and the activity of antioxidant systems (enzymatic and non-enzymatic) on the other hand. It seems that oxidative stress may cause the development and complications of several diseases including diabetes, atherosclerosis, neoplasms, inflammation, hypertension etc. Prooxidant--antioxidant imbalance in diabetes may be due to non-enzymatic protein glycation, glucose autooxidation, increased sorbitol pathway, decreased activity of antioxidant enzymes and depletion of some non-enzymatic scavengers. It seems that we may partially diminish the development and progression of diabetic angiopathies decreasing oxidative stress by means of scavengers supplementation, use of hypotensive drugs with antioxidant properties and antidiabetic oral agents with antiperoxidative activity.

[Lack of relationship between angiotensinogen gene m235t polymorphism and gene insertion/deletion (I/D-intron 16) and Pst I RFLP (P/M-intron 7) polymorphisms of the angiotensin I converting enzyme(ACE) gene and the development of H-gestosis. Preliminary results]. / Brak zwiazku polimorfizmu m235t genu angiotensynogenu i polimorfizmów insercja/delecja (I/D-intron 16) oraz Pst I RFLP (P/M-intron 7) genu enzymu konwertujacego angiotensyne I (ACE) z wystepowaniem H-gestozy. Doniesienie wstepne.

Genetic and familial factors may predispose to H-gestosis. The aim of our study was to answer the question if angiotensinogen gene m235t polymorphism, and ACE gene I/D and Pst I RFLP polymorphisms may be markers of genetic predisposition to the H-gestosis. 246 pregnant women (median age 26 years) were studied (the studied group consisted of 116 women with H-gestosis and the control group consisted of 130 healthy pregnant women). Genotyping was performed using polymerase chain reaction method. Statistical analysis was done by means of Statistica for Windows. Genotype distribution was analyzed using chi 2 test. P < 0.05 was considered as statistically significant. In our study we did not receive statistically significant differences in ACE and angiotensinogen genes genotype distributions and allele frequencies between the investigated groups. Based on results of the study we may suggest that I/D and Pst I RFLP ACE gene polymorphism and angiotensinogen gene m235t polymorphism do not play any significant role in the pathogenesis of H-gestosis.

Reduced insulin-mediated glucose uptake by euglycemic clamp in offspring of patients with type 2 diabetes.

Family studies point to an important genetic element in the genesis of type 2 diabetes. A variety of metabolic abnormalities have been documented in offspring of patients with type 2 diabetes. It has not been shown, however, at what age reduced insulin sensitivity is demonstrable using the sensitive the euglycemic clamp technique. To address this issue we screened 425 consecutive type 2 diabetic patients and examined all available (n = 48) normotensive, normoglycemic, non-smoking offspring (mean age 31.4+/-0.9 years) and compared them to 22 healthy offspring of non-diabetic parents (controls). The two groups were of similar age and BMI. Measurements in offspring and controls included baseline IRI, tissue glucose uptake (TGU, using euglycemic hyperinsulinemic clamp technique), and 24 hour ambulatory blood pressure (ABP). TGU was significantly (p < 0.001) lower in offspring of diabetic parents (338.8+/-19.9 (mol/kg/min) when compared to controls (516.6+/-22.2 micromol/kg/min). 24 h systolic ABP was significantly higher (p < 0.02) in propositi compared to controls (121.2+/-2.2 mm Hg and 113.8+/-1.7 mm Hg, respectively). No difference in triglycerides concentration was found. A borderline negative correlation was observed, however, between triglyceride levels and TGU (R = -0.48, p < 0.001). TGU was not related to the presence or absence of diabetic nephropathy in the parents. We conclude: Insulin resistance and various facets of the metabolic syndrome are demonstrable even at age 30 years in young non-obese, normotensive offspring of patients with type 2 diabetes. These disturbances are not related to the presence of microvascular complications in parents.

[Is PstI polymorphism of the angiotensin I converting enzyme gene associated with nephropathy development in non-insulin-dependent diabetes mellitus (preliminary study)]. / Czy polimorfizm PstI genu enzymu konwertujacego laczy sie ze zwiekszonym ryzykiem zapadalnosci na nefropatie u chorych na cukrzyce insulino-niezalezna (doniesienie wstepne).

Nephropathy is a frequent complication of long term diabetes. Diabetic nephropathy is the major determinant of premature morbidity and mortality both in insulin-dependent (IDDM) and in non-insulin dependent-diabetes mellitus (NIDDM). There is good evidence that genetic predisposition plays a major role in development of diabetic nephropathy. This hypothesis is based on the observation that diabetic nephropathy clusters within families, both in IDDM and NIDDM. Components of the renin-angiotensin system (RAS) are plausible candidate genes to examine for a association with microalbuminuria and diabetic nephropathy. In this study we compared the distribution of PstI melting polymorphism at the ACE locus among NIDDM patients with diabetic nephropathy and in patients who, despite long duration of NIDDM, remain without this complication. The 220 NIDDM patients for whom DNA was available were classified into two groups according to their renal status: normoalbuminuric control subjects (n = 80) who are NIDDM patients with an A/C ratio < 2.5 and nephropathy cases (n = 140) who are NIDDM patients with A/C ratio > 2.5. Albumin excretion rate was assayed by radioimmunoassay. HbA1c was assayed using HPLC methods, creatinine--using Jaffe methods and DNA analysis using PCR reaction, and then after the amplification product was digested with PstI enzyme. The study revealed that PstI sequence differences ("+/= and -") in the ACE gene do not contribute to genetic susceptibility to diabetic nephropathy in NIDDM.

Nephropathy of type II diabetes: evidence for hereditary factors?

Family studies point to an important genetic element in the genesis of diabetic nephropathy, but it is not known whether renal abnormalities are present prior to the onset of diabetes. To address this issue we examined all consecutive patients suffering from type II diabetes with a duration of more than 10 years who attended a diabetes outpatient clinic. Ninety-four patients had nephropathy, 307 did not. All offspring who were phenotypically normal (no hypertension, normal oral glucose tolerance, non-smoking) and agreed to participate were examined, 26 from nephropathic and 30 from non-nephropathic diabetic parents. They were compared with 30 offspring matched for age, gender and BMI from non-diabetic parents as controls. We measured urinary albumin excretion under baseline conditions and at several time points after ingestion of 300 g cooked beef and submaximal treadmill exercise, respectively. In addition, casual blood pressure, ambulatory blood pressure, urinary albumin and urinary alpha-1-microglobulin were measured. Primary renal disease was excluded by clinical examination. Under baseline conditions, median urinary albumin excretion rate (AER; microgram/min) was significantly (P < 0.005) higher in offspring of nephropathic type II diabetic patients (7.8; range 1.04 to 19.5) than in the offspring of non-nephropathic type II diabetic patients (4.8; 0.36 to 17.5) and controls (4.4; 0.16 to 18.4). Submaximal treadmill exercise caused a greater proportional increase of AER in offspring of nephropathic type II diabetics (median 16-fold) than in offspring of non-nephropathic diabetic patients (6.3-fold) or controls (4.8-fold). In offspring of nephropathic diabetic patients casual and particularly ambulatory systolic blood pressures were significantly higher, but AER was not correlated with blood pressure. In summary, higher values, albeit within the normal range, for baseline and postexercise albuminuria were noted in phenotypically normal offspring of parents with type II diabetes and nephropathy. The observation suggests that changes in transglomerular albumin traffic are demonstrable prior to the onset of diabetes and diabetic nephropathy in subjects with a potential genetic predisposition to these conditions.

Increased prevalence of salt sensitivity of blood pressure in IDDM with and without microalbuminuria.

In insulin-dependent diabetes mellitus (IDDM) elevated exchangeable sodium (Na) levels are found even in the absence of hypertension, but it is not known whether this is associated with increased sensitivity of blood pressure to sodium level. To clarify this issue we compared 30 patients with IDDM (19 without and 11 with microalbuminuria, i.e. more than 30 mg albumin/day) and 30 control subjects matched for age, gender and body mass index. The subjects were studied on the 4th day of a low-salt diet (20 mmol/day) under in-patient conditions and were subsequently changed to the same diet with a high-salt supplement, yielding a total daily intake of 220 mmol Na/day. Circadian blood pressure, plasma renin activity (PRA), plasma atrial natriuretic factor (p-ANF), plasma cyclic guanosine 5'-phosphate (p-cGMP) and urinary albumin were measured. The proportion of salt-sensitive subjects, i.e. showing increment of mean arterial pressure > or = 3 mmHg on high-salt diet, was 43% in diabetic patients (50% of diabetic patients with and 37% without microalbuminuria) and 17% in control subjects (p < 0.05). Lying and standing PRA levels on low- or high-salt diet were significantly lower in diabetic patients than in control subjects. Salt-sensitive diabetic patients had significantly higher lying ANF on high-salt (38.7 +/- 4.2 pmol/l vs 20.1 +/- 2.3 pmol/l, p < 0.005) than on low-salt diet. The results suggest that (i) the prevalence of sodium sensitivity is high in IDDM (ii) sodium sensitivity is found even in the absence of nephropathy as indicated by albuminuria.

[Activity of the renin-angiotensin-aldosterone system in euglycemic type I diabetic patients on intensive insulin treatment without diabetic neuropathy]. / Aktywnosc ukladu renina-angiotensyna-aldosteron u chorych na cukrzyce typu I, leczonych intensywna insulinoterapia bez towarzyszacej neuropatii autonomicznej w okresie wyrównania metabolicznego.

Arterial hypertension increase progression of late diabetic complications. Renin-angiotensin-aldosterone system plays an important role in the regulation of arterial pressure. The aim of the study was the assessment of plasma renin activity (PRA) and aldosterone (aldo) in type I euglycaemic diabetic patients on intensive insulin treatment without autonomic neuropathy. 30 type I diabetic patients (including 11 with nephropathy defined as urinary albumin excretion > 30 mg/24 h and 19 without albuminuria) were admitted into the trial. Mean age 31.9 + 1.4 years, duration time of disease was 9.1 + 1.5 years, HbA1c level 7.6 + 0.25%; GFR 124.7 + 3.9 ml/min/1.73 m2 (135.8 + 5.1 in subgroup with nephropathy and 118.2 + 5.08 in non-nephropathic group). Blood samples were taken during normal sodium intake (120 mmol/24 h) after 0.5 h supine. PRA was significantly lower in type I diabetics vs control (0.27 + 0.04, 0.61 + 0.09 pmol/l/s respectively-p < 0.005). PRA was significantly lower both in nephropathic and non-nephropathic diabetic group vs control (respectively 0.22 + 0.06 and 0.31 + 0.05-p < 0.05). Aldo in diabetic patients and in subgroups with and without nephropathy was significantly lower vs controls (respectively 173 + 12.9, 165.1 + 14.4, 182.1 + 18.8 and 257.1 + 24.1 pmol/l; p < 0.01, p < 0.05). Significant differences in hormonal changes between diabetic patients with and without nephropathy were not found. Basing upon the results we conclude that in euglycemic intensively insulin treated type I diabetic patients without neuropathy presented decreased level of PRA and aldo. Early stage of diabetic nephropathy does not influence the examined hormones level.

[Does an association between angiotensin I converting enzyme gene polymorphism and the prevalence of diabetic nephropathy in patients with diabetes type II exist?]. / Czy istnieje zwiazek pomiedzy polimorfizmem genu konwertazy angiotensyny I a wystepoaniem nefropatii u chorych na cukrzyce typu II?

In type I diabetic patients association has been found between the insertion/deletion (I/D) polymorphism in the gene of angiotensin converting enzyme and the presence of diabetic nephropathy. The aim of that study was to assess this association in a cohort of type II diabetics. We examined 109 patients of more than 10 years duration of type II diabetes. Nephropathy (defined as at least confirmed albuminuria > 30 mg/24h) was present in 37 subjects. The I/D polymorphism was analyzed with PCR technique. Allele frequencies in the overall diabetic population did not differ significantly from the normal population. Distribution of genotypes was not significantly different between examined patients with and those without nephropathy. We conclude that the distribution of ACE gene polymorphism is similar in diabetic subjects and in general population and there is not association between I/D polymorphism and nephropathy in type II diabetic patients.

[Lipid peroxidation, antioxidant enzyme activity and trace element concentration in II and III trimester of pregnancy in pregnant women with diabetes]. / Peroksydacja lipidów, aktywnosc enzymów antyoksydacyjnych oraz stezenie metali sladowych w II I III trymestrze ciazy u ciezarnych z cukrzyca.

UNLABELLED: The aim of the study was to evaluate the concentration of malondialdehyde (MDA)--end product of lipid peroxidation, activity of antioxidant enzymes: superoxide dismutase (CuZn-SOD), glutathione peroxidase (GSH-Px), and catalase (Cat) as well as selenium (Se), zinc (Zn) and copper (Cu) concentration in erythrocytes in 63 patients divided into the three groups: I--control group, II--normal pregnancy, III--pregnant type I diabetics. All parameters were investigated in hemolysate of erythrocytes. MDA concentration increased significantly in pregnant women when compared with control group, as well as in pregnant diabetics when compared with healthy pregnant women. The activity of GSH-Px decreased significantly in pregnant diabetics in comparison with groups I and II. The activity of CuZn-SOD and Cat was significantly lower in III group than in control group. The concentration of Se and Zn decreased, and the concentration of Cu increased significantly in pregnant diabetics in comparison with the other groups. No differences in concentration of MDA, Se, Zn, Cu and activity of GSH-Px were found between particular trimesters in studied patients. The activity of CuZn-SOD and Cat were significantly higher in III trimester than in II one in pregnant diabetics while the activity of GSH-Px remained unchanged during pregnancy. CONCLUSIONS: Increased lipid peroxidation and the lack of compensatory mechanisms--an increase in antioxidant enzymes activity as well as disorder of trace elements concentration are found in pregnant type I diabetics.

[Level of beta endorphins and insulin in blood of obese subjects. Effect of surgical treatment for obesity on higher exchange parameters]. / Stezenie beta-endorfiny i insuliny we krwi u otylych. Wplyw leczenia operacyjnego otylosci na wyzej wymienione parametry.

The basal and hyperglycaemia-stimulated secretion of glucose, IRI and beta-endorphin (BE) were studied in subjects who had gone surgical treatment for obesity few years ago and the results were compared with those of obese subjects and lean controls. 58 persons were divided into the following groups: A-obese subjects BMI > 30, B--obese subjects 25 < BMI < 30, C--subjects treated by truncal vagotomy and gastric banding, D--subjects treated by jejunoileostomy, E--control group BMI < 25. Oral glucose (75 g) tolerance test was performed in all subjects. Blood concentration of glucose, and serum concentration of IRI and BE were studied before and 30, 60, 90 and 120 minutes after ingestion of glucose. The basal levels and areas over basal values (AOBV) of investigated parameters were evaluated. Both the basal and glucose stimulated levels of IRI and BE were higher in the obese subjects than in the control group. Truncal vagotomy and gastric banding or jejunoileostomy resulted in reduction of IRI secretion without any decrease in BE levels. The alteration of the opioid system may play some role in the pathogenesis of obesity.