Biomedical subjects

D K Yue

Publications and source records attributed to D K Yue.

At least 37 records · Page 2Linked to original sources

PubMed1999

Angiotensin converting enzyme inhibition and arterial endothelial function in adults with Type 1 diabetes mellitus.

AIMS: Arterial endothelial dysfunction is a key early event in atherogenesis, and occurs in asymptomatic adults with Type 1 diabetes mellitus (DM). As angiotensin converting enzyme (ACE) inhibitors have been reported to reverse microvascular endothelial dysfunction acutely, we assessed the longer term effect of ACE inhibition on large vessel endothelial physiology in a randomized, crossover double-blind controlled clinical trial. METHODS: Flow-mediated arterial dilatation (FMD), which is largely due to endothelial release of nitric oxide, was assessed by vascular ultrasound in 20 Type 1 DM subjects with known endothelial dysfunction. These subjects, aged 28+/-5 years, were studied before and after 12 weeks oral therapy with either the ACE inhibitor perindopril 4 mg daily or the diuretic hydrene (triamterene 50 mg with hydrochlorothiazide 25 mg) daily. RESULTS: Although perindopril lowered both systolic and diastolic blood pressure by 2.7/3.2 mmHg, respectively (F3,78 = 4.7, P= 0.006; F3,78 = 3.2, P = 0.03), there was no significant effect of either perindopril or hydrene on FMD (baseline FMD before perindopril 4.6+/-2.5%, after 4.1+/-3.4%, baseline FMD before hydrene 5.4+/-3.6%, after 6.0+/-3.3%; F3,78= 1.9, P=0.1). Glycaemic control deteriorated slightly on hydrene whilst lipid levels, heart rate, resting blood flow and the arterial responses to nitroglycerine, a smooth muscle dilator, were unaffected by the treatment given. CONCLUSION: ACE inhibitor therapy for 3 months did not improve arterial endothelial function in Type 1 DM subjects.

Adult↗

PubMed1999

Competitive RT-PCR for measuring metalloproteinase gene expression in human mesangial cells exposed to a hyperglycemic environment.

Competitive reverse transcription (RT)-PCR is now considered a reliable technique for determining the relative or absolute copy number of target mRNAs in tissue or cells. The method relies on a synthetic RNA competitor molecule with identical sequences to the PCR primers that is added to the RT step allowing reproducible quantitation between samples. In this report, we demonstrate a strategy for developing competitive RT-PCR assays using a multi-template RNA competitor molecule that is synthesized using solely PCR-based techniques. The approach we describe is both cost- and time-effective and importantly, the approach saves RNA because it allows the simultaneous quantitation of three target mRNAs from as little as one microgram of total RNA. The procedure for preparing the RNA competitor molecule, the RT-PCR protocol and the use of the competitor molecule in our studies of diabetic nephropathy are described in detail.

Actins↗

PubMed1999

Augmentation of central arterial pressure in type 1 diabetes.

OBJECTIVE: Atherosclerosis is more severe in individuals with diabetes. Whether diabetic subjects have accelerated arterial hardening (i.e., arteriosclerosis) is less clear. Arteriosclerosis increases pulse-wave velocity and can augment central arterial pressure due to early wave reflection. The aim of this study was to determine whether subjects with type 1 diabetes had evidence of increased arterial stiffness by using pulse-wave analysis. RESEARCH DESIGN AND METHODS: Radial artery pressure waveforms were obtained noninvasively by applanation tonometry (PWV Medical Blood Pressure Analysis System, Sydney). A central aortic waveform can be derived by using a transfer function used in previous studies during cardiac catheterization. A total of 89 subjects with type 1 diabetes (46 men and 43 women, aged 34.0 +/- 11.0 years, duration of diabetes 13.1 years [interquartile range 5.8-24.3], HbA1c 8.2 +/- 1.7%) and 95 control subjects (44 men and 51 women, aged 36.1 +/- 12.0 years) were studied. The central aortic waveform allowed the determination of 1) the aortic augmentation index (AAI), a parameter that reflects the degree to which central arterial pressure is augmented by wave reflection, and 2) the subendocardial viability ratio (SEVR), which is a measure of myocardial perfusion relative to cardiac workload. RESULTS: In multivariate analysis, diabetes was an important determinant of AAI (P = 0.001). The higher AAI was mainly evident in the men, for whom diabetes was a highly significant covariate (P = 0.006); this was not the case for diabetic women (P = 0.2). Nondiabetic men had a lower AAI than nondiabetic women (103.7 +/- 18.6 vs. 117.0 +/- 22.3%, respectively, P = 0.002), but this difference was abolished by diabetes (110.7 +/- 18.5 vs. 116.1 +/- 18.7%, respectively, P = 0.2). Subjects with type 1 diabetes had a significantly lower mean SEVR compared with control subjects (139.2 +/- 28.3 vs. 163.6 +/- 27.4%, respectively, P < 0.0001). In multivariate analysis, diabetes was an important determinant of SEVR (P = 0.001). A significant interaction between diabetes and age was evident (P = 0.0001), which suggests that the effect of age is modified by diabetes. CONCLUSIONS: These findings suggest that central systolic blood pressure is increased in relatively young individuals with type 1 diabetes, although myocardial perfusion related to cardiac workload is decreased. These changes can be explained by more rapid pulse-wave velocity resulting from arterial stiffening.

Adolescent↗

PubMed1999

Possible sources of discrepancies in the use of the Semmes-Weinstein monofilament. Impact on prevalence of insensate foot and workload requirements.

OBJECTIVE: The purpose of this study was to evaluate the effects of different testing sites and buckling strengths on the sensitivity and specificity of using the Semmes-Weinstein monofilament to detect patients with insensate foot. The impact on workload required to educate and follow up these high-risk individuals was estimated by modeling in our patient population with a documented status of neuropathy. RESEARCH DESIGN AND METHODS: Using the 5.07/10-g monofilament, one observer tested 132 randomly selected subjects with diabetes at five sites on the right foot. The sensitivity and specificity of each site and combinations of sites in detecting vibration perception threshold > 40 was calculated. In addition, two monofilaments, one with a buckling force of 5 g and the other with a force of 15 g, were compared by testing 200 randomly selected patients. An estimate of the prevalence of insensate foot and workload was made by modeling the findings to the 5,270 patients with neuropathy status registered on our computerized database. RESULTS: Specificity of the 5.07/10-g monofilament to detect insensate foot at each of the five sites is high, at approximately 90%, but there is considerably more variation and lower sensitivity, ranging from 44-71%. Data derived from the use of different combinations of sites showed that more stringent criteria are associated with lower sensitivity but higher specificity. If the foot is considered insensate when either of sites 3 and 4 (plantar aspect of the first and fifth metatarsal heads, respectively) cannot feel the monofilament, there is reasonable sensitivity and specificity (80-86%, respectively). By modeling on our diabetes center population, it can be demonstrated that the choice of different methodologies leads to different conclusions about the prevalence of severe neuropathy, ranging from 3.4 to 29.3%. CONCLUSIONS: Using a combination of sites 3 and 4 for monofilament testing gives a reasonable compromise for time, sensitivity, and specificity. Minor changes in sensitivity and specificity can lead to major changes in the prevalence of neuropathy, with implications for workload.

Australia↗

PubMed1999

The role of the mesangial cell and its matrix in the pathogenesis of diabetic nephropathy.

Mesangial cells are pericyte-like cells which are found the glomeruli of the kidney. It is well known that they have important contractile and synthetic properties regulating the function of the glomerulus. During diabetes the synthesis of various extracellular matrix (ECM) components by mesangial cells are increased. In recent years it has been recognized that degradation of ECM may also be decreased in diabetes, contributing to the process of mesangium accumulation. The major enzymes responsible for ECM degradation are a large group of enzymes collectively known as matrix metalloproteinases (MMPs). The physiology of MMPs is complex and their activity is tightly regulated at many levels. The MMPs are synthesized as proenzymes and require activation via catalytic cleavage to become fully active. In this regard it is of importance that the mesangial cell and its pericellular matrix have a very active plasminogen cascade that can liberate plasmin locally to mediate matrix degradation both directly and indirectly, by activating the MMPs. In addition, the MMPs are regulated by transforming growth factor beta (TGF-beta). There is evidence that each of these pathways regulating the matrix degradation is affected by the diabetic environment and this will be the subject of this contribution.

Diabetic Nephropathies↗

PubMed1998

Use of the Semmes-Weinstein 5.07/10 gram monofilament: the long and the short of it.

The Semmes-Weinstein monofilament has been developed for the detection of patients at risk of neuropathic ulceration. In this study we evaluated how the physical characteristics of the monofilaments can impact on their performance. Commercially purchased monofilaments from the Hansen's Disease Center (HDC) and a batch produced 'in-house' (RPAH) were calibrated using a Mettler Balance. To assess the effects of varying lengths on buckling force, the monofilaments were tested repeatedly while the length of the filament was reduced stepwise from 4.1 to 3.1 cm. The correct length of the monofilament to generate a buckling force of 10 g was also determined theoretically by applying the Euler's Buckling Equation. Results showed neither batch of monofilaments buckled at a strength of 10 g (HDC 6.8 g, CI 5.7-7.9, and RPAH 7.2 g, CI 7.1-7.3). In addition HDC showed a wide interfilament variation range, 4.1-10.3 g with CV 29% versus corresponding figures of range 7.1-7.9 g, CV 4.9% for the RPAH monofilaments. As predicted by Euler's Buckling Theory, buckling force can be increased by reducing the length of the filament. These results demonstrate that the physical characteristics of the monofilament are important determinants of buckling force and are not necessarily uniform in commercial filaments. The clinical relevance of variance in buckling force remains to be determined.

Diabetic Neuropathies↗

PubMed1998

Better glycaemic control and risk reduction of diabetic complications in Type 2 diabetes: comparison with the DCCT.

OBJECTIVE: To construct dose response curves relating the development of diabetic complications (retinopathy and microalbuminuria) to mean glycaemic exposure in a cohort of Type 2 patients followed over a period of several years. This allows a comparison with similar data on Type 1 subjects reported by the Diabetes Control and Complications Trial (DCCT) and provides a rational basis for deciding what levels of glycaemic control should be aimed for in advising individual patients and in setting guidelines for conducting health services. RESEARCH DESIGN AND METHODS: This was an analysis of data prospectively collected in our computerized data base for Type 2 patients who attended and were followed up at the Complications Assessment Service of our Diabetes Center. The initial development of retinopathy and microalbuminuria was analyzed with respect to the mean HbA1c during the follow up period. Statistical procedures identical to those employed in the DCCT were used to construct the dose response curve. RESULTS: A smooth relationship between the development of retinopathy with increasing hyperglycaemia was found. For every 10% decrease in HbA1c, there was a 24%) (confidence interval (CI): 16-32) reduction in relative risk, about 2/3 of that reported for insulin-dependent diabetes mellitus (IDDM) patients. The relationship between microalbuminuria and HbAc was more linear and less steep with a relative risk reduction of 9% (CI: -2-19%) for any 10% fall in HbA1c, about 1/3 of that reported for IDDM subjects. No threshold of HbA1c can be found for the relative risk of developing complications. However, more cases of complications are prevented by the same degree of improvement in glycaemic control at higher levels of HbA1c. CONCLUSIONS: The development of diabetic retinopathy in Type 2 subjects is also related to the magnitude of hyperglycaemia although the degree of dependence is less than that in Type 1. Glycaemic control has less influence on microalbuminuria in Type 2. In terms of relative risk, no threshold of 'safe HbA1c' can be found but in absolute terms more cases of diabetic complications can be prevented by improving the glycaemic control of the very hyperglycaemic patients.

Albuminuria↗

PubMed1998

The use of Acarbose in Type 2 diabetic patients in secondary failure: effects on glycaemic control and diet induced thermogenesis.

Acarbose, an alpha-glucosidase inhibitor, delays the absorption of complex carbohydrates and sucrose, thereby lowering post-prandial blood glucose. In this study, we evaluated the effects of Acarbose on glycaemic control in Type 2 diabetic patients in secondary oral hypoglycaemic agent failure. Due to its mode of action, we also used indirect calorimetry to examine its effects on energy expenditure (EE), diet induced thermogenesis (DIT) and respiratory quotient (RQ) after a standard breakfast (440 calories with 60 g carbohydrates). A total of 12 patients (male/female, 8/4; age, 56+/-9 years; duration of diabetes 10.1+/-4.6 years; body mass index (BMI) 29.6 + 2.7 kg/m2) with poor glycaemic control (HbA1c, 8.8+/-0.9%) completed 8 weeks treatment with Acarbose (100 mg). After treatment, HbAlc was lower compared to the baseline (8.8+/-0.9% vs. 8.0+/-0.9%; t = 2.7; P = 0.02). Acarbose acutely lowered post-prandial blood glucose and insulin area under the curve by a mean of 16.9% and 9.2%, respectively. Long term changes in HbA1c correlated strongly with acute changes in blood glucose area due to Acarbose administration (r = 0.87; P < 0.01). There was a significant effect of Acarbose on EE and DIT for the first 120 min post meal (F3,92 = 3.4; P = 0.03, F2,69 = 6.3; P = 0.008, respectively). After Acarbose treatment, RQ was lower at 30 min compared to the baseline (0.86+/-0.04 before, and 0.83+/-0.05 after; t = 2.8; P = 0.02). In conclusion, Acarbose improves glycaemic control and changes post-prandial energy expenditure of Type 2 diabetic patients in secondary failure. The magnitude of long term reduction in hyperglycaemia differs amongst individuals. This is largely due to intrinsic variations in patients' response to Acarbose rather than differences in medication compliance or dietary composition.

Acarbose↗

PubMed1998

Does insulin therapy have a hypertensive effect in type 2 diabetes?

In this prospective study, the 24-h blood-pressure profile of 12 patients with type 2 diabetes was monitored before, at 6, and at 12 weeks after initiation of insulin therapy, to determine whether commencement of insulin therapy increases blood pressure in these patients. Insulin dosage adjustment was carried out by using a predetermined algorithm according to body weight and degree of hyperglycemia. The mean insulin dosage at 12 weeks was 72.9 +/- 3.9 units/day. This was associated with an increase in systolic blood pressure from 134.6 +/- 4.3 mm Hg to 144.8 +/- 4.5 mm Hg (p = 0.0001), diastolic blood pressure from 71.9 +/- 2.6 mm Hg to 74.9 +/- 2.2 mm Hg (p = 0.0001), and body mass index (BMI) from 27.2 +/- 0.8 kg/m2 to 29.6 +/- 0.8 kg/m2 (p = 0.0001). Multiple regression analysis showed insulin dosage to be a significant independent factor (p = 0.0003) accounting for 63% of the variance in blood pressure change after adjusting for age, diastolic blood pressure, and base HbA1c. We conclude that insulin therapy may have a deleterious effect on blood pressure in patients with type 2 diabetes. However, in the clinical setting, it is difficult to isolate this from the confounding effect of weight gain.

Blood Pressure Monitoring, Ambulatory↗

PubMed1998

Effect of glucose on matrix metalloproteinase activity in mesangial cells.

Mesangial cells are known to secrete matrix metalloproteinases (MMPs). These enzymes play a major role in the degradation and remodelling of extracellular matrix, and alterations in their activity may contribute to the mesangium enlargement of diabetic nephropathy. MMPs are secreted as latent forms which are cleaved in the pericellular environment to form active enzymes. In this study, we used a biosynthetically labelled matrix as substrate and conditioned medium obtained from mesangial cells, as a source of enzymes to investigate the effect of a high glucose concentration on degradative capacity. Inhibitor studies showed that MMPs were responsible for 72.2% of the degradation. A high glucose concentration caused a significant reduction in matrix degradation (low glucose 33.5 +/- 5.6%, high glucose 24.2 +/- 4.8%). Addition of aminophenyl mercuric acetate to activate latent MMPs increased matrix degradation by 2.3-fold in both low- and high-glucose media, but the decreased degradation caused by a high glucose concentration was still apparent. Activation with plasmin also increased matrix degradation and abolished the effect of the high glucose concentration. Gelatin zymography showed that mesangial cells grown at a low glucose concentration secreted both 72- and 92-kD gelatinases; however, at high glucose concentrations the 92-kD gelatinase was no longer apparent. These results suggest that a high glucose concentration causes a reduction in the amount of MMPs secreted by the mesangial cells. This reduction may contribute to the mesangium enlargement of diabetic nephropathy.

Cells, Cultured↗

PubMed1998

Administration of ascorbic acid and an aldose reductase inhibitor (tolrestat) in diabetes: effect on urinary albumin excretion.

The important role of ascorbic acid (AA) as an anti-oxidant is particularly relevant in diabetes mellitus where plasma concentrations of AA are reduced. This study was conducted to evaluate the effects of treatment with AA or an aldose reductase inhibitor, tolrestat, on AA metabolism and urinary albumin excretion in diabetes. Blood and urine samples were collected at 0, 3, 6, 9, and 12 months from 20 diabetic subjects who were randomized into two groups to receive either oral AA 500 mg twice daily or placebo. Systolic and diastolic blood pressures, HbA1c, plasma lipids, urinary albumin, and total glycosaminoglycan excretion were measured at all time points, and heparan sulphate (glycosaminoglycan) was measured at 0 and 12 months. The same parameters, as well as urinary AA excretion, were determined at 0 and 3 months for 16 diabetes subjects receiving 200 mg tolrestat/day. AA treatment increased plasma AA (ANOVA, F ratio = 12.1, p = 0.004) and reduced albumin excretion rate (AER) after 9 months (ANOVA, F ratio = 3.2, p = 0.03), but did not change the other parameters measured. Tolrestat lowered plasma AA (Wilcoxon's signed-rank test, p < 0.05), but did not change AER or the other parameters measured. The ability of AA treatment to decrease AER may be related to changes in extracellular matrix or improvement in oxidative defence mechanism. Unlike the rat model of diabetes, inhibition of aldose reductase did not normalize plasma AA or AER in humans. In fact, tolrestat reduced the plasma AA concentration, a phenomenon which may be due to increased utilization of AA. Dietary supplementation of AA in diabetic subjects may have long-term benefits in attenuating the progression of diabetic complications.

Administration, Oral↗

PubMed1997

Changes in the molecular structure of hair in insulin-dependent diabetes.

Low-angle synchrotron X-ray diffraction has revealed clear and consistent changes in the molecular structure of alpha-keratin of hair in insulin-dependent diabetes (IDDM) both for human IDDM subjects and for baboons with streptozocin induced diabetes. These changes in both meridional and equatorial intensity distributions are fully explained by a newly developed hexagonally packed model for keratin which locates the modification produced in hair in IDDM in the labile structure of the matrix at established intermediate filament linkage sites. The nature of the extracellular bonding suggests that the change is endogenous, occurring via the blood during the aggregation of the IFs in the follicle. The reproducibility of these changes indicate that hair may represent an easily accessible tissue for the study of how hyperglycaemia can modify extracellular matrix materials which lead to diabetic complications.

Adult↗

PubMed1997

High glucose reduces generation of plasmin activity by mesangial cells.

Mesangium enlargement is a central feature of diabetic nephropathy and almost certainly plays a pathogenic role in this condition. Previous studies have shown that mesangium degradation is reduced in a high glucose mileau. Plasmin has been shown to play an important role in extracellular matrix degradation, both directly and through its ability to activate the matrix metalloproteinases. We therefore investigated how high glucose concentration may affect the various components of the plasminogen cascade on mesangial cells and whether it impairs the ability of the mesangial cell to generate plasmin activity. Result showed decreased binding of plasminogen and the urokinase type plasminogen activator to the mesangial cell surface while the tissue type plasminogen activator and the plasminogen activator-1 associated with mesangial cells were increased. The net effect of these changes was a reduced capacity of mesangial cell layers to generate plasmin activity in a high glucose environment. We postulate that this may be of importance in the reduced mesangium degradation which occurs in diabetes.

Cell Membrane↗

PubMed1997

Very low calorie diet (VLCD): a useful alternative in the treatment of the obese NIDDM patient.

Conventional treatment of obese noninsulin dependent diabetes mellitus (NIDDM) patients is often unsatisfactory. In this study the efficacy of Modifast, a commercial very low calorie diet (VLCD), was evaluated in a population of obese poorly controlled NIDDM patients. The mechanisms of action of VLCD in these patients were also studied by comparing: (i) Plasma insulin and glucose profiles after a VLCD and an isocaloric mixed meal and (ii) plasma amino acid levels, both at baseline and after four weeks of VLCD treatment. A total of 14 obese NIDDM patients (M/F 7/7. median body mass index (BMI) 38.7 kg-2, interquartile range (IQ) 34.7-46.5 kg-2, waist circumference 116 cm, IQ 106-139 cm, insulin treated 7/14) with poor diabetic control (HbA1c 8.6%, IQ 7.8-10%) were studied. Patients were given a VLCD (425 kcal/day) for 12 weeks. At baseline, VLCD and isocaloric meal tests were performed on consecutive mornings. Fasting plasma amino acid levels were also determined at baseline and after 4 weeks of VLCD treatment. Weight, waist circumference, HbA1c, blood pressure, fasting plasma insulin, total cholesterol and triglyceride levels all fell significantly following VLCD treatment. Insulin therapy was able to be ceased in the seven insulin treated patients. Oral hypoglycaemic agent dosage fell from a median of eight (IQ 6-12) to two (IQ 0-8) tablets per day (P = 0.03) in patients initially on this form of therapy. Insulin secretion was higher after VLCD than isocaloric meal (P = 0.04). Fasting plasma alanine level fell from 512.0 (IQ 412.0-563.0) to 374.0 (IQ 342-472.0) mumol/l (P = 0.04) following VLCD treatment. In conclusion, the short term use of a VLCD is very effective in rapidly improving glycaemic control and promoting substantial weight loss in obese NIDDM patients. Moreover, a VLCD diet increases insulin secretion and reduces substrate for gluconeogenesis. Thus, VLCD treatment may improve glycaemic control by factors more than caloric restriction alone.

Adult↗

PubMed1997

Detection and treatment of hypertension in patients with non-insulin-dependent diabetes mellitus: does the 'rule of halves' apply to a diabetic population?

The extent to which hypertension is detected and adequately treated in the general population is often described by the 'rule of halves', but corresponding figures for patients with non-insulin-dependent diabetes mellitus (NIDDM), based on current American Diabetes Association (ADA) criteria, have not been previously reported. This study looked at the detection and management of hypertension among 2331 consecutive patients with NIDDM attending for annual complications assessment. Hypertension was defined according to ADA criteria, i.e. systolic blood pressure (sBP) > 140 mmHg and/or diastolic blood pressure (dBP) > 90 mmHg. A total of 69% of patients were hypertensive, with proportionately more women in the hypertensive group (48 versus 39%, P < 0.002). Among those with hypertension, 59% were taking antihypertensive drugs but only 31% of treated hypertensives were adequately controlled. Thus, hypertension affects roughly two-thirds of patients with NIDDM and compared with treatment strategies reported in the literature for the non-diabetic population (summarised in the 'rule of halves'), proportionately more hypertensive patients with NIDDM are treated with BP-lowering drugs (59%) but proportionately less (31%) have adequate BP control.

Australia↗

PubMed1997

High glucose inhibits effect of ascorbic acid on [35S] sulphate incorporation in mesangial cell and matrix proteoglycan.

Expansion of the glomerular mesangium is a consistent finding of diabetic nephropathy. Negatively charged proteoglycans are an integral part of the mesangium and their synthesis and degradation is disturbed in many forms of glomerulosclerosis. The metabolism of ascorbic acid (AA), which plays an important role in extracellular matrix regulation, is known to be abnormal in diabetes. The action of AA has also been shown to be inhibited by high glucose (HG) concentration. In this study we investigated the effect of AA and HG on proteoglycan (PG) synthesis by examining the incorporation of [35S] sulphate into PG in the cellular, matrix and media components of rat mesangial cell (MC) cultures. MC were grown in 9 or 25 mM glucose for 8 days, with and without the addition of AA. Sulphation of PG was measured by adding 50 microCi of [35S] sulphuric acid to the culture medium and precipitating 35S-labelled PG with cetylpyridinium chloride. In this study AA was shown to have a stimulatory effect on the overall incorporation of [35S] sulphate into cell and matrix PG and this was inhibited by 25 mM glucose. Correcting for protein synthesis and specific activity of [35S] sulphate showed that HG inhibits AA stimulation by decreasing sulphation of the individual PG molecules. These findings may be of particular importance in the pathophysiology of nephropathy in diabetes, a condition where AA concentration is already compromised.

Analysis of Variance↗

PubMed1996

Comparative effects of indapamide and captopril on blood pressure and albumin excretion rate in diabetic microalbuminuria.

Nephropathy affects about one third of diabetic patients and its onset can be predicted almost a decade in advance by detecting small quantities of albumin in the urine (microalbuminuria). Thus, detection of proteinuria or microalbuminuria in diabetic patients carries important implications and merits intervention. Strategies for delaying the relentless progression of microalbuminuria to diabetic nephropathy and ultimately end-stage renal failure are focused on improving glycemic control and reducing blood pressure. Studies with beta-blockers, calcium antagonists, diuretics, and angiotensin-converting enzyme (ACE) inhibitors in hypertensive diabetics with microalbuminuria have shown a significant reduction in urinary albumin excretion rates (AER), with effective lowering of blood pressure. In a crossover study, we compared the effects of captopril versus indapamide as monotherapy for 12 weeks on AER and blood pressure in 31 diabetic patients with established microalbuminuria. The 2 drugs were equally effective in reducing AER (average reduction 30-40%) and had comparable antihypertensive effects.

Albuminuria↗

PubMed1996

Reduction of leucocyte proteolytic enzyme activity in diabetic patients with microalbuminuria and proteinuria: its possible role in diabetic nephropathy.

Mesangium enlargement and glomerular basement membrane thickening are cardinal features of diabetic nephropathy. The reasons for these changes are uncertain but decreased degradation of extracellular matrix may play a role. Mesangium degradation can be modulated by factors intrinsic to the kidney or by factors in the circulation. In this study the capacity of leucocyte proteolytic enzymes to degrade mesangium matrix materials was investigated. Leucocytes were obtained from 57 patients with NIDDM (age 58.3 +/- 8.8 years, duration 9.4 +/- 7.3 years, body mass index (BMI) 30 +/- 6 kg m-2, HbA1c 7.7 +/- 2.0%) and 21 control subjects (age 55.1 +/- 14.6 years, BMI 25 +/- 4 kg m-2). Leucocyte lysates from control and NIDDM subjects with normal AER degraded matrix to the same extent (40.6 +/- 8.2% vs 42.9 +/- 13.5%) while lysates from patients with microalbuminuria and proteinuria were less able to degrade matrix (33.0 +/- 14.2% and 26.1 +/- 12.7%, respectively). There was a significant inverse correlation between matrix degradation and AER (r = -0.49) and multiple regression analysis showed that AER was the most important factor determining degradation rate (R2 = 0.24). Degree of metabolic control, age, and blood pressure were not significant factors. The major enzyme(s) responsible for the matrix degradation was identified as metalloproteinase(s). We conclude that leucocytes from diabetic patients with abnormal albumin excretion have a decreased proteolytic capacity to degrade extracellular matrix. This may play a role in the glomerular basement membrane thickening and mesangium expansion which occurs in diabetic nephropathy.

Albuminuria↗