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Summary: We tested whether GPRC6A, the putative receptor of undercarboxylated osteocalcin (ucOC), is present in mouse muscle and whether ucOC increases insulin sensitivity following ex vivo muscle contraction. GPPRC6A is expressed in mouse muscle and in the mouse myotubes from a cell line. ucOC potentiated the effect of ex vivo contraction on insulin sensitivity. Introduction: Acute exercise increases skeletal muscle insulin sensitivity. In humans, exercise increases circulating ucOC, a hormone that increases insulin sensitivity in rodents. We tested whether GPRC6A, the putative receptor of ucOC, is present in mouse muscle and whether recombinant ucOC increases insulin sensitivity in both C2C12 myotubes and whole mouse muscle following ex vivo muscle contraction. Methods: Glucose uptake was examined in C2C12 myotubes that express GPRC6A following treatment with insulin alone or with insulin and increasing ucOC concentrations (0.3, 3, 10 and 30 ng/ml). In addition, glucose uptake, phosphorylated (p-)AKT and p-AS160 were examined ex vivo in extensor digitorum longus (EDL) dissected from C57BL/6J wild-type mice, at rest, following insulin alone, after muscle contraction followed by insulin and after muscle contraction followed by recombinant ucOC then insulin exposure. Results: We observed protein expression of the likely receptor for ucOC, GPRC6A, in whole muscle sections and differentiated mouse myotubes. We observed reduced GPRC6A expression following siRNA transfection. ucOC significantly increased insulin-stimulated glucose uptake dose-dependently up to 10 ng/ml, in differentiated mouse C2C12 myotubes. Insulin increased EDL glucose uptake (∼30 %, p < 0.05) and p-AKT and p-AKT/AKT compared with rest (all p < 0.05). Contraction prior to insulin increased muscle glucose uptake (∼25 %, p < 0.05), p-AKT, p-AKT/AKT, p-AS160 and p-AS160/AS160 compared with contraction alone (all p < 0.05). ucOC after contraction increased insulin-stimulated muscle glucose uptake (∼12 % p < 0.05) and p-AS160 (<0.05) more than contraction plus insulin alone but without effect on p-AKT. In the absence of insulin and/or of contraction, ucOC had no significant effect on muscle glucose uptake. Conclusions: GPRC6A, the likely receptor of osteocalcin (OC), is expressed in mouse muscle. ucOC treatment augments insulin-stimulated skeletal muscle glucose uptake in C2C12 myotubes and following ex vivo muscle contraction. ucOC may partly account for the insulin sensitizing effect of exercise. [ABSTRACT FROM AUTHOR]

In studies of antihypertensive therapy, relative cardiovascular (CV) risk reduction is largely independent of attained systolic blood pressure (SBP). How this translates to absolute risk reduction (ARR) in diabetes is not clear. We have compared 5-year CV outcomes in 10 studies of intensive versus moderate or active versus placebo therapy in subjects with type 2 diabetes and attained SBP

BACKGROUND/OBJECTIVES:Single-slice abdominal computed tomography or magnetic resonance imaging (MRI) performed to measure visceral adipose tissue in individuals with obesity and diabetes mellitus can also image skeletal muscle. The aim of this study was to validate a method developed in cancer patients using a single abdominal cross-sectional image to estimate fat-free mass (FFM) and appendicular lean tissue mass index (LTMI), a total body skeletal muscle mass surrogate, in an obese cohort of subjects with and without type 2 diabetes.SUBJECTS/METHODS:In total, 49 obese subjects (22 with diabetes) recruited into a weight loss study underwent dual-energy X-ray absorptiometry (DXA) and abdominal MRI at baseline. DXA-derived FFM and LTMI were compared with skeletal muscle area at the level of the third lumbar vertebra (L3) on MRI.RESULTS:L3 skeletal muscle area correlated with FFM (R adj 2=0.825; P<0.001) and LTMI (R adj 2=0.6; P<0.001). A simple formula, previously shown to predict LTMI in cancer patients, produced a good estimation of LTMI from L3 skeletal muscle area (95% confidence interval −3.70, 2.56%) in our obese cohort. Equations incorporating age, sex, height, weight and diabetic status improved the relationship between L3 skeletal muscle area and estimated FFM (r=0.976, P<0.001) and LTMI (r=0.879, P<0.001).CONCLUSION:A single-axial slice at the L3 level can be used to estimate FFM and LTMI in obese diabetic and non-diabetic subjects, allowing precise analysis of body composition using a single imaging modality in clinical research and practice. [ABSTRACT FROM AUTHOR]

Summary: The purpose of this study was to examine if the reduction in glucose post-exercise is mediated by undercarboxylated osteocalcin (unOC). Obese men were randomly assigned to do aerobic or power exercises. The change in unOC levels was correlated with the change in glucose levels post-exercise. The reduction in glucose post-acute exercise may be partly related to increased unOC. Introduction: Osteocalcin (OC) in its undercarboxylated (unOC) form may contribute to the regulation of glucose homeostasis. As exercise reduces serum glucose and improves insulin sensitivity in obese individuals and individuals with type 2 diabetes (T2DM), we hypothesised that this benefit was partly mediated by unOC. Methods: Twenty-eight middle-aged (52.4 ± 1.2 years, mean ± SEM), obese (BMI = 32.1 ± 0.9 kg m) men were randomly assigned to do either 45 min of aerobic (cycling at 75% of VO) or power (leg press at 75% of one repetition maximum plus jumping sequence) exercises. Blood samples were taken at baseline and up to 2 h post-exercise. Results: At baseline, unOC was negatively correlated with glucose levels ( r = −0.53, p = 0.003) and glycosylated haemoglobin (HbA1c) ( r = −0.37, p = 0.035). Both aerobic and power exercises reduced serum glucose (from 7.4 ± 1.2 to 5.1 ± 0.5 mmol L, p = 0.01 and 8.5 ± 1.2 to 6.0 ± 0.6 mmol L, p = 0.01, respectively). Aerobic exercise significantly increased OC, unOC and high-molecular-weight adiponectin, while power exercise had a limited effect on OC and unOC. Overall, those with higher baseline glucose and HbA1c had greater reductions in glucose levels after exercise ( r = −0.46, p = 0.013 and r = −0.43, p = 0.019, respectively). In a sub-group of obese people with T2DM, the percentage change in unOC levels was correlated with the percentage change in glucose levels post-exercise ( r = −0.51, p = 0.038). Conclusions: This study reports that the reduction in serum glucose post-acute exercise (especially aerobic exercise) may be partly related to increased unOC. [ABSTRACT FROM AUTHOR]

Glomerular filtration rate is commonly elevated in early diabetes and patients with this symptom are arbitrarily considered to have hyperfiltration. The prevalence of hyperfiltration in type 1 diabetes varies from less than 25% to more than 75%. The corresponding figures in type 2 diabetes are significantly lower, ranging between 0% and more than 40%. Several factors, methodological and biological, may contribute to the wide variation in estimates of hyperfiltration prevalence. Methodological differences in measurement and evaluation of GFR apply in particular to the handling of plasma disappearance curves of filtration markers. Biological factors that may influence GFR in the hyperfiltration range include glycaemic control, diabetes duration, BMI, sex, pubertal status in type 1 diabetes and age in type 2 diabetes. Hyperglycaemia may influence GFR and albuminuria, and may therefore confound the evaluation of hyperfiltration as an independent risk factor for diabetic nephropathy. Adequate assessment of the relationship between glycaemic control, GFR and AER therefore requires serial measurements of all three variables followed by multivariate analysis. A recent meta-analysis of ten type 1 diabetes studies concluded that the presence of hyperfiltration at baseline more than doubled the risk of developing micro- or macroalbuminuria at follow-up. However, not all studies allowed for confounding factors or regression dilution bias. Future studies will therefore need to address the independent role of hyperfiltration, not only in the evolution of albuminuria, but also in the subsequent decline of GFR. [ABSTRACT FROM AUTHOR]

We assessed the effects of sodium chloride (NaCl) supplementation on the blood pressure response to treatment with telmisartan with or without hydrochlorothiazide in hypertensive patients with type 2 diabetes and habitually high (HDS, sodium excretion >200 mmol/24 h on two out of three consecutive occasions) or low (LDS, sodium excretion <100 mmol/24 h on two out of three consecutive occasions) salt intake. Patients received 4 weeks of telmisartan followed by 4 weeks of telmisartan plus hydrochlorothiazide. In a double-blind randomised fashion, patients received sodium chloride (NaCl, 100 mmol/24 h) or placebo capsules in addition to their habitual salt intake during the last 2 weeks of telmisartan and telmisartan plus hydrochlorothiazide therapy. The protocol was repeated with NaCl and placebo capsules administered in reverse order to allow each participant to act as his or her own control. At 0, 4, 8, 14, 18 and 22 weeks, 24 h ambulatory blood pressure (ABP) and 24 h urine collections were performed. No statistically significant differences were seen in the ABP response in the LDS vs HDS groups to any of the interventions ( p = 0.58). NaCl supplementation reduced the effect of telmisartan with or without hydrochlorothiazide on systolic BP by approximately 50% (−5.8 mmHg during NaCl supplementation vs −11.3 mmHg during placebo, mean difference 5.6 mmHg [95% CI 1.7–9.4 mmHg], p = 0.005), irrespective of habitual salt intake. By contrast, addition of hydrochlorothiazide increased the antihypertensive effect of telmisartan on systolic BP by approximately 35% ( p = 0.048) in both groups of patients. NaCl supplementation blunts the effectiveness of telmisartan with or without hydrochlorothiazide in hypertensive patients with type 2 diabetes, independently of habitual low or high salt intake. Australian Clinical Trials Registry ACTRN012606000128594 This work was supported by a Pfizer Cardiovascular-Lipid Research Grant and an unconditional educational grant from Boehringer Ingelheim. During the period of this work, E. I. Ekinci was supported by grants from the Austin Hospital Medical Research Foundation and the National Health and Medical Research Council. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: We compared the predictive performance of a GFR based on serum cystatin C levels with commonly used creatinine-based methods in subjects with diabetes. Subjects, materials and methods: In a cross-sectional study of 251 consecutive clinic patients, the mean reference (plasma clearance of 99mTc-diethylene-triamine-penta-acetic acid) GFR (iGFR) was 88±2 ml min-1 1.73 m-2. A regression equation describing the relationship between iGFR and 1/cystatin C levels was derived from a test population (n=125) to allow for the estimation of GFR by cystatin C (eGFR-cystatin C). The predictive performance of eGFR-cystatin C, the Modification of Diet in Renal Disease 4 variable formula (MDRD-4) and Cockcroft-Gault (C-G) formulas were then compared in a validation population (n=126). Results: There was no difference in renal function (ml min-1 1.73 m-2) as measured by iGFR (89.2±3.0), eGFR-cystatin C (86.8±2.5), MDRD-4 (87.0±2.8) or C-G (92.3±3.5). All three estimates of renal function had similar precision and accuracy. Conclusions/interpretation: Estimates of GFR based solely on serum cystatin C levels had the same predictive potential when compared with the MDRD-4 and C-G formulas. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: We sought to characterise the effect of the age-related decline of GFR on hyperfiltration in type 2 diabetes and to identify clinical characteristics associated with hyperfiltration. Materials and methods: GFR was measured in 662 type 2 diabetic patients by plasma disappearance of 99 m-technetium-diethylene-triaminepenta-acetic acid. The prevalence of hyperfiltration was calculated using both an age-unadjusted GFR threshold of »130 ml min-1 1.73 m-2 and an age-adjusted threshold incorporating a decline of 1 ml min-1 year-1 after the age of 40. The hyperfiltering patients were compared with type 2 diabetic subjects who had a GFR between 90 and 130 ml min-1 1.73 m-2 and were matched for age, sex and disease duration to allow for identification of modifiable factors associated with hyperfiltration. Results: The prevalence of hyperfiltration was 7.4% when age-unadjusted and 16.6% when age-adjusted definitions were used. The age-unadjusted vs -adjusted prevalence rates for hyperfiltration were 50 vs 50%, 12.9 vs 23.4% and 0.3 vs 9.0% for patients aged «40 years, 40 to 65 years and »65 years, respectively. Both the age-unadjusted and -adjusted hyperfiltration groups had lower mean diastolic blood pressure and lower serum creatinine levels than the control groups. Although the age-unadjusted hyperfiltration group had larger kidneys compared to the control group, this difference was no longer significant when the age-adjusted definition was used. There were no differences in HbA1c, mean arterial pressure, antihypertensive use, insulin therapy, dyslipidaemia, frequency of macro- or microvascular complications, BMI, urinary sodium, urea and albumin excretion between the groups. Conclusions/interpretation: Hyperfiltration was still more common among younger patients with type 2 diabetes even after adjusting for the expected age-related decline in GFR. Hyperfiltration was associated with a lower mean diastolic blood pressure independent of age. [ABSTRACT FROM AUTHOR]

Aims/hypothesis. Diabetic renal disease has been postulated to progress as a result of an interaction between metabolic and haemodynamic pathways. Our aim was to assess the functional, structural, molecular and cellular aspects of renal disease in an experimental model of diabetes with associated hypertension. Method. Streptozotocin-induced diabetic spontaneously hypertensive rats were randomised to no treatment, the ACE inhibitor, perindopril (2 mg/l), the AGE formation inhibitor, aminoguanidine (1 g/l) and a combination of both agents and were followed for 32 weeks. Results. Diabetes was associated with a considerable increase in albumin excretion rate. Both aminoguanidine and perindopril retarded the increase in albuminuria, which was completely abrogated by combination therapy. Glomerulosclerosis and tubulointerstitial damage was reduced by both monotherapies with further renoprotection afforded by combination therapy in both cases. Combination therapy was also associated with a superior restoration in diabetes-induced nephrin protein depletion compared to either monotherapy. TGFβ1 expression as assessed by in situ hybridisation was increased in the diabetic rats and reduced by perindopril and aminoguanidine. Conclusion/interpretation. These findings indicate that in the context of diabetes-related renal injury, blocking both the renin-angiotensin and advanced glycation pathways offers superior renoprotection and could be considered as a therapeutic strategy in the prevention and retardation of progressive-diabetic renal injury. [ABSTRACT FROM AUTHOR]

Aims/hypothesis. We aimed to examine the time course for the diabetes-related changes in renal lysosomal processing and to determine whether these changes can be prevented by aminoguanidine or ramipril treatment. Methods. The percentage desulphation of intravenously injected tritium labelled dextran sulphate ([3H]DSO4) in the urine, as determined by ion-exchange chromatography, was used as a marker of lysosomal sulphatase activity. Sulphatase activity was determined 1, 2, 3 and 4 weeks after the onset of diabetes in rats as well as in rats treated with either aminoguanidine or ramipril for twelve weeks. Results. The amount of totally desulphated [3H]DSO4 in urine collected from control rats was 65.6 ± 0.8 %. This was significantly reduced in diabetic rats two (57.4 ± 1.4 % desulphated), three (56.8 ± 1.3 % desulphated) and four (52.9 ± 2.2 % desulphated) weeks after the onset of diabetes. The significant decrease in the amount of totally desulphated [3H]DSO4 in the urine also found at 12 weeks after the onset of diabetes was not affected by drug treatment. There was no significant difference in the amount of partially desulphated [3H]DSO4 in the urine between all the study groups. However, the increase in totally sulphated [3H]DSO4 in the urine collected from diabetic rats (8.7 ± 1.7 % sulphated) compared with that of control rats (2.2 ± 0.5 % sulphated) was normalised by treatment with both aminoguanidine (4.8 ± 1.6 % sulphated) or ramipril (4.5 ± 0.8 % sulphated). Conclusions/interpretation.These results raise the possibility that the diabetes-induced changes in renal lysosomal processing may be one of the initial events in the development of diabetic nephropathy. Aminoguanidine and ramipril, known for their different mechanism of action, seem to prevent diabetes-induced changes in lysosomal processing either through their effects on enzyme activity within the lysosome or through their effects on the trafficking of molecules to and from the lysosome. [Diabetologia (2001) 44: 230–236] [ABSTRACT FROM AUTHOR]

Aims/hypothesis. ALT-946, an inhibitor of advanced glycation with a minimal inhibitory effect on nitric oxide synthase, was compared with aminoguanidine in experimental diabetic nephropathy.¶Methods. In vitro and in vivo assays were used to assess the ability of ALT-946 to inhibit AGE-protein cross-link formation. Diabetic animals were randomly allocated into groups receiving aminoguanidine for 32 weeks, ALT-946 or vehicle (untreated). As a delayed intervention protocol, an additional diabetic group was treated with ALT-946 from week 16 to week 32 of the study. Non-diabetic rats were studied concurrently. Systolic blood pressure, body weight, plasma glucose, glycated haemoglobin and urinary albumin excretion were measured serially. Accumulation of advanced-glycation end products in the kidney was assessed by immunohistochemistry.¶Results. The ALT-946 inhibitor was more potent than aminoguanidine in inhibiting AGE-protein cross-linking both in vitro and in vivo. Increased albuminuria observed in diabetic rats was attenuated in all three treatment groups. We found no difference in body weight, blood pressure or glycaemic control with any of the treatments. The untreated diabetic group had a twofold increase in glomerular staining for advanced-glycation end products compared with the diabetic groups which received treatment.¶Conclusion/interpretation. ALT-946 is a potent inhibitor of advanced renal glycation end-product accumulation and reproduces the renoprotective effects of aminoguanidine. Therefore, ALT-946 should be considered as a treatment for preventing or retarding diabetic nephropathy. [Diabetologia (2001) 44: 108–114] [ABSTRACT FROM AUTHOR]

Aims/hypothesis. Angiotensin converting enzyme (ACE) inhibition has been recently suggested to have retinoprotective actions in diabetic patients but the mechanism of this effect is not known. In vitro, angiotensin II stimulates expression of vascular endothelial growth factor (VEGF), a permeability-inducing and endothelial cell specific angiogenic factor which has been implicated in the pathogenesis of diabetic retinopathy in humans and in experimental animals. We sought to determine the effects of ACE inhibition on retinal VEGF expression and permeability in experimental diabetic retinopathy.¶Methods. Streptozotocin-induced diabetic rats and control animals were assigned at random to receive ACE inhibitor treatment or vehicle. At 24 weeks the retinal VEGF protein gene expression was assessed by northern blot analysis and in situ hybridisation. Retinal permeability to albumin was measured using a double isotope technique.¶Results. Experimental diabetes was associated with cell specific two to fourfold increase in retinal VEGF protein gene expression (p < 0.01) and a 2-fold increase in retinal vascular permeability to albumin (p < 0.01). The localization of VEGF expression in the retina was not altered in animals with experimental diabetes. Angiotensin converting enzyme inhibitor treatment of diabetic rats reduced diabetes-associated changes in VEGF gene expression and vascular permeability.¶Conclusion/interpretation. These findings implicate the renin-angiotensin system in the VEGF overexpression and hyperpermeability which accompany diabetic retinopathy and provide a potential mechanism for the beneficial effects of ACE inhibition in diabetic retinal disease. [Diabetologia (2000) 43: 1360–1367] [ABSTRACT FROM AUTHOR]

Aims/ hypothesis. Previous studies in our laboratory have shown that the vascular changes in diabetes include hypertrophy of the mesenteric vasculature and that this process can be attenuated by the inhibition of advanced glycation with aminoguanidine. Since aminoguanidine can also act as an inhibitor of nitric oxide synthase, the effect of a novel inhibitor of advanced glycation end-products, formation that does not inhibit nitric oxide synthase, known as 2,3 diaminophenazine (2,3 DAP) was evaluated. Methods. Initially, in vitro assessment of the ability of 2,3 diaminophenazine to inhibit formation of advanced glycation products was performed. Subsequently, in vivo studies evaluating 2,3 diaminophenazine and aminoguanidine were carried out. Animals were followed for 3 weeks after induction of diabetes and randomised to no treatment, aminoguanidine or 2,3 diaminophenazine. Mesenteric vessels were weighed and advanced glycation end-products were measured by radioimmunoassay in vessel and kidney homogenates. In addition, these products were assessed in mesenteric vessels by immunohistochemistry. Results. When compared with control animals, diabetes was associated with an increase in mesenteric vascular weight. Treatment of diabetic rats with aminoguanidine or 2,3 diaminophenazine resulted in attenuation of vascular hypertrophy. Both aminoguanidine and 2,3 diaminophenazine reduced the formation of advanced glycation end-products as measured by radioimmunoassay and as assessed immunohistochemically in these vessels. This reduction was also observed in the kidney. Conclusion/ interpretation. These data support the concept that the effects of aminoguanidine in reducing diabetes associated vascular hypertrophy are via inhibition of advanced glycation end-products dependent pathways. [Diabetologia (1999) 42: 472–479] [ABSTRACT FROM AUTHOR]

Advanced glycation end products (AGEs) have previously been shown to be increased in the diabetic kidney. Aminoguanidine, an inhibitor of advanced glycation, has been shown to attenuate the development of AGEs as well as the progression of renal disease in experimental diabetes. However, the precise mechanisms through which aminoguanidine acts remain to be elucidated since it is also able to act as an inhibitor of nitric oxide synthase (NOS). This study has therefore compared the effects of aminoguanidine with the effects of two other inhibitors of NOS, L -NAME and methylguanidine, on the development of experimental diabetic nephropathy. Diabetic rats were randomised to receive no treatment, aminoguanidine (1 g/l in drinking water), L -NAME (5 mg/l in drinking water) or methylguanidine (1 g/l in drinking water). Diabetic rats had increased levels of albuminuria and urinary nitrite/nitrate excretion when compared to control rats. Renal AGEs measured by fluorescence as well as by a carboxymethyllysine reactive radioimmunoassay, were elevated in diabetic rats. No changes in inducible NOS (iNOS) protein expression were detected in experimental diabetes nor did aminoguanidine affect iNOS expression. Aminoguanidine did not affect blood glucose or HbA1c but it did prevent increases in albuminuria, urinary nitrites/nitrates and renal AGE levels as measured by fluorescence and radioimmunoassay. L -NAME and methylguanidine did not retard the development of albuminuria, nor did they prevent increases in renal AGE levels, as assessed by fluorescence. However, these treatments did prevent increases in AGEs, as measured by radioimmunoassay. This study indicates that the renoprotective effect of aminoguanidine in experimental diabetes cannot be reproduced by L -NAME or methylguanidine. It is likely that the effect of aminoguanidine is mediated predominantly by decreased AGE formation rather than via NOS inhibition. It also raises the possibility that inhibition of fluorescent AGE formation may be more renoprotective than inhibition of the formation of carboxymethyllysine-containing AGEs. [Diabetologia (1997) 40: 1141–1151] [ABSTRACT FROM AUTHOR]

Renal enlargement is a characteristic feature of human and experimental diabetes mellitus that may be predictive of subsequent nephropathy. In the streptozotocin diabetic rat kidney growth rapidly follows the induction of experimental diabetes but the mechanisms responsible for this growth are poorly understood. Epidermal growth factor (EGF) is a potent mitogen for renal tubular cells. Thirty one male Sprague-Dawley rats aged 13 weeks were randomised to receive either streptozotocin (diabetic, n = 20) or buffer (control, n = 11). Animals were studied on days 1, 3, 5 and 7 following streptozotocin. Diabetes was associated with a 3-fold increase in urinary EGF excretion (223 ± 15 vs 59 ± 5 ng/day, mean ± SEM, diabetic vs control, p < 0.0001) and 3–6 fold increase in renal EGF mRNA relative to controls ( p < 0.001). A transient rise in kidney EGF protein was noted on day 1. There was no difference between diabetic and control animals with regard to intrarenal sites of EGF expression or in plasma EGF. These data suggest that the increased urinary EGF excretion in diabetic animals is the result of enhanced local production and that EGF is not stored for a prolonged period within renal tubular cells but is released following its synthesis. In the context of the known intrarenal actions of EGF this growth factor may play a role in the pathogenesis of diabetes related kidney growth. [Diabetologia (1997) 40: 778–785] [ABSTRACT FROM AUTHOR]

Advanced glycation is an important pathogenic mechanism in the development of diabetic complications. However, other biochemical processes, such as the polyol pathway or lipid and protein oxidation which can interact with advanced glycation can also yield tissue fluorescence and may also be implicated in the genesis of diabetic microangiopathy. Aminoguanidine is an inhibitor of advanced glycation, but it is not known if all of its effects are mediated by this mechanism. The present study explores the relative contributions of aldose reductase, oxidative stress and advanced glycation on the development of aortic and renal fluorescence and urinary albumin excretion in streptozotocin diabetic rats. The study groups included non-diabetic (control), streptozotocin diabetic rats and diabetic rats receiving aminoguanidine, the anti-oxidants butylated hydroxytoluene and probucol and the aldose reductase inhibitor, ponalrestat. Serial measurements of glycaemic control and urinary albumin excretion were performed every 8 weeks. At 32 weeks, animals were killed, tissues removed and collagen extracted for measurement of fluorescence. Diabetic rats had increased fluorescence in aorta, glomeruli and renal tubules. Aminoguanidine prevented an increase in fluorescence at all three sites suggesting that diabetes-related tissue fluorescence is predominantly due to advanced glycation. Ponalrestat retarded fluorescence in aorta only and butylated hydroxytoluene attenuated fluorescence at the renal sites but not in the aorta. Diabetic rats had increased renal cortical sorbitol levels. Ponalrestat normalized renal cortical sorbitol levels but aminoguanidine did not affect this parameter. The only agent to decrease plasma thiobarbituric acid reactive substances was butylated hydroxytoluene. Diabetic rats developed albuminuria over the 32-week period. This increase in urinary albumin excretion was only attenuated significantly by aminoguanidine therapy, but not by probucol or ponalrestat. The effects of butylated hydroxytoluene on albuminuria were intermediate between aminoguanidine-treated and untreated diabetic rats. The failure of either antioxidants or aldose reductase inhibition to reproduce the renal effects of aminoguanidine suggest that aminoguanidine may act predominantly via inhibition of advanced glycation and not via the alternative biochemical processes evaluated in this study. [ABSTRACT FROM AUTHOR]

This study has explored the temporal relationship between apoprotein(a), blood pressure and albuminuria over a mean interval of 11 years in a cohort of 107 diabetic patients of whom 26 (14 Type 2 (non-insulin-dependent), 12 Type 1 (insulin-dependent) had progressively increasing albuminuria ('progressors'). In Type 2 diabetic patients, no significant differences were noted for HbA, blood pressure, creatinine clearance or serum lipids between progressors and non-progressors. In Type 1 diabetic patients, final systolic and diastolic blood pressures were higher in progressors compared with non-progressors and progressors showed impairment of renal function in association with a rise in blood pressure at the macroalbuminuric stage. Initial apoprotein(a) levels were similar in progressors and non-progressors of either diabetes type. Apoprotein(a) levels increased exponentially with time in 12 of 14 Type 2 progressors but only in 5 of 12 Type 1 progressors ( p<0.01). In Type 2 diabetic patients, the annual increase in apoprotein(a) levels was 9.1±2.4%, which was significantly greater than in non-progressors, 2.0±1.2% ( p<0.01) and also exceeded the rates of increase of apoprotein(a) in progressors with Type 1 diabetes, 4.0±1.4%, ( p<0.05). Apoprotein(a) levels correlated significantly with albuminuria in 8 of 14 Type 2 progressors but only in 3 of 12 Type 1 progressors ( p<0.05). The rate of increase of apoprotein(a) levels was not related to mean HbA, creatinine or creatinine clearance levels, or to albuminuria. The rate of rise of apoprotein(a) was not influenced by initial apoprotein(a) levels, suggesting that specific apoprotein(a) isoforms do not influence albuminuria-related increases in apoprotein(a). The data are consistent with the hypothesis that apoprotein(a) levels increase in response to albuminuria and may be part of a self-perpetuating process. This study also suggests that increases in apoprotein(a) levels commence during the microalbuminuria stage in diabetic patients, which is earlier than has been documented in non-diabetic proteinuria. [ABSTRACT FROM AUTHOR]

Case histories of five patients are presented who developed severe postural hypotension after being treated with guanacline. The postural hypotension did not develop until treatment had been given for 3-4 months and has persisted following withdrawal of guanacline for 12-15 months. It is suggested that this drug causes irreversible depletion of noradrenaline stores in adrenergic nerve terminals in some patients. [ABSTRACT FROM AUTHOR]

In this issue of Diabetologia, two new approaches are described for the assessment of intra-renal blood flow in people with diabetes. The first approach used the technique of dynamic assessment of the resistance index (RI) in the renal interlobar arteries before and after administration of sublingual glyceryl trinitrate, and the second used MRI to assess total renal blood flow in relation to mean arterial pressure, thereby enabling direct measurement of overall renal RI. The results of the first study raise the possibility that dynamic evaluation of the intra-renal RI could be used as an early detector of vascular alterations in type 2 diabetes, before the onset of microalbuminuria. The results of the second study suggest that decreases in renal blood flow in people with longstanding type 1 diabetes reflect intra-renal vascular stiffening and raise the possibility that in microalbuminuric patients it may also reflect increased intraglomerular pressure. [ABSTRACT FROM AUTHOR]

This study has evaluated the effects of the angiotensin converting enzyme inhibitor Enalapril on glomerular ultrastructure and albuminuria in normotensive and hypertensive diabetic rats. Streptozotocin-diabetes was induced in Wistar Kyoto and spontaneously hypertensive rats. Enalapril was administered in drinking water in diabetic normotensive, control hypertensive and diabetic hypertensive rats. Enalapril therapy prevented an increase in glomerular basement membrane thickness in diabetic normotensive, control hypertensive and diabetic hypertensive rats without any significant effect on fractional mesangial volume. Enalapril decreased albuminuria in diabetic normotensive, control hypertensive and diabetic hypertensive rats. Thus, enalapril retards the development of glomerular basement membrane thickening and albuminuria in the rat, in the presence or absence of hypertension. [ABSTRACT FROM AUTHOR]

Discusses the role of the angiotensin II antagonist losartan in delaying the progression of nephropathy in patients with type 2 diabetes mellitus. Reduction in primary composite endpoint in angiotensin receptor blockade; Hospitalization for heart failure with losartan.