A justification for less restrictive guidelines on the use of metformin in stable chronic renal failure.

AIM: The aim was to justify less restrictive use of metformin in stable chronic renal failure, because a literature review reveals metformin is associated with a significantly lower incidence of cardiovascular events and mortality compared with other hypoglycaemic agents, and metformin-associated lactic acidosis is rare and causation uncertain. Studies on intentional metformin overdose and metformin bioavailability, renal clearance and plasma metformin in renal impairment provide evidence in support of a less restrictive use of metformin. METHODS: In metformin overdose (n = 22), lactic acidosis was not inevitable with a plasma metformin > 40 mg/l (therapeutic level c. 1 mg/l): Severe lactic acidosis (pH ≤ 7.21, plasma lactate ≥ 11 mmol/l, n = 8) did not occur unless plasma metformin was > 40 mg/l. Plasma lactate was a more consistent predictor of pH than plasma metformin, with plasma lactate ≤ 4.7 being associated with a pH ≥ 7.34. A likely 'safe' plasma lactate is < 3.5 mmol/l and plasma metformin < 10 mg/l. RESULTS: Plasma metformin can be predicted from estimated glomerular filtration rate and metformin dose. Reported plasma metformin in renal failure was always less than predicted plasma metformin. Predicted plasma metformin (mg/l), with an estimated glomerular filtration rate of 30 ml/min and metformin 2000 mg/day was 6.8; an estimated glomerular filtration rate of 20 ml/min and metformin 1500 mg/day was 5.1; an estimated glomerular filtration rate of 10 ml/min and metformin 500 mg/day was 4.4. CONCLUSION: Metformin accumulates in renal failure and, although accumulation does not always lead to lactic acidosis, dose modification to achieve a predicted plasma metformin < 10 mg/l is suggested. As plasma metformin is not routinely available, plasma lactate should be useful in monitoring the use of metformin in renal failure.

Liver transplantation for the treatment of homozygous familial hypercholesterolaemia in an era of emerging lipid-lowering therapies.

Homozygous familial hypercholesterolaemia (FH) causes severe premature coronary artery disease because of very high levels of low density lipoprotein (LDL)-cholesterol. Standard lipid-lowering drugs and LDL-apheresis may not be sufficiently effective. Liver transplantation replaces defective LDL receptors and vastly improves the lipid profile, and we present the first report of an Australian adult to receive this treatment. Emerging drug treatments for FH may be alternatives to LDL-apheresis and transplantation, but long-term safety and efficacy data are lacking for all of these options.

The effect of soil texture on the degradation of textiles associated with buried bodies.

There are many factors which affect the rate of decomposition in a grave site including; the depth of burial, climatic conditions, physical conditions of the soil (e.g. texture, pH, moisture), and method of burial (e.g. clothing, wrappings). Clothing is often studied as a factor that can slow the rate of soft tissue decomposition. In contrast, the effect of soft tissue decomposition on the rate of textile degradation is usually reported as anecdotal evidence rather than being studied under controlled conditions. The majority of studies in this area have focused on the degradation of textiles buried directly in soil. The purpose of this study was to investigate the effect of soil texture on the degradation and/or preservation of textile materials associated with buried bodies. The study involved the burial of clothed domestic pig carcasses and control clothing in contrasting soil textures (silty clay loam, fine sand and fine sandy loam) at three field sites in southern Ontario, Canada. Graves were exhumed after 2, 12 and 14 months burial to observe the degree of degradation for both natural and synthetic textiles. Recovered textile samples were chemically analyzed using infrared (IR) spectroscopy and gas chromatography-mass spectrometry (GC-MS) to investigate the lipid decomposition by-products retained in the textiles. The findings of this study demonstrate that natural textile in contact with a buried decomposing body will be preserved for longer periods of time when compared to the same textile buried directly in soil and not in contact with a body. The soil texture did not visually impact the degree of degradation or preservation. Furthermore, the natural-synthetic textile blend was resistant to degradation, regardless of soil texture, contact with the body or time since deposition. Chemical analysis of the textiles using GC-MS correctly identified a lipid degradation profile consistent with the degree of soft tissue decomposition. Such information may be important for estimating time since deposition in instances where only grave goods and associated materials are recovered from a burial site.

Safety and efficacy of inhaled insulin (AERx iDMS) compared with subcutaneous insulin therapy in patients with Type 1 diabetes: 1-year data from a randomized, parallel group trial.

AIMS: Assessment of the long-term safety and efficacy of liquid inhaled insulin via AERx insulin Diabetes Management System (iDMS) in a basal/bolus treatment regimen of adults with Type 1 diabetes. METHODS: Patients were randomized 2 : 1 to prandial inhaled (n = 205) or subcutaneous (s.c.) (n = 99) insulin, plus one/two daily injections of neutral protamine Hagedorn (NPH) insulin for 12 months. The primary endpoints were pulmonary function tests (PFT) and baseline changes in chest X-rays at 12 months. Safety and efficacy assessments were measured at regular intervals. RESULTS: PFTs after 12 months were comparable between the groups, except for reduced per cent of predicted carbon monoxide lung diffusing capacity with inhaled insulin (difference: -2.03%, P = 0.04) occurring after the first 3 months and then stabilizing. There were no apparent treatment differences in chest X-rays. Overall risk of hypoglycaemia [risk ratio (RR) 1.02, P = 0.83] and adverse events were comparable between groups. Risk of nocturnal hypoglycaemia was higher in the inhaled group (RR 1.58, P = 0.001). Cough [10% (inhaled); 3% (s.c.)] tended to be mild in nature. Inhaled insulin was non-inferior to s.c. insulin for change in glycated haemoglobin (HbA(1c)) after 12 months [difference 0.18% (CI 95%-0.04; 0.39)]. At trial end, mean laboratory measured fasting plasma glucose was lower in the inhaled group (inhaled 9.2 mmol/l; s.c. 11.7 mmol/l; difference: -2.53 mmol/l, P < 0.001). CONCLUSIONS: The safety and efficacy results in this trial were similar to those reported with other inhaled insulins; however, inhaled insulin using AERx iDMS requires further optimization to reduce nocturnal hypoglycaemia before it has comparable safety and efficacy to s.c. insulin aspart.

Long-term renoprotection by perindopril or nifedipine in non-hypertensive patients with Type 2 diabetes and microalbuminuria.

AIMS: To assess the efficacy of an angiotensin converting enzyme (ACE) inhibitor (perindopril), a dihydropyridine calcium channel blocker (sustained release nifedipine) and placebo in preventing the progression of albuminuria and decline in glomerular filtration rate (GFR) in patients with Type 2 diabetes and microalbuminaria. METHODS: A prospective, randomized, open, blinded end point study of 77 patients allocated to three treatment groups (23 perindopril, 27 nifedipine, 27 placebo). Drug doses were adjusted to achieve a decrease in diastolic blood pressure (DBP) of 5 mmHg in the first 3 months and additional therapy was given if hypertension developed (supine DBP > 90 mmHg and/or systolic blood pressure (SBP) > 140 mmHg if < or = 40 years; supine DBP > 90 mmHg and/or SBP > 160 mmHg if > 40 years). Median follow-up was 66 months, with 37 patients being followed for at least 6 years. RESULTS: Blood pressure remained within the non-hypertensive range in 83% of perindopril-, 95% of nifedipine- and 30% of placebo-treated patients (P < 0.01). In the first 12 months albumin excretion rate (AER) decreased by 47% only in the perindopril group (P = 0.04). From 12 to 72 months, AER gradients increased by 27% per year only in the placebo group (P < 0.01). After 6 years, macroalbuminuria had developed in 7/15 placebo compared with 2/11 in perindopril and 1/11 nifedipine-treated patients (P = 0.05). GFR did not change in the first 12 months, but thereafter the median GFR gradient (ml/min/1.73 m(2) per year) was -2.4 (P < 0.01) for perindopril-, -1.3 (P = 0.26) for nifedipine- and -4.2 (P = 0.01) for placebo-treated patients. The rate of decline in GFR for the study group as a whole from 12 months to the end of follow-up correlated negatively with mean arterial pressure (MAP) (r = -0.38, P < 0.01). During a 3-month treatment pause in 29 patients AER tended to increase only in the perindopril group (P < 0.07). CONCLUSIONS: Long-term control of blood pressure with perindopril or nifedipine stabilizes AER and attenuates GFR decline in proportion to MAP in non-hypertensive patients with Type 2 diabetes and microalbuminuria.

Early vitamin E supplementation attenuates diabetes-associated vascular dysfunction and the rise in protein kinase C-beta in mesenteric artery and ameliorates wall stiffness in femoral artery of Wistar rats.

AIMS/HYPOTHESIS: The impact of early vitamin E supplementation on vascular function in diabetes remains unresolved. Therefore, we examined the effects of vitamin E on functional and structural parameters and on chemical markers that are disturbed in diabetes in mesenteric and femoral arteries. METHODS: Segments of both arteries, taken from control and 8-week-old streptozotocin diabetic Wistar rats that were treated or not with vitamin E, were mounted on wire and pressure myographs, after which endothelium-dependent and -independent vasodilation was assessed. Passive mechanical wall properties and the localisation and levels of protein kinase C (PKC)-beta(2) and AGE were evaluated in these vessels. RESULTS: Vitamin E supplementation was associated with improved endothelium-dependent and -independent vasodilatation in mesenteric arteries from diabetic rats. Impaired endothelium-dependent vasodilatation in diabetic mesenteric vessels was associated with PKC-beta(2) up-regulation and this was prevented by vitamin E supplementation. Increased AGE accumulation and plasma isoprostane levels in diabetic rats were not changed by vitamin E. In the femoral artery, vitamin E supplementation had no effect on endothelium-dependent or -independent vasodilatation, but did prevent the wall stiffening associated with diabetes. CONCLUSIONS/INTERPRETATION: Early vitamin E supplementation has a beneficial effect on diabetes-induced endothelial dysfunction in resistance arteries. This benefit may arise from a direct effect on smooth muscle function, as a result of inhibition of the PKC-beta(2) isoform by vitamin E.

Comparison of effects of diabetes mellitus on an EDHF-dependent and an EDHF-independent artery.

The hypothesis tested in this study is that diabetes has a different impact on an artery in which endothelium-dependent responses derive from both nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) compared with responses in which NO predominates and EDHF is absent. The streptozotocin-treated rat model of diabetes was used, and the arteries were mounted on a wire myograph. In mesenteric arteries depolarized and constricted with phenylephrine, acetylcholine evoked hyperpolarization (31 +/- 2 mV) and complete relaxation; these responses were attributed to EDHF and NO. In femoral arteries, acetylcholine evoked a small, NO-mediated hyperpolarization (5 +/- 1 mV) and incomplete relaxation. Bradykinin evoked NO-dependent responses in mesenteric arteries. Whereas diabetes significantly impaired the EDHF-dependent hyperpolarization and relaxation in mesenteric arteries, NO-dependent responses in femoral and mesenteric arteries were preserved. 1-Ethyl-2-benzimidazolinone evoked hyperpolarization and relaxation in mesenteric arteries, and this was impaired in diabetes. In conclusion, NO-dependent responses are preserved in diabetes, whereas endothelial responses-dependent upon EDHF appear to be impaired. The putative channels responsible for mediating the EDHF response may be altered in diabetes.

Effect of anti-oxidant treatment and cholesterol lowering on resting arterial tone, metabolic vasodilation and endothelial function in the human forearm: a randomized, placebo-controlled study.

1. The aim of the present study was to determine whether anti-oxidant therapy with vitamin E and/or cholesterol-lowering therapy with simvastatin would augment resting forearm blood flow (FBF) and metabolic vasodilation in response to exercise and improve endothelial function in young patients with hypercholesterolaemia. 2. Endothelium-dependent and -independent, nitric oxide (NO)-mediated vasodilation have been shown to be impaired in young, otherwise healthy subjects with hypercholesterolaemia. Recent experimental and clinical studies suggest that vascular function may be improved with anti-oxidant or cholesterol- lowering therapy, although these treatments may be synergistic. 3. We compared FBF at rest, in response to isotonic exercise, the endothelium-dependent vasodilator acetylcholine (ACh), the endothelium-independent vasodilator sodium nitroprusside (SNP) and the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) in 26 young, otherwise healthy volunteers (mean (+/-SD) age 29+/-7 years; 14 female, 12 male) with hypercholesterolaemia, before and after 6 months treatment with vitamin E, simvastatin and/or placebo. Treatment was randomized, double-blinded in a 2 x 2 factorial design. Forearm blood flow was measured using venous occlusion plethysmography. 4. Vitamin E therapy increased plasma alpha-tocopherol from 39.5+/-9.6 to 75.7+/-33.8 micromol/L (P < 0.001). Simvastatin reduced total cholesterol from 6.9+/-1.7 to 4.9+/-0.8 mmol/L and low- density lipoprotein (LDL) from 4.8+/-1.7 to 3.0+/-0.7 mmol/L (both P < 0.001), although total and LDL-cholesterol also decreased slightly in the placebo group. Vitamin E increased resting FBF from 2.1+/-0.3 to 2.4+/-0.3 mL/100 mL per min (P = 0.04) and decreased resting forearm vascular resistance from 42.1+/-4.2 to 36.1+/-3.4 units (P = 0.01), but the reduction in resting FBF with L-NMMA was not affected. Vasodilation in response to isotonic exercise, ACh and SNP was similar before and after treatment in the placebo, vitamin E, simvastatin and in the combined vitamin E-simvastatin groups. NG-Monomethyl-L-arginine infusion reduced resting FBF and functional hyperaemia in response to exercise and these responses were not altered by treatment. 5. These data suggest that while vitamin E therapy augments resting FBF and reduces forearm vascular resistance in young hypercholesterolaemic subjects, these effects may not be via NO-dependent pathways. Metabolic vasodilation and responses to the NO-mediated vasodilators ACh and SNP were not favourably affected by anti-oxidant or cholesterol-lowering therapy, either alone or in combination.

Vasodilator prostanoids, but not nitric oxide, may account for skeletal muscle hyperaemia in Type I diabetes mellitus.

We and others have previously documented increased resting and exercise-induced skeletal muscle blood flow in young subjects with Type I (insulin-dependent) diabetes mellitus compared with healthy controls. Both NO and prostanoids are important regulators of vascular tone and may therefore contribute to this hyperaemia. The aim of the present study was to determine the contribution of NO and vasodilator prostanoids to this skeletal muscle hyperaemia in diabetes. We assessed the effects of infusion into the intrabrachial artery of the cyclo-oxygenase inhibitor acetylsalicylic acid (ASA; aspirin) and of the L-arginine analogue N(G)-monomethyl-L-arginine (L-NMMA) on skeLetal muscle blood flow in subjects with Type I diabetes mellitus (DM subjects) and control subjects. Blood flow was measured by venous occlusion plethysmography. Isotonic forearm exercise involved 2 min of wrist flexion and extension. Resting flow (forearm blood flow; FBF) was augmented in DM subjects, as was peak exercise-related blood flow (PFBF) and the volume repaid to the forearm 5 min after exercise (AUC 5, where AUC is area under the flow-time curve) (P<0.05), even when accounting for differences in basal flow. Infusion of L-NMMA reduced resting flow by 48% in controls (P<0.005) and by 12% in DM subjects (not significant). L-NMMA reduced PFBF and AUC 5 by 29% (P<0.05) and 39% (P<0.0005) respectively in controls, but had no significant effect on these parameters in DM subjects. Infusion of ASA reduced FBF, PFBF and AUC 5 in both DM (P<0.05) and control (P<0.05) subjects, but the magnitude of this reduction was greater in DM than in control subjects (ANOVA, P<0.05), even when differences in resting FBF were accounted for. Indeed, ASA eliminated the differences in FBF, PFBF and AUC 5 between DM and control subjects. Thus increased release of vasodilator prostanoids, rather than of NO, appears to account for skeletal muscle hyperaemia in Type I diabetes.

In vitro and in vivo antioxidant properties of gliclazide.

Diabetes is a state of increased oxidant stress and there is evidence that oxidation may play a role in the genesis of complications. Gliclazide, a sulfonylurea hypoglycemic drug, has been shown to possess free radical scavenging properties. This study examined the effects of in vitro supplementation with gliclazide and other sulfonylureas as on low-density lipoprotein (LDL) oxidation and the total plasma antioxidant capacity (TPAC). In a separate study, the effects of 10 months of oral gliclazide therapy on oxidative parameters were assessed in 44 type 2 diabetic patients. Gliclazide, but not glibenclamide, glimepiride, glipizide or tolbutamide, inhibited LDL oxidation and enhanced TPAC. With the addition of 1 microM gliclazide, oxidation lag time increased from 53.6+/-2.6 to 113.6+/-5.1 min (p<0.001), and TPAC increased from 1. 09+/-0.11 to 1.23+/-0.11 mM (p<0.01). Administration of either modified release or standard gliclazide to type 2 diabetic patients resulted in a fall in 8-isoprostanes, a marker of lipid oxidation, and an increase in the antioxidant parameters TPAC, SOD and thiols. These studies show that gliclazide possesses antioxidant properties that produce measurable clinical effects at therapeutic doses.

Vitamin E supplementation improves endothelial function in type I diabetes mellitus: a randomized, placebo-controlled study.

OBJECTIVES: We sought to determine, in a double-blind, placebo-controlled, randomized study, whether vitamin E supplementation (1,000 IU for three months) would improve impaired conduit and resistance vessel endothelial vasodilator function (EVF) and systemic arterial compliance (SAC) in type I diabetes mellitus (DM). BACKGROUND: Oxidative stress is thought to be important in the pathogenesis of impaired EVF. Consistent with this hypothesis, we have recently shown that impaired EVF is related to low density lipoprotein (LDL) vitamin E content (VEC) in young subjects with type 1 DM. METHODS: We assessed EVF in the brachial artery (using noninvasive ultrasound, flow-mediated vasodilation [FMD]; n = 41) and in the forearm resistance vessels (by flow responses to intrabrachial acetylcholine [ACh]; n = 21) and measured SAC (simultaneous aortic blood flow and carotid pressure measurements; n = 41) before and after active or placebo therapy. RESULTS: The LDL VEC was increased by 127% after supplementation, resulting in a significant reduction in the oxidative susceptibility of LDL. There was no time-dependent change in FMD or in the response to ACh or SAC in the placebo group. A significant improvement in FMD (2.6 +/- 0.6% to 7.0 +/- 0.7%, p < 0.005) and the dose response to ACh (p < 0.05) were observed in those randomized to vitamin E therapy. Systemic arterial compliance was not affected by vitamin E (0.41 +/- 0.03 vs. 0.49 +/- 0.06 arbitrary compliance units, p = NS). The change in FMD was related to the change in LDL VEC (r = 0.42, p < 0.05) and the change in the oxidative susceptibility of LDL (r = 0.64, p < 0.0001). CONCLUSIONS: Short-term daily oral supplementation with vitamin E improves EVF in both the conduit and resistance vessels of young subjects with type I DM.

Achievement of target plasma cholesterol levels in hypercholesterolaemic patients being treated in general practice.

A total of 1028 hypercholesterolaemic men and women aged 18-75 participated in an open label, randomised, parallel group, 6-month treatment-to-target study conducted in 240 general practices throughout Australia. The study compared atorvastatin monotherapy with simvastatin monotherapy or, if necessary, with the combination of simvastatin and cholestyramine in terms of their abilities to achieve a plasma total cholesterol target of<5.0 mmol/l. The initial daily dose of each drug was 10 mg. If the target was not achieved, the dose was doubled at 6 week intervals to a maximum daily dose of 80 mg atorvastatin or 40 mg simvastatin, with the simvastatin supplemented if necessary with 4 g cholestyramine. The percentage of patients achieving the target at 10 and 20 mg doses of atorvastatin were comparable to 20 and 40 mg of simvastatin, respectively. Despite relatively high baseline levels of plasma total cholesterol (mean levels of 7.41 and 7.31 mmol/l in the atorvastatin and simvastatin groups, respectively) the majority of patients in each group achieved the plasma total cholesterol target of<5.0 mmol/l. Treatment with atorvastatin achieved the target in 83% of patients, while simvastatin (or simvastatin plus cholestyramine) achieved the target in 66% of the patients (P<0.005). The target was achieved with 10 mg atorvastatin in 38% of patients and with 10 mg simvastatin in 26% of cases (P<0.005). In patients whose baseline cholesterol levels were between 5.6 and 6.5 mmol/l, 95% of the atorvastatin group and 86% of the simvastatin group reached the target. Even with baseline cholesterol levels between 7.6 and 8.5 mmol/l, the target was reached in 78% of the atorvastatin group and 61% of the simvastatin group. It is thus realistic for general practitioners to expect the majority of their at risk patients to achieve target plasma cholesterol levels that have been shown in population studies to be associated with relatively low rates of coronary heart disease. These targets are achieved in significantly more patients and at lower mg doses with atorvastatin than simvastatin.

Endothelial vasodilator function is related to low-density lipoprotein particle size and low-density lipoprotein vitamin E content in type 1 diabetes.

OBJECTIVES: We sought to determine whether endothelial vasodilator function (EVF) in patients with type 1 diabetes was related to low-density lipoprotein (LDL) particle size (LDLPS), LDL vitamin E content (LDLVE) or the susceptibility of LDL to oxidation (OxLDL). BACKGROUND: Impaired EVF is an early feature of diabetic vascular disease and may be related to oxidant stress. Although small, dense LDL and oxidized LDL are features of type 2 diabetes and predict the development of coronary artery disease, their role in type 1 diabetes is less clear. METHODS: Endothelium-dependent vasodilation was assessed in the brachial artery (flow-mediated vasodilation [FMD]) and in the forearm resistance circulation using venous occlusion plethysmography in response to graded doses of intrabrachial acetylcholine (ACh). Thirty-seven patients with type 1 diabetes mellitus (DM) and 45 matched controls underwent flow-mediated dilation, while a subset of 19 DM and 20 controls underwent plethysmography. RESULTS: Total, LDL and high-density lipoprotein cholesterol or triglycerides were not different in DM compared with controls, but LDLPS was smaller (25.6 +/- 0.06 vs. 26.1 +/- 0.1 nm, p < 0.05) and LDLVE was reduced (2.0 +/- 0.25 vs. 2.6 +/- 0.18 micromol/mmol LDL, p < 0.05). Oxidative susceptibility of LDL was not different. Flow-mediated vasodilation was impaired in DM compared with controls (3.6 +/- 0.6% vs. 7.1 +/- 0.5%, p < 0.005), as was the vasodilator response to ACh (p < 0.05). Flow-mediated vasodilation was directly related to LDLPS and LDLVE in both the entire study cohort and DM alone (p < 0.05), but not to other parameters of the standard lipid profile. Similarly, endothelium-dependent vasodilation in the resistance circulation was directly related to LDLPS and LDLVE, but not to OxLDL. CONCLUSION: These results suggest, but do not prove, that LDL particle size and LDL vitamin E may be determinants of conduit and resistance vessel endothelial vasodilator function in type 1 diabetes. Further work will be required to prove cause and effect.

Basal and exercise-induced skeletal muscle blood flow is augmented in type I diabetes mellitus.

Hyperaemia occurs early in the renal and retinal microcirculation of patients with type I (insulin-dependent) diabetes mellitus, and may be critical in the development of nephropathy and retinopathy. We therefore sought to determine whether resting and exercise-induced hyperaemia was also apparent in the skeletal muscle circulation of young subjects with type I diabetes. Blood flow was assessed by venous occlusion plethysmography in 18 diabetic (DM) subjects and 20 matched controls. Exercise entailed 2 min of isotonic exercise against no load. Endothelium-dependent and -independent vasodilator function was assessed following intra-arterial infusion of acetylcholine and sodium nitroprusside respectively. Forearm blood flow (FBF) was higher in DM subjects than in controls (3.3+/-0.3 and 2.2+/-0.2 ml x min(-1) x 100 ml(-1) forearm respectively; P<0.005). This was not due to differences in forearm or body size, blood pressure, heart rate, lipid status or glycaemic control. Peripheral insulin levels were higher in DM subjects than in controls (48.5+/-8 and 15.5+/-1.5 micro-units/ml respectively; P<0.005). Resting FBF was closely correlated with insulin levels (r(2)=0.4; P<0.005). Parameters of exercise-induced hyperaemia [including peak flow (16.4+/-1.4 and 12.0+/-0.7 ml x min(-1) x 100 ml(-1) forearm in DM and control subjects respectively; P<0.01) and the volume repaid to the forearm at 5 min post-exercise (32.1+/-3.1 and 23.1+/-1.4 ml x 100 ml(-1) forearm respectively; P<0.05)] were also significantly greater in DM subjects, even when differences in resting FBF were taken into account. Peak hyperaemic blood flow and the volume repaid at 5 min were also related to insulin levels (r(2)=0.16; P<0.05 and r(2)=0.27; P<0.005 respectively). The vasodilator response to acetylcholine was reduced in DM subjects (P<0.05; analysis of variance), and the slope of this dose-flow relationship was inversely related to insulin levels (r(2)=0.2; P<0.05). These data show that both resting and exercise-induced skeletal muscle blood flow are augmented in young patients with type I diabetes, possibly due to the vasodilatory effect of increased insulin levels. Diminished vasodilator responses to acetylcholine may also, in part, be a consequence of insulin-augmented resting muscle blood flow.

Systemic arterial compliance is reduced in young patients with IDDM.

Arterial elastic properties are altered with increasing age and in various disease states, including non-insulin-dependent diabetes mellitus (NIDDM). Whether young patients with insulin-dependent diabetes mellitus (IDDM) have reduced arterial compliance before developing endothelial dysfunction or overt micro- and macrovascular disease is unclear. Systemic arterial compliance and endothelium-dependent, flow-mediated vasodilation (FMD) was assessed in 25 individuals with uncomplicated IDDM (23 +/- 4 yr, 14 females and 11 males) and compared with 30 age-matched controls (15 females and 15 males). Arterial compliance was determined via simultaneous measurements of aortic blood flow and carotid arterial pressure. The relationship between arterial compliance and endothelial function (assessed by brachial artery FMD) was also examined. Arterial compliance was 29% lower in IDDM subjects compared with control subjects (0.46 +/- 0.05 vs. 0.65 +/- 0.07 arbitrary compliance units, P < 0.05). Blood pressure, lipid levels, and daily energy expenditure (a measure of physical activity levels) were not different between groups. Compliance in the IDDM group was not related to the integrity of endothelial vasodilator function, disease duration, or degree of glycemic control. Arterial compliance is reduced in young patients with IDDM before the development of overt micro- or macrovascular disease. Early assessment of arterial compliance may be useful in predicting the development of diabetic vascular complications.

Gemfibrozil treatment increases low-density lipoprotein particle size in Type 2 diabetes mellitus but does not alter in vitro oxidizability.

The aim of this study was to determine the effect of the lipid modifying agent gemfibrozil on lipid and coagulation risk factors in patients with Type 2 diabetes mellitus (Type 2 DM). Twenty-six subjects with Type 2 DM and dyslipidaemia were treated for 24 weeks with either gemfibrozil 600 mg orally twice daily or placebo in a double-blind randomized trial. Lipid profiles, fibrinogen, Factor VII, and plasminogen activator inhibitor-1 (PAI-1) were measured by routine laboratory methods. Low density lipoprotein (LDL) size was determined by gradient gel electrophoresis and the resistance of LDL to copper-induced oxidation was assessed by measuring absorbance at 234 nm. Gemfibrozil significantly reduced total cholesterol (-0.9 (-0.48, -1.32) mmol l(-1); p < 0.05) and triglycerides (-2.7 (-1.55, -1.35) mmol l(-1); p < 0.001) vs placebo. The fall in triglyceride was reflected by a fall in VLDL cholesterol levels in the gemfibrozil treated group vs placebo (-1.31 mmol l(-1); p < 0.001). LDL-cholesterol level did not change but LDL particle size increased by 0.5 nm (0.01, 0.93); P < 0.02. The increase in particle size was inversely correlated with the change of triglyceride level (r = -0.79, p < 0.0001) but did not result in any reduction of susceptibility to copper-induced oxidation. There were no significant changes in the coagulation parameters studied. Because of its ability to correct the lipid abnormalities associated with Type 2 DM particularly hypertriglyceridaemia, gemfibrozil provides a useful therapeutic option in the management of diabetic dyslipidaemia but it does not alter in vitro oxidizability of LDL.

Aminoguanidine has an anti-atherogenic effect in the cholesterol-fed rabbit.

Advanced glycosylation endproducts (AGEs) which result from the non-enzymatic interaction of proteins and glucose are implicated in the vasculopathy of diabetes and aging. Since aminoguanidine (A) inhibits the accumulation of AGEs, we explored its effects on the development of atherosclerosis. Male New Zealand white cross rabbits fed a high cholesterol (1%) diet were randomized to control (C) or increasing doses of A treatment (25, 50 and 100 mg/kg A body weight). The animals were sacrificed after 12 weeks. Sudan IV was used to stain the lipid containing plaques of the aortic arch, thoracic and abdominal aorta and the surface area occupied by atheroma was assessed. Increasing doses of A treatment were associated with reduction in plaque formation in the aorta. At a dose of 100 mg/kg A, there was a 30, 49 and 48% reduction in plaque formation in the aortic arch, thoracic and abdominal aorta, respectively. There was a correlation between AGE levels and the degree of atheroma in these cholesterol fed rabbits (control, r = 0.75, P < 0.01; 100 mg/kg A, r = 0.59, P = 0.02). These data suggest that advanced glycation may participate in atherogenesis and raise the possibility that inhibitors of advanced glycation may retard this process.