Sulfonylureas and cardiovascular mortality in diabetes: a class effect?
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Animals↗
Biomedical subjects
T C Wascher
Publications and source records attributed to T C Wascher.
Forearm composition contributes to differences in reactive hyperaemia between healthy men and women.
BACKGROUND: Post-ischaemic reactive hyperaemia in the forearm has been suggested as a marker of resistance vessel function. The contribution of forearm composition to the kinetics of reactive hyperaemia is largely unknown. The body composition of men and women differs in that women have a higher body fat content and less lean body mass. METHODS: In the present study, we investigated whether the kinetics of reactive hyperaemia in the forearm in 14 healthy subjects (seven men and seven women) show gender-specific differences and whether forearm composition contributes to such differences. RESULTS: Peak reactive hyperaemic flow as well as 1-min-flow debt repayment (measured by venous occlusion plethysmography) were significantly higher in male than in female study participants. This difference was explained to > 60% by gender-specific differences in forearm relative muscle mass (as determined by magnetic resonance imaging). The half-life of the reactive hyperaemic response, on the other hand, was not different between men and women and did not show an association with forearm muscle. CONCLUSION: Our results demonstrate that forearm composition must be considered if peak reactive hyperaemic or flow debt repayment is used as a target, and that dynamic measurements of the reactive hyperaemic process are more suitable to describe the function of resistance arteries than single-point observations.
Adipose Tissue↗
Contribution of the endothelium to transcapillary insulin transport in rat isolated perfused hearts.
Capillary endothelial cells are thought to limit the transport of insulin from the vascular to the interstitial space, resulting in attenuated hormonal action at target sites. This study examined the contribution of endothelial cells to the regulation of transcapillary insulin transport in rat hearts in vitro. Hearts were perfused with a protein-free buffer that resulted in the generation of a substantial amount of interstitial fluid (transudate) that was collected at the surface of ventricles. Insulin (0.05-1 U/l) was added to the perfusate, and its transfer kinetics to and clearance from the interstitium were analyzed from insulin measurements in transudate of hearts with intact or collagenase-disrupted endothelium. In endothelium-intact hearts (n = 5-8), the steady-state insulin concentration in transudate was 29 +/- 4, 30 +/- 2, 53 +/- 1, 103 +/- 6, and 97 +/- 4% of perfusate concentrations at 0.05, 0.1, 0.2, 0.5, and 1 U/l insulin, respectively. The corresponding apparent rate constants for transport (k(in)) increased from 0.03/min to -0.27/min, indicating a nonsaturable transport process. The transport rate for [3H]insulin (1.2 nmol/l; n = 5) was identical to an equimolar concentration of insulin (0.2 U/l), strongly indicating the same mode of transport. In endothelium-disrupted hearts (n = 3-5), the same perfusate/transudate concentration ratios were observed--that is, a gradient at low insulin concentrations (0.05-0.2 U/l) and complete equilibration at higher insulin concentrations, suggesting a contribution of reabsorption processes back into the vascular space in the generation of the gradient. Finally, inhibition of endothelial nitric oxide (NO) formation by NG-nitro-L-arginine (200 micromol/l) affected neither k(in) nor the extent of transendothelial insulin transport in the presence of an intact endothelium. We concluded that 1) capillary endothelial cells affect the transcapillary transport of insulin by slowing the transfer to the interstitium, 2) insulin is transported by a bidirectional convective transport rather than by a saturable receptor-mediated mechanism, and 3) endothelium-derived NO is without effect on transcapillary insulin transport in this model.
Animals↗
Vascular effects of L-arginine: anything beyond a substrate for the NO-synthase?
L-arginine supplementation is hypothesized to reduce endothelial dysfunction and atherogenesis via increased biosynthesis of nitric oxide. Here we describe superoxide scavenging properties of arginine as an additional aspect which needs to be considered. Furthermore, arginine reduced copper-induced lipid peroxidation, indicating that superoxide anions essentially contribute to this process. In intact endothelial cells, L-arginine but not D-arginine diminished superoxide release and reduced cell-mediated breakdown of nitric oxide. Our data indicate that the reported vascular effects of L-arginine supplementation might involve an increased bioavailability of nitric oxide due to its superoxide scavenging properties beside a potential increased NO biosynthesis.
Animals↗
Oral L-arginine supplementation in chronic heart failure.
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Administration, Oral↗
Antioxidants prevent high-D-glucose-enhanced endothelial Ca2+/cGMP response by scavenging superoxide anions.
Very recently we proposed that hyperactivity of endothelial Ca2+/cGMP signaling under hyperglycemic conditions is due to superoxide anion (O2-) release. The present study was designed to investigate changes in endothelial glutathione (GSH) levels in response to high D-glucose and possible prevention of the high-D-glucose-initiated changes in Ca2+/cGMP signal by antioxidants. Under hyperglycemic conditions, GSH content increased by 29% within 4 h. Co-incubation with 10 mM GSH during high-D-glucose treatment normalized the Ca2+/cGMP response associated with an increase in GSH content by 222%. Vitamin C (250 microM) markedly diminished the high-D-glucose-mediated hyperreactivity of endothelial Ca2+ entry (by 40%) and Ca2+ release (by 52%). Similar to GSH, co-incubation with vitamin E (alpha-tocopherol; 50 micrograms/ml) and probucol (50 microM) completely prevented the high-D-glucose-initiated hyperreactivity of the endothelial Ca2+/cGMP response. Vitamin E, probucol, GSH and vitamin C diminished the high-D-glucose-mediated O2- release by 78, 65, 89 and 46%, respectively. These data suggest that antioxidants prevent high-D-glucose-initiated changes in endothelial Ca2+/cGMP response by scavenging the overshoot of O2-.
Animals↗
Effects of low-dose L-arginine on insulin-mediated vasodilatation and insulin sensitivity.
The present study was carried out to evaluate the effect of a low-dose intravenous supplementation of L-arginine on insulin-mediated vasodilatation and insulin sensitivity. The study was performed in healthy subjects (n = 7) and patients with obesity (n = 9) and non-insulin-dependent diabetes mellitus (NIDDM) (n = 9). Insulin-mediated vasodilatation was measured by venous occlusion plethysmography during the insulin suppression test, evaluating insulin sensitivity. Experiments were performed twice in each subject in the presence or absence of a concomitant infusion of L-arginine (0.52 mg kg-1 min-1). L-Arginine restored the imparied insulin-mediated vasodilatation observed in obesity (22.4 +/- 4.1%, P < 0.01 vs. without L-arginine) and NIDDM (20.3 +/- 3.2%, P < 0.01 vs. without L-arginine). In healthy subjects, no effect on insulin mediated-vasodilatation was observed (24.8 +/- 3.1% vs. 21.4 +/- 3.1%). Insulin sensitivity was improved significantly (P < 0.001) in all three groups by infusion of L-arginine. No effect of L-arginine was observed on insulin, insulin-like growth factor I (IGF-I), free fatty acids (FFAs) or C-peptide levels during the insulin suppression test. Our data indicate that defective insulin-mediated vasodilatation in obesity and NIDDM can be normalized by intravenous L-arginine. Furthermore, L-arginine improves insulin sensitivity in obese patients and NIDDM patients as well as in healthy subjects, indicating a possible mechanism that is different from the restoration of insulin-mediated vasodilatation.
Adult↗
Endothelial transport processes and tissue metabolism: evidence for microvascular endothelial dysfunction in insulin-resistant diseases?
Clinical manifestations of the insulin resistance syndrome are accompanied by endothelial dysfunction at the level of conductance and resistance vessels. Other conditions, such as smoking, also associated with endothelial dysfunction, exhibit insulin resistance too. Hypercholesterolaemia, in contrast, despite being the classical disease of endothelial dysfunction, is not associated with insulin resistance. Furthermore, only in insulin-resistant diseases, markers of microvascular alteration, such as microalbuminuria or increased plasma concentrations of von Willebrand factor, are found. At capillary sites, in contrast, transendothelial transport of both insulin and glucose takes place. These transport processes are thought to contribute to overall insulin sensitivity. In this article, I not only hypothesize but also summarize existing experimental and clinical evidence that a distinct capillary endothelial dysfunction is closely involved in the insulin resistance syndrome.
Arteriosclerosis↗
Role of superoxide anions in changes of endothelial vasoactive response during acute hyperglycemia.
The effects of acute hyperglycemia on endothelial Ca2+ signaling, formation of endothelium-derived relaxing factor (EDRF) and bioactivity of EDRF were investigated. Hyperglycemia increased 2,5-tert-butyl-1,4-hydrochinone (BHQ)-initiated Ca2+ signaling and EDRF formation in a concentration-dependent manner. The effect of elevated D-glucose on Ca2+/EDRF response could be diminished by co-incubation with the antioxidants vitamin E, probucol, GSH, vitamin C and superoxide dismutase. Convincingly, hyperglycemic conditions yielded an increase in superoxide anion release from endothelial cells and the superoxide anion-generating mixture xanthine oxidase/hypoxanthine mimicked the effect of hyperglycemia on Ca2+/EDRF signaling. Besides an enhanced formation of the vasodilatatory NO compound EDRF, hyperglycemia enhanced NO degradation by endothelial cells and, thus, reduced bioactivity of EDRF. We suggest that vasoactivity during acute hyperglycemia depends on the superoxide anion scavenging properties of the vascular wall. In acute hyperglycemia and early stages of diabetes, radical scavenging capacity may be suitable to protect NO degradation, resulting in an enhanced vasodilation. In contrast, decreased free radical scavenging properties of the vasculature in prolonged hyperglycemia and in later stages of diabetes might promote NO degradation by an overshoot of superoxide anions, resulting in an attenuation of endothelium-dependent vasodilation.
Animals↗
[Value of antioxidants and vitamins in cardiovascular prevention and therapy].
Experimental as well as epidemiological data suggest the use of antioxidants for therapy of atherosclerosis. Feasible, however, seems only the use of antioxidant vitamins. Recent knowledge from published data seems to justify the use of low-dose supplementation in primary prevention of vascular disease. High-dose intervention in secondary prevention, despite promising results from intervention studies, needs further controlled studies, addressing optimal dose or combination therapies.
Animals↗
[Effect of chromium yeast and chromium picolinate on body composition of obese, non-diabetic patients during and after a formula diet].
The objective of this study was to assess the effects of chromium yeast and chromium picolinate on lean body mass during and after weight reduction with a very-low-calorie diet. 36 obese (BMI 33.7 +/- 5.4 kg/m2), non-diabetic patients aged 45 +/- 6 years undergoing a 8-week very-low-calorie diet followed by a 18-week maintenance period. During the whole 26 week treatment period subjects received either placebo or chromium yeast (200 micrograms/d) or chromium-picolinate (200 micrograms/d) in a double-blind manner. Body weight was measured as BMI and body composition after calculation from skinfold thickness. As a result all three groups showed comparable weight loss after 8 and 26 weeks. Lean body mass was reduced in all groups after 8 weeks. However, after 26 weeks chromium picolinate supplemented subjects showed increased lean body mass (p < 0.029) whereas the other treatment groups still had reduced lean body mass. Chromium picolinate, but not chromium yeast, is able to increase lean body mass in obese patients in the maintenance period after a very-low-calorie diet without counteracting the weight loss achieved.
Adult↗
Prevalence of coronary artery disease in obese versus lean men with angina pectoris and positive exercise stress test.
The present study assesses the extent of coronary artery disease in men with angina pectoris and definite signs of myocardial ischemia in relation to body mass index. Our results demonstrate that exercise-induced myocardial ischemia in the absence of coronary artery disease in men with angina pectoris is more (2.6-fold) frequent in obese than in lean patients.
Angina Pectoris↗
Increased prevalence of IgA-Chlamydia antibodies in NIDDM patients.
Chlamydia trachomatis oculogenital infection is a common disease in western societies. Despite the fact that diabetes is accompanied by increased risk for infections, no data on chlamydial infections in the non-insulin-dependent diabetic (NIDDM) patient exist. In our study Chlamydia antibodies were determined using an immunoperoxidase reaction in NIDDM patients (n = 79) and in a local nondiabetic control population (n = 125) which was randomly invited to a medical control visit without any preselection criteria. In total, 46% of diabetics and 55% of controls were IgG-Chlamydia antibody positive (ns). Using IgA-Chlamydia antibodies to define 'seroactive' chlamydial infection, 22% of NIDDM patients and 14% of controls were positive. Thus seroactive chlamydial infection of all patients with proven contact to Chlamydia (IgG-Chlamydia antibody positive) was 47% in diabetics versus 25% in controls, respectively (P < 0.05). Forming subgroups, significance was reached in females (52% vs. 32%, P < 0.05) only, but a similar trend was observed in males (36% vs. 21%, ns). Seroactivity was neither correlated with HbA1c nor with nephelometrically determined total serum immunoglobulins (IgG, IgA). Additionally we observed significantly elevated total IgM and IgA-levels in NIDDM patients whereas IgG-levels were comparable in both groups. In conclusion, seroactive chlamydial infections in subjects with proven contact to Chlamydia are more frequent in NIDDM patients than in nondiabetic controls. Additionally, higher IgM and IgA serum levels might indicate a higher susceptibility to active surface infections in NIDDM.
Adult↗
Involvement of the L-arginine-nitric oxide pathway in hyperglycaemia-induced coronary artery dysfunction of isolated guinea pig hearts.
The effects of hyperglycaemia and L-arginine on flow-induced reduction of coronary artery resistance were investigated in isolated guinea pig hearts. In the presence of indomethacin, hyperglycaemia caused an increase in flow-induced vasodilatation (P < 0.05). Hyperosmotic controls failed to mimic this effect. Addition of L-arginine strongly enhanced this effect. Addition of D-arginine failed to mimic the effects of L-arginine. The effect of L-arginine was abolished by co-administration of NG-nitro-L-arginine. In the absence of indomethacin and L-arginine, the effect of hyperglycaemia was blunted, suggesting the formation of vasoconstrictive prostanoids. Addition of L-arginine again resulted in a significant increase in flow-induced vasodilatation. In conclusion our results suggest that increased flow-induced vasodilatation under hyperglycaemic conditions depends on an adequate supply of L-arginine to maintain sufficient formation of nitric oxide.
Animals↗
Intracellular mechanism of high D-glucose-induced modulation of vascular cell proliferation.
Development of atherosclerosis in diabetes patients is thought to be associated with high D-glucose-induced changes in vascular cell proliferation. This study was designed to investigate the intracellular mechanisms of altered proliferation in porcine aortic endothelial and smooth muscle cells under high D-glucose conditions. Two different technical approaches were used for determination of cell proliferation, a cell counting procedure and bromodeoxyuridine incorporation. D-Glucose diminished endothelial cell proliferation (30.3%) and increased smooth muscle cell proliferation (143%) in a dose-dependent manner. Neither D-mannitol, sucrose nor L-glucose mimicked the effect of D-glucose. Inhibition of D-glucose uptake into vascular cells by cytochalasin B prevented the effect of high D-glucose on cell proliferation. The aldose-reductase inhibitors, sorbinil and zopolrestat, little affected high D-glucose-attenuated endothelial cell proliferation, while the enhanced proliferation of smooth muscle cells was prevented by aldose-reductase inhibitors. Elevation of cellular glutathione levels yielded protection of both cell types from high D-glucose-mediated changes in cell proliferation, suggesting that high D-glucose may act via generation of oxidative species. Finally, aminoguanidine was shown to constitute a very potent inhibitor of D-glucose-induced dysfunction in vascular cell proliferation. These data suggest that high D-glucose-induced changes in cell proliferation of endothelial and smooth muscle cells are related to specific D-glucose uptake rather than hyperosmolality. Aldose-reductase seems to be mainly involved in the effect of high D-glucose only on smooth muscle cell proliferation, while in endothelial cells there is (are) other factor(s) in addition to the sorbitol pathway involved in high D-glucose-induced changes in cell proliferation.
Aldehyde Reductase↗
Insulin resistance and membrane abnormalities.
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Diabetes Mellitus, Type 2↗
Severely depressed natural killer cell activity of patients with adrenoleukodystrophy under treatment with Lorenzo's oil.
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Adrenoleukodystrophy↗