Electrophysiological effects mediated by the stimulation of cardiac β2-adrenoceptors with tulobuterol

Summary We studied the electrophysiological effects of the specific ₂-agonist tulobuterol in the guinea-pig sinus node and in sheep cardiac Purkinje fibers. Stimulation of ₂-adrenoceptors by tulobuterol resulted in a slight increase in the rate of firing of the sinus node. In Purkinje fibers, however, automaticity was not affected up to concentrations of 10^–6 M. Consistently, tulobuterol (10^–8–10^–6 M) did not affect the pacemaker current studied under voltage-clamp conditions. In the same range of concentrations (10^–8–10^–6 M) tulobuterol dose-dependently increased the contractile force of driven Purkinje fibers. Tulobuterol, at a very high concentration (10^–5 M), had membrane depressant effects as demonstrated by the block of automaticity induced in the spontaneously beating Purkinje fibers and by the reduction of the maximum rate of depolarization in driven preparations.Our results suggest that stimulation of ₂-adrenoceptors with tulobuterol in sheep Purkinje fibers is associated with an inotropic rather than a chronotropic effect. On the whole, the data confirm the lack of cardiac side effects of tulobuterol.     

Is glycation of low density lipoproteins in patients with Type 2 diabetes mellitus a LDL pre-oxidative condition?

AIMS: The study aimed to evaluate whether low density lipoprotein (LDL) in diabetic patients is more glycated and susceptible to oxidation than in non-diabetic subjects and investigated the hypothesis that LDL glycation is associated with an increased plasma concentration of LDL- (a circulating electronegatively charged LDL), proposed as an index of in vivo oxidation. METHODS: LDL glycation was measured by a competitive enzyme immunoadsorbent assay, using a monoclonal antibody against glycated apoB in 24 Type 2 diabetic patients and 12 healthy controls. LDL- was separated by ion-exchange HPLC in LDL samples obtained after sequential preparative ultracentrifugation (density range 1.019-1.063). In vitro LDL susceptibility to oxidation was evaluated by following the kinetics of conjugated diene formation and by measuring the lag-phase time in the presence of copper (Cu2+) ions. RESULTS: The percentages of glycated apoB (3.33+/-2.54% vs. 1.24+/-0.71%) and of LDL- (3.88+/-1.49% vs. 2.34+/-1.03%) in total LDL were significantly higher in diabetic patients (P<0.01 for both). LDL- was positively correlated with glycated apoB (r = 0.68, P<0.001). LDL isolated from Type 2 diabetic patients showed a significant decrease (P<0.001) in the resistance to oxidative stress, as indicated by the shorter lag-phase time (91+/-12.6 vs. 120+/-24.5 min). The lag-phase time was inversely correlated with glycated apoB (r = -0.65, P<0.001) and LDL- concentrations (r = -0.69, P<0.001). CONCLUSIONS: In this population of Type 2 diabetic patients, LDL were more glycated, more susceptible to in vitro oxidation and had a higher percentage of electronegative LDL. The glycation of apoB is proposed to be associated with a significative increase of in vivo and in vitro LDL oxidation.     

Antihypertensive treatment in patients with type-2 diabetes mellitus: what guidance from recent controlled randomized trials?

BACKGROUND: Patients with type-2 diabetes have a high prevalence of hypertension and show an elevated incidence of cardiovascular events and nephropathy. OBJECTIVES: Recent randomized trials of antihypertensive therapy providing information about cardiovascular and renal risk in diabetes, blood pressure goals and best suitable drugs were reviewed. FINDINGS: Evidence that association of type-2 diabetes with hypertension markedly increases cardiovascular and renal risk is incontrovertible: even blood pressure values in the high-normal range represent a more relevant risk than in non-diabetics. More versus less intensive blood pressure lowering or active versus placebo treatment can significantly prevent cardiovascular and renal events, with a particularly consistent reduction of proteinuria and microalbuminuria. Although several of the trials showing significant reduction of cardiovascular or renal risk achieved diastolic blood pressure (DBP) between 75 and 82 mmHg, systolic blood pressure (SBP) 140 mmHg was never achieved in trials showing cardiovascular benefits and SBP 130 mmHg was only achieved in two trials in normotensive subjects showing proteinuria reduction. The recommendation given by all major guidelines to lower SBP 130 mmHg appears to be difficult to comply with. Evidence of the superiority or inferiority of different drug classes (angiotensin-converting enzyme inhibitors, calcium antagonists, diuretics and beta-blockers) is rather vague, especially for cardiovascular protection. As to angiotensin-receptor antagonists, losartan has shown significant cardiovascular protection over a beta-blocker, and irbesartan, although not showing cardiovascular benefits over a calcium antagonist, was significantly better in retarding renal dysfunction and failure. CONCLUSIONS: In most trials on hypertensive diabetics, the large majority of patients were on two, three and even four-drug therapy. Therefore, it appears reasonable that all effective and well tolerated antihypertensive agents can be used in association to achieve DBP 80 mmHg and, whenever possible, SBP 130 or 135 mmHg, with the regular inclusion of an angiotensin-receptor antagonist for its proven renoprotective action. Hopefully, better guidance will be provided by further trials.     

Type 2 diabetes mellitus and osteopenia: is there an association?

We report the results of bone mineral density (BMD) measurements in type 2 diabetic patients, in comparison to healthy controls. In this prospective study, a total of 277 subjects (aged 30–60 years) with type 2 diabetes mellitus, outpatients at the Cukurova Medical School Hospital, were evaluated for BMD at L₁–L₄ lumbar vertebrae and at the femur (neck, trochanter, Ward's triangle and total) by DEXA (dual energy X-ray absorptiometry). The patients' diabetes duration, treatment, glycemic control and chronic diabetic complications were recorded, and these data were evaluated for any relationship in respect to the BMD measurements. BMD results of the diabetic patients were compared with those of 262 healthy non-diabetic control subjects living in the same geographic region. BMD was found to be increased at the femoral neck among diabetic women and men aged 51–60 years. However, BMD values at lumbar regions of diabetic men where lower than control in all age group. There was no difference in values of BMD for both genders in the other regions. Type 2 diabetic patients may have lower, similar or higher BMD measurements at different ages and anatomic regions, so each patient should be evaluated individually. Further studies are needed to make a conclusion on this issue. Received: 18 October 2002 / Accepted in revised form: 2 April 2003 Correspondence to M. Sert     

Which basal insulin should be used in patients with type 2 diabetes mellitus?

The initiation of insulin therapy is a significant event for patients with diabetes and the physicians who care for them. Reluctance to begin insulin is multifactorial, with major stumbling blocks being the perceived complexity of insulin and fear of hypoglycemia. Recent guidelines supporting earlier introduction of insulin to achieve glycemic goals in patients with type 2 diabetes mellitus will require that traditional approaches to insulin therapy be altered and a new paradigm be introduced into clinical practice. In particular, an understanding of the role of basal insulin in the regulation of glucose and the development of strategies to implement basal insulin therapy can provide a transition that is rational and highly effective in most patients. The strategy also offers a unique approach to diabetes education that permits a focused and patient-specific correction to glucose abnormalities.     

Are complex coronary lesions more frequent in patients with diabetes mellitus?

BACKGROUND: Coronary atherosclerotic burden is excessive in diabetic patients. Diabetes mellitus (DM) is an independent predictor for both death and myocardial infarction. It is not known whether the prevalence of complex coronary lesions, such as bifurcation and ostial lesions, is different in diabetics from nondiabetics. OBJECTIVE: The aim of present study was to investigate the prevalence of these lesions in patients with DM. METHODS: One thousand fourteen consecutive patients (mean age 61.3+/-10.7 years) were investigated. Coronary angiograms were examined for bifurcation and ostial lesions using a digital quantitative system. Patients were classified as diabetic (n=281) or nondiabetic (n=733). RESULTS: Patient mean age, and rates of hypertension and hyperlipidemia were significantly higher in the diabetic group than in the nondiabetic group (P<0.0001), although smoking was significantly lower (P=0.001). Reasons for coronary angiography and treatment were comparable between the two groups. The prevalence of bifurcation lesions and ostial lesions was significantly greater in the diabetic group than in the nondiabetic group (9.8% versus 4.3% [P=0.001] and 38.4% versus 29.2% [P=0.003] in the diabetic group versus the nondiabetic group). The presence of DM and greater age were found to be independent predictors for bifurcation lesions (OR=2.27 [P=0.004] and OR=1.03 [P=0.01], for DM and age, respectively) and ostial lesions (OR=1.40 [P=0.027] and OR=1.02 [P=0.001], for DM and age, respectively) in multivariate analysis. CONCLUSIONS: Complex coronary lesions such as bifurcation and ostial lesions were significantly more common in diabetic patients than in nondiabetic patients. Greater age and the presence of DM were independent predictors for these complex lesions. These results may help to explain the poor prognosis of coronary artery disease among diabetic patients.     

Is β-cell failure in type 2 diabetes mellitus reversible?

BACKGROUND:

In the UK Prospective Diabetes Study (UKPDS), many subjects maintained glycemic goal (HbA_1c < 7.0%) at 9 years, showing that β-cell function was preserved and that the initial decline in β-cell function recovered with sulphonylureas. Moreover, obese subjects using high daily doses of insulin for several years rarely require insulin or oral hypoglycemic agents to maintain their glycemic goal following weight loss achieved by gastric bypass surgery. Thus, declining β-cell function during the course of type 2 diabetes mellitus (T2DM) is neither universal nor permanent.

OBJECTIVE:

To assess β-cell function in morbidly obese subjects before insulin withdrawal and on attaining the glycemic goal with weight loss and oral agents.

MATERIALS AND METHODS:

Serum C-peptide (CPEP) and glucose (G) concentrations were determined up to 180 min during an oral glucose tolerance test (OGTT) with 75 glucose in 10 obese men with T2DM, before insulin withdrawal, and on achieving the glycemic goal with metformin, glimepiride, and weight loss. Ten age-matched healthy men participated as controls. Cumulative responses (CR) of CPEP and G were calculated by adding differences between the level at each time-period during OGTT and fasting (F) concentration. β-Cell function was expressed as the FCPEP as well as the insulinogenic index (CRCPEP/CRG). Insulin sensitivity was determined as FCEP × FG.

RESULTS:

FCPEP was decreased, though still present, prior to insulin withdrawal. Moreover, on attaining the glycemic goal over 6-9 months, FCPEP, CRPEP/CRG, and FCPEP × FG improved markedly (P < 0.001).

CONCLUSION:

Decline in β-cell function in morbidly obese T2DM may not be progressive and is reversible on improving insulin sensitivity and on eliminating the inhibition by exogenous insulin.     

Serum salusin-β in relation to atherosclerosis and ventricular dysfunction in patients with type 2 diabetes mellitus

Background and aimsSalusin-β is a newly defined biomarker that plays a role in atherogenesis and in homeostasis. The study aimed to assess serum salusin-β level in relation to atherosclerosis and ventricular dysfunction in type 2 diabetes mellitus (T2DM) patients.MethodsSixty T2DM patients and twenty-five age-matched healthy controls were included. Serum salusin-β was determined by ELISA. Echocardiography and carotid ultrasonography were carried out for all individuals.ResultsSerum salusin-β level was significantly elevated in patients with T2DM than in controls (P < 0.001). It was positively correlated with obesity parameters, insulin resistance index (r = 0.280,P < 0.001), atherogenic dyslipidemia and with carotid intima media thickness (CIMT) (r = 0.411, P < 0.001). Echocardiographic findings showed a positive correlation between salusin-β and left ventricular hypertrophy (LVH) parameters and a negative correlation with left ventricular (LV) diastolic and systolic functions. Regression analysis showed that serum salusin-β level was a significant predictor of diastolic dysfunction.ConclusionSerum salusin-β may be associated with atherosclerosis and LV dysfunction in T2DM.     

Global myocardial perfusion and diastolic function are impaired to a similar extent in patients with type 2 diabetes mellitus and in patients with coronary artery disease—evaluation by contrast echocardiography and pulsed tissue Doppler

Aims/hypothesis Using modern echocardiography, we quantified the extent of global myocardial function and perfusion abnormalities in patients with type 2 diabetes and compared this with the hypothetically similar extent of impairments in patients with coronary artery disease (CAD).Subjects and methods This case–control study (66 patients) compared four age-matched groups: control, type 2 diabetic, CAD, and diabetic subjects with CAD (DCAD) and left ventricular ejection fraction >50%. CAD patients had 1–2 vessel disease. Diastolic and systolic myocardial velocities were assessed with pulsed tissue Doppler. Global myocardial perfusion was assessed with contrast echocardiography as indices of capillary blood volume and myocardial blood flow at maximal vasodilatation. In CAD and DCAD patients, functional and perfusion parameters were additionally assessed in the territory with a normal coronary angiogram reading, providing a model for comparison with the global data from control and diabetic patients.Results Comparing diabetic with control subjects, myocardial velocity at early diastole was impaired (8.8±1.8 vs 10.1±1.7 cm/s; p=0.02) and correlated inversely with age, HbA_1c and pulse pressure (R ²=0.761). Capillary blood volume (16.6±5.0 vs 24.4±4.9%) and blood flow (56±35 vs 114±40) were decreased (p=0.001). In CAD patients, myocardial velocity at early diastole was similarly decreased (p=0.02). CAD and DCAD patients were receiving more cardiovascular preventive therapy for the same extent of impaired global perfusion as in the less extensively treated diabetes group without CAD (p<0.002), but had superior perfusion of the ‘normal’ coronary territory than that group (p<0.05).Conclusions/interpretation In patients with diabetes, global diastolic function and myocardial capillary blood volume and blood flow are impaired to the same extent as in patients with CAD. These impairments could form the basis of new therapeutic concepts.     

Which patients with type 2 diabetes mellitus are perceived as ‘difficult’ by general practitioners?

AimsTo find factors that are associated with a general practitioner’s (GP’s) subjective impression of a patient being ‘difficult’ within a sample of patients with type 2 diabetes mellitus (T2DM).MethodsSecondary cross-sectional analysis of a cohort of GP patients with T2DM. GP questionnaire on clinical data and GPs’ subjective ratings of patient attributes (including ‘patient difficulty’). Patient questionnaire on sociodemographics and illness perceptions. Bivariate and multivariate analyses, adjusted for cluster-effect of GP practice.ResultsData from 314 patients from 49 GPs could be analysed. Independent associations with higher GP-rated difficulty were found for (odds ratio; 95% confidence interval): male patients from male GPs (1.27; 1.06–1.53), unmarried men (1.25; 1.04–1.51), men with non-German nationality (1.80; 1.24–2.61), patients perceiving more problems with diabetes (1.17; 1.04–1.30), patients with higher BMI (1.01; 1.00–1.02) and HbA1c values (1.06; 1.02–1.10), patients being perceived by the GP as less adherent (1.34; 1.22–1.46) and less health-literate (1.19; 1.04–1.35).ConclusionsThe impact of patients’ gender and illness perception yield new insights into GP-perceived complexity of care. Culturally and gender-sensitive communication techniques for adapting health care goals to patients’ problems (rather than norm values) may alleviate GPs’ work.     

Role of platelets in NOX2 activation mediated by TNFα in heart failure

Tumor necrosis factor (TNF) α may contribute to the deterioration of cardiovascular function in heart failure (HF) through various mechanisms, including the generation of reactive oxygen species (ROS). NADPH oxidase is the major source of ROS in the vascular system, but the interplay between TNFα and NADPH oxidase activation is elusive. As platelets possess NADPH oxidase enzyme, they represent an important tool to investigate the interplay between NADPH oxidase and TNFα in patients with HF. Serum gp91phox (NOX2), the catalytic core of NADPH oxidase, and serum TNFα were measured in 120 HF patients and in 60 healthy subjects. Compared with healthy subjects, HF patients had higher blood levels of NOX2 and TNFα with a progressive increase from NYHA I to NYHA IV classes. NOX2 levels in blood were independently associated with TNFα in HF patients. An in vitro study, performed on platelets from a subgroup of HF patients, shows that TNFα, at concentrations commonly found in HF patients’ peripheral circulation, activates platelet NOX2. Thus, TNFα increases ROS production and the extracellular levels of NOX2. These phenomena are inhibited by the NOX2-specific blocking peptide gp91ds-tat. The study provides evidence that circulating NOX2, as well as the activation of NOX2 on platelets, is increased in HF likely as a consequence of the underlying inflammatory process.     

Nitric oxide metabolites and arginase I levels in β-thalassemic patients: an Egyptian study

Stored red blood cells become deficient in nitric oxide that limits their ability to transfer oxygen to tissues that need it. The aims of this study are to assess the endogenous nitric oxide metabolites (NOx) and arginase I levels in transfusion-dependent β-thalassemic patients; to compare these levels in patients transfused with fresh RBCs with patients transfused with old RBCs, β-thalassemic minor patients, and normal control; and to correlate these levels with some clinical variables. Group I was composed of 23 patients with homozygous β-thalassemia on hypertransfusion regimen. They were adequately transfused with fresh RBC. Group II was composed of 17 patients with homozygous β-thalassemia on hypertransfusion regimen. They were adequately transfused with old RBCs. Group III was composed of 30 patients with homozygous β-thalassemia. They were adequately transfused with fresh RBCs. Group IV was composed of 18 patients with homozygous β-thalassemia. They were adequately transfused with old RBCs. Both group III and group IV were supposed to be on hypertransfusion regimen, but they did not follow the regimen. Group V was composed of 21 patients of β-thalassemia minor. Nineteen apparently healthy individuals (HbAA) served as a control group (group VI). In addition to routine laboratory investigations, plasma levels of NOx and serum levels of arginase I were assessed in all subjects. The mean values of plasma NOx were significantly decreased in groups III and IV compared to the other groups. Also, the levels of NOx were significantly decreased in patients who received old RBCs compared to the other groups. There were high serum levels of arginase I in groups III and IV compared to the other groups. There were significant negative correlations between plasma NOx and some hemolytic biochemical markers in groups III and IV. There were significant positive correlations between serum arginase I and some hemolytic biochemical markers in groups III and IV. Also, there was a significant negative correlation between plasma NOx and serum arginase I levels in groups III and IV. In non-adequately transfused patients with β-thalassemia major, inactivation of NO correlates with hemolytic rate and is associated with the erythrocyte release of cell-free hemoglobin, which consumes NO directly, and the simultaneous release of the arginine-metabolizing enzyme arginase, which limits bioavailability of the NO synthase substrate, arginine, during the process of hemolysis. New treatments aimed at improving arginine and NO bioavailability through arginase inhibition, suppression of hemolytic rate, oral arginine supplementation, predonation testing, and transfusion of fresh RBCs or use of NO donors represent potential therapeutic strategies for this common hemolytic disorder.     

Non-invasively estimated end-systolic elastance in patients with resistant hypertension and type 2 diabetes mellitus

Ventriculo-arterial coupling (VAC) has been shown to be impaired in patients with type 2 diabetes mellitus (type 2 DM) and hypertension, and to improve with antihypertensive treatment. We examined if VAC in patients with type 2 DM and hypertension improved after a period of intensified antihypertensive treatment. VAC was estimated as the ratio of effective arterial elastance (E _A) to end-systolic elastance (E _ES) using pressure and flow curves obtained non-invasively (applanation tonometry and echocardiography). Left ventricular (LV) systolic and diastolic functions were evaluated using LV volumes, ejection fraction (EF), mitral inflow pattern, and Doppler tissue mitral annulus velocities. In total, 180 patients were included and for 100 patients the data met the quality criteria. Patients were categorized as having controlled (CH, n = 34), uncontrolled (UH, n = 32) or resistant (RH, n = 34) hypertension. In patients with RH, EF at follow-up was reduced from 48 to 42 % (p = 0.005) and E _ES from 2.18 mmHg/ml to 1.47 mmHg/ml (p = 0.003). E_ES, however, was also reduced in patients with CH and UH (CH 2.41–2.26, p = 0.05, UH 2.51–2.04, p = 0.05). In the present study, intensified antihypertensive treatment did not improve VAC or LV function in patients with hypertension and type 2 DM despite better control of BP. We speculate whether this is due to a reduction in myocardial perfusion pressure or to a gradual progression of diabetic cardiomyopathy.