A polymorphism in the gene encoding AdipoR1 affects olfactory recognition.

Polymorphisms in the gene encoding adiponectin receptor 1 (AdipoR1) are associated with insulin resistance, fatty liver, increased risk for type 2 diabetes and cardiovascular disease. AdipoR1 is expressed in the central nervous system and in the olfactory mucosa of mice and humans. We therefore hypothesized that a common polymorphism in AdipoR1 might alter olfactory function. We investigated a group of 222 healthy subjects (male: n = 147, female: n = 75) for olfactory recognition, and genotyped them for the polymorphism rs6666089 in the human AdipoR1 gene. This polymorphism has been previously shown to be associated with insulin resistance. Olfactory recognition was tested using standardized sniffing sticks, and parameters of glucose metabolism and serum adiponectin levels were assessed. We found a significant olfactory impairment in carriers of the AdipoR1 polymorphism rs6666089 (olfactory recognition: GG: 89.4 ± 1.2%, GA: 86.9 ± 1.4%, AA: 77.2 ± 4.8%, additive model, P = 0.0004, adjusted for age). Adiponectin levels had no impact on olfactory recognition. Fasting plasma glucose, fasting plasma insulin, body mass index and HbA1c did not differ between the genotype groups. In conclusion, the presence of a genetic variation in AdipoR1 is associated with decreased olfactory recognition in healthy subjects. Adiponectin signalling may have an important role in olfactory function and regulation of appetite.

Preserved endothelial function in IDDM patients, but not in NIDDM patients, compared with healthy subjects.

OBJECTIVE: To examine endothelial function (EF) noninvasively in IDDM and NIDDM patients with long diabetes duration. RESEARCH DESIGN AND METHODS: We studied EF in 17 IDDM patients without diabetic complications and in 25 NIDDM patients with comparable glycemic control and with diabetic complications and compared both with nondiabetic control subjects matched for age, sex, and lumen diameter. Using high-resolution ultrasound, we measured the endothelial-dependent (FAD%) and independent vasodilation (GTN%); the blood flow at rest, postocclusive, and after application of 400 micrograms glyceroltrinitrate of the branchial artery; and the intima media thickness (IMT) of the common carotid artery. RESULTS: In the IDDM patients, neither FAD% (8.2 +/- 4.6 vs. 7.6 +/- 4.2%), GTN% (16.3 +/- 4.9 vs. 18.4 +/- 6.4%), nor postocclusive blood flow (40.6 +/- 19.1 vs. 39.3 +/- 23.6 cm/s) differed from the control subjects. IMT (0.59 +/- 0.10 vs. 0.55 +/- 0.14 mm) was slightly, but not significantly, elevated. In contrast, the NIDDM patients showed an impaired FAD% (3.8 +/- 3.3 vs. 6.9 +/- 4.4%, P < 0.01), no difference in GTN%, and a decreased postocclusive blood flow (18.5 +/- 13.8 vs. 32.7 +/- 20.0 cm/s, P < 0.01). IMT was significantly increased in NIDDM patients (0.77 +/- 0.14 vs. 0.62 +/- 0.10 mm, P < 0.001). CONCLUSIONS: In contrast to NIDDM patients with cardiovascular complications, IDDM patients with long diabetes duration and good long-term metabolic control do not have impaired EF compared with control subjects.

Perfusion-independent effect of bradykinin and fosinoprilate on glucose transport in Langendorff rat hearts.

Angiotensin-converting enzyme (ACE) inhibitor-stimulated glucose metabolism and perfusion in muscle tissue seem to be, at least in part, mediated by kinins. However, the relative contribution of direct metabolic or secondary hemodynamically induced effects is unclear. It was the aim of this study to characterize the effects of ACE inhibition and bradykinin on glucose transport while changes in cardiocoronary function that might influence glucose transport were minimized. Hearts from Wistar rats were perfused by a Langendorff preparation and a set of functional parameters were simultaneously measured. Bradykinin (10[-11] M) and fosinoprilate (10[-7] M) were administered at concentrations that did not affect coronary flow. Insulin was employed as reference at half-maximal concentration. The nonmetabolizable glucose analog 3-O-[14C]methyl-D-glucose and the nontransportable tracer L-[3H]glucose were coperfused for the calculation of glucose transport. Using a 2-compartment mathematical model we found that the glucose transport rate, which was doubled with insulin, was increased almost 3-fold by either bradykinin or fosinoprilate. In the presence of the B2 bradykinin receptor antagonist HOE 140 (D-Arg[Hyp3,Thi5,D-Tic7,Oic8]-bradykinin; icatibant), the effect of both agents was completely abolished. Both agents also induced minor changes in contractility/relaxation parameters that again were completely neutralized with icatibant. A perfusion-independent but B2-kinin receptor-dependent stimulating effect on glucose transport by either bradykinin or fosinoprilate is concluded. This effect could, in analogy to insulin be due to increased glucose transporter translocation, increased endothelium-derived nitric oxide formation, or--despite constant coronary flow conditions--secondary to altered cardiac function.

Comparison of peripheral endothelial dysfunction and intimal media thickness in patients with suspected coronary artery disease.

OBJECTIVE: Flow associated dilatation (FAD%) and intimal media thickness are established markers of early atherosclerosis. This study aimed to compare the ability of the non-invasive measurements FAD% and intimal media thickness to predict coronary artery disease. METHODS: FAD% and intimal media thickness were determined using high resolution ultrasound in 122 patients with clinically suspected coronary artery disease before coronary angiography. Results are given as mean (SD). RESULTS: Patients with coronary artery disease had reduced FAD% compared with those with angiographically normal coronary vessels (3.7 (4.1) v 7.0 (3.5)%, p < 0.001), whereas intimal media thickness tended to be increased in patients with coronary artery disease (0.58 (0.35) v 0.47 (0.11)mm, p = 0.054). There was a negative correlation between FAD% and intimal media thickness (R = -0.317, p = 0.0004). Receiver operating characteristic analysis showed that FAD% < or = 4.5% predicted coronary artery disease with a sensitivity of 0.71 (95% confidence interval 0.61 to 0.80) and a specificity of 0.81 (0.58 to 0.95). In contrast, intimal media thickness showed a positive correlation with the extent of coronary artery disease (number of vessels with a lesion > or = 50%) (R = 0.324, p = 0.0003), without a clear cut off point. CONCLUSIONS: In patients with clinically suspected coronary artery disease, FAD% discriminates between the presence or absence of coronary artery disease, whereas intimal media thickness is associated more with the extent of coronary artery disease.

Acute improvement of peripheral endothelial function in postmenopausal women with coronary artery disease after single oral intake of 17beta-estradiol valerate.

Chronic estrogen supplementation is known to improve endothelial function in postmenopausal women. We studied the acute effect of a single dose of orally administered 17beta-estradiol valerate (E2) on the peripheral endothelial dependent and independent vasodilatation in postmenopausal women with coronary artery disease (CAD). 20 postmenopausal women (age: 64.9 (7.2) y, height: 1.61 (0.04) m. weight: 68.6 (10.6) kg) with angiographically confirmed CAD were randomly examined for flow-associated vasodilatation (= FAD%, a marker for endothelial dependent vasodilatation) and for glyceryltrinitrate (400 microg, p.o.) induced vasodilatation (= GTN%, representing endothelial independent vasodilatation) two hours after placebo controlled, randomized crossover intake of 4 mg E2 p.o. After placebo FAD% was impaired (3.5 (1.7)%) compared to historic controls. After the oral intake of 4 mg E2, FAD% improved to 5.0 (2.8)% (P=0.02). GTN% was not significantly influenced by the oral E2 (E2: 12.6 (5.7) v placebo: 11.2 (6.9)%, P=0.14). Endothelial dysfunction can partially be restored by a single oral dose of 4 mg E2. This indicates an acute vasoprotective effect of E2 beyond its genomic and lipid modifying actions. It remains to be investigated if estrogen might play a beneficial role in the acute treatment of symptomatic coronary artery disease such as angina pectoris or preinfarct syndrome.

Lack of a lipoprotein-induced insulin resistance in hepatoma cells in culture.

A lipoprotein-induced resistance to the action of insulin has been postulated. To test this hypothesis, cultured rat-derived hepatoma cells, designated FAO, and human-derived hepatoma cells, designated HEP-G2, were incubated for 20 h in the presence or absence of lipoprotein; specific 125I-insulin receptor binding and labeled glucose incorporation into glycogen were then measured. Very low density lipoproteins (d less than 1.006 g/ml) in physiologic (0.5 mg/ml) or pathophysiologic (5 mg/ml) concentrations did not modify insulin receptor binding of FAO or HEP-G2 cells. This was true for very low density lipoproteins derived from normal human, diabetic human, and streptozotocin-diabetic rat plasma. Low density lipoproteins (d = 1.019 - 1.063 g/ml) isolated from normal human plasma similarly failed to modify insulin receptor binding. Concerning insulin action, the different very low density lipoprotein preparations did not modulate either basal or insulin-stimulated glucose incorporation into glycogen of the cells. Thus, very low density lipoproteins and low density lipoproteins did not induce insulin resistance in cultured hepatoma cells either at the insulin receptor level or at the post-receptor level.

Endothelial function, variables of fibrinolysis and coagulation in smokers and healthy controls.

OBJECTIVE: To asses endothelial function and variables of fibrinolysis and coagulation in smokers compared to healthy controls. METHODS: Flow-associated dilation as a marker for peripheral endothelial function and intima media thickness as a marker for early morphologic vascular changes were measured in otherwise healthy smokers (n = 30, 16 males and 14 females, age: 40.6 +/- 11.3 years, body mass index 24.9 +/- 3.7 kg/m(2)) and non-smoking controls matched for age and sex using high-resolution ultrasound. Variables of the coagulation system (thrombin-antithrombin III complex, fibrinogen) and fibrinolysis (tissue-plasminogen activator, plasmin-alpha(2)-antiplasmin complex) were determined by ELISA and plasminogen activator inhibitor activity by means of a chromogenic substrate test. RESULTS: Compared to the non-smoking controls, flow-associated vasodilatation was significantly reduced (6.9 +/- 4. 4 vs. 10.5 +/- 6.2%, p = 0.01) and intima media thickness tended to be increased (0.58 +/- 0.12 vs. 0.52 +/- 0.14 mm, p = 0.08) in smokers. The thrombin-antithrombin III complex, fibrinogen, plasmin-alpha(2)-antiplasmin complex, tissue-plasminogen activator and plasminogen activator inhibitor activity did not differ between smokers and controls. CONCLUSION: Our data indicate that peripheral endothelial dysfunction is common in smokers even without major alterations in molecular markers of the coagulation and fibrinolysis system.

Acquired generalized lipoatrophy (AGL): highly selective MR lipid imaging and localized (1)H-MRS.

Frequency-selective chemical shift magnetic resonance (MR) imaging was applied on the calf musculature and the abdomen of a patient with acquired generalized lipoatrophy (AGL; Lawrence syndrome), a very rare syndrome affecting selectively several types of adipose tissue accompanied by alterations in glucose and energy metabolism. In addition, (1)H-MRS was used for assessment of intra- (IMCL) and extramyocellular lipid stores (EMCL) in the skeletal musculature of the calf. Results from the AGL patient were compared with an age-matched group of five healthy volunteers. Fat-selective imaging of the calf revealed a total lack of subcutaneous adipose tissue. No EMCL signal was found in the spectra from the soleus muscle of the AGL patient. IMCL signals were present in the spectra but were clearly lower than in the controls (14% of normal value in the soleus muscle). In abdominal images, subcutaneous fat signal was not detectable, as in the calf, but nearly normal conditions were shown for visceral adipose tissue between abdominal organs. Fat-selective images showed the liver with high signal intensity, indicating hepatic steatosis combined with hepatosplenomegaly. Modern chemical shift-selective MR imaging and localized spectroscopy allow a noninvasive and quantitative assessment of tissue composition in patients with disorders of carbohydrate and lipid metabolism.

Noninvasive determination of endothelium-mediated vasodilation as a screening test for coronary artery disease: pilot study to assess the predictive value in comparison with angina pectoris, exercise electrocardiography, and myocardial perfusion imaging.

BACKGROUND: Peripheral endothelial dysfunction (ED) quantified by the determination of flow-mediated dilation (FMD%) of the brachial artery with the use of high-resolution ultrasound is an early marker of atherosclerosis. Although a positive correlation with coronary artery disease (CAD) has been reported, the unanswered clinical question is the validity of FMD% as a screening test in patients with clinical suspicion of CAD. Thus the aim of this study was to determine the predictive value of FMD% compared with angina pectoris, exercise electrocardiography, and myocardial perfusion imaging. METHODS AND RESULTS: In this pilot study, we measured ED in 122 patients scheduled for coronary angiography by using high-resolution ultrasound (13 MHz). We defined ED as FMD%

Utilisation of intramyocellular lipids (IMCLs) during exercise as assessed by proton magnetic resonance spectroscopy (1H-MRS).

Recently, a 1H-MRS method became available to quantify intramyocellular lipids (IMCL) non-invasively. Currently, little is known about the regulation of this lipid pool. During prolonged exercise of moderate intensity, non-plasma-derived fatty acids play an important role as an energy source; lipids located within the skeletal muscle are considered to be a major source for these fatty acids. To see whether IMCL are reduced by exercise, 12 male runners were studied before and after exercising at different workloads and duration. Six subjects participated in a non-competitive run (NCR), three runners in a competitive half marathon (HM, 21 km) and another three in a competitive marathon (M, 42 km). Intra- and extramyocellular lipids were quantified by 1H-MR spectroscopy in the tibialis anterior (TA) and soleus (SOL) muscles prior to and after the exercise bout. Moderate intensity (MI; 60-70% VO2max in NCR) with a mean exercise time (MET) ranging between 105-110 min decreased IMCL by 10 - 36% in both muscles. Prolonged MI exercise (MET 210-240 min; 68-70% VO2max in M) reduced IMCL by 42-57% in TA and 27 - 56% in SOL. In contrast, high intensity exercise (HI; MET 80-120 min; 83-85% VO2max in HM) did not alter IMCL in either muscle. Extramyocellular lipids (EMCL) did not show any significant change in any group. The data show that one bout of moderate-intensity (60-70% VO2max) aerobic exercise markedly reduces the IMCL in TA and SOL muscles in a time-dependent fashion as assessed by 1H-MRS. However, exercise of similar duration but higher workload (> 80% VO2max) does not reduce IMCL. These data suggest that both exercise duration and workload are important factors in determining the reduction of IMCL.