Andreas Moan

Relationship between hemorrheologic factors and insulin sensitivity in healthy young men.

The present study aimed at testing a possible relationship between hemorrheologic factors, such as hematocrit, fibrinogen, and whole-blood viscosity, and insulin sensitivity in healthy humans. Twenty-one 21-year-old men were studied with the hyperinsulinemic euglycemic glucose clamp technique. We found statistically significant negative correlations between the glucose disposal rate (GDR) and calculated whole-blood viscosity at both high (r = -.55, P = .01) and low (r = -.51, P = .01) shear rates. We observed negative associations between GDR and fibrinogen (r = -.66, P = .002), GDR and hematocrit (r = -.63, P = .002), GDR and body mass index (r = -.51, P = .007), and GDR and resting heart rate (r = -.46, P = .04). Using stepwise multiple regression considering whole-blood viscosity, body mass index, mean arterial blood pressure, and heart rate as independent variables, we found that only whole-blood viscosity and body mass index were independent explanatory variables of the GDR. Together they accounted for 63% of the variability in the GDR in our subjects. These results suggest hemorrheologic, and therefore indirectly hemodynamic, factors as correlates to insulin sensitivity.

The Effect of Angiotensin II Receptor Blockade on Insulin Sensitivity and Sympathetic Nervous System Activity in Primary Hypertension

The objective of this study was to investigate the effect of Losartan (NK-954, DuP-753), a new selective angiotensin II receptor antagonist, on insulin sensitivity and sympathetic nervous system activity in patients with severe primary hypertension. Five patients with a record of diastolic blood pressure (DBP) > or = 115 mmHg, currently either untreated or with DBP > 95 mmHg on antihypertensive treatment, were examined in an open study with the euglycemic glucose clamp examination before and after being treated with Losartan for an average of 6 weeks. The glucose disposal rate increased from 6.2 +/- 2.6 to 7.9 +/- 2.6 mg/kg x min (27%, p < 0.05) during treatment with Losartan. The insulin sensitivity index (glucose disposal rate divided by mean insulin concentration during clamp) increased from 7.7 +/- 4.5 to 10.1 +/- 4.1 arbitrary units (30%, p < 0.05). Plasma noradrenaline decreased from 1.87 +/- 0.53 to 1.11 +/- 0.13 nmol/l (40%, p < 0.05), while plasma adrenaline was unchanged (0.23 +/- 0.10 vs. 0.22 +/- 0.11 nmol/l, n.s.). Mean blood pressure decreased from 132 +/- 10 to 119 +/- 13 mmHg (p < 0.05) and heart rate was unchanged during treatment with Losartan. Thus, antihypertensive treatment with the new selective angiotensin II receptor antagonist Losartan seems to improve insulin sensitivity. A decrease in plasma noradrenaline on Losartan suggests a sympathicolytic effect which together with vasodilation may explain the fall in blood pressure and the improvement in insulin sensitivity.

The effect of angiotensin II receptor antagonism with losartan on glucose metabolism and insulin sensitivity

Objective To investigate the metabolic effects of losartan (Cozaar®) in patients with essential hypertension. Methods Twenty patients with mild hypertension (office blood pressure>140/95 mmHg and home diastolic blood pressure>90 mmHg) were examined in a double-blind, placebo-controlled cross-over study of 4 weeks of treatment with 50-100 mg losartan. The effects on glucose metabolism were assessed by euglycaemic glucose clamp examinations [glucose disposal rate (GDR, mg/kg per min)] and oral glucose-tolerance tests (OGTT). Results Supine blood pressure was reduced from 146 + 3/90 ± 3 mmHg on placebo to 134 ±4/83 ± 3 mmHg on losartan and the difference was maintained during 120 min of insulin infusion and glucose clamping. GDR was 6.2 ± 0.5 mg/kg per min on placebo and 6.4 ± 0.5 mg/kg per min on losartan. The glucose and insulin responses (the area under the curve) during OGTT were similar with placebo and losartan (0.86 ± 0.3 versus 0.88 ± 0.4 and 341 ± 60 versus 356 ± 60, respectively; arbitary units). Serum cholesterol was 5.3 ± 0.2 mmol/l on placebo and 5.1 ± 0.2 mmol/l with losartan treatment. High-density lipoprotein cholesterol and triglycerides were, respectively, 1.1 ± 0.1 and 1.5 ± 0.2 mmol/l with placebo, and 1.1 ± 0.1 and 1.4 ± 0.1 mmol/l with losartan treatment. Conclusion In mildly hypertensive patients, selective angiotensin II receptor antagonism with losartan for 4 weeks lowers blood pressure at rest and during 120 min of glucose clamping, and has neutral effects on insulin sensitivity, glucose metabolism and serum lipids.

Insulin sensitivity, sympathetic activity, and cardiovascular reactivity in young men

The present study was undertaken to examine the relationships between insulin sensitivity, blood pressure (BP), and cardiovascular reactivity, and to assess sympathetic nervous system influence. Insulin sensitivity (GDR/I; euglycemic glucose clamp technique) was related to BP and heart rate (HR) in different situations in 40 healthy young men: in the laboratory, during a mental arithmetic stress test, and during baseline conditions at home. GDR/I correlated with supine diastolic BP in the laboratory and with maximum diastolic BP during mental stress (r = -0.46, P = .003; r = -0.62, P = .0001, respectively), but not so strongly with diastolic BP measured at home (r = -0.29, P = .09). Diastolic BP during stress and body mass index were the only independent explanatory variables of GDR/I in multiple regression analysis (multiple R = 0.71, R2 = 0.50, P < .0001). GDR/I and systolic BP were not significantly correlated at any time. GDR/I correlated negatively with HR in the laboratory and with maximum HR during mental stress, but not with HR at home. Maximum plasma epinephrine during stress correlated with stress BP and HR (r = 0.53, P = .001; r = 0.70, P < .0001, respectively) and negatively with GDR/I (r = -0.36, P < .05). In the present study, GDR/I is related to diastolic but not to systolic BP, and more closely correlated to diastolic BP and HR measured during mental stress than to diastolic BP and HR during baseline conditions at home.(ABSTRACT TRUNCATED AT 250 WORDS)

Whole-blood viscosity and the insulin-resistance syndrome

Background In a previous study we found that elevated blood viscosity was linked to the insulin resistance syndrome, and we proposed that high blood viscosity may increase insulin resistance. That study was based on calculated viscosity. Objective To determine whether directly measured whole-blood viscosity was related to the insulin-resistance syndrome in the same way as calculated viscosity had been found to be. Methods Healthy young men were examined with the hyperinsulinemic isoglycemic glucose clamp technique, and we related insulin sensitivity (glucose disposal rate) to other metabolic parameters and to blood viscosity. We established a technique for direct measurement of whole-blood viscosity. Results There were statistically significant negative correlations between glucose disposal rate and whole-blood viscosity at low and high shear rates (r = −0.41, P = 0.007 for both, n = 42). Whole-blood viscosity was correlated positively (n = 15) to serum triglyceride (r = 0.54, P = 0.04) and total cholesterol (r = 0.52, P = 0.05), and negatively with high-density lipoprotein cholesterol (r = −0.53, P = 0.04) concentrations. Insulin sensitivity index was correlated positively to high-density lipoprotein cholesterol (r = 0.54, P = 0.04) and negatively to serum triglyceride (r = −0.69, P = 0.005) and to total cholesterol (r = −0.81, P = 0.0003) concentrations. Conclusions The present results demonstrate for the first time that there is a negative relationship between directly measured whole-blood viscosity and insulin sensitivity as a part of the insulin-resistance syndrome. Whole-blood viscosity contributes to the total peripheral resistance, and these results support the hypothesis that insulin resistance has a hemodynamic basis.

Relationship Between Insulin Sensitivity and Maximal Forearm Blood Flow in Young Men

Insulin resistance is a part of the metabolic cardiovascular syndrome. We aimed to test the hemodynamic hypothesis of insulin resistance, which suggests that a decreased skeletal muscle blood supply with subsequent reduced nutritional flow causes insulin resistance in skeletal muscle. We assessed determinants of peripheral blood flow such as maximal forearm blood flow (MFBF), minimal forearm vascular resistance (MFVR), and whole blood viscosity (WBV) in 27 young men with borderline elevation of blood pressure. Insulin sensitivity measured as glucose disposal rate (GDR) correlated with MFBF (r=0.55, P=0.003), MFVR (r=-0.58, P=0. 002), and WBV (r=-0.39, P=0.046 at shear rate 201 s-1). There was no correlation between GDR and myocardial thickness or left ventricular mass. In a stepwise multiple regression analysis, MFVR and WBV explained 54% of the variation in GDR. The relative increase in mean arterial blood pressure during a mental stress test, as a marker of reactivity or an alert reaction, was correlated with MFVR (r=0.56, P=0.002) and inversely with GDR (r=-0.45, P=0.018) and MFBF (r=-0.49, P=0.01) but not with cardiac dimensions. In a stepwise multiple regression analysis, 48% of the increase in blood pressure during a mental stress test was explained by MFVR and WBV. Fasting insulin correlated with MFVR (r=0.41, P=0.036) and GDR (r=-0.62, P=0.001). These data show a positive association between the appearance of peripheral structural vascular changes as quantified through a hemodynamic technique and insulin resistance in young men with borderline elevation of blood pressure. The cause-effect relationship of this finding needs further evaluations.

Effect of Angiotensin II Receptor Blockade on Fibrinolysis During Acute Hyperinsulinemia in Patients With Essential Hypertension

We performed the present study to investigate indirectly the in vivo effects of angiotensin II on fibrinolysis and catecholamines by treatment with losartan, a selective angiotensin II type 1 receptor antagonist. The effects were evaluated in basal conditions as well as in two different models of acute hyperinsulinemia physiologically induced by oral glucose ingestion and by a euglycemic glucose clamp technique. Twenty subjects with moderate hypertension were included in a randomized, double-blind, placebo-controlled crossover study of 4-week treatment periods. Plasma levels of catecholamines, tissue plasminogen activator activity and antigen, and plasminogen activator inhibitor type 1 activity and antigen were unchanged in the basal state after 4 weeks of treatment. During both models of hyperinsulinemia, plasminogen activator inhibitor activity and antigen decreased significantly (both P<.001), and tissue plasminogen activator activity increased significantly (P<.Ol). Norepinephrine did not change during any of the procedures, whereas epinephrine increased significantly after 3 hours of the oral glucose tolerance test. Changes from baseline did not differ between the treatment and placebo regimens during the hyperinsulinemic procedures with regard to either of the fibrinolytic variables or the catecholamines. In conclusion, we could not demonstrate any effects of 4 weeks of treatment with losartan on plasma levels of fibrinolytic variables or catecholamines either in basal conditions or during acute hyperinsulinemia. However, the present findings do not preclude more direct effects of angiotensin II or involvement of other receptor subtypes on fibrinolysis.

Whole Blood Viscosity, Blood Pressure and Cardiovascular Risk Factors in Healthy Blood Donors

Whole blood viscosity contributes to the total peripheral resistance and has been suggested to be a risk factor for cardiovascular disease. Whole blood viscosity was measured using a direct technique in 105 healthy blood donors and in addition to establishing our reference values, the relationship to blood pressure and other cardiovascular risk factors was assessed. Whole blood viscosity correlated with systolic blood pressure (r = 0.29, p = 0.003), cholesterol (r = 0.21, p = 0.034), cholesterol/HDL cholesterol ratio (r = 0.33, p = 0.01), triglycerides (r = 0.37, p < 0.0005), body mass index (r = 0.29, p = 0.003) and waist-hip ratio (r = 0.30, p = 0.002). Subjects with systolic blood pressure > 130 mmHg (n = 16) had higher whole blood viscosity (p = 0.017) than those with lower blood pressure. Whole blood viscosity was significantly lower in women (n = 52) than in men at all shear rates (0.045 > p > 0.001). These results suggest that even in a population of healthy normotensive blood donors of a wide age range and either gender, there are positive correlations between directly assessed whole blood viscosity and a number of the components of the metabolic cardiovascular syndrome including systolic blood pressure, weight and blood lipids.

The sympathetic nervous system may modulate the metabolic cardiovascular syndrome in essential hypertension

Summary: The association between blood pressure and coronary artery disease may be caused by a concurrence of atherogenic biochemical abnormalities in hypertensive patients, i.e., the metabolic cardiovascular syndrome (increased total cholesterol, triglycerides, and insulin; decreased high-density lipoprotein (HDL) cholesterol; and insulin resistance, glucose intolerance, and blood platelet dysfunction). There are numerous reports of sympathetic nervous system overactivity in hypertensive subjects that could be of importance for the pathophysiology of the high blood pressure. Plasma catecholamines have metabolic hormonal effects at concentrations slightly above low normal resting levels. Even transiently and certainly chronically raised plasma catecholamine levels may cause biochemical abnormalities. Catecholamines may raise total cholesterol, triglycerides, and insulin, decrease HDL cholesterol, and cause insulin resistance and glucose intolerance, and recent evidence supports an in vivo influence of epinephrine on blood platelets, causing dysfunction in hypertensive subjects. Thus, the sympathetic nervous system may modulate the metabolic cardiovascular syndrome in essential hypertension. Hypertensive subjects may respond to environmental stimuli with larger sympathoadrenal responses than normal subjects. Furthermore, emotional stress has been associated with coronary artery disease. Thus, the metabolic hormonal effects of catecholamines, by causing the metabolic cardiovascular syndrome, may be the crucial link between “stress” and cardiovascular disease.

Mental stress increases glucose uptake during hyperinsulinemia: Associations with sympathetic and cardiovascular responsiveness

Infusion of epinephrine and norepinephrine reduces insulin-mediated glucose disposal, ie, induces insulin resistance. Mental stress increases concentrations of both plasma catecholamines. However, the effect of acute mental stress on insulin-mediated glucose uptake has not been examined. We observed in pilot studies that a mental stress test (MST) during a euglycemic glucose clamp decreased blood glucose concentration. In a prospective study, euglycemic hyperinsulinemia was established during 120 minutes of glucose clamping; the subjects (N = 74) then underwent 5 minutes of intense mental arithmetics with infusion rates of glucose and insulin kept constant. During MST, plasma epinephrine and norepinephrine increased (by 0.23 +/- 0.02 and 0.50 +/- 0.05 nmol/L) together with blood pressure ([BP] by 18 +/- 8/9 +/- 1 mm Hg) and heart rate ([HR] by 21 +/- 1 beats per minute), with P less than .0001 for all changes. During mental stress, blood glucose concentration decreased by 0.4 +/- 0.1 mmol/L (P < .0001), followed by full recovery after another 10 minutes. Serum insulin was unchanged, indicating an acute but transient increase in glucose uptake. This finding was unrelated to age, sex, body mass, and BP status. Fifty-nine subjects with a decrease in glucose concentrations during MST were characterized by accentuated epinephrine response to MST (a change of 0.25 +/- 0.03 v 0.12 +/- 0.02 nmol/L, P = .001), increase in systolic BP (by 20 +/- 2 v 10 +/- 3 mm Hg, P = .008), and increase in HR (by 23 +/- 2 v 15 +/- 2 beats per minute, P = .008) as compared with 15 subjects with unchanged/increased glucose concentration.(ABSTRACT TRUNCATED AT 250 WORDS)