Arvo Hänni

Vitamin D is related to blood pressure and other cardiovascular risk factors in middle-aged men

A previous study has shown that serum levels of the active vitamin D metabolite 1,25-(OH)2-vitamin D were inversely related to blood pressure levels while the prohormone 25-OH-vitamin D was found to be related to insulin metabolism. Also other clinical and experimental data support the view that vitamin D metabolism is involved in blood pressure regulation and other metabolic processes. The present study was conducted in order to see if the above mentioned relationships between the vitamin D endocrine system and blood pressure, as well as other cardiovascular risk factors, could be found in a cross-section population-based study. Serum levels of 1,25-(OH)2-vitamin D, 25-OH-vitamin D, and blood pressure were therefore measured in 34 middle-aged men and metabolic cardiovascular risk factors were evaluated by means of intravenous glucose and fat tolerance tests, euglycemic hyperinsulinemic clamp, lipoprotein measurements, and lipoprotein lipase activity determinations. Serum levels of 1,25-(OH)2-vitamin D were found to be inversely correlated to the blood pressure (r = -0.42, P < .02), VLDL triglycerides (r = -0.47, P < .005), and to triglyceride removal at the intravenous fat tolerance test (r = 0.34, P < .05), while serum levels of 25-OH-vitamin D were correlated to fasting insulin (r = -0.35, P < .05), insulin sensitivity during clamp (r = 0.54, P < .001), and lipoprotein lipase activity both in adiposal tissue (r = 0.48, P < .005) and skeletal muscle (r = 0.38, P < .03).(ABSTRACT TRUNCATED AT 250 WORDS)

Left ventricular hypertrophy in hypertension is associated with the insulin resistance metabolic syndrome

Objective To investigate whether left ventricular hypertrophy is associated with the insulin resistance syndrome. Methods Fifty patients with untreated hypertension were evaluated by recording office blood pressure during regular antihypertensive treatment and 24-h ambulatory blood pressure and office blood pressure after 4–6 weeks on placebo, echocardiog-raphy with M-mode measurements of left ventricular wall thickness and pulsed-wave Doppler measurements of mitral flow in diastole and the hyperinsulinaemic euglycaemic clamp, for determination of insulin sensitivity. Results The left ventricular wall thickness was found to be significantly related to blood pressure [r = 0.44, P < 0.004 for 24-h ambulatory systolic blood pressure (SBP)], fasting insulin level (r = 0.32, P<0.03) and haematocrit level (r = 0.37, P<0.009) and inversely related to insulin sensitivity (r = −0.59, P<0.0001). Multiple regression analysis with these relationships together with confounding factors age, sex, body mass index and waist: hip ratio as independent variables showed insulin sensitivity to be the only significant variable, explaining 43% of the variation in left ventricular wall thickness, whereas 24-h ambulatory SBP explained a further 7%. Left ventricular diastolic filling, as evaluated by the mitral Doppler early: atrial ratio, was significantly correlated with insulin sensitivity (r = 0.42, P<0.003) and inversely related to blood pressure (r = −0.41, P < 0.02 for 24-h ambulatory SBP), left ventricular wall thickness (r = −0.34, P<0.02) and serum fibrinogen level (r = −0.63, P<0.0001). However, multiple regression analysis showed that insulin sensitivity was more closely related to diastolic filling than to blood pressure or left ventricular wall thickness. Conclusion The present study showed left ventricular wall thickness to be closely associated with insulin resistance. Because diastolic dysfunction of the left ventricle was also related to a decreased insulin sensitivity, these findings suggest that left ventricular hypertrophy and diastolic dysfunction are associated with the insulin resistance metabolic syndrome.

Serum levels of parathyroid hormone are related to the mortality and severity of illness in patients in the emergency department

Hypocalcaemia is a common finding in intensive care patients. In addition, raised levels of parathyroid hormone (PTH) have been described. The explanation and clinical importance of these findings are yet to be revealed. To investigate the occurrence of hypocalcaemia and elevated PTH levels and their relationship to morality and the severity of disease, serum levels of PTH, ionized calcium (Ca2+) and the cytokines interleukin 6 (IL‐6) and tumour necrosis factor alpha (TNF‐α) were measured on arrival in the emergency department in a broad spectrum of 140 acutely ill patients patients suffering from common diseases such as stroke, acute abdominal disorders, obstructive lung diseases, heart failure, acute myocardial infarction, angina pectoris, trauma and infectious diseases. A score (APACHE II) was calculated to assess the severity of disease. Elevated PTH levels (> 55 pg mL−1) were seen in 16% of the patients, being most frequent in patients with myocardial infarction (28%) and congestive heart failure (42%). The levels were significantly correlated with the APACHE II score (r = 0.48, P < 0.0001) and with the length of stay in hospital (r = 0.26, P < 0.002). PTH was also significantly (P < 0.03) elevated in non‐survivors compared with survivors and was found to be a stronger predictor of mortality (P < 0.01) than the APACHE II score (P < 0.02) in Coxs proportional hazard analysis. No close relationships were found between the cytokine levels and the indices of calcium metabolism. In conclusion, a rise in serum levels of PTH was common and related to the severity of disease and mortality in a mixed emergency department population.

On the use of ambulatory blood pressure recordings and insulin sensitivity measurements in support of the insulin-hypertension hypothesis

Objective To determine the possible correlations between ambulatory blood pressure and insulin sensitivity, compared with correlations between office blood pressure and insulin. Design Observational study. Setting Policlinic at the Department of Geriatrics, Uppsala, Sweden. Patients Caucasian patients (n = 149) of both sexes with untreated essential hypertension. Main outcome measures The hyperinsulinaemic euglycaemic clamp and office blood pressure in all subjects. In subgroups, also the oral glucose-tolerance test (n = 96) and 24-h ambulatory blood pressure (n = 84). Results Significant correlations were seen between the insulin sensitivity index and ambulatory blood pressure recordings, whereas fasting plasma insulin levels were uncorrelated with office blood pressure. The insulin sum and the 2-h insulin level of the oral glucose-tolerance test were more closely correlated with ambulatory blood pressure recordings than was the fasting insulin level. In multiple regression analyses the night-time diastolic blood pressure showed a significant correlation with the insulin sensitivity index even after controlling for the effects of sex, age and body mass index. Conclusion The apparent association between blood pressure and insulin resistance not only is obscured by measurement error, but is also affected by the particular measures of insulin resistance and blood pressure used. The present study provides further evidence that a relationship exists between blood pressure and hyperinsulinaemia or insulin resistance.

Associations of serum adiponectin with skeletal muscle morphology and insulin sensitivity

CONTEXT Skeletal muscle morphology and function are strongly associated with insulin sensitivity. OBJECTIVE The objective of the study was to test the hypothesis that circulating adiponectin is associated with skeletal muscle morphology and that adiponectin mediates the relation of muscle morphology to insulin sensitivity. DESIGN, SETTINGS, AND PARTICIPANTS This was a cross-sectional investigation of 461 men aged 71 yr, participants of the community-based Uppsala Longitudinal Study of Adult Men study. MAIN OUTCOME MEASURES Measures included serum adiponectin, insulin sensitivity measured with euglycemic insulin clamp technique, and capillary density and muscle fiber composition determined from vastus lateralis muscle biopsies. RESULTS In multivariable linear regression models (adjusting for age, physical activity, fasting glucose, and pharmacological treatment for diabetes), serum adiponectin levels rose with increasing capillary density (beta, 0.30 per 50 capillaries per square millimeter increase; P = 0.041) and higher proportion of type I muscle fibers (beta, 0.27 per 10% increase; P = 0.036) but declined with a higher proportion of type IIb fibers (beta, -0.39 per 10% increase; P = 0.014). Using bootstrap methods to examine the potential role of adiponectin in associations between muscle morphology and insulin sensitivity and the associations of capillary density (beta difference, 0.041; 95% confidence interval 0.001, 0.085) and proportion of type IIb muscle fibers (beta difference, -0.053; 95% confidence interval -0.107, -0.002) with insulin sensitivity were significantly attenuated when adiponectin was included in the models. CONCLUSIONS Circulating adiponectin concentrations were higher with increasing skeletal muscle capillary density and in individuals with higher proportion of slow oxidative muscle fibers. Furthermore, our results indicate that adiponectin could be a partial mediator of the relations between skeletal muscle morphology and insulin sensitivity.

Circulating angiotensin converting enzyme levels are increased in concentric, but not eccentric, left ventricular hypertrophy in elderly men

Objective To study the cross-sectional relationship between circulating angiotensin converting enzyme (ACE) activity and echocardiographically determined left ventricular geometry in a study of 380 70-year-old men participating in a health-survey reexamination and 50 patients with hypertension. Methods Two-dimensional guided M-mode and Doppler echocardiography. Fluorometric assay of serum ACE activity. Results The serum ACE activity was higher in the elderly men with left ventricular concentric hypertrophy than it was in men with normal geometry and left ventricular eccentric hypertrophy (32, 27, and 26 U/l, respectively, P < 0.01 for both comparisons before and after adjustment for the 24 h mean arterial pressure, body mass index, and use of antihypertensive medication). The serum ACE activity correlated with the thickness of the left ventricular interventricular septum (r = 0.12, P = 0.0095), the left ventricular relative wall thickness (r = 0.13, P = 0.0053), and the total peripheral resistance (r = 0.16, P = 0.0034), but not with the left ventricular mass (r = −0.039, P = 0.45) of these elderly men. The serum ACE activity in the hypertensive patients also correlated with the left ventricular interventricular septum thickness (r = 0.34, P = 0.020) independently of the 24 h mean arterial blood pressure, age, sex, body mass index, and insulin sensitivity. Conclusion Levels of serum ACE activity are associated with left ventricular geometry.

The Interaction between Impaired Acute Insulin Response and Insulin Resistance Predict Type 2 Diabetes and Impairment of Fasting Glucose

Background: Impaired acute insulin response (AIR) and insulin resistance (IR) are characteristics of Type 2 diabetes (T2DM). The aim was to develop risk models for T2DM and impaired fasting glucose (IFG), reflecting estimates both of AIR and IR, and of their interaction, as predictors over 20 years of follow-up. Methods: We developed predictive models using hierarchic multiple regression analyses in a population-based cohort of 1227 men with normal fasting blood glucose at baseline (1970-73) and were reinvestigated after 10 and after 20 years. Using IVGTT-variables correlated either to AIR or to IR, separate models were developed. Combined models were also estimated from which prediction scores, representing individual risk, were calculated. Results: In combined models, interaction between prediction scores reflecting AIR and IR predicted T2DM and IFG. Lowest tertile of AIR and the highest tertile of IR showed a relative risk (RR) of 15.3 (95%-CI=5.58-41.84) for T2DM compared to the contrast group (high AIR and low IR). Corresponding RR for IFG was 13.23 (95%-CI=6.53-26.78). C-statistic increased from 0.76 to 0.79 (p=0.018) for T2DM and from 0.77 to 0.80 for IFG (p=0.062) taking interaction into account. Main effects of lowest tertile of AIR and highest tertile of IR versus best were: RR for T2DM, 8.80 (95%-CI=4.25-18.21) and 6.31 (95%-CI=3.26-12.21); for IFG, 9.07, (95%-CI=5.38-15.29) and 4.49 (95%-CI=2.98-6-76). Conclusion:. The interaction between low AIR and high IR revealed a high relative risk for T2DM or IFG reflecting the interplay between these factors over long time on worsening glucose tolerance and development of manifest disease.

Regression of left ventricular wall thickness during ACE-inhibitor treatment of essential hypertension is associated with an increase in insulin mediated skeletal muscle blood flow

UNLABELLED Left ventricular hypertrophy (LVH) has been associated with insulin resistance, a condition with an impaired insulin-mediated vasodilation in skeletal muscle. ACE-inhibitors have been reported to be superior to most other antihypertensive drugs in inducing a regression of LVH. In a double-blind study with parallel groups, 50 patients with essential hypertension were randomized to treatment with either fosinopril (20 mg o.d.) or atenolol (50 mg o.d.) for 12-16 weeks. Left ventricle wall thickness (LVWT, defined as the sum of interventricular septum and posterior wall), diastolic function (represented by the ratio between the E-wave and the A-wave of mitral blood flow) and femoral artery blood flow (FBF) were evaluated using ultrasonic measurements. FBF was measured at normoinsulinemia and after 2 h of euglycemic hyperinsulinemia. Before treatment, the insulin-induced increase in FBF was inversely related to the LVWT (r = -0.52, p < 0.02). The reduction in ambulatory 24-h SBP/DBP was 13/9 mmHg for fosinopril and 15/14 for atenolol, ambulatory DBP being significantly more reduced by atenolol (p = 0.03 for difference in treatment effect). However, only fosinopril treatment resulted in a significant reduction in LVWT (from 20.5 mm to 19.4 mm, p < 0.05). The degree of reduction in LVWT was related to the increase in FBF in the fosinopril group (r = -0.45, p < 0.05). For fosinopril (but not for atenolol), there was a positive relationship between the change in E/A ratio and the change in femoral artery stroke volume (r = 0.80, p < 0.01). CONCLUSION Impaired insulin-induced stimulation of leg blood flow was related to an increased LVWT. Furthermore, during fosinopril treatment, regression of LVWT was associated with enhanced skeletal muscle blood flow during hyperinsulinemia. This indicates that impaired peripheral blood flow (and thereby increased afterload) may be a possible mechanism explaining the previously found association between insulin resistance and cardiovascular hypertrophy.

The effect of euglucaemic hyperinsulinaemia on forearm blood flow and glucose uptake in the human forearm

Abstract Insulin-mediated stimulation of blood flow to skeletal muscle has been proposed to be of major importance for insulin-mediated glucose uptake. The aim of this study was to investigate the relative importance of blood flow and glucose extraction as determinants of insulin-mediated glucose uptake in the human forearm. Forearm blood flow (FBF), glucose extraction and oxygen consumption were evaluated for 100 min during the euglycaemic hyperinsulinaemic clamp (92 mU/l) in nine healthy subjects. FBF was measured by venous occlusion plethysmography. Forearm glucose uptake increased sevenfold during the hyperinsulinaemia (P<0.001). Forearm glucose extraction showed a minor increase during the first 10 min of hyperinsulinaemia, but the most marked increase took place between 10 and 20 min (+170%). Thereafter, only a minor further increase was seen. During the first 10 min of hyperinsulinaemia FBF was unchanged. Thereafter, FBF increased steadily to a plateau reached after 60 min (+50%, P<0.001). A close relationship between whole body glucose uptake and FBF was seen at the end of the clamp (r = 0.75, P<0.02), but at this time the relationship between whole body glucose uptake and forearm glucose extraction was not significant. The modest increase in O2 consumption seen at the beginning of the clamp (+19%) was not related to FBF during the early phase of the clamp. In conclusion, the early course of insulin-mediated glucose uptake in the human forearm was mainly due to an increase in glucose extraction. However, with time the insulin-mediated increase in blood flow increased in importance and after 100 min of hyperinsulinaemia FBF was the major determinant of glucose uptake.

Epidemiological and Clinical Studies on Insulin Resistance and Diabetes

Abstract In Uppsala, extensive epidemiological and clinical studies on insulin resistance and diabetes have been ongoing for the past 30 years. A prospective cohort study of men born 1920-24, living in Uppsala County, was initiated during 1969-74 (the Uppsala Longitudinal Study of Adult Men, ULSAM). Risk factors for cardiovascular disease were examined in 2,322 men, and re-examinations have been performed every 10 years. At the first follow-up, when the men were 60 years old, insulin resistance was found to be a risk factor for development of hypertension and diabetes. In addition, treatment with antihypertensive medication was an independent risk factor for development of diabetes. These findings resulted in a series of clinical studies on metabolic effects of antihypertensive agents. At the second follow-up, when the men were 70 years old, the development of hypertension and diabetes was once again in focus, but at this time, cross-sectional and prospective studies of other cardiovascular determinants, such as circadian blood pressure pattern, left ventricular geometry and function, muscle morphology, ion status, fibrinolysis and cognitive function, were also performed. The cohort has furthermore been linked to the Swedish census and hospital discharge and cause of death registries, it has been used for studies on relationships between birth weight and cardiovascular disease, and genetic analyses have been performed, taking advantage of the long observation time obtained in this cohort. The cohort is currently being re-examined for the third time, and will hopefully continue to provide valuable information on the epidemiology of diabetes and cardiovascular disease in the future.