Insulin sensitivity, proinsulin and insulin as predictors of coronary heart disease. A population-based 10-year, follow-up study in 70-year old men using the euglycaemic insulin clamp.

AIMS/HYPOTHESIS: The association between CHD and insulin sensitivity (Si) measured by the euglycaemic insulin clamp has not been examined previously. Earlier studies found a relationship between CHD and elevated plasma insulin, an analysis that may have been confounded by co-determination of proinsulin, which has evolved as a stronger predictor of CHD. The aim was to determine the longitudinal relationships between Si, intact proinsulin, 32-33 split proinsulin, specific insulin and subsequent CHD. METHODS: This was a population-based cohort study of 815 men in Uppsala, Sweden, aged 70 years at baseline with a follow-up of up to 10 years. Baseline insulin sensitivity was determined by euglycaemic insulin clamp. Fasting proinsulin, 32-33 split proinsulin and specific insulin concentrations were analysed using specific two-site immunometric assays. CHD was taken as diagnosed, if stated (in the event of death) on the Cause of Death Registry, or for subjects hospitalised for the first time with CHD, if CHD was recorded in the Hospital-Discharge Registry. The associations were analysed using Cox's proportional hazards, presented as hazard ratios (HRs) with their 95% CIs for a one-SD increase in the predictor. RESULTS: In multivariate analysis, Si (HR:0.80, CI:0.65-0.97) adjusted for serum cholesterol, systolic blood pressure, fasting plasma glucose, BMI and smoking predicted CHD. Intact proinsulin (HR:1.18, CI:1.01-1.38), adjusted as the model above, predicted CHD, whereas 32-33 split proinsulin (HR:1.13, CI:0.95-1.35) or specific insulin (HR:1.07, CI:0.89-1.30) did not. CONCLUSIONS/INTERPRETATION: Insulin resistance measured by the euglycaemic insulin clamp predicts subsequent CHD in elderly men. Proinsulin provides a better prediction of CHD than insulin.

The cost-effectiveness of candesartan-based antihypertensive treatment for the prevention of nonfatal stroke: results from the Study on COgnition and Prognosis in the Elderly.

Patients who survive a first stroke are often left with permanent disabilities, and have significant needs for rehabilitation and long-term care. Antihypertensive treatment reduces the risk of cardiovascular events such as stroke. The purpose of this study was to investigate the cost-effectiveness of candesartan-based antihypertensive treatment for the prevention of nonfatal stroke. The cost-effectiveness analysis was based on data from Study on COgnition and Prognosis in the Elderly (SCOPE), where patients were randomly assigned to receive the angiotensin receptor blocker candesartan or placebo, with open-label active antihypertensive treatment added as needed. The analysis was carried out using a Markov model, which combined clinical and resource utilization data from SCOPE with Swedish retail prices for drugs and unit costs for in-patient stays, and outpatient visits. The cost per patient was 1949 EUR in the candesartan group and 1578 EUR in the control group. The largest share of the cost was attributed to antihypertensive treatment in the candesartan group and to the long-term cost of stroke in the control group. Candesartan-based antihypertensive treatment was associated with 0.0289 additional quality-adjusted life-years (QALYs) per patient and an incremental cost per QALY gained of approximately 13,000 EUR. Sensitivity analyses showed that these results were fairly stable. In conclusion, the cost per QALY gained with candesartan-based antihypertensive treatment lies within the range of society's willingness to pay for health gains. The results indicate that candesartan-based antihypertensive treatment is cost-effective for the prevention of nonfatal stroke.

Health-related quality of life during treatment of elderly patients with hypertension: results from the Study on COgnition and Prognosis in the Elderly (SCOPE).

The Study on COgnition and Prognosis in the Elderly (SCOPE) was a multinational, randomised, double-blind study to assess the effects of candesartan 8-16 mg daily on cardiovascular events and cognitive function in elderly patients (aged 70-89 years) with mild to moderate hypertension. A total of 4937 patients were randomised to candesartan or placebo with other antihypertensive drugs (mostly diuretics, beta-blockers, and calcium antagonists) added as needed to control blood pressure. Only 16% of the patients in the control group received placebo alone. The mean follow-up was 3.7 years. The aim of this health-related quality of life (HRQL) substudy analysis was to investigate changes in HRQL during antihypertensive treatment, and possible differences in patients receiving candesartan-based or other antihypertensive treatment. Three validated HRQL instruments were used: the Psychological General Well-being (PGWB) Index, the Subjective Symptoms Assessment Profile (SSA-P), and the EuroQoL Health Utility Index (EuroQoL). The HRQL was generally good at baseline and well preserved during follow-up in the presence of substantial blood pressure reductions in both treatment groups. Several of the observed changes in score from baseline to last visit favoured candesartan-based compared to control treatment, particularly the changes in PGWB Anxiety (-0.5 vs -1.0, P=0.01), PGWB Positive well-being (-0.8 vs -1.1, P=0.04), SSA-P Cardiac symptoms (0.03 vs 0.10, P=0.03), and EuroQoL Current health (-3.1 vs -5.3, P=0.008). This favourable result may be related to the somewhat lower blood pressure associated with candesartan-based treatment. In conclusion, there should be no reason to withhold modern antihypertensive therapy in elderly patients due to concerns for a negative effect on HRQL.

A new Q/QS pattern on the resting electrocardiogram is associated with impaired insulin secretion and a poor prognosis in elderly men independently of history of myocardial infarction.

OBJECTIVES: To evaluate risk factors and prognosis of subjects who had developed a new Q/QS pattern on the resting electrocardiogram (ECG) in relation to history of myocardial infarction (MI). DESIGN: Cross-sectional and prospective population-based cohort study. SETTING: Uppsala, Sweden. SUBJECTS: In 1970-73, all 50-year-old men in Uppsala, were invited to participate in a health survey aimed at identifying risk factors for cardiovascular disease. The present study included the 1221 subjects who also were re-examined at age 70. RESULTS: Subjects with a new Q/QS pattern on the resting ECG at age 70 were characterized by impaired insulin secretion compared with those without Q/QS, and a higher prevalence of diabetes compared with the control group. In Cox proportional hazard analysis a new Q/QS pattern at age 70 was a significant predictor of cardiovascular mortality (hazard ratio : 1.67, 95% CI: 1.22-2.26) and total mortality (hazard ratio: 1.31, 95% CI: 1.04-1.62) (after age 70) during 9.4 years follow-up, also when adjusted for other risk factors and MI diagnosis. CONCLUSION: The finding of a new Q/QS pattern on the resting ECG, regardless of history of MI was associated with impaired insulin secretion and was an independent predictor of total and cardiovascular mortality. Therefore, these subjects must be given a high priority to preventive measures against both coronary heart disease and diabetes.

Blood flow is an important determinant of forearm glucose uptake following a mixed meal.

Insulin-mediated vasodilation has been suggested to be of importance for glucose uptake during normoglycemic hyperinsulinemia. If this also is valid after an ordinary mixed meal remains to be evaluated. Forearm blood flow (FBF) and forearm glucose uptake change (evaluated by venous occlusion plethysmography) and glucose arteriovenous differences were evaluated over 120 minutes in 10 healthy volunteers following an ordinary mixed meal (700-900 kcal, 34% of energy from fat). Fasting arterial glucose level was 4.9+/-0.9 mmol/l, and the maximum glucose level was reached 30 minutes after the start of ingestion (6.6+/-0.8 mmol/l, p<0.0001). Plasma insulin levels were increased four-fold. FBF increased rapidly within 20 minutes after the start of ingestion and reached its maximum after 50 minutes (94% higher than baseline level, p<0.01). After 2 hours FBF was still substantially elevated (75% above baseline level, p<0.01). Forearm glucose uptake increased fivefold already after 20 minutes ( p<0.01). During the 2 hours, the increase in FBF contributed to 41% of the forearm glucose uptake ( p<0.05). The present study showed that the increase in FBF seen after an ordinary mixed meal is important for the change in forearm glucose uptake. These results support the view that modulation of limb blood flow is a determinant of glucose uptake.

Proinsulin and acute insulin response independently predict Type 2 diabetes mellitus in men--report from 27 years of follow-up study.

AIMS/HYPOTHESIS: Defects in insulin secretion and insulin action, resulting in compensatory hyperinsulinaemia, are the major abnormalities in the development of Type 2 diabetes mellitus (Type 2 diabetes). The most frequently used conventional immunoreactive assays for insulin cross-react with proinsulin. In short-term studies (<5 years), proinsulin predicts the development of Type 2 diabetes. We studied, with a 27-year follow-up, the longitudinal relationships between intact proinsulin, 32-33 split proinsulin, specific and immunoreactive insulin (IRI), acute insulin response (AIR) after an intravenous glucose load and the development of Type 2 diabetes in a population-based cohort of 50-year-old men. METHODS: Fasting peptide concentrations were measured in plasma samples, stored since 1970-73 using specific two-site immunometric assays. IRI was measured at baseline using radioimmunoassay. Associations between development of Type 2 diabetes and predictor variables, were analysed with logistic regression. Results are shown as odds ratios (ORs) with their 95% confidence intervals (CIs) for a one standard deviation increase in a predictor variable. RESULTS: Cumulative incidence of Type 2 diabetes was 33% over 27 years of follow-up. Intact proinsulin (OR, 1.57, CI, 1.16-2.14), and 32-33 split proinsulin (OR, 1.70, CI, 1.20-2.39) were associated with development of Type 2 diabetes, independent of AIR, adjusted for BMI and fasting glucose, whereas specific insulin was not (OR, 1.31, CI, 0.98-1.77), nor was IRI (OR, 1.25, CI, 0.96-1.63). Proinsulin and AIR interacted in the development of Type 2 diabetes (p<0.05). CONCLUSION/INTERPRETATION: Proinsulin predicts the development of Type 2 diabetes mellitus over a 27-year period.

Fetal growth and subsequent risk of breast cancer: results from long term follow up of Swedish cohort.

OBJECTIVE: To investigate whether size at birth and rate of fetal growth influence the risk of breast cancer in adulthood. DESIGN: Cohort identified from detailed birth records, with 97% follow up. SETTING: Uppsala Academic Hospital, Sweden. PARTICIPANTS: 5358 singleton females born during 1915-29, alive and traced to the 1960 census. MAIN OUTCOME MEASURES: Incidence of breast cancer before (at age <50 years) and after (> or = 50 years) the menopause. RESULTS: Size at birth was positively associated with rates of breast cancer in premenopausal women. In women who weighed > or =4000 g at birth rates of breast cancer were 3.5 times (95% confidence interval 1.3 to 9.3) those in women of similar gestational age who weighed <3000 g at birth. Rates in women in the top fifths of the distributions of birth length and head circumference were 3.4 (1.5 to 7.9) and 4.0 (1.6 to 10.0) times those in the lowest fifths (adjusted for gestational age). The effect of birth weight disappeared after adjustment for birth length or head circumference, whereas the effects of birth length and head circumference remained significant after adjustment for birth weight. For a given size at birth, gestational age was inversely associated with risk (P=0.03 for linear trend). Adjustment for markers of adult risk factors did not affect these findings. Birth size was not associated with rates of breast cancer in postmenopausal women. CONCLUSIONS: Size at birth, particularly length and head circumference, is associated with risk of breast cancer in women aged <50 years. Fetal growth rate, as measured by birth size adjusted for gestational age, rather than size at birth may be the aetiologically relevant factor in premenopausal breast cancer.

Lipids and antioxidative effects of estradiol and sequential norethisterone acetate treatment in a 3-month randomized controlled trial.

OBJECTIVE: To determine the influence of hormone replacement therapy on serum lipids and antioxidative factors associated with the risk of coronary heart disease. METHODS: The effect of a sequential estradiol-norethisterone acetate regimen or placebo on lipid metabolism, antioxidative variables and fatty acid composition in serum was measured during the peak-estrogen phase in a randomized, double-blind, placebo-controlled study of 42 healthy postmenopausal women for 3 months. RESULTS: Active treatment significantly reduced lipoprotein(a) by 15% (p = 0.005, compared with placebo), low-density lipoprotein (LDL) cholesterol by 10% (p = 0.005) and the LDL cholesterol/high-density lipoprotein (HDL) cholesterol ratio by 11% (p = 0.016). Serum triglycerides increased by 21% (p = 0.045). No effect was observed on HDL cholesterol, on apolipoproteins apo A(1) or apo B, or on non-esterified fatty acids in serum. No treatment effect was seen in the proportions of monounsaturated and polyunsaturated fatty acids. The concentration of malondialdehyde in serum did not change with the estrogen-progestin treatment. CONCLUSIONS: This sequential estrogen-progestin therapy has a beneficial effect on apolipoprotein(a) and LDL cholesterol, but no effect on non-esterified fatty acids or the level of lipid peroxidation products in serum.

Muscle morphology, self-reported physical activity and insulin resistance syndrome.

In a population-based sample of 475 men the associations between muscle morphology, self-reported physical activity (PA) and insulin resistance (IR) syndrome were investigated. Also, we studied to what degree muscle morphology contributes to the association between PA and IR syndrome. Muscle morphology and the components of IR syndrome were compared in four groups categorized according to self-reported habitual PA data. We found a significantly higher percentage of type I fibres, fibre area and number of capillaries around the fibres and a lower proportion of type IIB fibres with higher level of PA. The relative distribution of type I fibres and capillarization were positively related to high density lipoprotein (HDL) cholesterol and negatively to serum triglycerides (TG) and plasminogen activator inhibitor-1 (PAI-1) activity. The percentage of type IIB fibres was were inversely related to HDL cholesterol and positively to serum TG, PAI-1 activity and resting heart rate. Insulin sensitivity was positively and independently related to PA level (P < 0.001). Regression analysis including all relevant variables regarding insulin sensitivity indicated that the significant explanatory variables left in the equation were body mass index (BMI), glucose intolerance, PAI-1 activity, serum free fatty acid concentration, proportion of type IIB fibres, HDL cholesterol level, drug treatment, PA level, and waist-to-hip ratio, which together explained 55% of the variation in the insulin sensitivity index. In conclusion, both fibre type distribution and muscle capillary density might contribute to the beneficial effect of PA on IR syndrome.

Plasminogen activator inhibitor-1 and relations to fatty acid composition in the diet and in serum cholesterol esters.

High plasminogen activator inhibitor (PAI)-1 levels and poor dietary fat quality are potential risk factors for cardiovascular disease. The aim was to investigate the cross-sectional associations between PAI-1 activity and dietary nutrient intake, focusing on fat quality, in a population-based study of 871 men aged 70 years. The relationship between PAI-1 and the fatty acid composition in serum cholesterol esters (n=381 men) was also studied. The estimated total fat intake was positively associated with PAI-1 activity. The intake of both monounsaturated and polyunsaturated fatty acids was positively associated with PAI-1 activity, whereas the intake of saturated fatty acids was not. In serum cholesterol esters, higher proportions of palmitoleic and dihomo-gamma-linolenic acid, a lower proportion of linoleic acid, and reduced estimated Delta5-desaturase activity were associated with higher PAI-1 levels. These associations were confounded by factors representing the insulin resistance syndrome. PAI-1 activity was positively associated with gamma-linolenic and arachidonic acid, independent of potential confounders. In conclusion, this study demonstrates that dietary intake of unsaturated fatty acids is positively associated with PAI-1 activity, whereas intake of saturated fatty acids is not. The associations present between PAI-1 activity and the fatty acid proportions in serum cholesterol esters are partly influenced by metabolic syndrome-related factors.

Ageing impairs insulin-mediated vasodilatation but not forearm glucose uptake.

BACKGROUND: It is unclear if insulin-mediated vasodilatation is altered by ageing and if this affects insulin-mediated glucose uptake. MATERIAL AND METHODS: A 2-h euglycaemic hyperinsulinaemic clamp (56 mU m(-2) min(-1)) was performed in 10 healthy, nonobese elderly men (70-75 years) and 13 young men (23-28 years). Forearm blood flow (FBF) was measured by venous occlusion plethysmography and forearm glucose uptake was calculated by arterial and venous serum glucose determinations in the forearm. RESULTS: Insulin induced an increase in FBF in the younger men (from 3.9 +/- 1.1 SD to 5.9 +/- 2.2 mL min(-1) 100(-1)mL tissue, P < 0.001), but this insulin-mediated vasodilatation was completely blunted in the elderly subjects. Glucose extraction during the clamp was significantly higher in the elderly subjects (1.2 +/- 0.76 vs. 0.82 +/- 0.37 mmol L(-1) at 120 min, P < 0.01), resulting in a similar forearm glucose uptake in the two groups. On the other hand, whole-body glucose uptake was significantly decreased in the elderly subjects (5.3 +/- 1.8 vs. 8.0 +/- 1.1 mg kg(-1) min(-1), P < 0.001). CONCLUSION: The present study showed that the ability of insulin to induce vasodilatation is blunted in the forearm in healthy, nonobese elderly subjects. However, the elderly compensate for this impairment with an increased glucose extraction from arterial blood to maintain an unaltered forearm glucose uptake.

Education, lifestyle factors and mortality from cardiovascular disease and cancer. A 25-year follow-up of Swedish 50-year-old men.

BACKGROUND: There is a well-established inverse relation between education and mortality from cardiovascular disease and cancer. The reasons for this are still in part unclear. We aimed to investigate whether differences in traditional vascular risk factors, adult height, physical activity, and biomarkers of fatty acid and antioxidant intake, could explain this association. METHODS: In all, 2301 50-year-old men in Uppsala, Sweden (82% of the background population) were examined with regard to educational level, blood pressure, blood glucose, body mass index, serum lipids, smoking, body height, physical activity, serum beta carotene, alpha tocopherol, selenium, and serum fatty acids in cholesterol esters. Cause-specific mortality was registered 25 years later. RESULTS: Low education was associated with a higher rate of mortality from cardiovascular disease (crude relative risk [RR] = 1.67, 95% CI : 1.17-2.39), and from cancer (crude RR = 1.94, 95% CI : 1.21-3.10), compared to high educational attainment. Men with high education had an overall more beneficial risk factor profile concerning traditional cardiovascular risk factors, physical activity, and biomarkers of dietary intake of antioxidants and fat. After adjustment for all examined risk factors, the inverse gradient between education and cardiovascular mortality disappeared (RR in low education = 1.01. 95% CI : 0.67-1.52). Controlling for smoking, physical activity and dietary biomarkers explained less than half of the excess cancer mortality in the lower educational groups. Smoking (adjusted RR = 1.89, 95% CI : 1.37-2.61), and high proportions of palmitoleic acid in serum cholesterol esters (adjusted RR per 1 SD = 1.39, 95% CI : 1.07-1.82) predicted cancer mortality, independently of all other factors. There were no independent relations between serum antioxidants and mortality. CONCLUSIONS: These data indicate that modifiable lifestyle factors mediate the inverse gradient between education and death from cerebro- and cardiovascular disease. Smoking, physical activity and dietary factors explained half of the excess cancer mortality in lower educated groups. Further studies are needed to explore the proposed association between palmitoleic acid, a marker of high intake of animal and dairy fat, and cancer.

Systolic blood pressure alterations during hyperinsulinemia are related to changes in ionized calcium status.

BACKGROUND: A correlation between changes in ionized calcium status and changes in systolic blood pressure (BP) has previously been observed during induced euglycemic hyperinsulinemia in patients with essential hypertension. The objective of this study was to evaluate associations between alterations in ion status and BP changes during euglycemic hyperinsulinemia in healthy normotensive subjects. METHODS: Ion status in plasma and BP were measured before and at the end of euglycemic hyperinsulinemic clamp tests performed in 41 healthy normotensive volunteers. RESULTS: During euglycemic hyperinsulinemia plasma sodium increased by 1% (P < .0001), ionized calcium (iCa) by 5% (P < .0001), and ionized magnesium (iMg) by 4% (P < .01), whereas potassium decreased by 10% (P < .0001). The changes in plasma iCa and iMg correlated significantly to changes in systolic BP (r = -0.38, P < .02; r = -0.32, P < .05, respectively), but the correlation between changes in iMg and changes in systolic BP did not remain significant in a multiple regression model. The glucose infusion rate correlated inversely to the change in iMg (r = -0.39, P < .01). CONCLUSIONS: The group mean systolic BP was unaltered during induced euglycemic hyperinsulinemia in healthy normotensive subjects; however, a more pronounced increase in the circulating iCa concentration was associated with a greater decline in systolic BP, which is in accordance with previous observations in patients with essential hypertension. The group mean diastolic BP was decreased; however, the lowered diastolic BP was not correlated to changes in ion status.

Several factors associated with the insulin resistance syndrome are predictors of left ventricular systolic dysfunction in a male population after 20 years of follow-up.

BACKGROUND: The epidemiologic data on heart failure are scarce. This study aimed at identifying predictors of left ventricular systolic dysfunction in a cohort of middle-aged men with a 20-year follow-up. METHODS: A population-based cohort of 431 50-year-old men was examined with blood pressure and anthropometric measurements together with lipid, glucose, and insulin determinations. A reinvestigation 20 years later also included echocardiography, ambulatory blood pressure monitoring, hyperinsulinemic euglycemic clamp, and oral glucose tolerance test. Sixteen subjects were found to have left ventricular systolic dysfunction at age 70 years, defined as an ejection fraction 0.40, was used in a nested case-control analysis. RESULTS: At age 50 years, heart rate (P <.01), plasma proinsulin (P <.05), and the proportion of dihomogammalinolenic acid in serum cholesterol esters (P <.05) were increased and serum phosphate decreased (P <.01) in the subjects identified with left ventricular systolic dysfunction at age 70 years compared with controls. No major metabolic abnormalities were associated with left ventricular systolic dysfunction at age 70 years compared with controls. CONCLUSION: Factors associated with insulin resistance precede left ventricular systolic dysfunction independently of ischemic heart disease and hypertension after 20 years of follow-up.

Studies of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2) gene in relation to insulin sensitivity among glucose tolerant caucasians.

AIMS/HYPOTHESIS: We examined whether the Pro12-Ala polymorphism of the human peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2) gene was related to altered insulin sensitivity among glucose-tolerant subjects or a lower accumulated incidence or prevalence of IGT and Type II (non-insulin-dependent) diabetes mellitus among Scandinavian Caucasians. METHODS: The Pro12Ala polymorphism was examined using PCR-RFLP Whole-body insulin sensitivity measured under hyperinsulinaemic-euglycaemic conditions was estimated in a population-based sample of 616 glucose tolerant Swedish Caucasian men at age 70. In addition, insulin sensitivity index was measured using IVGTT and Bergman minimal modelling in a population-based sample of 364 young healthy Danish Caucasians. Finally, we evaluated whether the polymorphism predicted Type II diabetes and IGT in 841 seventy-year-old Swedish men. A case-control study was carried out in 654 unrelated Danish Type II diabetic patients and 742 Danish glucose tolerant subjects matched for age and sex. RESULTS: Whole-body insulin sensitivity was significantly improved in carriers compared with non-carriers of the Ala-allele of the codon 12 polymorphism in Swedish Caucasian men (6.0+/-2.5 vs 5.6+/-2.5 mg kg(-1) x min(-1) x mU/l](-1) x 100, p = 0.044). The same tendency, but not significant, was observed in the insulin sensitivity index among the group of young healthy Danish Caucasians. The incidence of Type II diabetes and IGT among the Swedish subjects at the age of 70 was similar in the three genotype-groups of the Pro12Ala variant and the Ala-allele was not related to a lower prevalence of Type II diabetes in Danish Caucasians. CONCLUSION/INTERPRETATION: The Ala-allele of the PPAR-gamma2 polymorphism is associated with improved whole body insulin sensitivity among Swedish Caucasians.

Serum magnesium status during lipid-lowering drug treatment in non-insulin-dependent diabetic patients.

Serum magnesium concentration (S-Mg) has been reported to be inversely associated with atherogenic lipid fractions and with blood glucose concentrations. In some studies on humans, oral magnesium supplementation has been found to improve the lipoprotein balance. Against this background the present study was undertaken to determine whether reductions in atherogenic lipid fractions are associated with S-Mg alterations. Total S-Mg was measured in 23 patients with non-insulin-dependent diabetes mellitus (NIDDM) treated with the lipid-lowering drugs gemfibrozil and simvastatin in a double-blind cross-over study. The mean S-Mg at the end of the initial placebo period, ie, before active treatment, was 0.80 (SD 0.06) mmol/L. Treatment with gemfibrozil 600 mg twice daily for 4 months decreased S-Mg by 0.02 mmol/L (P =.02), and treatment with simvastatin 10 mg daily for 4 months again decreased S-Mg by 0.02 mmol/L (P =.10; not significant [NS]) The changes in S-Mg during the 2 different treatment periods were closely correlated (r = 0.66, P <.001). Fasting plasma glucose concentrations increased significantly by 17% during both drug regimens. The changes in fasting plasma glucose and S-Mg were significantly correlated both during gemfibrozil treatment (r = -0.56, P <.01) and during treatment with simvastatin (r = -0.44, P <.05). Changes in glucose tolerance or insulin sensitivity did not correlate to changes in S-Mg. The associations between changes in serum very-low-density lipoprotein (VLDL) fractions and S-Mg did not reach statistical significance (r = -0.37, P <.10). Changes in low-density lipoprotein (LDL) cholesterol and S-Mg did not correlate. In conclusion, total S-Mg concentration decreased during treatment with gemfibrozil and simvastatin in patients with NIDDM. During both drug regimens changes in S-Mg status were inversely correlated to changes in plasma glucose concentrations, while changes in lipid status were not significantly correlated with changes in S-Mg.

Insulin-mediated changes in leg blood flow are coupled to capillary density in skeletal muscle in healthy 70-year-old men.

The aim of this study was to investigate to what degree the capillarization in the skeletal muscle explains the leg blood flow (LBF) changes during hyperinsulinaemia. Fifteen normotensive men from a population-based cohort of 70-year-old men in Uppsala, Sweden, were investigated. Their metabolic status (oral glucose tolerance test and euglycemic, hyperinsulinaemic clamp test results), serum lipid profile, muscle fiber distribution (myosin adenosine triphosphatase staining), and capillary supply (amylase-periodic acid-Schiff method) was evaluated. Doppler ultrasound was used before and after the clamp test to detect insulin-induced changes in LBF. Physiologic hyperinsulinemia (serum insulin, 107 mU/L) caused a moderate increase in LBF (15% +/- 11%; P =.07). Change in LBF was closely related to capillary density (r =.66; P <.01) independent of obesity, smoking and level of physical activity. An association was observed between LBF and serum free fatty acid (FFA) concentrations (r = -.57; P <.05). In multiple regression analysis, capillary density and serum FFA level together explained 71% of the variation in insulin-mediated LBF changes. Capillary rarefaction and elevated serum FFA values were associated with a vasoconstrictive effect of insulin. In conclusion, capillarization in skeletal muscle and serum FFA concentration seem to be determinants of endothelial function.

An ordinary mixed meal transiently impairs endothelium-dependent vasodilation in healthy subjects.

This study was designed to evaluate the effects of an ordinary mixed meal on endothelium-dependent vasodilation. Ten young healthy volunteers were given a mixed meal (minced meat sauce with rice, 900 kcal, 34% of the energy content was fat). In the fasting state, at 60 and 120 min after the start of the meal, endothelium-dependent vasodilation and endothelium-independent vasodilation were evaluated by local infusion of metacholine (4 microg min (-1)) and sodium nitroprusside (10 microg min (-1)) in the brachial artery. Blood flow in the forearm was measured using venous occlusion plethysmography. Endothelium-dependent vasodilation decreased from 15.4 +/- 3.3 (mean +/- SD) at fasting to 13.7 +/- 3.5 mL min (-1) (100 mL tissue)-1 (P < 0.01) 60 min after feeding, but had returned to the fasting level at 120 min. At 60 min, but not in the fasting state, the serum level of free fatty acids was inversely related to endothelium-dependent vasodilation (r=-0.74, P < 0.05), although no significant net changes in FFA levels were seen. Endothelium-independent vasodilation was not affected by the mixed meal. No similar attenuations in endothelium-dependent vasodilation were seen during control meals. In conclusion, an ordinary mixed meal transiently attenuated endothelium-dependent vasodilation. Free fatty acids may be involved in this effect on endothelial function.

Serum lipid profile improved by ultra-low doses of 17 beta-estradiol in elderly women.

To determine whether ultra-low doses of estradiol (E(2)) affect the serum lipid profile in elderly women, we analyzed changes in serum lipids and lipoproteins in 70 healthy women, 60 yr and older, randomly assigned to parenteral E(2) (7.5 microg per 24 h) delivered by a vaginal ring (Estring; Pharmacia-Upjohn, Malmö, Sweden) or no treatment for 12 months. Baseline serum estrone sulfate (E1S), but not E(2) or serum FSH, was negatively associated with serum total cholesterol (P = 0.026), low-density lipoprotein (LDL) cholesterol (P = 0.053), and apolipoprotein B levels (P = 0.023). Compared with no treatment, Estring treatment yielded nonsignificant increases within the normal postmenopausal range in serum E1S (+16%) and E(2) (+13%), but significantly reduced serum LDL cholesterol by 7.6% (-0.32 mmol/L; 95% confidence interval, -0.58, -0.07; P = 0.014) and LDL to high-density lipoprotein (HDL) ratio by 7.3% (-0.19 mmol/L; 95% confidence interval, -0.44, -0.06; P = 0.030). In Estring users values were significantly reduced in total cholesterol (by 4%), LDL cholesterol (by 7%), LDL to HDL ratio (by 7%), and apolipoprotein B (by 4%), and significantly increased in serum HDL triglyceride (by 25%) but not triglycerides. No significant changes were found in the untreated group. There was a significant interaction between age and both baseline serum E(2)/sex hormone-binding globulin (P = 0.006) and sex hormone-binding globulin (P = 0.009) and a marginal interaction between age and E1S (P = 0.083) with regard to effects on changes in LDL cholesterol levels during Estring treatment. We conclude that ultra-low doses of E(2), which previously were considered to have only local effects, may improve serum lipid profile in elderly women with a pattern and magnitude similar to that reported after conventional estrogen doses or first-generation lipid-lowering agents. The reduction in LDL cholesterol tended to be greater with a combination of high age and low baseline levels of biologically active estrogens.