Identification of the semaphorin receptor PLXNA2 as a candidate for susceptibility to schizophrenia.

The discovery of genetic factors that contribute to schizophrenia susceptibility is a key challenge in understanding the etiology of this disease. Here, we report the identification of a novel schizophrenia candidate gene on chromosome 1q32, plexin A2 (PLXNA2), in a genome-wide association study using 320 patients with schizophrenia of European descent and 325 matched controls. Over 25,000 single-nucleotide polymorphisms (SNPs) located within approximately 14,000 genes were tested. Out of 62 markers found to be associated with disease status, the most consistent finding was observed for a candidate locus on chromosome 1q32. The marker SNP rs752016 showed suggestive association with schizophrenia (odds ratio (OR) = 1.49, P = 0.006). This result was confirmed in an independent case-control sample of European Americans (combined OR = 1.38, P = 0.035) and similar genetic effects were observed in smaller subsets of Latin Americans (OR = 1.26) and Asian Americans (OR = 1.37). Supporting evidence was also obtained from two family-based collections, one of which reached statistical significance (OR = 2.2, P = 0.02). High-density SNP mapping showed that the region of association spans approximately 60 kb of the PLXNA2 gene. Eight out of 14 SNPs genotyped showed statistically significant differences between cases and controls. These results are in accordance with previous genetic findings that identified chromosome 1q32 as a candidate region for schizophrenia. PLXNA2 is a member of the transmembrane semaphorin receptor family that is involved in axonal guidance during development and may modulate neuronal plasticity and regeneration. The PLXNA2 ligand semaphorin 3A has been shown to be upregulated in the cerebellum of individuals with schizophrenia. These observations, together with the genetic results, make PLXNA2 a likely candidate for the 1q32 schizophrenia susceptibility locus.

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.

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.

In vitro and in vivo studies of a naturally occurring variant of the human p85alpha regulatory subunit of the phosphoinositide 3-kinase: inhibition of protein kinase B and relationships with type 2 diabetes, insulin secretion, glucose disappearance constant, and insulin sensitivity.

In humans, the Met326Ile missense variant of the p85alpha regulatory subunit of the phosphoinositide 3-kinase (PI3K) has been associated with either significant reductions in glucose effectiveness and intravenous glucose tolerance in Caucasians or a significantly higher insulin secretory response in Pima Indians. In the present study, we genotyped 1,190 Caucasian males to evaluate the impact in vivo of the Met326Ile variant of the p85alpha subunit of PI3K on the acute insulin response, intravenous glucose tolerance, insulin-mediated glucose uptake, and the prevalence of type 2 diabetes after 20 years of follow-up. We also expressed the variant in vitro to evaluate the impact on insulin-stimulated activation of protein kinase B (PKB). The Met326Ile variant of p85alpha was not associated with type 2 diabetes or with alterations in insulin secretion, insulin sensitivity, or intravenous glucose tolerance in vivo. Expressed in vitro, the Ile326 and the Met326 variant acted equally as a dominant-negative and prevented (60-70% inhibition) insulin-mediated activation of PKB by inhibiting the phosphorylation of PKB at Thr308. We conclude that the Met326Ile variant of the p85alpha regulatory subunit of PI3K is likely to be as functionally normal in vivo as in vitro.

Serum aldosterone changes during hyperinsulinemia are correlated to body mass index and insulin sensitivity in patients with essential hypertension.

OBJECTIVE: To measure the effects of hyperinsulinemia on serum electrolyte status and associated hormones, and on serum free fatty acid (FFA) concentrations, in patients with essential hypertension. DESIGN AND METHODS: The serum electrolyte status (Na, K, Ca, ionized Ca, Mg, P, pH) and associated hormones [plasma renin activity (PRA), serum parathyroid hormone (PTH) and aldosterone concentrations], and FFA were measured during an euglycemic hyperinsulinemic clamp test in 49 patients with untreated essential hypertension. RESULTS: Serum potassium, phosphate, PTH, and FFA concentrations decreased during hyperinsulinemia, while serum ionized calcium concentration, pH, and PRA increased significantly (P < 0.05). The changes in serum potassium and magnesium were both inversely related to the insulin-mediated glucose uptake (r= -0.62, P< 0.0001; r= -0.31, P< 0.05, respectively). Both body mass index (BMI) and insulin-mediated glucose disposal were significantly correlated to the changes in serum aldosterone concentration during hyperinsulinemia (r = 0.41, P < 0.01; r = -0.40, P < 0.01, respectively). The change in serum aldosterone during the clamp test was not significantly related to the change in PRA, but tended to correlate to the change in potassium concentration (r= 0.25, P= 0.10). A less pronounced reduction in FFA during induced hyperinsulinemia was associated with low insulin sensitivity (r= -0.35, P< 0.05). CONCLUSION: Hypertensive patients with normal BMI and a more pronounced glucose uptake showed a larger serum potassium decline and lowered aldosterone concentrations during induced euglycemic hyperinsulinemia. Insulin-resistant patients showed a less pronounced reduction in FFA during hyperinsulinemia. The observations in the present study may indicate that alterations in aldosterone and FFA metabolism might be linked to the insulin resistance metabolic syndrome.

Epidemiological and clinical studies on insulin resistance and diabetes.

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.

Polymorphism in the glycogen-associated regulatory subunit of type 1 protein phosphatase (PPP1R3) gene and insulin sensitivity.

A polymorphism (PP1ARE) in the 3'-untranslated region of the gene encoding the glycogen-associated regulatory subunit of type 1 protein phosphatase PPP1R3 is associated with insulin resistance in Pima Indians. The aim of this study was to investigate whether two common variants in the PPP1R3 gene, Asp905Tyr and PP1ARE, are associated with reduced insulin sensitivity or can predict the development of impaired glucose tolerance (IGT) or type 2 diabetes during a 20-year follow-up period in 696 50-year-old Caucasian men. The allelic frequency of Tyr905 was 0.11 (95% CI 0.09-0.13) and of PP1ARE 0.34 (0.31-0.37) and the two polymorphisms were in linkage disequilibrium (chi2 = 46, P < 0.0001, Fisher's exact test). None of the polymorphisms was associated with the development of IGT or type 2 diabetes, but the PP1ARE polymorphism was weakly correlated to whole-body insulin sensitivity (r = -0.08, P = 0.04). In conclusion, we found no evidence in Swedish men that the PP1ARE or the Asp905Tyr variants over a 20-year period predict the development of IGT or type 2 diabetes, but the PP1ARE polymorphism could have a higher penetrance in other populations.

Blood pressure changes in relation to sodium and calcium status in induced hyperinsulinemia.

Insulin increases renal sodium reabsorption which may contribute to hypertension. However, acute insulin administration may result in vasodilation. The aim of the present study was to investigate effects on blood pressure and alterations in ion status during hyperinsulinemia. Blood pressure and serum sodium and ionized calcium concentrations were measured before and at the end of euglycemic hyperinsulinemic clamp tests performed in 45 patients with essential hypertension. Both the systolic and the diastolic blood pressure decreased, by 4% (p < 0.05) and 3% (p < 0.05), respectively. Circulating ionized calcium concentration increased by 2% (p < 0.001), and the ratio between circulating sodium and ionized calcium concentrations decreased. The changes in circulating sodium concentration correlated to changes in systolic blood pressure (SBP; r = 0.36, p = 0.05). Both ionized calcium concentrations and the ratio between circulating sodium and ionized calcium concentrations correlated to changes in SBP during hyperinsulinemia (r = -0.41, p = 0.03, r = 0.56, p < 0.01, respectively). The changes in ion status were not significantly correlated to age, body mass index or insulin sensitivity. In conclusion, a more pronounced increase in circulating ionized calcium concentration and reduction in the ratio between sodium and ionized calcium concentrations was associated with a greater blood pressure decline during the hyperinsulinemic clamp test when performed in hypertensive patients.

Relationships between muscle morphology and insulin sensitivity are improved after adjustment for intra-individual variability in 70-year-old men.

The purpose of this investigation was to examine to what extent variability in the muscle morphology and insulin sensitivity influence the correlation between them. Reproducibility of muscle characteristics was estimated in duplicate biopsies from the same thigh of 23 subjects from a cohort of 70-year-old men. The coefficient of variation (CV) for different characteristics of muscle morphology was between 11 and 42% in duplicate biopsies. Coefficient of variation for markers of insulin sensitivity ranged between 12 and 39%. The variability reflected by intra-class correlation ranged from 0.23 to 0.60 for muscle morphology and from 0.68 to 0.96 for estimates of insulin sensitivity. The correlation analysis between muscle morphology and insulin resistance was performed in a sample of 515 men from the cohort, correlation coefficients were calculated with (rtrue) and without (r) adjustment for intra-individual variation. Insulin sensitivity showed a positive relationship with percentage of type I fibres (rtrue=0.33, r=0.21; P < 0.0001) and capillary density (rtrue=0.43, r=0.21; P < 0. 0001) and negative correlations with percentage of type IIB fibres (rtrue=-0.35, r=-0.24; P < 0.0001). Capillary density was inversely correlated to insulin. Thus, an obvious improvement of the correlation was seen after correcting intra-individual variation. In conclusion, owing to the low degree of reproducibility of muscle morphology variables and insulin sensitivity, implying a noticeable underestimation of correlations, the r-values should be adjusted for within-subject variation in order to demonstrate a more accurate estimate of the strength of the relationships studied.

Alterations in skeletal muscle morphology in glucose-tolerant elderly hypertensive men: relationship to development of hypertension and heart rate.

OBJECTIVE: To compare the muscle morphology in hypertensive subjects with that in controls and to test the hypothesis of a relation between heart rate, development of hypertension and muscle morphology that is independent of glucose intolerance. PATIENTS AND METHODS: We studied 43 glucose-tolerant, untreated hypertensive subjects and 113 healthy controls in a longitudinal cohort of 70-year-old men. Metabolic status (oral glucose tolerance test and euglycemic, hyperinsulinaemic clamp test), muscle fibre distribution (myosin ATPase staining) and capillary supply (amylase-PAS method) were evaluated. Blood pressure and heart rate data were available from both ages 50 and 70 years. RESULTS: Hypertensive subjects had a significantly smaller mean number of capillaries per fibre than controls (1.53 versus 1.64; P = 0.04). In hypertensive subjects, the proportions of type I and type II fibres were correlated to mean arterial pressure (r = -0.56 and r= 0.52, respectively, P < 0.05 for both). The increase in mean arterial pressure over 20 years was closely correlated to capillary density in mm2 (r= -0.62; P< 0.0001). Capillary supply was inversely related to resting heart rate both at ages 50 and 70 years. CONCLUSIONS: Skeletal muscle of glucose tolerant hypertensive subjects showed a lower capillary supply than that of controls. This capillary rarefaction was correlated to increase in mean arterial pressure over two decades and to supine heart rate. This is compatible with the suggestion that higher sympathetic drive might generate structural alterations in muscle capillarization.

Induction of insulin resistance by beta-blockade but not ACE-inhibition: long-term treatment with atenolol or trandolapril.

The effects on glucose metabolism by the beta-blocker atenolol and the angiotensin-converting enzyme (ACE)-inhibitor trandolapril were investigated in a randomised double-blind parallel group study of patients with primary hypertension. Twenty-six patients were treated with 50-100 mg atenolol and 27 patients with 2-4 mg trandolapril o.d. Intravenous glucose tolerance tests, euglycaemic hyperinsulinaemic clamps and serum lipid measurements were performed after 8 and 48 weeks of active treatment. After 48 weeks insulin sensitivity was reduced by 23% by atenolol while it remained unchanged during trandolapril treatment (+0.5%, P = 0.0010 for difference between treatments, ANCOVA). The effect on triglycerides (+22% vs -8.5%) and high-density lipoprotein cholesterol (-13% vs +0.7%) also differed significantly between atenolol and trandolapril. Results after 8 weeks were similar. Glucose tolerance was not affected by either drug. Atenolol reduced diastolic blood pressure (DBP) better than trandolapril (-15.3 mm Hg vs -6.6 mm Hg for supine DBP after 48 weeks, P = 0.012). The difference in effect on insulin sensitivity between the drugs corresponded to 25% of the baseline values of insulin sensitivity, and persisted over 48 weeks of treatment. The choice of antihypertensive treatment could influence the risk of diabetes associated with treated hypertension. Journal of Human Hypertension (2000) 14, 175-180.

Pharmacogenomics to predict drug response.

From theory to proof-of-concept, pharmacogenomics promises to improve future general healthcare in a number of ways. By identifying individuals who will respond to a particular drug treatment compared to those who have a low probability of response, pharmacogenomic test development hopes to aid the physician in prescribing the optimal medication for each patient. This approach promises faster relief from symptoms, a lowering of side effect risks and a reduction in healthcare costs. Pharmacogenomic tests used by the pharmaceutical companies themselves can be used to help identify suitable subjects for clinical trials, aid in interpretation of clinical trial results, find new markets for current products and speed up the development of new treatments and therapies. This type of approach should also see fewer compounds failing during later phases of development. The questions we are faced with as we enter the new millennium, however, are if and when the promises of pharmacogenomnics in improving healthcare will be fulfilled. Currently, there are only a handful of pharmacogenomic tests and associated products which are commercially available and it remains to be seen what impact these will have on the market and on healthcare in general.

Search for variants of the gene-promoter and the potential phosphotyrosine encoding sequence of the insulin receptor substrate-2 gene: evaluation of their relation with alterations in insulin secretion and insulin sensitivity.

AIMS/HYPOTHESIS: The aim of this study was to screen part of the putative promoter sequence in addition to 14 potential phosphotyrosine residues of human IRS-2 for genetic variability which might cause changes in protein expression or function. Furthermore, the potential impact on insulin secretion and sensitivity of a previously identified IRS-2 variant (Gly1057Asp) was analysed. METHODS: The screenings were carried out by the SSCP-heteroduplex technique on DNA from Type II (non-insulin-dependent) diabetic patients. The impact of the Gly1057Asp variant was analysed in four glucose-tolerant Scandinavian study groups. RESULTS: The results showed no nucleotide substitutions in the promoter sequence, however, a novel heterozygous amino acid variant was identified (Leu647Val). In an association study, the new variant was found in 3 of 413 diabetic patients and in none of 280 glucose tolerant subjects. The variant did not affect the binding of IRS-2 to the insulin receptor or p85alpha of phosphatidylinositol 3-kinase when measured in the yeast two-hybrid system. Examination of the common Gly1057Asp variant in 363 young healthy subjects and in 228 glucose tolerant offspring of one diabetic parent showed no differences in insulin secretion or insulin sensitivity after an intravenous glucose tolerance test. Glucose tolerant middle-aged subjects homozygous for the polymorphism (n = 31), however, had on average a 25 % decrease in fasting serum insulin concentrations (p = 0.009) and 28 % (p = 0.01) and 34 % (p = 0.003) reductions in serum insulin concentrations at 30 and 60 min, respectively, during an OGTT compared with wildtype carriers (n = 107). In a cohort of 639 elderly Swedish men the amino acid variant did not have any detectable impact on insulin secretion after an OGTT. CONCLUSION/INTERPRETATION: No genetic variability was found in the IRS-2 promoter. A rare IRS-2 variant at codon 647 has been identified in Type II diabetic patients. The prevalent codon 1057 polymorphism had no consistent effect on insulin secretion or insulin sensitivity. [Diabetologia (1999) 42: 1244-1249]

Skeletal muscle angiotensin-converting enzyme and its relationship to blood pressure in primary hypertension and healthy elderly men.

The aim of this study was to investigate the relationships between angiotensin-converting enzyme (ACE) activity in serum and skeletal muscle to blood pressure and the long-term antihypertensive effects of fosinopril and atenolol. We examined 50 hypertensive patients randomized to receive 20 mg fosinopril or 50 mg atenolol daily for 16 weeks. ACE activity was measured in biopsy specimens from skeletal muscle. Measurements of office and ambulatory blood pressure, serum ACE, and left ventricular wall thickness were also performed. The same investigations were performed in a cross-sectional study of 50 healthy elderly men. Muscle ACE correlated inversely to blood pressure in cross-sectional analyses in both populations (p < 0.05). During atenolol treatment muscle ACE activity tended to increase (14%, p = 0.059), and this increase correlated inversely to the changes in standing systolic and diastolic blood pressure (r = -0.62, p = 0.0044, and r = 0.54, p = 0.016, respectively). Muscle ACE was also inversely correlated to left ventricular wall thickness when the two populations were pooled (r =-0.29, p = 0.0053). In the fosinopril group, muscle ACE activity was not different during treatment than at baseline (-2. 1%, p = 0.68). The inverse relationship between blood pressure and muscle ACE levels in this study indicate that muscle tissue ACE levels are influenced by haemodynamic factors in humans.

The haemodynamic response to hyperinsulinaemia in hypertensive subjects.

In order to study if the vasodilatory action of insulin is impaired in essential hypertension, 24 untreated patients were challenged with a 2 h euglycaemic hyperinsulinaemic clamp (56 E/m2). Cardiac index (CI) was measured by thoracic impedance cardiography and leg blood flow (LBF) by Doppler ultrasound. During the clamp procedure a significant decline in blood pressure was seen (3.0-5.6% over 120 min, P < 0.001). However, no significant effects on ejection fraction (+6 +/- 8 s.d.%), CI (-1 +/- 2%), heart rate (+2 +/- 1%) or total peripheral resistance (TPRI, -0.5 +/- 2%) were found. LBF increased by 22 +/- 35% (P < 0.005). These haemodynamic effects of insulin were not related to age, sex, body mass index, blood pressure or the insulin-mediated glucose uptake during the clamp. In conclusion, insulin increased LBF, but no changes in CI and TPRI were seen in the hypertensive patients. Furthermore, no association between the ability of insulin to induce vasodilatation and to promote glucose uptake was seen.

Relation between plasma tumor necrosis factor-alpha and insulin sensitivity in elderly men with non-insulin-dependent diabetes mellitus.

Human obesity is associated with an increased tumor necrosis factor-alpha (TNF-alpha) mRNA expression in adipose tissue. TNF-alpha decreases insulin-dependent glucose uptake by inhibiting autophosphorylation of the insulin receptor, suggesting that TNF-alpha may play a role in insulin resistance. In this study, we analyzed plasma levels of TNF-alpha in 40 70-year-old men with newly detected non-insulin-dependent diabetes mellitus and in 20 age-matched controls. Twenty of the patients had a moderate level of insulin resistance and 20 were severely insulin resistant. The plasma levels of TNF-alpha were higher in patients (4.00+/-1.53 pg/mL in moderately insulin resistant and 4.91+/-1.43 pg/mL in severely insulin resistant subjects) than in controls (3.27+/-0.79 pg/mL, P<0.001). TNF-alpha was significantly related to body mass index, fasting glucose levels, and serum triglyceride levels and inversely related to the high density lipoprotein cholesterol level. The finding of an association between high plasma levels of TNF-alpha and several metabolic abnormalities characteristic for the insulin resistance syndrome suggests that TNF-alpha may be involved in the pathogenesis of non-insulin-dependent diabetes mellitus.

Insulin resistance in essential hypertension is related to plasma renin activity.

A high plasma renin activity (PRA) has previously been related to several cardiovascular risk factors as well as to later cardiovascular events. As insulin resistance has been suggested as the unifying factor in the insulin resistance metabolic syndrome, insulin resistance was evaluated by the euglycaemic hyperinsulinaemic clamp technique in 50 untreated hypertensive subjects in whom PRA and serum aldosterone were measured together with lipids and an intravenous glucose tolerance test (IVGTT). PRA was inversely related to insulin-mediated glucose disposal during the clamp (r=-0.31, P < 0.05), as well as to fasting insulin (r=0.32, P < 0.05) and to insulin at 60 min at the IVGTT (r=0.30, P < 0.05), but not to other risk factors. Serum aldosterone was not related to any of the metabolic risk factors. In conclusion, the present investigation showed that insulin resistance is associated with elevated levels of PRA in patients with untreated essential hypertension. It thus seems as if a high activity in the renin system should be included in the disturbances included in the insulin resistance metabolic syndrome, a syndrome with a major impact on future cardiovascular events.

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.