Insulin as a vascular and sympathoexcitatory hormone: implications for blood pressure regulation, insulin sensitivity, and cardiovascular morbidity

The past several years have witnessed a major surge of interest in the cardiovascular actions of insulin. This interest has stemmed on the one hand from epidemiological studies that demonstrated an association between obesity, insulin resistance, and hypertension, leading to the so-called insulin hypothesis of hypertension. On the other hand, this interest has been stimulated by experimental evidence suggesting that the vascular actions of insulin may play a role in its main action, namely the promotion of glucose uptake in skeletal muscle tissue. Two tenets have emerged about how insulin may exert its cardiovascular actions. First, it is now firmly established that acute insulin administration stimulates sympathetic nerve activity in both animals and humans. Second, there is increasing evidence that insulin stimulates muscle blood flow, an effect that appears to be mediated at least in part by an endothelium-dependent mechanism. This review summarizes the current understanding and gaps in knowledge on cardiovascular actions of insulin in humans and pathophysiological consequences of derangements of such actions.     

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.     

Ambulatory blood pressure, nocturnal blood pressure reduction and plasma catecholamines

OBJECTIVE AND DESIGN: Controversial data have been reported on plasma catecholamines in hypertensives. Aims of this study were to find whether 24-hour ambulatory blood pressure was correlated with circulating catecholamines and to investigate whether nocturnal blood pressure reduction was associated with baseline plasma catecholamines. Samples for catecholamine determination were obtained in 34 consecutive male subjects after a 30-minute rest and before ambulatory blood pressure monitoring. RESULTS: Hypertensive patients (n = 22; 24-hour blood pressure: 145 +/- 14/94 +/- 6 mm Hg) showed similar norepinephrine and epinephrine levels when compared with normotensives (n = 12; 24-hour blood pressure: 124 +/- 6/81 +/- 6 mm Hg), and higher dopamine values (hypertensives: 64.6 +/- 58; normotensives: 26.2 +/- 31 pg/ml; p < 0.05). A positive correlation was observed between dopamine and diastolic nocturnal blood pressure (p < 0.05) while a negative correlation was found between dopamine and nocturnal diastolic blood pressure reduction (p < 0.025). No significant relationship was observed between both norepinephrine and epinephrine, and 24-hour blood pressures. CONCLUSIONS: Since previous reports have documented malfunctioning of dopaminergic system in hypertension, the higher levels of circulating plasma dopamine found in hypertensive patients in the present study may account for a peripheral compensatory increase. The correlation between dopamine and nocturnal blood pressure fall seems to indicate that the impairment of dopaminergic system may influence the 24-hour blood pressure profile, affecting the nocturnal blood pressure reduction.     

Urinary kallikrein: a marker of blood pressure sensitivity to salt

We evaluated if a rat strain inbred for low urinary kallikrein excretion differs from normal-kallikrein Wistar rats regarding blood pressure levels in basal conditions and during alterations in sodium balance. Blood pressure was measured in unanesthetized rats on normal sodium intake. Then, blood pressure sensitivity to salt was evaluated over a period of 20 days of high sodium diet (0.84 mmol per g chow). Low-kallikrein rats showed greater systolic blood pressure levels (125 +/- 3 vs. 114 +/- 2 mm Hg in controls, P < 0.01) at nine weeks of age. Systolic blood pressure was increased after sodium loading in the low-kallikrein group and remained unchanged in controls (150 +/- 6 vs. 112 +/- 2 mm Hg, P < 0.01). This effect was associated with a reduced cumulative urinary excretion of sodium in the low-kallikrein rats. No group difference was found in the clearance of endogenous creatinine in basal conditions. Urinary creatinine excretion decreased during sodium loading, particularly in the low-kallikrein group. The group-difference in urinary kallikrein excretion found in basal conditions (6.85 +/- 0.31 vs. 20.74 +/- 1.71 nkat/24 hr in controls, P < 0.01) was enhanced by high salt diet (2.96 +/- 0.67 vs. 22.07 +/- 2.47 nkat/24 hr in controls, P < 0.01). In addition, renal kallikrein activity and content were reduced in low-kallikrein rats. The latter group showed a greater ratio of heart weight to body wt both in basal conditions and after sodium loading. The ratio of kidney weight to body wt was reduced after sodium loading. These results indicate that a genetically-determined defect in urinary kallikrein excretion is associated with a greater blood pressure sensitivity to salt, possibly due to altered renal sodium handling.     

Lack of association between both insulin resistance and plasma insulin levels with blood pressure values in essential hypertension

AIM: To evaluate the role of insulin resistance and hyperinsulinaemia in the genesis of essential arterial hypertension (EAHT). SUBJECTS AND METHODS: We studied 49 patients (age 44 +/- 8 y., body mass index (BMI: 29.5 +/- 3.2 kg.m-2) with mild or moderate EAHT (systolic blood pressure: 156 +/- 13 mmHg, diastolic blood pressure: 100 +/- 6 mmHg). Patients with BMI > 27 kg.m-2 were classed as obese. Arterial pressure was measured with a mercury sphygmomanometer after the patient had been lying down for 15 min. For each patient, the results of a frequently sampled intravenous glucose tolerance test (FSIGT) were used to estimate insulin sensitivity (using the minimal model of glucose metabolism) and to characterize insulin secretion in response to intravenous glucose (area of the insulin curve above basal during the 180 min of the FSIGT test). Correlations were evaluated by means of Spearman's correlation coefficient. RESULTS: Neither fasting insulinaemia, glucose-induced insulin secretion nor insulin sensitivity correlated significantly with arterial pressure, either in the whole sample or in the obese and non-obese subsamples. CONCLUSIONS: These results suggest that neither insulin nor insulin sensitivity are important physiological regulators of arterial pressure, and lend no support to the hypothesis that insulin is related to essential arterial hypertension.     

Relationship between nifedipine sensitivity of aortae and blood pressure of stroke-prone spontaneously hypertensive rats

1. We have previously described an increased sensitivity to inhibition by nifedipine of noradrenaline-induced contractures of blood vessels in hypertension. In this study we have investigated whether changes in blood pressure (BP) change the sensitivity to nifedipine and K+ of aortic rings from normotensive (Wistar-Kyoto rats, WKY) and stroke-prone spontaneously hypertensive rats (SHRSP). 2. SHRSP were treated with: hydralazine plus hydrochlorothiazide; captopril plus hydrochlorothiazide; hydralazine plus guanethidine; or captopril alone. WKY rats were treated with deoxycorticosterone acetate (DOCA) and NaCl. Treatment commenced from 5 weeks of age and continued until 13-15 weeks. 3. The SHRSP treatments produced similar reductions in BP, and the BP of all the treated groups were significantly lower than the mean BP of untreated SHRSP (201.0 +/- 7.7 mmHg). The mean BP of the treated WKY rats (134.2 +/- 7.6 mmHg) was significantly higher than the mean BP of the untreated WKY rats (86.8 +/- 7.4 mmHg). 4. An area-under-curve (AUC) analysis of the inhibitory effects of nifedipine on responses of aortae to noradrenaline showed no differences between treated and untreated SHRSP groups (overall mean 40.6 +/- 1.9% and 43.4 +/- 3.4% inhibition of control AUC, respectively), or between DOCA-salt treated WKY and untreated WKY groups (58.8 +/- 5.9 and 64.8 +/- 2.3, respectively). Noradrenaline-induced contractures of aortae from all SHRSP groups were significantly more sensitive to inhibition by nifedipine than aortae from both WKY groups. 5. The molar concentration of agonist required to evoke 50% of the maximum response (EC50) values for potassium chloride (KCl) were significantly increased in the aortae of all treated SHRSP groups in comparison to those from untreated SHRSP (treated SHRSP groups, 15.53 +/- 0.68 mmol/L vs untreated SHRSP group, 11.36 +/- 1.10 mmol/L). The EC50 values for KCl for the aortae from the DOCA-treated WKY rats were significantly less than those from aortae of the untreated WKY (11.80 +/- 0.80 and 17.08 +/- 1.50 mmol/L, respectively). 6. We conclude that reduction (in SHRSP) or increase (in WKY) of the BP has no effect on the sensitivity of aortic smooth muscle to the inhibitory effects of nifedipine on responses to noradrenaline, suggesting that alterations in voltage-dependent Ca2+ mechanisms may be a primary phenomenon in the SHRSP. In contrast, the fact that sensitivity to KCl changes in the treated SHRSP and WKY aortae suggests such sensitivity is secondary to the BP and thus a separate phenomenon from voltage-dependent Ca2+ mechanisms.     

Salt intake, blood pressure, and cardiovascular structure

Epidemiologic data revealed that a low sodium intake might have a favorable influence on blood pressure throughout an individual's lifetime. Sodium restriction was reported to lead to a modest fall in blood pressure in some studies, although a few groups of hypertensive patients experienced a rise in blood pressure. Left ventricular hypertrophy has been demonstrated to be related to cardiovascular morbidity and mortality independent of other risk factors. Dietary salt intake participates in the hypertrophic process independent of other determinants. Thus, 24-hour urinary sodium excretion has been reported to correlate with left ventricular mass independent of levels of arterial pressure. Three different mechanisms may link dietary salt intake to myocardial hypertrophy: the renin-angiotensin-aldosterone system, the sympathetic nervous system, and fluid volume homeostasis. Whether salt restriction reduces cardiovascular structural damage independent of arterial pressure has not been determined.     

Troglitazone, an insulin action enhancer, improves glycaemic control and insulin sensitivity in elderly type 2 diabetic patients

The management of Type 2 diabetes mellitus with currently available oral agents may be complicated in the elderly by an increased frequency of side-effects. The effects of troglitazone, an insulin action enhancer, were studied in elderly patients with Type 2 diabetes in a double-blind, parallel-group, placebo-controlled trial. A total of 229 patients (41% male), mean age 75 (range 69-85) years, with two fasting capillary blood glucose values > or =7 and < or =15 mmol l(-1) (and within 4.0 mmol l(-1) of each other) and previously treated with either diet alone (30%) or oral hypoglycaemic agents, were randomized to placebo or troglitazone 400 mg once daily or 200 mg twice daily, or 800 mg once daily or 400 mg twice daily, for 12 weeks. After 12 weeks' treatment, fasting serum glucose was significantly lower in troglitazone-treated patients (troglitazone, adjusted geometric mean 9.4-10.4 mmol l(-1) vs placebo 12.7 mmol l(-1), p < 0.001). Adjusted geometric mean fructosamine was also lower in troglitazone-treated patients by 5 to 15% compared to placebo (P < 0.05 at all doses except 400 mg od). There was no significant difference between troglitazone doses for improvement in glycaemic control. Troglitazone lowered adjusted geometric mean fasting plasma insulin by 27-34% compared to placebo (P < 0.001) and insulin sensitivity (HOMA-S) improved by 9-15% in all troglitazone dose groups (p < 0.001). Troglitazone also lowered serum non-esterified fatty acids and triglyceride. Adverse event incidence in troglitazone-treated patients was similar to that in patients treated with placebo. No weight gain or symptomatic hypoglycaemia was recorded at any of the doses studied. Troglitazone is effective and well tolerated in elderly patients with Type 2 diabetes mellitus, providing improved glycaemic control in the absence of weight gain.     

Association of body mass index, blood pressure and serum levels of triglycerides and high-density lipoprotein cholesterol in childhood with the insulin sensitivity index in young adulthood: a 13-year follow-up

The 77 (47 females, 30 males) in-patient referrals to the Psychiatric Department of the University College Hospital, Ibadan, Nigeria, over a 1-year period, were compared with a control sample of 75 (45 females, 30 males) unreferred patients. The low referral rate of 0.8%, after excluding deliberate self-harm (relatively infrequent in Nigeria), was comparable to reports in Western literature. Treatable minor psychiatric morbidity, mainly anxiety and depressive disorders, occurred in 41.3% of the controls. Sixty-eight percent of those referred had definite mental disorders, most commonly psychoses (50.7%), especially delirium (29.9%). Infectious disorders, notably Salmonella typhi infection, were the most predominant physical etiological factors. The results are discussed and the implications highlighted.     

Insulin sensitivity and blood pressure in a biethnic sample: the Miami Community Health Study

An association between blood pressure and insulin sensitivity among normotensive African-Americans has not been demonstrated consistently in epidemiologic studies. Part of the discrepancy may be due to studying persons with profound obesity-an insulin-resistant state itself. The association between insulin-mediated glucose uptake (i.e., insulin sensitivity) and blood pressure was examined among 25 nondiabetic African-American and 28 white non-Hispanic persons aged 25-44 years who ranged from normal weight to obese, using the hyperinsulinemic euglycemic clamp technique. In bivariate analyses, insulin sensitivity was inversely related to systolic (p < 0.01) and diastolic blood pressure (p = 0.08) among African-American persons and to diastolic blood pressure among white non-Hispanic subjects (p < 0.05). Covariate adjustment for age and sex had only a marginal effect on these results. When the data were pooled and further adjusted for ethnicity, insulin sensitivity remained significantly associated with both systolic and diastolic blood pressure (p < 0.01 for each). To consider the effect of obesity, body mass index (BMI) was divided at the sample median (26.5 kg/m2) and the analyses were repeated within each stratum. Among those whose BMI was below the median value, each increment in insulin sensitivity was associated with a 2-mmHg decrease in systolic blood pressure (p = 0.02). These results suggest that ethnicity was not a strong effect modifier in this sample and indicated that insulin sensitivity was inversely related to blood pressure level in these normotensive African-American and white, non-Hispanic participants.     

Relationship between pain sensitivity and resting arterial blood pressure in patients with painful temporomandibular disorders

OBJECTIVE: Patients experiencing temporomandibular disorders (TMD) show greater sensitivity to painful stimuli than age- and gender-matched control subjects. This enhanced pain sensitivity may result, at least in part, from an alteration in pain regulatory systems that are influenced by resting arterial blood pressure. In this study, we examined the relationship between resting systolic blood pressure and pain perception in 64 female TMD and 23 age-matched pain-free female subjects. METHOD: Resting arterial blood pressure and measures of thermal and ischemic pain threshold and tolerance were determined for each participant. Subjective ratings of thermal pain evoked by suprathreshold noxious thermal stimuli (45-49 degrees C) using a magnitude matching procedure were also obtained for both groups. RESULTS: TMD patients had lower thermal and ischemic pain thresholds and tolerances than pain-free subjects (ps < .05). Both groups provided equivalent intensity ratings to suprathreshold noxious thermal stimuli. A median split of each group based on resting systolic blood pressure revealed an influence of blood pressure on both thermal and ischemic pain perception for the Pain-Free group. The Pain-Free high resting blood pressure subgroup had higher thermal pain tolerances, higher ischemic pain thresholds, and provided lower magnitude estimates of the intensity of graded heat pulses compared with the Pain-Free low blood pressure subgroup. A trend toward a significant effect of blood pressure level on ischemic pain tolerance was also observed for the Pain-Free group. In contrast to the Pain-Free group, blood pressure level did not influence ischemic or thermal pain perception for TMD patients. Similar to the lack of effect of resting blood pressure on experimental pain perception in TMD patients, resting blood pressure was not related to measures of clinical orofacial pain in TMD patients. CONCLUSIONS: These findings confirm our previous findings that TMD patients are more sensitive to noxious stimuli and suggest that painful TMD may result, at least in part, from an impairment in central pain regulatory systems that are influenced by resting arterial blood pressure.     

Association between insulin and blood pressure in relation to the influence of body mass index

The relationship between plasma insulin level and systolic blood pressure (SBP) was investigated by multiple linear regression procedure in 410 Chinese non-diabetics. The significant positive correlation between SBP and 2-hour plasma insulin (INS 2h) after 75g glucose load was found in the BMI (body mass index) 15.9-27.0 group (n = 287) after the adjustment for age, sex, BMI, smoking and plasma cholesterol (P = 0.01). However, this significant correlation was gradually diminished with the expansion of the BMI range, ie. P = 0.04 in the BMI 15.9-29.0 (n = 356) group, P = 0.07 in the BMI 15.9-31 (n = 389) group, and P = 0.12 in the BMI 15.9-33 (n = 402) group after the same adjustment of variables. Interestingly, the significant inverse correlation between insulin-BMI interaction term (product of BMI and insulin) and SBP was found (P = 0.04) in the presence of the significant positive correlation between 2-hour plasma insulin and SBP (P = 0.02) after adjustment of the above mentioned five factors in the whole group (BMI 15.9-42.2, n = 410). These results indicated that SBP is independently correlated with plasma insulin level in the studied population, and that the severer obesity may interfere the net effects of insulin on the elevating of blood pressure.     

Insulin sensitivity, insulin action, and fibrinolysis activity in nondiabetic and diabetic obese subjects

Because inconsistencies occur with regard to the relative contribution of insulin to the hypofibrinolysis characteristic of obesity and diabetes, we explored the relationship between insulin and fibrinolysis, assessing both insulin sensitivity and insulin action. Seventeen markedly obese subjects (body mass index [BMI], 34.0+/-1.6 kg/m2; 12 nondiabetic and five diabetic) were studied using the three-step euglycemic-hyperinsulinemic clamp technique. Since the circadian rhythm of the fibrinolytic system may obscure a true effect of insulin, variations in fibrinolysis parameters observed during the glucose clamp were compared with those occurring spontaneously because of the circadian rhythm. Compared with six normal-weight subjects (BMI, 21.0+/-0.9 kg/m2), all obese subjects exhibited basal hyperinsulinism (fasting plasma insulin, 16.0+/-1.4 v 9.8+/-1.3 microU/microL, P < .001; fasting plasma C-peptide, 1.4+/-0.2 v 0.5+/-0.2 ng/mL, P < .001), hypofibrinolysis (euglobulin lysis time [ELT], 378+/-29 v 222+/-31 minutes, P=.01; tissue plasminogen activator [tPA] antigen, 7.8+/-0.9 v 4.2+/-0.5 ng/mL, P=.04; plasminogen activator inhibitor type 1 [PAI-1] activity, 22.2+/-2.5 v3.9+/-0.6 AU/mL, P=.004), and marked insulin resistance (M value, ie, the maximal glucose disposal rate, 9.1+/-0.6 v 18.6+/-0.8 mg/(kg x min), P < .001). The M value correlated inversely with tPA antigen (r=-.46, P=.05). During insulin infusion, values for fibrinolysis parameters decreased, but were not different compared with variations due to the circadian rhythm. In conclusion, our findings together with previously reported data reinforce the idea that chronic hyperinsulinism is linked to hypofibrinolysis, but insulin does not seem to acutely regulate the fibrinolysis system.     

Glucose effectiveness, peripheral and hepatic insulin sensitivity, in obese and lean prepubertal children

Vascular injuries in lumbar disk surgery, although rare, are serious complications which may be overlooked due to a broad range of clinical manifestations. It is important that surgeons and radiologists be aware of these potentially fatal complications and develop an appropriate symptom-based diagnostic paradigm. We reviewed 8099 consecutive cases of lumbar disk surgery, performed over a 14-year period at a single institution, for postoperative vascular complications. We identified four patients (0.05%) with lumbar disk surgery-related vascular complications: intraoperative lacerations of the abdominal aorta and median sacral artery, an arteriovenous fistula between the left common iliac artery and vein detected 19 days postdiskectomy, and a partially thrombosed aortic aneurysm with an arteriovenous fistula between the aneurysm and the inferior vena cava, diagnosed 11 months after surgery. The majority of cases in the literature of vascular injury in lumbar disk surgery were reported prior to 1965. Diagnostic approaches described in that period do not reflect the great range of diagnostic techniques available today. Angiography remains the gold standard for diagnosis and guidance as to surgical repair. However, a high index of suspicion based on clinical signs and/or the use of sonography or CT is important in the detection of these complications.     

Rhythms and blood pressure

The time (chronos) structure of life (bios) is the topic of a computer-implemented science (logos), chronobiology. Chronobiologic methods for resolving physiologic time structure provide a more reliable mean, the MESOR, and other parametric dynamic measures of blood pressure variability. The amplitude is a measure of predictable extent of change and the acrophase a measure of timing of overall high values within each cycle of the rhythmic function. Such chronobiologic endpoints are often more sensitive than the mean for separating groups at different risk of developing high blood pressure. About 24-h (circadian) rhythms account for a sizeable part of predictable variability in blood pressure. Methodology to assess the characteristics of circadian blood pressure rhythms also provides time-varying reference limits for the interpretation of single measurements. Deviant blood pressures can be quantified by reference to such circadian-stage-dependent limits, derived from the automatically monitored blood pressure profiles of healthy peer groups. Excess or deficit in blood pressure can also be assessed as a hypertensive or hypotensive index integrated over 24 h. Chronobiologic monitoring has wide uses in practice as well as research, whether it is carried out by self- or automatic measurements, once the data are analyzed by appropriate computer methods that are now readily available.     

The acute impact of ethanol on glucose, insulin, triacylglycerol,and free fatty acid responses and insulin sensitivity in type 2 diabetes

The aim of the present study was to evaluate the acute effect of ethanol on insulin sensitivity, and glucose, insulin, free fatty acid (FFA), and triacylglycerol responses in ten patients with non-insulin-dependent (type 2) diabetes. In the test study an oral dose of 0.66 g ethanol/kg followed by continuous intravenous infusion of 0.1 g ethanol/kg per h was given to maintain a constant ethanol level in the blood. In the control study identical volumes of oral water and intravenous saline (9 g NaCl/l) were given. After 90 min insulin sensitivity was determined by the hyperinsulinaemic, euglycaemic clamp technique. Ethanol caused no change in blood glucose or insulin concentrations. The FFA level was suppressed by ethanol while the triacylglycerol level was unaffected. The insulin sensitivity was not affected by ethanol. No major acute effect of ethanol on the glycaemic control in fasting type 2 diabetic patients was found in comparison with what is seen in healthy people. The present study, along with the sparse literature, indicates that the ability of ethanol to induce hypoglycaemia is attenuated or absent in diet-treated type 2 diabetes. Furthermore, we found no change in insulin sensitivity. Consequently, the risk of acute ethanol-induced aberrations in carbohydrate metabolism in diet-treated type 2 diabetes seems to be less than previously expected, when alcohol is not taken as a part of a meal.