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Biomedical subjects

A Natali

Publications and source records attributed to A Natali.

At least 37 records · Page 2Linked to original sources
PubMed2000

Functional adenosine receptors in human corpora cavernosa.

We have demonstrated that adenosine has potent relaxant activity on the rabbit corpus cavernosum, acting through the A2a subtype receptor for adenosine. We now report studies on the identification and functional characterization of adenosine receptors in human penile vessels. To identify A2 receptors in human corpora cavernosa (HCC) we performed binding studies using the selective radioligand [125I]PAPA-APEC in membranes from HCC. We found the presence of a single class of high affinity (Kd= 0.23 +/- 0.06 nM), low capacity (Bmax=134 +/- 37 fmoles/mg protein) binding sites. Adenosine and CGS 21680 completely displaced [125I]PAPA-APEC binding (Kd= 146.7 +/- 64 microM and 51.52 +/- 27 nM, respectively). Accordingly, in functional studies adenosine relaxed phenylephrine precontracted HCC with an IC50=2.28 +/- 0.17 mM. The effect of adenosine was independent from nitric oxide (NO), and was counteracted by the A2 antagonist CGS 15943. In order to evaluate the in vivo effect of adenosine, increasing concentrations (6, 60, 600 microg) of adenosine or prostaglandin E1 (PGE1) (10 microg) were injected into the corpora cavernosa of four healthy volunteers. Blood flow and erectile response were evaluated at different times by duplex sonography and visual inspection, respectively. It was found that adenosine increased cavernosal peak blood flow velocity in a time- and dose-dependent manner. The highest concentrations of injected adenosine elicited a response that was not statistically different from that of PGE1 (10 microg). However, in contrast to PGE1, a full or partial erection was never obtained. To further investigate the lack of effect of adenosine on penile tumescence (despite the substantial increase in cavernosal blood flow), in vitro experiments were performed on human deep dorsal penile veins (DDPV) obtained from surgical ligation for impotence. Adenosine did not affect basal tone, but it induced almost complete relaxation in noradrenaline-precontracted vein strips with an IC50=1.6 +/- 0.22 mM. Conversely, PGE1 stimulated a sustained increase in basal tone. Therefore, the lack of effect of adenosine on penile tumescence could be due to a simultaneous relaxing activity on penile corpora cavernosa and veins. In conclusion, our study indicates that adenosine relaxes HCC as well as penile veins without affecting erection, at least at the concentrations we have used. Conversely, PGE1 relaxes corpora cavernosa as well as adenosine but strongly stimulates vein contraction, allowing penile tumescence.

Adenosine↗
PubMed2000

Coronary artery disease and arterial hypertension: clinical, angiographic and follow-up data.

OBJECTIVES: To evaluate how the presence of arterial hypertension affects coronary atherosclerosis and prognosis in patients with, or at high risk of, ischaemic heart disease. DESIGN: Retrospective analysis of clinical records and follow-up data. SETTINGS: Single referral centre for ischaemic heart disease. SUBJECTS: All consecutive patients (n = 1700, 38% with hypertension) undergoing coronary angiography for the evaluation of ischaemic heart disease during 1983-92. RESULTS: On angiography, the likelihood of having three-vessel disease was higher amongst hypertensives (odds ratio = 1.41; 95% confidence interval [CI] = 1.08-1.85) after adjustment for age, sex, and angina symptoms. The sum of all visible stenoses (an index of overall atherosclerotic involvement) was 19% higher in hypertensives (262 +/- 204 vs. 220 +/- 194 units, P < 0.005). By multivariate analysis, the presence of hypertension made a modest (+ 28 units), albeit statistically significant, independent contribution to the total atherosclerosis score. On follow-up (median = 96 months), cardiovascular mortality was slightly higher in the hypertensive patients than in the normotensive group (P < 0.05 in a Kaplan-Meier analysis), but a proportional hazard analysis adjusting for age and gender showed no significant independent contribution of hypertension. Hypertensive patients, however, remained at higher risk of non-fatal myocardial infarction following discharge (adjusted odds ratio = 1.21, 95% CI = 1.03-1.46; P < 0.05). CONCLUSIONS: In this referral population, hypertension is a risk factor for presence of three-vessel disease. Distribution, severity and extension of coronary stenosis are similar to those of normotensive patients, and prognosis is only marginally affected.

Adult↗
PubMed2000

Dose-response characteristics of insulin action on glucose metabolism: a non-steady-state approach.

The traditional methods for the assessment of insulin sensitivity yield only a single index, not the whole dose-response curve information. This curve is typically characterized by a maximally insulin-stimulated glucose clearance (Cl(max)) and an insulin concentration at half-maximal response (EC(50)). We developed an approach for estimating the whole dose-response curve with a single in vivo test, based on the use of tracer glucose and exogenous insulin administration (two steps of 20 and 200 mU x min(-1) x m(-2), 100 min each). The effect of insulin on plasma glucose clearance was calculated from non-steady-state data by use of a circulatory model of glucose kinetics and a model of insulin action in which glucose clearance is represented as a Michaelis-Menten function of insulin concentration with a delay (t(1/2)). In seven nondiabetic subjects, the model predicted adequately the tracer concentration: the model residuals were unbiased, and their coefficient of variation was similar to the expected measurement error (approximately 3%), indicating that the model did not introduce significant systematic errors. Lean (n = 4) and obese (n = 3) subjects had similar half-times for insulin action (t(1/2) = 25 +/- 9 vs. 25 +/- 8 min) and maximal responses (Cl(max) = 705 +/- 46 vs. 668 +/- 259 ml x min(-1) x m(-2), respectively), whereas EC(50) was 240 +/- 84 microU/ml in the lean vs. 364 +/- 229 microU/ml in the obese (P < 0.04). EC(50) and the insulin sensitivity index (ISI, initial slope of the dose-response curve), but not Cl(max), were related to body adiposity and fat distribution with r of 0.6-0.8 (P < 0.05). Thus, despite the small number of study subjects, we were able to reproduce information consistent with the literature. In addition, among the lean individuals, t(1/2) was positively related to the ISI (r = 0.72, P < 0.02). We conclude that the test here presented, based on a more elaborate representation of glucose kinetics and insulin action, allows a reliable quantitation of the insulin dose-response curve for whole body glucose utilization in a single session of relatively short duration.

Adipose Tissue↗
PubMed2000

Effect of vitamin C on forearm blood flow and glucose metabolism in essential hypertension.

In 9 patients with essential hypertension, we tested whether a high-dose (12 mg. min(-1)) vitamin C infusion into the brachial artery, by improving endothelium-dependent vasodilatation, would also attenuate the insulin resistance of deep forearm tissues. We measured the effect of vitamin C on acetylcholine (Ach)-induced vasodilatation and on forearm glucose uptake during systemic hyperinsulinemia; in all studies, the contralateral forearm served as the control. Intrabrachial Ach infusion produced a stable increase in forearm blood flow, from 2.6+/-0.3 to 10.6+/-2.1 mL. min(-1). dL(-1); when vitamin C was added, a further rise in forearm blood flow (to 13.4 mL. min(-1). dL(-1); P<0.03 vs Ach alone) was observed. In response to insulin, blood flow in both the infused and control forearms did not significantly change from baseline values (+10+/-16% and +2+/-11%, respectively). In contrast, when vitamin C was added, blood flow in the infused forearm increased significantly (to 3.7+/-0.7 mL. min(-1). dL(-1); P<0.02 vs 2.8+/-0.6 mL. min(-1). dL(-1) in the control forearm). Insulin stimulated whole-body glucose disposal to 20+/-2 micromol. min(-1). kg(-1), compatible with the presence of marked insulin resistance. Forearm glucose uptake was similarly stimulated after 80 minutes of insulin infusion (to 2.11+/-0.42 and 2.06+/-0.43 micromol. min(-1). dL(-1), infused and control, respectively). When intrabrachial vitamin C was added, no difference in glucose uptake was observed between the 2 forearms (infused, 2.37+/-0.44 micromol. min(-1). dL(-1)and control, 2.36+/-0. 53 micromol. min(-1). dL(-1)). Forearm O(2) uptake at baseline was also similar in the 2 forearms (infused, 9.7+/-0.7 micromol. min(-1). dL(-1) and control, 9.6+/-1.1 micromol. min(-1). dL(-1)) and was not changed by either insulin or vitamin C. We conclude that in the deep forearm tissues of patients with essential hypertension and insulin resistance, an acute improvement in endothelial function, obtained with pharmacological doses of vitamin C, restores insulin-mediated vasodilatation but does not improve insulin-mediated glucose uptake. Thus, the endothelial dysfunction of essential hypertension is unlikely to be responsible for their metabolic insulin resistance.

Ascorbic Acid↗
PubMed2000

Influence of obesity and type 2 diabetes on gluconeogenesis and glucose output in humans: a quantitative study.

The contribution of gluconeogenesis (GNG) to endogenous glucose output (EGO) in type 2 diabetes is controversial. Little information is available on the separate influence of obesity on GNG. We measured percent GNG (by the 2H2O technique) and EGO (by 6,6-[2H]glucose) in 37 type 2 diabetic subjects (9 lean and 28 obese, mean fasting plasma glucose [FPG] 8.3 +/- 0.3 mmol/l) and 18 control subjects (6 lean and 12 obese) after a 15-h fast. Percent GNG averaged 47 +/- 5% in lean control subjects and was significantly increased in association with both obesity (P < 0.01) and diabetes (P = 0.004). By multivariate analysis, percent GNG was independently associated with BMI (partial r = 0.27, P < 0.05, with a predicted increase of 0.9% per BMI unit) and FPG (partial r = 0.44, P = 0.0009, with a predicted increase of 2.7% per mmol/l of FPG). In contrast, EGO was increased in both lean and obese diabetic subjects (15.6 +/- 0.5 micromol x min(-1) x kg(-1) of fat-free mass, n = 37, P = 0.002) but not in obese nondiabetic control subjects (13.1 0.7, NS) as compared with lean control subjects (12.4 +/- 1.4). Consequently, gluconeogenic flux (percent GNG x EGO) was increased in obesity (P = 0.01) and markedly elevated in diabetic subjects (P = 0.0004), whereas glycogenolytic flux was reduced only in association with obesity (P = 0.05). Fasting plasma glucagon levels were significantly increased in diabetic subjects (P < 0.05) and positively related to EGO, whereas plasma insulin was higher in obese control subjects than lean control subjects (P = 0.05) and unrelated to measured glucose fluxes. We conclude that the percent contribution of GNG to glucose release after a 15-h fast is independently and quantitatively related to the degree of overweight and the severity of fasting hyperglycemia. In obese individuals, reduced glycogenolysis ensures a normal rate of glucose output. In diabetic individuals, hyperglucagonemia contributes to inappropriately elevated rates of glucose output from both GNG and glycogenolysis.

Adipose Tissue↗
PubMed1999

Ultrasound velocity and attenuation in cancellous bone samples from lumbar vertebra and calcaneus.

We report a study of ultrasound velocity and broadband ultrasound attenuation (BUA) in human cancellous bone samples. The influence of density and microarchitecture on ultrasound propagation in cancellous bone was examined. A total of 20 samples from vertebra L1 and 21 from calcanei were studied. The direction of ultrasound propagation was anteroposterior in the vertebra and lateromedial in the calcaneus. The relationships between ultrasonic parameters and density of bone samples, apparent ash density, trabecular bone volume (BV/TV) and trabecular thickness (Tb.Th) were analyzed using a simple linear model and a multiple regression model. Velocity of ultrasound and BUA were positively correlated with density and morphometric parameters, in both vertebra and calcaneus. The best correlation was found between velocity and bone sample density in vertebra (r = 0.961, p < 0.0001) and the worst between velocity and trabecular thickness in calcaneus (r = 0.632, p = 0.002). The best correlation for BUA was with BV/TV in vertebra (r = 0.960, p < 0.0001). Using the stepwise regression procedure, BV/TV only was selected as significant for BUA and apparent ash density with Tb.Th for velocity, in both vertebra and in calcaneus. The possible influence of trabecular configuration on ultrasonic parameters is discussed, emphasizing the different slopes of regression lines obtained for vertebra and calcaneus, sites with different architecture of trabecular bone.

Adolescent↗
PubMed1999

Insulin: new roles for an ancient hormone.

Recent research has greatly expanded the domain of insulin action. The classical action of insulin is the control of glucose metabolism through the dual feedback loop linking plasma insulin with plasma glucose concentrations. This canon has been revised to incorporate the impact of insulin resistance or insulin deficiency, both of which alter glucose homeostasis through maladaptive responses (namely, chronic hyperinsulinaemia and glucose toxicity). A large body of knowledge is available on the physiology, cellular biology and molecular genetics of insulin action on glucose production and uptake. More recently, a number of newer actions of insulin have been delineated from in vitro and in vivo studies. In sensitive individuals, insulin inhibits lipolysis and platelet aggregation. In the presence of insulin resistance, dyslipidaemia, hyper-aggregation and anti-fibrinolysis may create a pro-thrombotic milieu. Preliminary evidence indicates that hyperinsulinaemia per se may be pro-oxidant both in vitro and in vivo. Insulin plays a role in mediating diet-induced thermogenesis, and insulin resistance may therefore be implicated in the defective thermogenesis of diabetes. In the kidney, insulin spares sodium and uric acid from excretion; in chronic hyperinsulinaemic states, these effects may contribute to high blood pressure and hyperuricaemia. Insulin hyperpolarises the plasma membranes of both excitable and non-excitable tissues, with consequences ranging from baroreceptor desensitisation to cardiac refractoriness (prolongation of QT interval). Under some circumstances insulin is vasodilatory-the mechanism involving both the sodium-potassium pump and intracellular calcium transients. Finally, by crossing the blood-brain barrier insulin exerts a host a central effects (sympatho-excitation, vagal withdrawal, stimulation of corticotropin releasing factor), collectively resembling a stress reaction. Description and understanding of these new roles, their interactions, the interplay between insulin resistance and hyperinsulinaemia, and their implications for cardiovascular disease have only begun.

Animals↗
PubMed1999

Studies on the mechanisms involved in the ATP-induced relaxation in human and rabbit corpus cavernosum.

The effect of ATP in human and rabbit corpus cavernosum (CC) smooth muscle was investigated. Strips of human CC were vertically mounted in an organ bath and the tonic tension was recorded. ATP (0.1-3 mM) induced a concentration-dependent relaxant effect, with a pD2 value of 3.01+/-0.3. The purine-induced relaxation was not affected by L-NAME (100 microM). In rabbit CC, ATP also induced a concentration-dependent relaxation, which was not influenced by L-NAME or by indomethacin (3 microM), with a pD2 value of 3.1 +/-0.4. The ATP-induced relaxant effect in rabbit CC was increased by both the inhibitor of adenosine reuptake, dipyridamole (3 microM) and by the inhibitor of adenosine deaminase, EHNA (0.3 microM). Moreover CGS 15943 (3 microM), an A2a adenosine antagonist, reduced the ATP-induced relaxation. UTP was not able to produce relaxation. The two ATP analogues 2-methylthioATP and alpha,beta-methylene ATP were able to induce relaxation in rabbit CC, with the following order of potency: 2-methylthioATP > ATP > alpha,beta-methylene ATP thus suggesting a role for P2y receptors. However, reactive blue (500 microM), an unspecific P2y antagonist, did not modify the ATP relaxant response. The inhibition of phospholipase C by U73122 (3 microM) and of the endoplasmic reticulum Ca2+ATPase by thapsigargin (1 microM) did not modify the ATP-induced relaxation. The P2x specific antagonist PPADS (30 microM) and suramine (500 microM) were not able to modify the ATP relaxation either in the absence or presence of CGS 15943 (3 microM). These results confirm that ATP acts as a potent and NO-independent relaxant agent of human and rabbit CC. Our findings also show that the ATP effect is partially attributable to the metabolic breakdown of ATP to adenosine, which acts through A2a receptor stimulation, but is also due to a direct stimulation of P2 receptors that are different from the classical P2y and P2X receptor subtypes for ATP.

Adenine↗
PubMed1998

Natural and 'in vitro' selected antigenic variants of influenza A virus (H2N2).

We provide data on the prevalence of SRH antibody to influenza A/Singapore/1/57 (H2N2). Approximately 10.3% of sera had antibody to the influenza A (H2N2) subtype virus in comparison to the 36.9% of positive sera to a representative influenza A (H3N2) and 31.5% to influenza A (H1N1) viruses. The percentage of subjects with antibody constantly decreased from the older to the younger age groups. Persons born after 1968 were essentially seronegative, whereas subjects born before 1900, and in the decade 1950-1959, showed the highest antibody levels to influenza A (H2N2) viruses. These age groups also appeared to have 'protective' levels of anti-HA antibody to influenza A (H2N2) virus. An antigenic variant of A/Singapore/1/57 virus was selected in the laboratory using a monoclonal antibody to HA. Serological comparison of the new in vitro variant with the parental virus and two naturally occurring viruses, namely A/England/12/64 and Tokyo/3/67, showed that certain human sera were able to distinguish the variant, indicating a restricted antibody repertoire in these adult and children's sera, providing an explanation of how such variants could actually arise in nature.

Adult↗
PubMed1998

Influence of duration of obesity on the insulin resistance of obese non-diabetic patients.

OBJECTIVE: To investigate whether duration of obesity has an independent impact on insulin resistance. DESIGN: Case-control study. SUBJECTS: 30 non-diabetic obese subjects (age, 34+/-12 y, body mass index (BMI), 33.5+/-0.8 kg x m[-2]) with a range (1-35 y) of self-reported duration of obesity, and 12 age- and gender-matched non-obese controls (BMI, 22.1+/-0.6 kg x m[-2]). MEASUREMENTS: Oral glucose tolerance (40 g x m[-2]), insulin sensitivity (by the euglycaemic insulin clamp technique), and insulin secretion (as the product of post-hepatic insulin clearance and plasma insulin concentration). RESULTS: The obese group presented hyperinsulinaemia in the basal state and after glucose loading (insulin area = 58+/-5 vs 33+/-3 nmol x I[-1] x 2 h, P = 0.005), insulin resistance (M value = 37.4+/-4.8 vs 50.6+/-2.6 micromol x min[-1] x kg FFM[-1], P = 0.002), and insulin hypersecretion (61.9+/-6.0 vs 33.9 +/- 4.0 nmol x 2 h, P = 0.007); endogenous glucose production was similar in the two groups. In the whole dataset, insulin resistance was directly related to BMI, the waist-to-hip ratio (WHR), endogenous glucose production, insulin secretion, and fasting serum triglycerides and uric acid concentrations. When the obese subjects were stratified by duration of obesity, insulin resistance was progressively lower with longer obesity duration (P = 0.04). When simultaneously adjusting by age, gender and BMI, obesity duration was independently associated with greater insulin sensitivity (P = 0.003), lower plasma insulin response to oral glucose (P = 0.001), and lower fasting and glucose-stimulated insulin release (P = 0.01 for both). CONCLUSIONS: In obese subjects with preserved glucose tolerance, duration of obesity is associated with better insulin sensitivity irrespective of the degree of overweight.

Adult↗
PubMed1998

Effects of acute alpha 2-blockade on insulin action and secretion in humans.

We tested whether acute alpha 2-blockade affects insulin secretion, glucose and fat metabolism, thermogenesis, and hemodynamics in humans. During a 5-h epinephrine infusion (50 ng.min-1.kg-1) in five volunteers, deriglidole, a selective alpha 2-receptor inhibitor, led to a more sustained rise in plasma insulin and C-peptide levels (+59 +/- 14 vs. +28 +/- 6, and +273 +/- 18 vs. +53 +/- 14 pM, P < 0.01 vs. placebo) despite a smaller rise in plasma glucose (+0.90 +/- 0.4 vs. +1.5 +/- 0.3 mM, P < 0.01). Another 10 subjects were studied in the postabsorptive state and during a 4-h hyperglycemic (+4 mM) clamp, coupled with the ingestion of 75 g of glucose at 2 h. In the postabsorptive state, hepatic glucose production, resting energy expenditure, and plasma insulin, free fatty acid (FFA), and potassium concentrations were not affected by acute alpha 2-blockade. Hyperglycemia elicited a biphasic rise in plasma insulin (to a peak of 140 +/- 24 pM), C-peptide levels (1,520 +/- 344 pM), and insulin secretion (to 410 +/- 22 pmol/min); superimposed glucose ingestion elicited a further twofold rise in insulin and C-peptide levels, and insulin secretion. However, alpha 2-blockade failed to change these secretory responses. Fasting blood beta-hydroxybutyrate and glycerol and plasma FFA and potassium concentrations all declined with hyperglycemia; time course and extent of these changes were not affected by alpha 2-blockade. Resting energy expenditure (+25 vs. +16%, P < 0.01) and external cardiac work (+28% vs. +19%, P < 0.01) showed larger increments after alpha 2-blockade. We conclude that acute alpha 2-blockade in humans 1) prevents epinephrine-induced inhibition of insulin secretion, 2) does not potentiate basal or intravenous- or oral glucose-induced insulin release, 3) enhances thermogenesis, and 4) increases cardiac work.

Adrenergic alpha-2 Receptor Antagonists↗
PubMed1998

Vasodilation with sodium nitroprusside does not improve insulin action in essential hypertension.

The vasodilation induced by systemic insulin infusion is mediated by nitric oxide and is impaired both in obese subjects and patients with essential hypertension. Whether this vascular defect explains the metabolic resistance to insulin action is uncertain. In 8 overweight male patients with essential hypertension, we used the double forearm (ie, infused versus control) technique, combined with the euglycemic hyperinsulinemic clamp, to test whether sustained vasodilation (induced by intra-arterial sodium nitroprusside infusion) improves insulin-mediated glucose uptake. During the clamp, whole-body glucose disposal rose to 24.4+/-2.9 micromol x min(-1) x kg(-1). Forearm blood flow in the control forearm was stable (3.1+/-0.4 versus 2.9+/-0.3 mL x min[-1] x dL[-1]), while in the infused forearm it increased from 3.4+/-0.5 to 10.6+/-1.3 mL x min(-1) x dL(-1) in response to sodium nitroprusside. During insulin administration, tissue glucose extraction rose from 2+/-1% to 21+/-4% (P<.001) in the control forearm and from 2+/-1% to 8+/-3% in the infused forearm (P<.02 versus baseline for both); the calculated net glucose uptake reached similar plateaus in the two forearms (3.5+/-0.7 versus 3.7+/-0.6 micromol x min(-1) x kg(-1), control versus infused, P=.6). We conclude that in overweight male patients with essential hypertension, increasing forearm perfusion with sodium nitroprusside does not attenuate the insulin resistance of forearm tissues.

Adult↗
PubMed1998

Autonomic and hemodynamic responses to insulin in lean and obese humans.

To study the acute effects of insulin on autonomic control of cardiac function, we performed spectral analysis of heart rate variability and measured cardiac dynamics (by two-dimensional echocardiography) in 18 obese (BMI = 35 +/- 1 kg.m-2) and 14 lean (BMI = 24 +/- 1 kg.m-2) subjects in the basal state and in response to physiological hyperinsulinemia (1 mU.min-1.kg-1 insulin clamp). In the lean group, insulin promptly (within 20 min) and consistently depressed spectral powers, both in the low-frequency and high-frequency range. These changes were twice as large as accounted for by the concomitant changes in heart rate (68 +/- 2 to 70 +/- 2 beats/min). At the end of the 2-h clamp, stroke volume (67 +/- 4 to 76 +/- 9 ml.min-1) and cardiac output (4.45 +/- 0.21 to 5.06 +/- 0.55 l.min-1) rose, whereas peripheral vascular resistance fell. The low-to-high frequency ratio increased from 1.7 +/- 0.2 to 2.3 +/- 0.3 (P < 0.01), indicating sympathetic shift of autonomic balance. In the obese group, all basal spectral powers were significantly lower (by 40% on average) than in the lean group, and were further reduced by insulin administration. The low-to-high frequency ratio was higher than in controls at baseline (2.4 +/- 0.4, P < 0.03), and failed to increase after insulin (2.2 +/- 0.3, P = ns). Furthermore, obesity was associated with higher resting stroke volume (89 +/- 5 vs. 67 +/- 4 ml.min-1, P < 0.01) and cardiac output (6.01 +/- 0.31 vs. 4.45 +/- 0.21 l.min-1, P = 0.001) but lower peripheral vascular resistance (15.1 +/- 0.8 vs. 19.2 +/- 1.1 mmHg.min.L-1, P = 0.002), whereas mean arterial blood pressure was similar to control (90 +/- 2 vs. 86 +/- 2 mmHg, P = not significant). We conclude that physiological hyperinsulinemia causes acute desensitization of sinus node activity to both sympathetic and para-sympathetic stimuli, sympathetic shift of autonomic balance, and a high-output, low-resistance hemodynamic state. In the obese, these changes are already present in the basal state, and may therefore be linked with chronic hyperinsulinemia.

Adult↗
PubMed1997

Insulin resistance and hypersecretion in obesity. European Group for the Study of Insulin Resistance (EGIR).

Insulin resistance and insulin hypersecretion are established features of obesity. Their prevalence, however, has only been inferred from plasma insulin concentrations. We measured insulin sensitivity (as the whole-body insulin-mediated glucose uptake) and fasting posthepatic insulin delivery rate (IDR) with the use of the euglycemic insulin clamp technique in a large group of obese subjects in the database of the European Group for the Study of Insulin Resistance (1,146 nondiabetic, normotensive Caucasian men and women aged 18-85 yr, with a body mass index (BMI) ranging from 15 to 55 kg.m-2). Insulin resistance, defined as the lowest decile of insulin sensitivity in the lean subgroup (608 subjects with a mean BMI of 29 kg.m-2). Insulin sensitivity declined linearly with BMI at an age- and sex-adjusted rate of 1.2 micromol.min-1.kg FFM-1 per BMI unit (95% confidence intervals = 1.0-1.4). Insulin hypersecretion, defined as the upper decile of IDR, was significantly (P<0.0001) more prevalent (38%) than insulin resistance in the obese group. In the whole dataset, IDR rose as a function of both BMI and insulin resistance in a nonlinear fashion. Neither the waist circumference nor the waist-to-hip ratio, indices of body fat distribution, was related to insulin sensitivity after adjustment for age, gender, and BMI; both, however, were positively associated (P<0.001) with insulin hypersecretion, particularly in women. In nondiabetic, normotensive obese subjects, the prevalence of insulin resistance is relatively low, and is exceeded by the prevalence of insulin hypersecretion, particularly in women with central obesity. In the obese with preserved insulin sensitivity, risk for diabetes, cardiovascular risk, and response to treatment may be different than in insulin resistant obesity.

Adolescent↗
PubMed1997

Insulin sensitivity, vascular reactivity, and clamp-induced vasodilatation in essential hypertension.

BACKGROUND: Insulin resistance and vascular abnormalities have both been described in patients with essential hypertension. Whether these defects are associated with one another in the same individual has not been established. METHODS AND RESULTS: Whole-body insulin sensitivity (by the insulin clamp technique), forearm minimal vascular resistances, and the dose-response curve to acetylcholine, sodium-nitroprusside, and norepinephrine were measured in a group of 29 male patients with untreated essential hypertension. When the patients were divided into tertiles according to their level of insulin sensitivity, resistant and sensitive hypertensives were matched on several potential confounders of insulin action and vascular function. These subgroups showed similar minimal vascular resistances (2.5+/-0.2 versus 3.2+/-0.6 mm Hg per mL x min(-1) x dL(-1)) and superimposable responses to graded intraarterial infusions of acetylcholine, sodium-nitroprusside, and norepinephrine. No correlation was found between the vascular parameters (slope of the curve or maximal response) and insulin-mediated glucose uptake in the whole group. During the clamp, insulin sensitive patients tended to have greater increments in forearm blood flow when compared to their insulin resistant counterparts (+53+/-21 versus +9+/-7%, P=.06); in the whole group, clamp-induced vasodilatation was weakly related to insulin-mediated glucose uptake (r=.44, P<.02) as well as to the slope of the acetylcholine dose-response curve (r=.40, P<.04). Together, these two responses explained 30% (multiple r=.55, P<.01) of the variability in insulin-induced vasodilatation. CONCLUSIONS: Metabolic insulin resistance in essential hypertension is not associated with abnormalities in vascular structure, acetylcholine or nitroprusside-induced vasodilatation, or vascular adrenergic reactivity. Degree of insulin sensitivity and acetylcholine sensitivity explain a small portion of the variability of the clamp-induced vasodilatation in hypertensive patients.

Acetylcholine↗
PubMed1997

Reciprocal association between insulin sensitivity and the haematocrit in man.

In epidemiological studies, a high haematocrit has been associated both with increased cardiovascular risk and with hyperinsulinaemia, a surrogate of insulin resistance. To examine directly the relationship between the haematocrit and insulin sensitivity, we studied 12 healthy volunteers and 12 patients with non-insulin-dependent diabetes mellitus (NIDDM) with the use of a 4-hour hyperinsulinaemic [1 mU min-1 kg-1] isoglycaemic clamp. In the whole group, insulin sensitivity (as the ratio of insulin-mediated glucose clearance to steady-state plasma insulin concentrations) was inversely related to the haematocrit (r = 0.50, P < 0.01). To test whether acute changes in the haematocrit affect insulin sensitivity, in two NIDDM patients and three healthy subjects the clamp study was repeated after lowering (-18%) the haematocrit by erythro-apheresis. In all five subjects, the lower haematocrit was associated with slightly reduced (-7% on average, P = NS) rather than increased insulin sensitivity. We conclude that insulin sensitivity is inversely related to the haematocrit independently of the glucose tolerance status. The association does not result from acute haemodynamic effects on insulin sensitivity, and may therefore reflect an action of insulin resistance/ hyperinsulinaemia on blood viscosity, or the presence of a common determinant.

Adult↗