Characterization of cellular defects of insulin action in type 2 (non-insulin-dependent) diabetes mellitus.

Seven non-insulin-dependent diabetes mellitus (NIDDM) patients participated in three clamp studies performed with [3-3H]- and [U-14C]glucose and indirect calorimetry: study I, euglycemic (5.2 +/- 0.1 mM) insulin (269 +/- 39 pM) clamp; study II, hyperglycemic (14.9 +/- 1.2 mM) insulin (259 +/- 19 pM) clamp; study III, euglycemic (5.5 +/- 0.3 mM) hyperinsulinemic (1650 +/- 529 pM) clamp. Seven control subjects received a euglycemic (5.1 +/- 0.2 mM) insulin (258 +/- 24 pM) clamp. Glycolysis and glucose oxidation were quantitated from the rate of appearance of 3H2O and 14CO2; glycogen synthesis was calculated as the difference between body glucose disposal and glycolysis. In study I, glucose uptake was decreased by 54% in NIDDM vs. controls. Glycolysis, glycogen synthesis, and glucose oxidation were reduced in NIDDM patients (P < 0.05-0.001). Nonoxidative glycolysis and lipid oxidation were higher. In studies II and III, glucose uptake in NIDDM was equal to controls (40.7 +/- 2.1 and 40.7 +/- 1.7 mumol/min.kg fat-free mass, respectively). In study II, glycolysis, but not glucose oxidation, was normal (P < 0.01 vs. controls). Nonoxidative glycolysis remained higher (P < 0.05). Glycogen deposition increased (P < 0.05 vs. study I), and lipid oxidation remained higher (P < 0.01). In study III, hyperinsulinemia normalized glycogen formation, glycolysis, and lipid oxidation but did not normalize the elevated nonoxidative glycolysis or the decreased glucose oxidation. Lipid oxidation and glycolysis (r = -0.65; P < 0.01), and glucose oxidation (r = -0.75; P < 0.01) were inversely correlated. In conclusion, in NIDDM: (a) insulin resistance involves glycolysis, glycogen synthesis, and glucose oxidation; (b) hyperglycemia and hyperinsulinemia can normalize total body glucose uptake; (c) marked hyperinsulinemia normalizes glycogen synthesis and total flux through glycolysis, but does not restore a normal distribution between oxidation and nonoxidative glycolysis; (d) hyperglycemia cannot overcome the defects in glucose oxidation and nonoxidative glycolysis; (e) lipid oxidation is elevated and is suppressed only with hyperinsulinemia.

Transmembrane glucose transport in skeletal muscle of patients with non-insulin-dependent diabetes.

Insulin resistance for glucose metabolism in skeletal muscle is a key feature in non-insulin-dependent diabetes mellitus (NIDDM). Which cellular effectors of glucose metabolism are involved is still unknown. We investigated whether transmembrane glucose transport in vivo is impaired in skeletal muscle in nonobese NIDDM patients. We performed euglycemic insulin clamp studies in combination with the forearm balance technique (brachial artery and deep forearm vein catheterization) in six nonobese NIDDM patients and five age- and weight-matched controls. Unlabeled D-mannitol (a nontransportable molecule) and radioactive 3-O-methyl-D-glucose (the reference molecular probe to assess glucose transport activity) were simultaneously injected into the brachial artery, and the washout curves were measured in the deep venous effluent blood. In vivo transmembrane transport of 3-O-methyl-D-glucose in forearm muscle was determined by computerized analysis of the washout curves. At similar steady-state plasma concentrations of insulin (approximately 500 pmol/liter) and glucose (approximately 5.15 mmol/liter), transmembrane inward transport of 3-O-methyl-D-glucose in skeletal muscle was markedly reduced in the NIDDM patients (6.5 x 10(-2) +/- 0.56 x 10(-2).min-1) compared with controls (12.5 x 10(-2) +/- 1.5 x 10(-2).min-1, P < 0.005). Mean glucose uptake was also reduced in the diabetics both at the whole body level (9.25 +/- 1.84 vs. 28.3 +/- 2.44 mumol/min per kg, P < 0.02) and in the forearm tissues (5.84 +/- 1.51 vs. 37.5 +/- 7.95 mumol/min per kg, P < 0.02). When the latter rates were extrapolated to the whole body level, skeletal muscle accounted for approximately 80% of the defect in insulin action seen in NIDDM patients. We conclude that transmembrane glucose transport, when assessed in vivo in skeletal muscle, is insensitive to insulin in nonobese NIDDM patients, and plays a major role in determining whole body insulin resistance.

[Laparoscopic lymphadenectomy as treatment of endometrial cancer]. / Linfoadenectomia laparoscopica nel trattamento del carcinoma endometriale.

AIM: This study compares the effects of laparoscopic lymphadenectomy versus those of abdominal lymphadenectomy in patients with endometrial cancer. METHODS: A prospective randomized study was performed among 80 patients randomly assigned to laparoscopic lymphadenectomy and to abdominal lymphadenectomy in the treatment of endometrial cancer. Clinical outcomes and complications were compared for 1 year of follow-up. RESULTS: Forty patients were assigned to laparoscopic lymphadenectomy and 40 patients to abdominal lymphadenectomy. The laparoscopic approach was associated with a longer operative time (234.1 min vs 137.3 min) but was less painful (VAS 5.3 vs 7.9; P<0.000) and resulted in a shorter hospital stay (4.4+/-1 vs 7.9+/-1.2 days; P<0.000). At 6 weeks the quality of life was better in patients who had laparoscopic lymphadenectomy (SF-12). CONCLUSION: Laparoscopic lymphadenectomy was associated with a significantly lower rate of major and minor postoperative complications and a better short term quality of life.

[Laparoscopic supracervical hysterectomy versus laparoscopic total hysterectomy: a prospective randomized study]. / Isterectomia sopracervicale laparoscopica versus isterectomia totale laparoscopica: studio prospettico randomizzato.

AIM: The aim of this study was to compare surgical complications and clinical outcomes after supracervical versus total laparoscopic hysterectomy for the control of abnormal uterine bleeding or symptomatic uterine leiomyomata. METHODS: We conducted a prospective randomized trial on 141 patients who had laparoscopic hysterectomy for symptomatic uterine leiomyomata, abnormal bleeding refractory to hormonal treatment, or both. Patients were randomly assigned to receive a supracervical or total laparoscopic hysterectomy. We compared surgical complications and clinical outcomes for 2 years after randomization. RESULTS: Seventy-one participants were assigned to supracervical laparoscopic hysterectomy (SLH) and 70 to total laparoscopic hysterectomy (TLH). Hysterectomy by either techniques led to statistically significant reductions in most symptoms, including pelvic pain or pressure, back pain and urinary incontinence. Patients assigned to SLH tended to have more hospital readmissions than those randomized to TLH. There were no statistically significant differences in the rate of complications, degree of symptoms improvement, or activity limitation. Participants weighing more than 100 kg at study entry were more than twice as likely to be readmitted to the hospital during the 2-year of follow-up (OR 2.48, 95% CI 0.11; 1.91, P=0.04). CONCLUSIONS: We did not observe statistically significant differences between SLH and TLH in surgical complications and clinical outcomes during the 2-years of follow-up.

Risk factors for hypoglycemia in patients with type 2 diabetes, hospitalized in internal medicine wards: Findings from the FADOI-DIAMOND study.

AIMS: Hypoglycemia is a potential risk in the management of patients suffering from type 2 diabetes (T2DM) and hospitalized in internal medicine units (IMUs). The aim of this analysis was to evaluate incidence of hypoglycemia and related risk factors in a group of patients admitted to IMUs. METHODS: We used the FADOI-DIAMOND study carried out in 53 Italian IMUs. The DIAMOND design included two cross-sectional surveys interspersed with an educational program. In both phases each center reviewed the charts of the last 30 hospitalized patients with known T2DM (n=3167), including information about hypoglycemia during hospital stay. The association between occurrence of hypoglycemia and potential predictors was evaluated by means of a multivariable logistic regression analysis. RESULTS: A total of 385 symptomatic hypoglycemic events were observed (rate=12%). Advanced age, cognitive dysfunction, and nephropathy were associated with hypoglycemia. Hypoglycemia occurred in 19.4% of patients treated according to the insulin sliding-scale method versus 11.4% of patients treated with basal bolus (p<0.01). More patients with hypoglycemia received sulfonylureas versus the no-hypoglycemia group (28.3% versus 20.6%, p<0.001). Significantly longer length of hospital stay and increased in-hospital mortality were found in the group with hypoglycemia compared with the no-hypoglycemia group (12.7±10.9 versus 9.6±6.5 days; 8.8% versus 4.8%, p<0.01). CONCLUSIONS: Hypoglycemia in hospitalized patients with diabetes is associated with increased length of hospitalization and in-hospital mortality. Identification of patients at increased risk of hypoglycemia may be important for optimally adapting treatment and patient management.

The metabolic profile of NIDDM is fully established in glucose-tolerant offspring of two Mexican-American NIDDM parents.

NIDDM patients with overt fasting hyperglycemia are characterized by multiple defects involving both insulin secretion and insulin action. At this point of the natural history of NIDDM, however, it is difficult to establish which defects are primary and which are acquired secondary to insulinopenia and chronic hyperglycemia. To address this question, we have studied the glucose-tolerant offspring (probands) of two Mexican-American NIDDM parents. Such individuals are at high risk for developing NIDDM later in life. The probands are characterized by hyperinsulinemia in the fasting state and in response to both oral and intravenous glucose. Insulin-mediated glucose disposal (insulin clamp technique), measured at two physiological levels of hyperinsulinemia (approximately 240 and 450 pM [approximately 40 and 75 microU/ml]), was reduced by 43 and 33%, respectively. During both the low- and high-dose insulin clamp steps, impaired nonoxidative glucose disposal, which primarily represents glycogen synthesis, was the major defect responsible for the insulin resistance. During the lower dose insulin clamp step only, a small decrease in glucose oxidation was observed. No defect in suppression of HGP by insulin was demonstrable. The ability of insulin to inhibit lipid oxidation (measured by indirect calorimetry) and plasma FFA concentration was impaired at both levels of hyperinsulinemia. These results indicate that the glucose-tolerant offspring of two NIDDM parents are characterized by hyperinsulinemia and manifest all of the metabolic abnormalities that characterize the fully established diabetic state, including insulin resistance, a major impairment in nonoxidative glucose disposal, a quantitatively less important defect in glucose oxidation, and a diminished insulin-mediated suppression of lipid oxidation and plasma FFA concentration.

In vivo glucose metabolism in obese and type II diabetic subjects with or without hypertension.

This study examined whether the presence of hypertension, an insulin-resistant condition, exacerbates the defect in insulin action observed in obesity and type II diabetes mellitus. Glucose metabolism in the basal state and in response to insulin was quantitated by using the euglycemic insulin (20 mU.min-1 x m-2) clamp in combination with 3-[3H]glucose infusion and indirect calorimetry in 20 obese nondiabetic subjects (10 hypertensive and 10 normotensive), 26 type II diabetic subjects (13 hypertensive and 13 normotensive), and 11 normal nondiabetic subjects. The two groups of obese subjects and the two groups of diabetic subjects were matched for sex, age, race, body mass index, and fat distribution. Both in the basal state and during insulin infusion, glucose disposal rates (total, oxidative, and nonoxidative) were similar in obese subjects with or without hypertension. Compared with control subjects, both groups of obese subjects were markedly insulin resistant. Similarly, type II diabetic individuals, whether normotensive or hypertensive, were equally insulin resistant. The severity of insulin resistance was nearly identical in obese and diabetic groups. In diabetic subjects, the inhibitory effect of insulin on hepatic glucose output, lipolysis, and lipid oxidation was blunted compared with normal subjects. In obese subjects the ability of insulin to inhibit lipolysis and lipid oxidation was impaired. However, hypertension did not alter the suppressive effects of insulin on hepatic glucose production, plasma free fatty acid levels, or lipid oxidation in either obese or type II diabetic subjects. These results indicate that hypertension does not confer a greater severity of insulin resistance than that already is present in obesity and type II diabetes mellitus.

Total body fat content and fat topography are associated differently with in vivo glucose metabolism in nonobese and obese nondiabetic women.

In this study, total body fat content and fat topography were related to glucose metabolism in the basal and insulin-stimulated states in 18 nonobese and 18 obese premenopausal nondiabetic women. All subjects received a euglycemic insulin (20 mU.min-1.m2) clamp study in combination with [3-3H]-D-glucose infusion and indirect calorimetry to quantitate total body glucose uptake, glucose oxidation, and nonoxidative glucose disposal. Total body fat content was determined with tritiated water, whereas body fat distribution was estimated from the WHR, the STR, and the VSR (measured by magnetic resonance imaging). In the postabsorptive state, total body glucose utilization, glucose oxidation, and nonoxidative glucose disposal rates were similar in nonobese and obese women, whereas during the insulin clamp all three metabolic parameters were reduced significantly in the obese group. In nonobese women, total body fat content was related inversely to both total and nonoxidative glucose disposal during the insulin clamp, whereas no relationship was found between glucose metabolism (total, oxidative, and nonoxidative) and WHR, STR, or VSR. In contrast, in obese women, no relationship was observed between total body fat content and any measure of insulin-mediated glucose metabolism. However, both WHR and VSR were related inversely to total, oxidative, and nonoxidative glucose disposal rates during the insulin clamp. These results suggest that total body fat content and body fat topography are associated differently with insulin-mediated glucose metabolism in nonobese and obese women. In the nonobese women, total body fat mass appears to be a primary determinant of tissue sensitivity to insulin, whereas in obese women, body fat topography exerts a more dominant effect.

Roles of glucose transport and glucose phosphorylation in muscle insulin resistance of NIDDM.

Insulin resistance for glucose metabolism in skeletal muscle is a key feature in NIDDM. The quantitative role of the cellular effectors of glucose metabolism in determining this insulin resistance is still imperfectly known. We assessed transmembrane glucose transport and intracellular glucose phosphorylation in vivo in skeletal muscle in nonobese NIDDM patients. We performed euglycemic insulin clamp studies in combination with the forearm balance technique (brachial artery and deep forearm vein catheterization) in five nonobese NIDDM patients and seven age- and weight-matched control subjects (study 1). D-Mannitol (a nontransportable molecule), 3-O-[14C]methyl-D-glucose (transportable, but not metabolizable) and D[3-3H]glucose (transportable and metabolizable) were simultaneously injected into the brachial artery, and the washout curves were measured in the deep venous effluent blood. In vivo rates of transmembrane transport and intracellular phosphorylation of D-glucose in forearm muscle were determined by analyzing the washout curves with the aid of a multicompartmental model of glucose kinetics in forearm tissues. At similar steady-state concentrations of plasma insulin (approximately 500 pmol/l) and glucose (approximately 5.0 mmol/l), the rates of transmembrane influx (34.3 +/- 9.1 vs. 58.5 +/- 6.5 micromol x min(-1) x kg(-1), P < 0.05) and intracellular phosphorylation (5.4 +/- 1.6 vs. 38.8 +/- 5.1 micromol x min(-1) x kg(-1), P < 0.01) in skeletal muscle were markedly lower in the NIDDM patients than in the control subjects. In the NIDDM patients (study 2), the insulin clamp was repeated at hyperglycemia, (approximately 13 mmol/l) trying to match the rates of transmembrane glucose influx measured during the clamp in the controls. The rate of transmembrane glucose influx (62 +/- 15 micromol x min(-1) x kg(-1)) in the NIDDM patients was similar to the control subjects, but the rate of intracellular glucose phosphorylation (16.6 +/- 7.5 micromol x min(-1) x kg(-1)), although threefold higher than in the patients during study 1 (P < 0.05), was still approximately 60% lower than in the control subjects (P < 0.05). These data suggest that when assessed in vivo, both transmembrane transport and intracellular phosphorylation of glucose are refractory to insulin action and add to each other in determining insulin resistance in skeletal muscle of NIDDM patients. It will be of interest to compare the present results with the in vivo quantitation of the initial rate of muscle glucose transport when methodology to perform this measurement becomes available.

Insulin sensitivity is not impaired in Mexican-American women without a family history of diabetes.

OBJECTIVE: The purpose of this research was to compare insulin sensitivity in Mexican-Americans and non-Hispanic whites without a family history of diabetes to establish whether insulin resistance is a defect intrinsically related to subjects of Mexican origin. RESEARCH DESIGN AND METHODS: In study A, we compared insulin sensitivity in 12 Mexican-American and 12 non-Hispanic white women with normal glucose tolerance and no family history of diabetes. In study B, we compared insulin sensitivity in two groups of normal glucose-tolerant Mexican-Americans, nine with a positive (FHD+) and nine with a negative (FHD-) family history of diabetes. In both studies, the groups were closely matched for age, total body fat content, and fat topography. Insulin sensitivity was assessed with the euglycemic insulin clamp (20 microU.min-1.m2 surface area) which was performed in combination with tritiated glucose infusion and indirect calorimetry. Total fat mass and fat-free mass (FFM) were assessed by a tritiated water dilution technique, and regional fat distribution was evaluated by anthropometry and magnetic resonance imaging. RESULTS: During a 4-h euglycemic insulin clamp (study A), rates (mg.min-1.kg FFM-1) of total (6.32 +/- 0.64 vs. 6.62 +/- 0.81), oxidative (3.54 +/- 0.24 vs. 3.51 +/- 0.19), and nonoxidative (2.78 +/- 0.48 vs. 3.11 +/- 0.75) glucose utilization were similar in Mexican-Americans and non-Hispanic whites; hepatic glucose production (0.33 +/- 0.13 vs. 0.35 +/- 0.13) was suppressed similarly in both groups. During a 2-h euglycemic insulin clamp (study B), Mexican-Americans with FHD+ had lower rates of insulin-mediated total (3.55 +/- 0.39 vs. 5.93 +/- 0.59, P < 0.001), oxidative (3.31 +/- 0.25 vs. 4.32 +/- 0.17, P < 0.01), and nonoxidative (0.24 +/- 0.28 vs. 1.61 +/- 0.49, P < 0.01) glucose disposal than subjects with FHD-; suppression of hepatic glucose production (0.24 +/- 0.14 vs. 0.18 +/- 0.12) was similar in both groups. CONCLUSIONS: These results indicate that in the absence of a family history of non-insulin-dependent diabetes mellitus, Mexican-American women are not less sensitive to insulin than non-Hispanic white women.

Regional cerebral blood flow and cerebrovascular reactivity in IDDM.

OBJECTIVE: To investigate both rCBF and cerebrovascular reactivity, evaluated as pre- and post-ACZ rCBF differences in a group of IDDM patients with differences in duration of disease and severity of complications. RESEARCH DESIGN AND METHODS: rCBF was measured by the 133Xenon inhalation method in 20 IDDM patients and in 15 healthy control subjects before and after an intravenous injection of ACZ, a carbonic anhydrase inhibitor commonly used to assess cerebrovascular reactivity. RESULTS: Basal global CBF (the mean of 32 regional values) was within the normal range in all patients but 1, who showed slight hyperperfusion; moreover, in 3 patients with long-lasting disease, some hypoperfused regions were found. ANOVA showed an inverse correlation between basal global CBF (P < 0.01) and duration of diabetes, but no correlation with Hb, MABP, serum glucose concentration, or GHb. Compared with control subjects, the percentage of global CBF increment after ACZ administration was significantly impaired in 4 patients and gave a borderline response in 2 patients; 4 of these poor ACZ responders had retinopathy, and 1 had suffered from a TIA. Duration of diabetes, Hb, MABP, serum glucose concentration, and GHb did not correlate with the percentage of post-ACZ global CBF changes, and did not differ among the 6 poor ACZ responders and the other diabetic patients or control subjects. CONCLUSIONS: These results confirm that global CBF is within the normal range in most IDDM patients, although it is significantly influenced by the duration of diabetes; pathophysiological correlates of the altered cerebrovascular reactivity need to be further investigated. rCBF measurements, before and after ACZ administration, seem to represent a safe and reliable tool for assessing cerebrovascular function in IDDM.

Evidence of parasympathetic impairment in some patients with cardiac syndrome X.

OBJECTIVES: Cardiac syndrome X (SX) is a clinical condition characterised by angina, positive exercise stress test and negative coronary angiography; it has often been attributed to sympathetic hyperactivity. Here we tested the hypothesis that a parasympathetic, rather than a sympathetic, dysfunction could be the cause of the autonomic imbalance observed in SX. METHODS: In 20 subjects with diagnosed SX and in 12 age-matched controls, we studied autonomic function by performing spectral analysis of RR interval and finger arterial pressure (SAP), in supine position and during head-up tilting. We also carried out a set of tests of parasympathetic function. RESULTS: The group of SX patients did not differ significantly from control subjects in any of the variables tested. In a subgroup of 13 SX, however, tilting increased the low-frequency power of SAP, but did not induce the expected increase in low-frequency and decrease in high-frequency power of RR. These patients, in supine position, had significantly lower sinus arrhythmia and a higher ratio of low to high frequency of RR, in comparison with control subjects. We interpreted these differences as signs of reduced parasympathetic, but essentially normal sympathetic, activity. The parasympathetic tests confirmed vagal impairment in the same SX subjects. On the other hand, all the tests indicated normal parasympathetic functions in the control subjects and in those SX patients who displayed the expected spectral changes in tilting. CONCLUSIONS: In about two thirds of the patients with SX, the pathophysiological mechanism causing the symptoms could be related to the reduced parasympathetic tone, rather than to an augmented sympathetic activity.

Hyperamylinemia is associated with hyperinsulinemia in the glucose-tolerant, insulin-resistant offspring of two Mexican-American non-insulin-dependent diabetic parents.

Several investigations have presented evidence that amylin inhibits insulin secretion and induces insulin resistance both in vitro and in vivo. However, basal and postmeal amylin concentrations proved similar in non-insulin-dependent diabetes mellitus (NIDDM) patients and controls. Since hyperglycemia may alter both amylin and insulin secretion, we examined basal and glucose-stimulated amylin secretion in eight glucose-tolerant, insulin-resistant Mexican-American subjects with both parents affected with NIDDM (offspring) and correlated the findings with the insulin sensitivity data acquired by an insulin clamp. Eight offspring and eight Mexican-Americans without any family history of diabetes (controls) underwent measurement of fat free mass (3H2O dilution method), 180-minutes, 75-g oral glucose tolerance test (OGTT), and 40-mU/m2, 180-minute euglycemic insulin clamp associated with 3H-glucose infusion and indirect calorimetry. Fasting amylin was significantly increased in offspring versus controls (11.5 +/- 1.4 v 7.0 +/- 0.8 pmol/L, P < .05). After glucose ingestion, both total (3,073 +/- 257 v 1,870 +/- 202 pmol.L-1.min-1, P < .01) and incremental (1,075 +/- 170 v 518 +/- 124 pmol.L-1.min-1, P < .05) areas under the curve (AUCs) of amylin concentration were significantly greater in offspring. The amylin to insulin molar ratio was similar in offspring and controls at all time points. Basal and postglucose insulin and C-peptide concentrations were significantly increased in the offspring. No correlation was found between fasting amylin, postglucose amylin AUC or IAUC, and any measured parameter of glucose metabolism during a euglycemic-hyperinsulinemic clamp (total glucose disposal, 7.21 +/- 0.73 v 11.03 +/- 0.54, P < .001; nonoxidative glucose disposal, 3.17 +/- 0.59 v 6.33 +/- 0.56, P < .002; glucose oxidation, 4.05 +/- 0.46 v 4.71 +/- 0.21, P = NS; hepatic glucose production, 0.29 +/- 0.16 v 0.01 +/- 0.11, P = NS; all mg.min-1.kg-1 fat-free mass, offspring v controls). In conclusion, these data do not support a causal role for amylin in the genesis of insulin resistance in NIDDM.

Cross-spectral analysis of cardiovascular variables in supine diabetic patients.

Cardiovascular autonomic neuropathy in diabetes is associated with a high risk of mortality, which makes its early identification clinically important. An easy method for identification of subjects with autonomic dysfunction would be of clinical benefit. We evaluated the autonomic function in 28 diabetic patients and 21 control subjects recording 12 min time series of heart period (RR) and systolic arterial pressure (SAP, Finapres) during supine rest and 60 degrees head-up tilt. The power of the high (respiratory) and low (LF approximately 0.1 Hz) frequency oscillations was quantified by spectral analysis. The central frequency of the LF oscillations (LF_freq), phase shift, and the transfer function gain between RR interval and SAP fluctuations were provided by cross-spectral analysis, and measured at the point of maximal coherence. In the supine position 15 patients (LF-) displayed atypical LF variability with the LF_freq being shifted towards lower frequencies (about 0.06 Hz). They also showed larger phase angle, lower values or even absence of coherence and smaller transfer function gain between RR and SAP fluctuations. 13 patients (LF+) and the controls showed the LF_freq around 0.1 Hz, higher coherence and transfer function gain values. The orthostatic maneuver induced the expected changes in the spectral parameters (increase in the LF components of both RR and SAP and decrease in the HF variability of RR) into the LF+ patients and all the control subjects and abnormal response in the other 15 LF-patients. These findings indicate that diabetic subjects with uncharacteristic response to the orthostatic test present abnormal LF variability already in the supine position. Crossspectral parameters while supine may be used for the identification of these subjects.

Spectral and cross-spectral autoregressive analysis of cardiovascular variables in subjects with different degrees of orthostatic tolerance.

The mechanisms leading to vasovagal syncope are still unclear. A simple discriminating test for the identification of syncope-prone subjects is not presently available. Fifty-two subjects had a stepwise orthostatic test with 60 degrees tilt and -20 and -40 mm Hg lower-body negative pressure before the appearance of impending syncope symptoms. Spectral and cross-spectral analyses of heart period and systolic pressure time series were performed to estimate the power of the high-frequency (approximately equals 0.25 Hz) and low-frequency (approximately equals 0.1 Hz) oscillations, the coherence between heart period and systolic pressure, and the mean low-frequency and high-frequency central frequency, phase shift, and transfer function at maximal coherence. According to time to presyncope, the 52 subjects were divided into two groups: 25 with normal orthostatic tolerance, and 27 with poor orthostatic tolerance. In the supine positions, the mean central low-frequency was significantly lower in poor-tolerance group than in normal-tolerance group, discriminating poor from normal orthostatic tolerance with 80% specificity and 83% sensitivity, and was significantly correlated to time to presyncope. In the 2 to 3 minutes preceding syncope, subjects with poor orthostatic tolerance had less tachycardia, lower low-frequency power of systolic pressure, higher respiratory frequency, and a less negative phase shift in high-frequency range. In presyncope, sympathetic activation is reduced in subjects with poor orthostatic tolerance. In addition, the higher breathing frequency and the smaller negativity of phase shift in high-frequency range, which may indicate an inadequate engagement of the baroreflex, suggest a causal role of respiration in the development of syncope. Supine central values of low frequency may be proposed as a valuable clinical index of orthostatic intolerance.

Does low-frequency variability of heart period reflect a specific parasympathetic mechanism?

Low frequency (LF, approximately 0.1 Hz) spontaneous oscillations of heart period in humans have been attributed to and correlated with the sympathetic efferent control of the heart. However, this interpretation is controversial, because sympathetic blockade does not suppress these oscillations, while parasympathetic blockade strongly affects them. The sympathetic origin of LF of arterial pressure, on the contrary, has been convincingly demonstrated. Four 10 min cycle-by-cycle time series of R-R interval (RR), and systolic (SAP) and diastolic (DAP) arterial pressure were produced by automatic analysis of data obtained with non-invasive methods in 10 healthy humans during supine rest and while standing, both before and after beta 1-selective blockade (atenolol). Time series were analysed by autoregressive transfer function analysis. beta-blockade failed to induce systematic changes on the power of the LF peak of RR, in any condition. The coherence between RR and SAP in the same region remained high (0.77 +/- 0.03) and a constantly negative phase (approximately 50-60 degrees, corresponding to a delay of 1-2 heart beats of RR on SAP) was always seen. beta-blockade decreased the power of the LF peak of SAP, increased the transfer function gain between SAP and RR at LF, and the HF power of RR. We conclude that LF oscillations of RR are not directly generated by the sympathetic drive to the heart but reflect mainly the parasympathetic activity. The results suggest that the LF oscillations of the vagal outflow, and of RR, are generated by the baroreceptor reflex, driven by sympathetically-induced blood pressure LF waves.

Post-exercise recovery of autonomic cardiovascular control: a study by spectrum and cross-spectrum analysis in humans.

The recovery of the baseline autonomic control of cardiovascular activity after exercise has not been extensively studied. In 12 healthy subjects, we assessed the time-course of recovery by autoregressive spectrum and cross-spectrum analysis of heart period and systolic blood pressure during the 3 h after the end of 20 min of steady-state exercise at 50% (light workload, LW) and 80% (moderate workload, MW) of the individual's anaerobic threshold. The electrocardiogram and non-invasive blood pressure were simultaneously recorded during 10 min periods in the sitting position, at rest before exercise, and at 15, 60 and 180 min of recovery after exercise. At 15 min we observed a persistent tachycardia and relative hypotension; after MW, at 60 min heart rate was still slightly higher. Spectrum and cross-spectrum analysis showed, at 15 min, an increase in the low frequency component of systolic blood pressure, a reduction in the high frequency component of heart rate (larger in MW), and a decrease in baroreceptor sensitivity. After 60 and 180 min none of these parameters was significantly different from those at rest, although, in MW, some subjects still displayed signs of sympathetic activation after 1 h. We concluded that, after 15 min of recovery, the cardiovascular reflexes were blunted, that sympathetic nerve activity was still enhanced, and that the tone in the vagus had not fully recovered. Only the persistent vagal restraint seemed to be exercise intensity-dependent. For complete restoration of autonomic control after LW 1 h of rest was sufficient, and just enough after MW.

Baroreflex and oscillation of heart period at 0.1 Hz studied by alpha-blockade and cross-spectral analysis in healthy humans.

1. Parameters derived from frequency-domain analysis of heart period and blood pressure variability are gaining increasing importance in clinical practice. However, the underlying physiological mechanisms in human subjects are not fully understood. Here we address the question as to whether the low frequency variability (approximately 0.1 Hz) of the heart period may depend on a baroreflex-mediated response to blood pressure oscillations, induced by the alpha-sympathetic drive on the peripheral resistance. 2. Heart period (ECG), finger arterial pressure (Finapres) and respiratory airflow were recorded in eight healthy volunteers in the supine position with metronome respiration at 0.25 Hz. We inhibited the vascular response to the sympathetic vasomotor activity with a peripheral alpha-blocker (urapidil) and maintained mean blood pressure at control levels with angiotensin II. 3. We performed spectral and cross-spectral analysis of heart period (RR) and systolic pressure to quantify the power of low- and high-frequency oscillations, phase shift, coherence and transfer function gain. 4. In control conditions, spectral analysis yielded typical results. In the low-frequency range, cross-spectral analysis showed high coherence (> 0.5) and a negative phase shift (-65.1 +/- 18 deg) between RR and systolic pressure, which indicates a 1-2 s lag in heart period changes in relation to pressure. In the high-frequency region, the phase shift was close to zero, indicating simultaneous fluctuations of RR and systolic pressure. During urapidil + angiotensin II infusion the low-frequency oscillations of both blood pressure and heart period were abolished in five cases. In the remaining three cases they were substantially reduced and lost their typical cross-spectral characteristics. 5. We conclude that in supine rest conditions, the oscillation of RR at low frequency is almost entirely accounted for by a baroreflex mechanism, since it is not produced in the absence of a 0.1 Hz pressure oscillation. 6. The results provide physiological support for the use of non-invasive estimates of the closed-loop baroreflex gain from cross-spectral analysis of blood pressure and heart period variability in the 0.1 Hz range.