Hyperglycemia markedly enhances skeletal muscle glycogen synthase activity in diabetic, but not in normal conscious rats.

Both hyperinsulinemia and hyperglycemia stimulate skeletal muscle glucose uptake. However, the intracellular metabolic fate of the phosphorylated glucose may be different when the prevalent stimulus for glucose uptake is hyperinsulinemia or hyperglycemia. To define the impact of hyperglycemia on the intracellular glucose disposal, we studied control and diabetic conscious rats under four experimental conditions: 1) basal insulin and basal glucose; 2) basal insulin and high glucose; 3) high insulin and basal glucose; and 4) high insulin and high glucose. Under both basal insulin (130 pM) and high insulin (2500 pM), hyperglycemia (15 mM) increased glucose uptake and muscle and liver glycogen synthesis similarly in control and diabetic rats. Hyperglycemia resulted in a more significant decline in the muscle G-6-P concentration in diabetic rats than in control rats, suggesting activation of intracellular glucose metabolism. The diabetic skeletal muscle glycogen synthase was severely resistant to insulin stimulation compared with control (FV0.1 = 0.31 +/- 0.04 vs. 0.49 +/- 0.03; Km = 0.19 +/- 0.05 vs. 0.10 +/- 0.01 mM; P < 0.01), but it was markedly responsive to glucose stimulation under both basal (FV0.1 = 0.38 +/- 0.03 vs. 0.21 +/- 0.03; Km = 0.10 +/- 0.01 vs. 0.35 +/- 0.08 mM) and high insulin (FV0.1 = 0.65 +/- 0.07 vs. 0.31 +/- 0.04; Km = 0.11 +/- 0.02 vs. 0.19 +/- 0.05 mM). By contrast, in control rats, hyperglycemia did not exert any stimulatory effect on skeletal muscle glycogen synthase. Thus, some metabolic alteration associated with the diabetic state renders the skeletal muscle glycogen synthase selectively responsive to glucose stimulation. This may represent a compensatory mechanism for the severe impairment in insulin's activation of this enzyme in diabetes.

Effects of beta-adrenergic blockade on insulin-mediated glucose disposal in hypertensive and normotensive rats.

OBJECTIVE: To evaluate the impact of beta-adrenergic blockade in spontaneously hypertensive rats (SHR) and in their normotensive controls, Wistar-Kyoto (WKY) rats, on whole-body glucose disposal under metabolic steady state conditions, in unrestrained and conscious animals. METHOD: SHR (n = 13) and WKY rats (n = 12) underwent a 240 min insulinaemic clamp study with or without a super-infusion (120th to 240th minutes; second step) of propranolol. RESULTS: From 0 to 120 min (the first step) SHR showed significantly increased glucose uptake, muscle glycogen synthesis and glycogen synthase activity compared with WKY rats. When propranolol was superinfused, glucose uptake and muscle glycogen synthesis in SHR returned to levels similar to those observed in WKY rats during the first step. No significant differences were found for whole-body glycolysis in SHR and WKY in the first and second steps. CONCLUSION: Hypertensive rats display an increased insulin sensitivity compared with controls. Beta-Blockade is associated with a reduction in overall glucose metabolism in SHR, but not in WKY rats.

Glycogen synthase activity in two rat models of hypertension.

Several studies on both humans and animal models have reported a pathogenetic relationship among hyperinsulinism, insulin resistance, and hypertension. We have previously evaluated whole body glucose disposal and insulin sensitivity in different models of hypertensive rats, showing an increase rather than an impairment of glucose metabolism, which in turn was due to an improved ability of insulin to channel the absorbed glucose towards the nonoxidative disposal. Aiming to confirm our previous findings we performed the direct assay of skeletal muscle glycogen synthase on tissue samples from the previous clamp studies, as a rate limiting step enzyme of glycogen synthesis, under conditions of physiologic hyperinsulinemia and euglycemia. Glycogen synthase was assayed on samples from rectus muscle tissues of spontaneously hypertensive rats and high sodium, one kidney, one figure-8 hypertensive rats. Compared to controls, our data show an increased activity of glycogen synthase in the hypertensive animals, which is consistent with the increased glycogen synthesis previously reported. In conclusion, under our experimental conditions, hypertension and chronic hyperadrenergism are associated with an increased ability of insulin to stimulate glucose uptake and disposal. These latter effects are mainly due to an increase in nonoxidative disposal and glycogen synthase activity.

Effects of high altitude exposure on plasma and urinary digoxin-like immunoreactive substance.

Six young healthy subjects underwent a 20 day exposure to altitude, at 4930 m (16,174 ft), to evaluate possible plasma and urine digoxin-like immunoreactive substance (DLIS) changes accompanying the altered water and electrolyte balance induced by hypoxia. We studied DLIS, plasma renin activity (PRA), aldosterone, atrial natriuretic peptide (ANP), and arginine vasopressin (ADH) in serial blood and urine samples. An increase in DLIS in plasma (P less than .005) and urine (P less than .01) was found, while aldosterone was decreased (P less than .02). PRA, ADH, and ANP did not change significantly. A trend to a greater loss of sodium through urinary excretion, correlated with urinary DLIS values (r = 0.47, P less than .01), was observed. Data suggest a possible important role of DLIS in adaptive response of human organism to high altitude.

Modified autonomic balance in offsprings of diabetics detected by spectral analysis of heart rate variability.

This study was performed to evaluate the influence of family history for non-insulin-dependent diabetes mellitus (NIDDM) on autonomic balance. The latter was assessed by spectral analysis of heart rate variability (SA-HRV) and by analyzing the relative contribution of low-frequency (LF) and high-frequency (HF) components. Twenty glucose normotolerant offsprings of NIDDM parents and 20 controls underwent a 1-hour continuous electrocardiogram (ECG). LF and HF (mean +/- SEM in normalized units [NU]), respectively increased and decreased in offspring versus controls. The LF/HF ratio (mean +/- SEM) significantly increased (LF/HF = 3.25 +/- 0.7 v 1.45 +/- 0.5, P <.0001 offsprings v controls). To test a stimulated response, a passive tilting (+ 90 degrees ) after 30 minutes of bed rest (0 degrees ) was performed in a subsample of subjects (10 offsprings v 10 controls). During bed rest, we found significantly higher values of the LF/HF ratio in offsprings versus controls (1.93 +/- 0.3 v 1.08 +/- 0.2, P <.05), whereas in the head-up position, the LF/HF ratio value increased to the same levels in the 2 groups (6.48 +/- 1.3 v 6.89 +/- 1.4, not significant [NS]). NIDDM family history is characterized in the basal condition by an imbalance of the autonomic system, which, compared with controls, is expressed by a higher weight of sympathetic and a lower weight of parasympathetic components. No significant differences can be found under stimulated conditions.

Endocrine and psychophysiological aspects of human adaptation to the extreme.

Human beings need to adapt to any extreme, unknown, or isolated environment. This adaptation requires changes in the normal regulation of psychophysiological homeostasis, as described in terms of stress reaction. The aim of the present study was to monitor the processes of human adaptation to cold and isolated areas in Antarctica during the 12th expedition of the Italian National Research Program. Nine healthy subjects (experimental subjects), members of the expedition, and nine controls in Italy, were studied over a period of 2 months. Anterior pituitary hormone secretion, insulin, and melatonin, plus routine blood test, blood pressure, and ECG were performed. In addition, psychophysiological correlates were also recorded before and after the expedition period. In experimental subjects results of metabolic data suggested the presence of an increased peripheral insulin sensitivity at the end of the permanence in the station and a significant increased of total cholesterol. Hematocrit also significantly increased due to the conditions of hypobaric hypoxia. Results of endocrine data showed a significant decrease (p < 0.05) of hormone levels, which was associated with a significant decrement of the Galvanic Skin Response (GSR) activity to a standardized cognitive stress. No significant differences were reported in the controls. The data suggest that the exposure to the extreme environment develops a possible psychophysiological mechanism(s) that decreases the individual arousal.

Potentiation of human polymorphonuclear leukocyte activation by atrial natriuretic peptide. Inhibitory effect of carnitine congeners.

Polymorphonuclear leukocytes (PMN), atrial natriuretic peptide (ANP) and leukotriene B4 (LTB4) reportedly play a major role in ischemia/reperfusion states of coronary artery disease. We sought to determine whether ANP and LTB4 cooperate in inducing PMN activation with consequent modulation of membrane molecules required for adherence to endothelium and myocardial cells, namely CD11b and L-selectin and the release of toxic oxygen radicals. ANP (from 10(-16) to 10(-8) M), LTB4 (from 10(-10) to 10(-6) M) and combinations of the two were incubated with normal PMN at 37 degrees C for 15 minutes. Membrane molecules modulation was measured by flow cytometry using specific monoclonal antibodies. Hydrogen peroxide production, an indicator of the capacity of PMN to release toxic oxygen species was quantified by flow cytometry using the peroxide-sensitive fluorescent probe dichlorofluorescein diacetate. ANP, uneffective when used alone, dose-dependently potentiated the PMN response to LTB4 (10(-9) M) as evidenced by an up-regulation of CD11b expression and peroxide production, and a down-regulation of L-selectin expression. These effects were prevented dose-dependently by the protein kinase C (PKC) inhibitor staurosporine (from 10 to 160 microM). Two carnitine congeners, palmytoylcarnitine (tested from 125 pg to 2 micrograms/ml) that also possesses an established ability to antagonise PKC and L-carnitine (tested from 12 to 200 ng/ml) were also effective. These data indicate that ANP potentiates LTB4 in inducing PMN mobilization and activation with a possible consequent detrimental effect on cardiac tissue and evisages the usefulness of PMN metabolism modulators.

Reduced sympathetic outflow and adrenal secretory activity during a 40-day stay in the Antarctic.

Human adaptation to unknown and extreme environments requires changes in the psychological and physical homeostasis. We previously reported a significant decrease of anterior pituitary and adrenal hormonal levels and a significant modification of psychophysiological correlates of stress, such as galvanic skin response, after exposure to Antarctica, suggesting a possible decrease of individual arousal. The latter was hypothesized to be correlated with a modification of autonomic balance, mainly represented by a possible reduction of adrenergic output. The aim of the present study was to assess the patterns of hormonal circadian rhythms and the autonomic nervous system balance by means of spectral analysis of heart rate variability (HRV). These parameters were evaluated during 3 sessions (baseline, session 1 and session 2), before, at the beginning and after a 40-day stay in Antarctica (Station of Terra Nova Bay; average temperature in the study period: -11 degrees C, 24 h of light, sea level). In each of the sessions, 6 healthy male subjects underwent a 24-h electrocardiogram and blood sampling (08.00, 12.00, 16.00, 20.00, 24.00 and 08.00 h) for hormonal determinations. The data showed a remarkable decrease of hormonal levels without significant changes in circadian rhythms. Spectral analysis of HRV showed an imbalance of the autonomic nervous system with a relative significant decrease of the low frequency band (0.1 Hz) in session 1 and 2 compared to baseline, which can be functionally interpreted as a relative decrement of the sympathetic component. In conclusion, the exposure to a cold and extreme environment seems to affect autonomic balance over a 40-day period. This is followed by a significant reduction of the anterior pituitary and adrenal hormonal secretory patterns with preserved hormonal circadian rhythms (within the same time period of 40 days). This pattern is suggestive of a trophotropic neurovegetative adaptive process.

Is there a hypercoagulable state in military fighter pilots?

BACKGROUND: A hypercoagulable state is associated with an increased incidence of cardiovascular disease, the most important cause of permanent grounding of flying personnel. HYPOTHESIS: The aim of our study was to investigate whether a hypercoagulable state is present in jet pilots, and whether it can be due to flight activity. METHOD: To this purpose we studied Fibrinopeptide A (FPA), Thrombin-Antithrombin complexes (TAT) and D-Dimer (DD), sensitive biochemical markers of blood coagulation and fibrinolysis activation, in 10 jet pilots after a standardized training flight mission, and in a control group. Also evaluated before flight were 6 jet pilots. RESULTS: We were able to show increased thrombin and plasmin activity both in jet pilots compared to the control group, and after flight in the 6 pilots who were evaluated twice. CONCLUSION: We conclude that a hypercoagulable state due to flight activity is present in jet pilots after flight. Possible mechanisms involve an effect of psycho-physical stress mediated by a neuroendocrine response to flight activity, or an effect of chronic +Gz exposure on cardiovascular structure and function.

Effect of acute exposure to hypoxia on electrolytes and water metabolism regulatory hormones.

BACKGROUND: Many studies suggest the hypothesis that the pathology of high altitude could be due to an early alteration of the hormones that regulate sodium homeostasis. HYPOTHESIS: The aim of this study was to evaluate the behavior of these hormones during an acute exposure to hypobaric hypoxia. METHODS: We studied 26 young healthy pilot students (23.1 +/- 2.9 yrs) in a hypobaric chamber, for 3 h (samples collected at time 0, 120, and 180 min), at 5000 m ASL. RESULTS: The results show an early increase of plasma renin activity (PRA) paradoxically associated to a decrease of aldosterone plasma levels. This later returned to the baseline values at 180 min, whereas PRA remained increased throughout the exposure. Both arginine-vasopressin (ADH) and the atrial natriuretic peptide (ANP) significantly increased, while a new putative hormone, the so-called digoxin-like substance (DLS) did not show significant changes. CONCLUSIONS: Our data demonstrate a specific sensitivity of the hormonal systems to hypoxia, which may be influenced by the time of the exposure. The relationship with results previously reported is also addressed.

Influence of stress on lymphocyte subset distribution--a flow cytometric study in young student pilots.

Stressors can induce sizable modifications on immunocompetent cells. Major circulating lymphocyte subsets were quantitated in Italian Air Force student pilots undergoing intensive training and continuous evaluation, a stressful situation both physically and psychologically. Instructor pilots matched for age and assayed in parallel were used as controls. A typical flight training session was not able per se to induce immediate significant modifications of the lymphocyte subset distribution either in the students or instructors, although it did affect plasma levels of stress-related hormones such as growth hormone, prolactin and cortisol in the former. Irrespective of the time of flying, however, the percentage of CD4+ lymphocytes and the CD4/CD8 ratio were lower in students than in instructors, and the absolute number of CD8+ lymphocytes was higher in students than in instructors. In a second series of experiments, 30 student pilots were tested at the beginning and at the end of a flight course (duration 30 days). Although the percentage of CD29+ lymphocytes comprised in the CD8+ subset was reduced at the end of the course in all individuals, such a reduction was more evident in those students who failed to pass the final examination, an additional cause of psychological stress. In light of the functional significance of the lymphocyte subsets investigated, it is suggested that the present stress-induced alterations may have practical implications.

The effects of hypobaric hypoxia on specific B cell responses following immunization in mice and humans.

In order to get some insight on the physiology of the immune system during prolonged exposure to hypobaric hypoxia we evaluated the effects of high altitude on the in vivo immune response to a T-independent antigen. A group of 18 men who participated in a scientific project EV-K2-CNR to Mount Poumori, Nepal for 20 d at 4,930 m (16,174 ft) were immunized with a single subcutaneous dose of antimeningococcal vaccine Menpovax A + C (Sclavo) containing 50 micrograms of polysaccharide A (PsA) and 50 micrograms of polysaccharide C (PsC) of N. meningitidis. A group of 18 men of comparable age were vaccinated at sea level. Antibody titers against both polysaccharides were determined by enzyme-linked immunosorbent assay (ELISA) before and 18 d after vaccination. All subjects examined developed a good antibody response and no statistically significant differences were observed between the two groups. Spectrotypic analysis of antibody response to PsC was also performed by isoelectric focusing. No qualitative differences in the antibody response to PsC were found in the hypoxia-exposed group with respect to the control group. A group of 10 BALB/c inbred mice were kept in a hypobaric chamber at 5,500 m (18,000 ft) for 30 d. After 10 d, the mice were vaccinated with 1 micrograms of Menpovax A + C. Anti-PsA and anti-PsC antibodies were quantified by ELISA in sera collected at day 0 and 30. A control group of 10 mice of the same strain underwent the same study protocol but at sea level. Both groups developed a good antibody response to both polysaccharides and no significant differences were observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Lipoprotein (a) and apoprotein B in an apparently healthy population of fighter pilots and ground personnel: their significance as potential markers of atherosclerosis.

BACKGROUND: Individuals who carry cardiovascular risk factors (CVRF) have a higher incidence of cardiovascular pathology. Among the most commonly screened CVRF are apoprotein A and B and lipoprotein (a), which represent 'independent' risk factors for atherosclerosis. In the air force community, cardiovascular pathology has been reported as the primary reason for grounding pilots. DESIGN: The aim of this study was to evaluate the frequency of CVRF in an apparently healthy population of military fighter pilots (group B, n = 50), and military ground personnel (group A, n = 50) who were matched for age, sex and body mass index but not involved in flight activity, and to evaluate whether any particular pattern of CVRF might be related to flight. METHODS: Each subject fasted overnight, and underwent the following measurements: blood pressure and resting ECG recording; and determination of serum levels of total and high-density lipoprotein cholesterol, triglycerides, uric acid and plasma levels of glucose. In addition, serum levels of apolipoprotein A, B and lipoprotein (a) were detected. RESULTS: An overall risk index for coronary artery disease was calculated using the Framingham equation. This risk index was slightly but not significantly increased in group A compared with group B. By contrast, a significant increase in both apoprotein B (P < 0.005) and lipoprotein (a) (P < 0.0005) was found in group B compared with group A. No significant differences between groups were detected for the other parameters evaluated. CONCLUSIONS: We suggest the presence in group B of an underlying trend towards the development of atherosclerosis, which may not be identified by a routine approach. Moreover, on a purely theoretical basis with no experimental evidence, the issue of the possible pathophysiological mechanism of these findings and their relationship to flight environment is also addressed.

Evaluation of stress induced by flight activity by measuring the hormonal response.

The aim of the present study was to quantitatively investigate the different levels of adaptation to flight and to evaluate the hormonal response to flight activity as a possible reliable tool to quantify the level of stress induced by flight. The hormonal response of growth hormone (GH), cortisol, and prolactin (PRL) to flight activity was evaluated in a group of student pilots (n = 11; all male; age 20 +/- 2 years) and flight instructors (n = 11; all male; age 27 +/- 2 years) of an Italian Air Force flight school. Blood samples were obtained immediately before and after a training flight session. Hormonal determination by RIA technique after flight showed a significant increase of plasma hormonal levels of GH, PRL, and cortisol in the students. Conversely, in the instructors only GH showed a significant increase versus preflight values, whereas PRL and cortisol did not show significant differences. Moreover, preflight hormonal levels of GH and PRL were significantly higher for student pilots compared to the same values for flight instructors. The data lead to establishing a close correlation between the hormonal response to flight activity and the level of tolerance and adaptation to flight-induced stress.

[Effects of acute and protracted hypoxia on plasma levels of atrial natriuretic factor]. / Effetti dell'ipossia acuta e protratta sui livelli plasmatici di fattore natriuretico atriale.

Acute hypoxia stimulates the release of atrial natriuretic factor (ANF) from isolated rat and rabbit hearts. Increased ANF plasma levels have been found in rats exposed to chronic hypoxia and recently some studies have been conducted on men, with discordant results. The aim of the present study was to verify changes in ANF plasma levels during acute and prolonged hypoxia in young healthy men. We studied 22 subjects (aged 20-28 years, mean 22.7 years) during a simulated exposure to altitude (5000 m) in a hypobaric chamber for 3 hours (A), and 6 subjects (aged 24-51 years, mean 36.5 years) during the scientific expedition to mount Poumori (Nepal 4930 m altitude) with an exposure at maximum altitude for 20 days (B). ANF was measured by the radioimmunoassay method. Results (pg/ml): (A) baseline: 29.4 +/- 18.6; 120 min: 32.0 +/- 17.4 (NS); 180 min: 35.4 +/- 17.1 (p less than 0.05). (B) baseline: 39.6 +/- 13.3; third day: 38.2 +/- 14.1; fifth day: 31.3 +/- 11; seventh day: 29.1 +/- 13.5; tenth day: 32.2 +/- 20.8; fifteenth day: 37.9 +/- 20.2; twentieth day: 34.6 +/- 23.7 (all differences were not significant). In (B) we observed a higher dispersion of values perhaps due to individual variability. The different behaviour of ANF plasma levels in acute and chronic conditions might be due to the adaptive modification of different physiological parameters as loss of plasma volume, natriuresis and attenuation of tissue hypoxia by enhanced erythropoiesis, observed more evidently during prolonged exposure.

Circulating interleukin-1-beta levels after acute and prolonged exposure to low temperatures: human and rat studies.

In this study we have investigated whether IL-1 acts as a mediator of stress responses elicited by exposure to low temperatures. We also sought whether IL-1 is released from the adrenal gland under basal conditions or after exposure to low temperatures. Normal and adrenalectomized (ADX) rats were used for acute studies, whereas the effects of a prolonged exposure were investigated in a group of human subjects during a 45-day stay in Antarctica. Circulating levels of interleukin-1beta (IL-1beta) were taken as a marker of systemic IL-1 production both in humans and rats. In the latter, serum corticosterone (Cort) was also estimated. In intact rats, exposure to low temperatures (-25 or -35 degrees C) for 30 or 90 min did not modify circulating IL-1beta levels with respect to controls taken at +20 degrees C. Adrenalectomy was associated with an increase in cytokine levels only in the group exposed to -35 degrees C for 90 min; such increase is statistically significant compared to all groups of normal rats, whatever the experimental condition, as well as to ADX rats exposed to +20 degrees C and -25 degrees C for 30 and 90 min. In normal rats, the increase in circulating Cort levels was already maximal after exposure to -25 degrees C for 30 min. In humans, circulating IL-1beta levels after 45 days in Antarctica were significantly lower than those measured on arrival in the same subjects. Thus, no change in circulating IL-1beta was associated with acute low-temperature stress in rats, whereas a marked decrease in serum cytokine was observed in humans after prolonged exposure to a cold environment. Experiments with ADX rats indicated that the contribution of the adrenal glands to total-body IL-1beta production is negligible or absent.

Multiple metabolic effects of CGRP in conscious rats: role of glycogen synthase and phosphorylase.

Calcitonin gene-related peptide (CGRP) is a neuropeptide that is released at the neuromuscular junction in response to nerve excitation. To examine the relationship between plasma CGRP concentration and intracellular glucose metabolism in conscious rats, we performed insulin (22 pmol.kg-1.min-1) clamp studies combined with the infusion of 0, 20, 50, 100, 200, and 500 pmol.kg-1.min-1 CGRP (plasma concentrations ranging from 2 x 10(-11) to 5 x 10(-9) M). CGRP antagonized insulin's suppression of hepatic glucose production at plasma concentrations (approximately 10(-10) M) that are only two- to fivefold its basal portal concentration. Insulin-mediated glucose disposal was decreased by 20-32% when CGRP was infused at 50 pmol.kg-1.min-1 (plasma concentration 3 x 10(-10) M) or more. The impairment in insulin-stimulated glycogen synthesis in skeletal muscle accounted for all of the CGRP-induced decrease in glucose disposal, while whole body glycolysis was increased despite the reduction in total glucose uptake. The muscle glucose 6-phosphate concentration progressively increased during the CGRP infusions. CGRP inhibited insulin-stimulated glycogen synthase in skeletal muscle with a 50% effective dose of 1.9 +/- 0.36 x 10(-10) M. This effect on glycogen synthase was due to a reduction in enzyme affinity for UDP-glucose, with no changes in the maximal velocity. In vitro CGRP stimulated both hepatic and skeletal muscle adenylate cyclase in a dose-dependent manner. These data suggest that 1) CGRP is a potent antagonist of insulin at the level of muscle glycogen synthesis and hepatic glucose production; 2) inhibition of glycogen synthase is its major biochemical action in skeletal muscle; and 3) these effects are present at concentrations of the peptide that may be in the physiological range for portal vein and skeletal muscle. These data underscore the potential role of CGRP in the physiological modulation of intracellular glucose metabolism.

Hyperinsulinaemia in offspring of Type 2 diabetic patients: impaired response of carbohydrate metabolism, but preserved cardiovascular response.

AIMS: To investigate the effects of endogenous insulin on haemodynamics in nine offspring of Type 2 diabetic patients (P), compared with 18 subjects without family history of diabetes (C), all with normal glucose tolerance. METHODS: All subjects underwent a 180-min oral glucose tolerance test with continuous blood pressure and ECG recording. Low-to-high frequency ratio (LF/HF), an index of the sympatho-vagal balance, was calculated by heart rate spectral analysis. RESULTS: At baseline, LF/HF correlated with fasting plasma insulin (r = 0.44, P < 0.03) and with insulin/glucose ratio (r = 0.46, P < 0.03). Plasma insulin, basally similar in the two groups, was significantly increased in P (342 +/- 34.2) when compared to C (177.6 +/- 25.2 pmol/l), P < 0.005 from time 30min onward. Blood glucose, also similar at baseline, remained not significantly different in P (5.74 +/- 0.25) vs. C (5.08 +/- 0.27 mmol/l), throughout the study. Diastolic blood pressure significantly decreased in P, but not in C during the first hour of the study. Finally, LF/HF ratio significantly increased in P (2.5 +/- 0.4 vs. C, 1.7 +/- 0.2) during the first hour. CONCLUSIONS: In conclusion, the offspring of Type 2 diabetic patients with normal glucose tolerance display an increased insulin secretion; however, they are not resistant to the haemodynamic effects of insulin, as suggested by the reduction of diastolic blood pressure. This, in turn, may determine a chronic sympathetic activation, which could be involved in the pathogenesis of Type 2 diabetes mellitus.