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Biomedical subjects

D Santoro

Publications and source records attributed to D Santoro.

At least 55 records · Page 3Linked to original sources
PubMed1993

Insulin resistance of stress: sites and mechanisms.

1. Stress is associated with a severe, yet reversible, form of insulin resistance. The aim of this study was to quantify the kinetics of insulin action (sensitivity and responsiveness) on intermediary metabolism during post-surgical stress. 2. We studied nine patients 6-8 h after major uncomplicated surgery, and eight healthy subjects matched for age, weight, glucose tolerance and duration of fast. A three-step isoglycaemic insulin clamp was combined with indirect calorimetry, [6-3H]glucose infusion and the forearm technique. 3. The following significant (P < 0.05 or less) abnormalities were found in the patients. Hepatic glucose production was higher at baseline, and less suppressed by insulin. Whole-body glucose disposal was impaired at all insulin doses (by 33-60%). Glucose oxidation was depressed throughout the dose range but its increments in response to insulin were normal. In contrast, non-oxidative glucose disposal was essentially unresponsive. At all insulin levels, forearm glucose extraction was markedly depressed and forearm lactate release was in excess of concurrent glucose uptake, suggesting ongoing glycogenolysis despite insulin. Total lipolysis (plasma free fatty acid and glycerol levels) promptly responded to insulin but remained higher than in the control subjects throughout. In the forearm, even the highest insulin dose could not suppress net free fatty acid and glycerol release. Total lipid oxidation was increased throughout the insulin range, and calculated direct free fatty acid (as opposed to plasma free fatty acid) oxidation was virtually unaffected by insulin. Protein oxidation was slightly (35%) increased, but was suppressed normally in response to insulin. Energy expenditure was 20% higher at baseline, and failed to rise with insulin. Arterial blood pH values were consistently (if slightly) lower, and net forearm proton release was higher, both at baseline and during insulin infusion. 4. Post-surgical insulin resistance is characterized by normal sensitivity but decreased responsiveness of glucose oxidation, lipolysis and plasma free fatty acid oxidation, whereas glycogen synthesis and direct free fatty acid oxidation are virtually unresponsive. For both glucose and lipid metabolism, the insulin resistance is particularly severe in forearm tissues, in which mild metabolic acidosis may play an additional role.

Blood Glucose↗
PubMed1993

Metabolic and hemodynamic effects of insulin on human hearts.

Myocardial muscle is considered to be a target tissue for insulin action, but direct measurements of insulin's effects on cardiac hemodynamics and intermediary metabolism in humans are scarce. We combined great cardiac vein (GCV)/arterial catheterization with the euglycemic insulin clamp technique and thermodilution in six healthy middle-aged (53 +/- 2 yr) volunteers. In the fasting state, the myocardium extracted free fatty acid (FFA), lactate, pyruvate, glycerol, and beta-hydroxybutyrate (6.4 +/- 0.8, 6.2 +/- 1.0, 0.58 +/- 0.12, 0.44 +/- 0.15, and 11 +/- 2 mumol/min, respectively) and consumed 0.26 +/- 0.02 mmol/min oxygen. As fasting plasma insulin (73 +/- 6 pmol/l) was raised and clamped at 503 +/- 16 pmol/l for 100 min while maintaining euglycemia (approximately 5 mmol/l), arterial levels of lactate and pyruvate rose (by 121 and 159%, respectively), whereas FFA, glycerol, and beta-hydroxybutyrate fell (by 69, 48, and 85%, respectively, all P < 0.001). Correspondingly, net myocardial uptake of glucose, lactate, and pyruvate increased to 18.9 +/- 3.5, 32.0 +/- 2.3, and 2.7 +/- 0.5 mumol/min, respectively, whereas net extraction of circulating FFA, glycerol, and beta-hydroxybutyrate was abolished (all P < 0.001). The stimulation of lactate and pyruvate uptake was the result of both increased arterial supply and enhanced myocardial extraction ratio (from 19 +/- 3 to 51 +/- 6% for lactate, from 26 +/- 5 to 44 +/- 5% for pyruvate, P < 0.001 for both). This shift from fat to carbohydrate fuel usage occurred in the absence of changes in oxygen consumption, heart rate, GCV blood flow, aortic pressures, coronary vascular resistance, and left ventricular end-diastolic pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Hydroxybutyric Acid↗
PubMed1993

Metabolic and thermogenic effects of lactate infusion in humans.

Lactate has been suggested to interfere with intermediary metabolism by restricting both lipolysis and glucose utilization. To test this hypothesis, in paired studies in healthy volunteers, sodium lactate (25 mumol.min-1 x kg-1) or saline was infused for 1 h in the fasting state and during 2 h of euglycemic (4.75 mM) hyperinsulinemia (approximately 400 pmol/l). Hyperlactatemia (approximately 2 mM) had no inhibitory effect on fasting free fatty acid or glycerol levels nor did it alter the suppressive action of insulin on these substrates. Likewise, sodium lactate infusion did not influence hepatic glucose production ([3-3H]glucose technique) or its suppression by insulin. During the clamp, hyperlactatemia was associated with a small increase in whole body glucose disposal (34.9 +/- 4.1 vs. 30.3 +/- 3.7 mumol.min-1 x kg-1, P < 0.05) with no major change in the pattern of substrate (carbohydrate vs. lipid) oxidation. By simultaneously measuring arteriovenous gradients across the deep tissues of the forearm (forearm technique), it was found that hyperlactatemia did not impede insulin-mediated glucose uptake; furthermore, it could be estimated that muscle tissues were responsible for the disposal of roughly one-fifth of the lactate load. Whole body energy expenditure was stimulated above the level achieved with hyperinsulinemia when lactate was also infused. Thus, under the present experimental conditions, physiological hyperlactatemia did not interfere with lipolysis, hepatic glucose production, or whole body or forearm muscle glucose utilization, or with insulin action on these processes, and was accompanied by a strong thermogenic effect.

Adult↗
PubMed1992

Potassium as a link between insulin and the renin-angiotensin-aldosterone system.

PURPOSE: To focus on the interactions between insulin secretion, glucose tolerance and insulin sensitivity on the one hand and the renin-angiotensin-aldosterone system on the other. EFFECTS ON INSULIN: Insulin is a potent stimulus for hypokalaemia, sparing body potassium from urinary excretion by transporting it into cells. Potassium also appears to play a key role in the antinatriuretic effect of insulin. Insulin-induced hypokalaemia increases plasma renin and angiotensin II levels while decreasing the serum aldosterone concentration. In turn, the renin-angiotensin-aldosterone system affects glucose tolerance by modulating plasma potassium levels, which act as a stimulus for glucose-induced insulin release. EFFECTS OF ANGIOTENSIN CONVERTING ENZYME (ACE) INHIBITION: Interference with the renin-angiotensin-aldosterone system by ACE inhibition blunts the hypokalaemic response to insulin, thereby improving glucose-induced insulin release and oral glucose tolerance. ACE inhibition, however, does not cause major changes in insulin sensitivity. POTASSIUM AND BLOOD PRESSURE: Plasma potassium levels are inversely related to blood pressure, both in population surveys and in intervention studies. In addition, in patients with essential hypertension, the level of plasma potassium appears to predict the blood pressure response to ACE inhibition. SUMMARY: Potassium metabolism is an important link between carbohydrate metabolism and the renin-angiotensin-aldosterone system by way of a double-feedback mechanism. Through the potential effects on blood pressure control, plasma levels of potassium represent a link between insulin and blood pressure in humans.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1992

Effects of chronic angiotensin converting enzyme inhibition on glucose tolerance and insulin sensitivity in essential hypertension.

The relation between the renin-angiotensin-aldosterone (RAA) system and carbohydrate metabolism and insulin sensitivity in essential hypertension has not been investigated systematically. Twenty nondiabetic patients (age, 49 +/- 1 years; body mass index (BMI), 26.1 +/- 0.4 kg/m2) with essential hypertension (blood pressure, 155 +/- 3/105 +/- 1 mm Hg) received an oral glucose tolerance test (OGTT) at the end of a 1-month placebo period and again monthly during 3 months of angiotensin converting enzyme (ACE) inhibition (cilazapril, 5 mg/day). Furthermore, a two-step euglycemic insulin clamp was performed after placebo and again at the end of treatment. Blood pressure fell by 7 +/- 4/10 +/- 3 mm Hg (p less than 0.001), while BMI remained stable. On the euglycemic clamp, insulin-mediated (plasma insulin, 470 pM) whole body glucose use averaged 42.5 +/- 1.6 mumol.min-1.kg-1 before and 43.6 +/- 1.9 after ACE inhibition (p = NS). Substrate concentrations and oxidative rates and energy expenditure (as estimated by indirect calorimetry) were not altered by ACE inhibition, either in the fasting state or in response to insulin. In contrast, oral glucose tolerance was significantly (p less than 0.05) improved after treatment (area under OGTT curve (AUC), 240 +/- 24 versus 282 +/- 23 mmol 2 hr.l-1). The latter change was associated with enhanced (+16%, p less than 0.05) insulin responsiveness to glucose (estimated as the insulin AUC divided by the glucose AUC) throughout the 3 months of ACE inhibition. At baseline, both the OGTT and the clamp had a marked hypokalemic effect (mean decrements in plasma potassium of 0.75 +/- 0.05 and 0.92 +/- 0.05 mmol/l, respectively) in association with plasma aldosterone reductions of 30% and 50%. Chronic ACE inhibition caused a further 20% (p less than 0.03) lowering of plasma aldosterone concentrations but attenuated insulin-induced hypokalemia. Plasma sodium, which was unaltered by the pretreatment tests, fell during the posttreatment tests (by 3 mmol/l, p less than 0.001). In the urine, the ratio of the fractional excretion of potassium to that of sodium was decreased by both oral glucose (-22%, p less than 0.01) and ACE inhibition (-21%, p less than 0.001). Higher plasma potassium levels before treatment predicted a better blood pressure response to ACE inhibition (r = 0.60, p less than 0.005).(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Oral↗
PubMed1991

Monocyte-derived neutrophil chemotactic factor/interleukin-8 is a potential mediator of crystal-induced inflammation.

The physical interaction of particulates with resident mononuclear phagocytes is a consistent feature in certain forms of crystal-induced inflammation. In this study, we observed that monosodium urate crystals stimulated the rapid release of neutrophil chemotactic activity from monocytes, and that this activity steadily increased over 24 hours. Because the release of monocyte-derived neutrophil chemotactic activity was markedly diminished by pretreatment of the monocytes with cycloheximide, and was completely removed from conditioned media by adsorption to heparin-agarose, we addressed the possibility that monocyte-derived neutrophil chemotactic factor/interleukin-8 (IL-8), a heparin-binding neutrophil-activating polypeptide, might modulate these activities. Urate crystal-induced IL-8 secretion from monocytes was verified by radioimmunoassay. In addition, an IL-8-specific antibody markedly inhibited the neutrophil-activating capacity of the conditioned media from monocytes activated by urate crystals, as well as by inflammatory silica crystals. Last, IL-8 was significantly increased in gouty synovial fluids (range 3.0-16.8 ng/ml, mean 8.4 ng/ml, n = 6) relative to osteoarthritic synovial fluids (range 1.1-1.7 ng/ml, mean 1.5 ng/ml, n = 6) (P = 0.006). We conclude that microcrystal-induced secretion of IL-8 by mononuclear phagocytes may mediate a number of forms of crystal-induced inflammation.

Arthritis, Gouty↗
PubMed1991

Impaired insulin action on skeletal muscle metabolism in essential hypertension.

Previous studies have shown that essential hypertension is frequently associated with insulin resistance. The tissues responsible for this metabolic alteration have not been defined. We tested the hypothesis that skeletal muscle is the site of insulin resistance of essential hypertension with the use of the perfused forearm technique. Eight hypertensive (age 42 +/- 3 years, body mass index 27 +/- 1 kg/m2, intra-arterial mean blood pressure 126 +/- 4 mm Hg) and seven normotensive (age 48 +/- 3 years, body mass index 26 +/- 1 kg/m2, mean blood pressure 95 +/- 4 mm Hg) male volunteers were studied. After glucose ingestion (40 g/m2), normal glucose tolerance in the patients was maintained at the expense of a heightened plasma insulin response, suggesting the presence of insulin resistance. During graded, local (intra-arterial) hyperinsulinemia encompassing the physiological range (12-120 milliunits/l), glucose uptake by forearm tissues was significantly (p less than 0.03) reduced in the hypertensive subjects as compared with the controls at each of five insulin steps, by 43% on the average. In addition, forearm lactate and pyruvate release were significantly less stimulated in the hypertensive than in the normotensive group (p less than 0.01 for both), presumably as a consequence of the decreased glucose influx. Forearm exchange of oxygen, carbon dioxide, lipid substrates (free fatty acids, glycerol, and beta-hydroxybutyrate), and potassium were similar in the hypertensive and normotensive groups in the basal state. Insulin had no effect on oxygen consumption, carbon dioxide production, and respiratory quotient in either study group, whereas it stimulated free fatty acids, glycerol, and potassium uptake to the same extent in the hypertensive and normotensive groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Effects of insulin on hemodynamics and metabolism in human forearm.

We investigated the vascular response (blood flow and resting vascular resistance) and the metabolic response (exchange of metabolites and respiratory gases) to local insulin administration in the forearms of healthy young volunteers with the use of the perfused-forearm technique. In the postabsorptive state, the deep tissues of the forearm (mostly skeletal muscle) took up glucose (mean +/- SE 1.09 +/- 0.17 mumol.min-1.dl-1 forearm vol), beta-hydroxybutyrate (0.267 +/- 0.130 mumol.min-1.dl-1), and O2 (9.96 +/- 1.02 mumol.min-1.dl-1) and released lactate (0.284 +/- 0.098 mumol.min-1.dl-1), glycerol (0.029 +/- 0.012 mumol.min-1.dl-1), citrate (0.091 +/- 0.030 mumol.min-1.dl-1), alanine (0.184 +/- 0.044 mumol.min-1.dl-1), CO2 (7.36 +/- 0.97 mumol.min-1.dl-1), and protons (12.1 +/- 1.4 pmol.min-1.dl-1). Forearm blood flow (by venous occlusion plethysmography) was 2.95 +/- 0.18 ml.min-1.dl-1, and intra-arterial systolic/diastolic blood pressure was 116 +/- 3/76 +/- 2 mmHg. Local indirect calorimetry indicated dominance of fat as the oxidative substrate (RQ 0.76 +/- 0.09) and an energy expenditure rate of 1.03 +/- 0.11 cal.min-1.dl-1 forearm vol. One hundred minutes of intra-arterial insulin infusion (deep venous plasma insulin concn of 125 +/- 11 microU/ml) had no detectable effect on forearm blood flow, resting forearm vascular resistance, heart rate, or blood pressure. Local hyperinsulinemia significantly stimulated glucose uptake (to 4.79 +/- 0.61 mumol.min-1.dl-1 forearm vol, P less than 0.001), lactate and pyruvate release (to 0.710 +/- 0.093 and 0.032 +/- 0.016 mumol.min-1.dl-1 forearm vol, respectively; P less than 0.01 for both), potassium uptake (0.76 +/- 0.22 mueq.min-1.dl-1, P less than 0.001), and free fatty acid uptake (0.123 +/- 0.041 mumol.min-1.dl-1 forearm vol, P less than 0.05); glycerol balance switched to a net uptake (P less than 0.001), alanine release was restrained by 33% (P less than 0.05), and beta-hydroxybutyrate and citrate release were unchanged. Despite these metabolic changes, local rates of substrate oxidation and energy expenditure were not altered by insulin. In contrast, forearm proton release was significantly stimulated by insulin (to 14.8 +/- 1.4 pmol.min-1.dl-1, P less than 0.02). Proton release was also found to be directly related to resting forearm vascular resistance independent of the effect of insulin (multiple r = 0.64, P less than 0.001).(ABSTRACT TRUNCATED AT 400 WORDS)

3-Hydroxybutyric Acid↗
PubMed1989

Teicoplanin in the treatment of infections by staphylococci, Clostridium difficile and other gram-positive bacteria.

Eighty-three episodes of Gram-positive infection in 82 patients were treated with teicoplanin in an open study. Infectious episodes included endocarditis (6 cases), bacteraemia (7), osteomyelitis (8), pseudomembranous colitis (13), cellulitis (11), urinary tract infection (5), pneumonia (1), wound and post-surgical infections (9) and erysipelas (23). Four patients affected by an overwhelming Gram-positive infection as well as eight cases of Gram-positive-Gram-negative mixed infections received teicoplanin in combination with other antibiotics. The average duration of treatment was 16 days (range 5-70). In pseudomembranous colitis teicoplanin was given by mouth for ten days. Staphylococcus aureus (11 methicillin-sensitive and 13 methicillin-resistant strains) and Clostridium difficile (13 isolates) were the most frequent pathogens. Overall 89% (74/83) of the infections were cured, 3.6% (3/83) improved and 3.6% (3/83) failed. Relapse and superinfection were observed in 2.4% (2/83) and 1.2% (1/83) episodes respectively. All pseudomembranous colitis cases were clinically cured and C. difficile was eradicated in all but one patient. The MIC range, MIC50 and MIC90 (mg/l) of teicoplanin for C. difficile were less than 0.125-0.250, less than 0.125 and 0.250 respectively. Pharmacokinetic studies in patients given a single iv daily maintenance dose of 400 mg showed that the steady-state trough teicoplanin concentrations in serum were reached on day 8. Assays of skin-subcutaneous tissue biopsies showed that teicoplanin penetrated well into these structures. Side effects were observed in six of the 82 treated patients (7.3%) and teicoplanin had to be discontinued in four cases. The results of the study show that teicoplanin is a safe and useful new agent for the treatment of infections caused by Gram-positive organisms, including methicillin-resistant staphylococci and C. difficile.

Adolescent↗
PubMed1989

Third generation cephalosporins as a risk factor for Clostridium difficile-associated disease: a four-year survey in a general hospital.

The main clinical features of patients who developed pseudomembranous colitis (PMC) or Clostridium difficile-associated diarrhoea (CDAD) during their stay at the S. Anna General Hospital, Como, over the period February 1984 to May 1988, are reported. Forty patients developed either CDAD (ten cases) or PMC (30 cases). Twenty-seven (65.7%) had undergone surgery and 32 (80.0%) had received prolonged antibiotic treatment. Three patients (7.5%) were given three doses only of ceftriaxone. Five patients (12.5%) had not received any antibiotic treatment; but three were nursed in a bed next to a patient with PMC-CDAD. The number of cases diagnosed were correlated retrospectively with the cumulative consumption of different groups of antibiotics on wards in which PMC or CDAD occurred. A significant difference (P less than 0.01) between third generation cephalosporins (16 cases) and ureidopenicillins (one case), was found. Twenty-five patients were treated with oral vancomycin. Two died of the underlying disease and 23 were cured. The disease recurred clinically in three, and follow-up cultures were positive in another asymptomatic case. Fifteen patients (all PMC cases) were treated with oral teicoplanin. All were clinically cured and remained asymptomatic and all but one were also cleared of C. difficile. No adverse reactions were observed in patients given either drug. Third generation cephalosporins, even when administered as short-term perioperative prophylaxis, but not ureidopenicillins, are significantly associated with C. difficile-related diseases. Teicoplanin proved to be very effective and safe in the treatment of PMC, and should be further evaluated there.

Cephalosporins↗
PubMed1989

Treatment of Clostridium difficile-associated disease with teicoplanin.

Forty-seven patients affected by Clostridium difficile-associated disease were treated orally with either vancomycin (patients hospitalized from February 1984 to February 1987) or teicoplanin (from March 1987 to December 1988). All patients given teicoplanin remained asymptomatic after discontinuation of treatment, and all but one were also cleared of C. difficile. In the vancomycin group, clinical symptoms recurred in 3 of 23 evaluable patients, and follow-up cultures were positive in another asymptomatic case.

Anti-Bacterial Agents↗
PubMed1989

The association of essential hypertension and diabetes.

Diabetes may be associated with systolic hypertension secondary to atherosclerosis, renal hypertension secondary to diabetic nephropathy, and essential hypertension. The latter is by far the most prevalent, and a wealth of epidemiologic data suggests that such an association is independent of age and obesity. Considerable evidence indicates that the link between diabetes and essential hypertension is hyperinsulinemia. Thus, when hypertensive subjects, whether obese or of normal body weight, are compared to age- and weight-matched normotensive controls, a heightened plasma insulin response to a glucose challenge is found consistently. A state of cellular resistance to insulin action subtends the observed hyperinsulinism. With the use of the glucose clamp technique coupled with tracer glucose infusion and indirect calorimetry, it can be shown that the insulin resistance of essential hypertension is located in peripheral tissues (muscle), is limited to nonoxidative pathways of glucose disposal, and is directly correlated with the severity of hypertension. The reasons for the association of insulin resistance and essential hypertension can be sought in at least four general types of mechanisms--sodium retention, sympathetic nervous system overactivity, disturbed membrane ion transport, and altered muscle fiber composition. Physiologic maneuvers such as caloric restriction in the overweight individual and regular physical exercise can improve tissue sensitivity to insulin; good preliminary evidence shows that these measures can also lower blood pressure in both normotensive and hypertensive individuals. A strong case can therefore be made for the use of physiologic intervention in the treatment of essential hypertension.

Body Weight↗
PubMed1988

Immune response to hepatitis B vaccine given at different injection sites and by different routes: a controlled randomized study.

Two-hundred-ninety-nine hospital workers were randomly allocated to receive MSD hepatitis B vaccine in different injection sites and by different routes (intramuscularly by gluteal or deltoid injections or subcutaneously in the arm) or Pasteur vaccine subcutaneously. Highest rates of seroconversion and highest mean anti-HB, titres were found in subjects given MSD vaccine by intramuscular injection into the deltoid muscle.

Adult↗