Biomedical subjects

Livio Luzi

Publications and source records attributed to Livio Luzi.

28 records · Page 2Linked to original sources

PubMed2003

Fasting plasma leptin, tumor necrosis factor-alpha receptor 2, and monocyte chemoattracting protein 1 concentration in a population of glucose-tolerant and glucose-intolerant women: impact on cardiovascular mortality.

OBJECTIVE: Leptin and tumor necrosis factor (TNF)-alpha are associated with insulin resistance and cardiovascular disease. In vitro studies suggested that these effects may be mediated via overproduction of monocyte chemoattracting protein (MCP)-1/CCL2, which is a chemokine involved in the pathogenesis of atherosclerosis. RESEARCH DESIGN AND METHODS: In this study, fasting plasma leptin, soluble TNF-alpha receptor 2 (TNF-alpha-R2), and MCP-1/CCL2 concentrations were measured in 207 middle-aged women (age 61 +/- 12 years, BMI 30.1 +/- 6.6 kg/m(2)), including 53 patients with type 2 diabetes, 42 with impaired glucose tolerance, and 112 with normal glucose tolerance, to assess cross-sectionally their relationship with markers of atherosclerosis and, longitudinally over 7 years, whether their circulating levels were associated with cardiovascular disease (CVD) mortality. RESULTS: At baseline, leptin and TNF-alpha-R2 were not different among groups; meanwhile, MCP-1/CCL2 was increased in type 2 diabetes (P < 0.05). All showed significant associations with biochemical risk markers of atherosclerosis. In a univariate analysis, age, fasting insulin, leptin, and MCP-1/CCL2 were associated with CVD mortality at 7 years. When a multivariate analysis was performed, only age, leptin, and insulin retained an independent association with CVD mortality, with leptin showing a protective effect (hazard ratio 0.88; P < 0.02). CONCLUSIONS: In middle-aged women, MCP-1/CCL2, leptin, and TNF-alpha-R2 were all related to biochemical risk markers of atherosclerosis. MCP-1/CCL2 concentration was the only one to be increased in type 2 diabetes with respect to nondiabetic women and the only one to be associated with increased risk of CVD mortality after a 7-year follow-up period in the univariate analysis. In the multivariate analysis, neither MCP-1/CCL2 nor TNF-alpha-R2 was associated with CVD mortality, and inspection of the data showed that leptin, in both the univariate and multivariate analysis, was associated with a protective effect.

Aged↗

PubMed2003

Contribution of abnormal insulin secretion and insulin resistance to the pathogenesis of type 2 diabetes in myotonic dystrophy.

OBJECTIVE: Myotonic dystrophy (MyD), the most common adult form of muscular dystrophy, is often complicated by diabetes. MyD is dominantly inherited and is due to heterozygosity for a trinucleotide repeat expansion mutation in a protein kinase gene able to induce derangement of RNA metabolism responsible of an aberrant insulin receptor expression. RESEARCH DESIGN AND METHODS: To assess insulin sensitivity and secretion before the onset of diabetes, we studied 10 MyD patients, 10 offspring of type 2 diabetes (OFF), and 10 healthy subjects with no family history of diabetes (control subjects) with dual X-ray energy absorption, euglycemic-hyperinsulinemic clamp (40 mU/[m(2). min]) combined with infusion of [6,6-D(2)]-glucose and oral glucose tolerance test (OGTT). RESULTS: MyD had reduced lean body mass, but peripheral insulin sensitivity was not different to that of control subjects in contrast to OFF, which showed insulin resistance. Insulin secretion, obtained by deconvolution of OGTT data, was also shown to be comparable with that of OFF and control subjects (index of beta-cell function = Phi; P = 0.91) even if increased parameters of insulin secretion were found during the first 30 min (Phi(30); P = 0.05) of the oral glucose challenge. Fasting plasma proinsulin concentrations (P = 0.01) and the ratio to insulin (P = 0.01) were increased in MyD patients. The proinsulin levels also failed to be suppressed during the clamp and showed exaggerated response after the OGTT. Increased proinsulin levels were shown to be peculiar of MyD patients when compared with OFF. CONCLUSIONS: In nondiabetic, young MyD patients, insulin sensitivity was preserved, and an increased early secretory response to oral glucose was detected. Abnormal plasma proinsulin levels in the fasting state, during the clamp, and during the OGTT were shown to be secretory dysfunctions peculiar of MyD patients and may be more important than insulin resistance in determining the high risk to develop diabetes in these patients.

Adult↗

PubMed2002

Insulin action on protein metabolism in acromegalic patients.

Insulin resistance in acromegaly causes glucose intolerance and diabetes, but it is unknown whether it involves protein metabolism, since both insulin and growth hormone promote protein accretion. The effects of acromegaly and of its surgical cure on the insulin sensitivity of glucose and amino acid/protein metabolism were evaluated by infusing [6,6-(2)H(2)]glucose, [1-(13)C]leucine, and [2-(15)N]glutamine during a euglycemic insulin (1 mU x kg(-1) x min(-1)) clamp in 12 acromegalic patients, six studied again 6 mo after successful adenomectomy, and eight healthy controls. Acromegalic patients, compared with postsurgical and control subjects, had higher postabsorptive glucose concentration (5.5 +/- 0.3 vs. 4.9 +/- 0.2 micromol/l, P < 0.05, and 5.1 +/- 0.1 micromol/l) and flux (2.7 +/- 0.1 vs. 2.0 +/- 0.2 micromol x kg(-1) x min(-1), P < 0.01, and 2.2 +/- 0.1 micromol x kg(-1) x min(-1), P < 0.05) and reduced insulin-stimulated glucose disposal (+15 +/- 9 vs. +151 +/- 18%, P < 0.01, and 219 +/- 58%, P < 0.001 from basal). Postabsorptive leucine metabolism was similar among groups. In acromegalic and postsurgical subjects, insulin suppressed less than in controls the endogenous leucine flux (-9 +/- 1 and -12 +/- 2 vs. -18 +/- 2%, P < 0.001 and P < 0.05), the nonoxidative leucine disposal (-4 +/- 3 and -1 +/- 3 vs. -18 +/- 2%, P < 0.01 and P < 0.05), respectively, indexes of proteolysis and protein synthesis, and leucine oxidation (-17 +/- 6% in postsurgical patients vs. -26 +/- 6% in controls, P < 0.05). Within 6 mo, surgery reverses insulin resistance for glucose but not for protein metabolism. After adenomectomy, more leucine is oxidized during hyperinsulinemia.

Acromegaly↗

PubMed2002

Intramyocellular lipid accumulation and reduced whole body lipid oxidation in HIV lipodystrophy.

Antiretroviral therapy in human immunodeficiency virus (HIV)-positive patients can induce a lipodystrophy syndrome of peripheral fat wasting and central adiposity, dyslipidemia, and insulin resistance. To test whether in this syndrome insulin resistance is associated with abnormal muscle handling of fatty acids, 12 HIV-1 patients (8 females/4 males, age = 26 +/- 2 yr, HIV duration = 8 +/- 1 yr, body mass index = 22.0 +/- 1.0 kg/m(2), on protease inhibitors and nucleoside analog RT inhibitors) and 12 healthy subjects were studied. HIV-1 patients had a total body fat content (assessed by dual-energy X-ray absorptiometry) similar to that of controls (22 +/- 1 vs. 23 +/- 2%; P = 0.56), with a topographic fat redistribution characterized by reduced fat content in the legs (18 +/- 2 vs. 32 +/- 3%; P < 0.01) and increased fat content in the trunk (25 +/- 2 vs. 19 +/- 2%; P = 0.03). In HIV-positive patients, insulin sensitivity (assessed by QUICKI) was markedly impaired (0.341 +/- 0.011 vs. 0.376 +/- 0.007; P = 0.012). HIV-positive patients also had increased total plasma cholesterol (216 +/- 20 vs. 174 +/- 9 mg/dl; P = 0.05) and triglyceride (298 +/- 96 vs. 87 +/- 11 mg/dl; P = 0.03) concentrations. Muscular triglyceride content assessed by means of (1)H NMR spectroscopy was higher in HIV patients in soleus [92 +/- 12 vs. 42 +/- 5 arbitrary units (AU); P < 0.01] and tibialis anterior (26 +/- 6 vs. 11 +/- 3 AU; P = 0.04) muscles; in a stepwise regression analysis, it was strongly associated with QUICKI (R(2) = 0.27; P < 0.0093). Even if the basal metabolic rate (assessed by indirect calorimetry) was comparable to that of normal subjects, postabsorptive lipid oxidation was significantly impaired (0.30 +/- 0.07 vs. 0.88 +/- 0.09 mg x kg(-1) x min(-1); P < 0.01). In conclusion, lipodystrophy in HIV-1 patients in antiretroviral treatment is associated with intramuscular fat accumulation, which may mediate the development of the insulin resistance syndrome.

Adipose Tissue↗

PubMed2002

Amino acid- and lipid-induced insulin resistance in rat heart: molecular mechanisms.

Lipids compete with glucose for utilization by the myocardium. Amino acids are an important energetic substrate in the heart but it is unknown whether they reduce glucose disposal. The molecular mechanisms by which lipids and amino acids impair insulin-mediated glucose disposal in the myocardium are unknown. We evaluated the effect of lipids and amino acids on the insulin stimulated glucose uptake in the isolated rat heart and explored the involved target proteins. The hearts were perfused with 16 mM glucose alone or with 6% lipid or 10% amino acid solutions at the rate of 15 ml/min. After 1 h of perfusion (basal period), insulin (240 nmol/l) was added and maintained for an additional hour. Both lipids and amino acids blocked the insulin effect on glucose uptake (P<0.01) and reduced the activity of the IRSs/PI 3-kinase/Akt/GSK3 axis leading to the activation of glucose transport and glycogen synthesis. Amino acids, but not lipids, increased the activity of the p70 S6 kinase leading to the stimulation of protein synthesis. Amino acids induce myocardial insulin resistance recruiting the same molecular mechanisms as lipids. Amino acids retain an insulin-like stimulatory effect on p70 S6 kinase, which is independent from the PI 3-Kinase downstream effectors.

Amino Acids↗

PubMed2002

Resting energy expenditure in diabetic and nondiabetic patients with liver cirrhosis: relation with insulin sensitivity and effect of liver transplantation and immunosuppressive therapy.

BACKGROUND: Hypermetabolism, insulin resistance, and diabetes are common in patients with liver cirrhosis. OBJECTIVE: We assessed whether diabetes and insulin resistance influence postabsorptive energy homeostasis in these patients and whether liver transplantation (LTx) and immunosuppressive drugs affect these relations. DESIGN: Twenty-six patients with liver cirrhosis (16 with and 10 without diabetes) were studied with an insulin clamp and indirect calorimetry. Eleven of these subjects were studied 9 mo after LTx to longitudinally assess its effects. To cross-sectionally explore a longer follow-up period, we studied 65 patients 6, 14, and 32 mo after LTx. Seven patients with chronic uveitis (receiving immunosuppressive therapy) and 20 healthy subjects served as control subjects. RESULTS: Diabetic and nondiabetic patients with cirrhosis had insulin resistance (S(I(clamp)); P < 0.03) and higher measured resting energy expenditure (REE) as a percentage of predicted REE than did healthy subjects (107.6 +/- 1.8% compared with 97.4 +/- 2.3%; P < 0.03), and these 2 alterations were associated (R(2) = 0.119, P = 0.0002). The longitudinal study showed an improvement in the 2 variables after LTx, but full restoration was not achieved. The cross-sectional analysis confirmed this observation in patients studied 6 mo (n = 28) after LTx. In patients studied 14 (n = 21) and 32 mo (n = 16) after LTx, S(I(clamp)) and measured REE as a percentage of predicted REE were not significantly different from those in control subjects. CONCLUSIONS: In patients with liver cirrhosis, higher-than-normal postabsorptive REE was associated with insulin resistance regardless of diabetes. This abnormality persisted in patients studied 6-9 mo after LTx but improved simultaneously with the improvement in insulin sensitivity thereafter.

Basal Metabolism↗

PubMed2002

Normal insulin sensitivity and IMCL content in overweight humans are associated with higher fasting lipid oxidation.

Intramyocellular lipid (IMCL) storage is considered a local marker of whole body insulin resistance; because increments of body weight are supposed to impair insulin sensitivity, this study was designed to assess IMCL content, lipid oxidation, and insulin action in individuals with a moderate increment of body fat mass and no family history of diabetes. We studied 14 young, nonobese women with body fat <30% (n = 7) or >30% (n = 7) and 14 young, nonobese men with body fat <25% (n = 7) or >25% (n = 7) by means of the euglycemic-insulin clamp to assess whole body glucose metabolism, with indirect calorimetry to assess lipid oxidation, by localized (1)H NMR spectroscopy of the calf muscles to assess IMCL content, and with dual-energy X-ray absorptiometry to assess body composition. Subjects with higher body fat had normal insulin-stimulated glucose disposal (P = 0.80), IMCL content in both soleus (P = 0.22) and tibialis anterior (P = 0.75) muscles, and plasma free fatty acid levels (P = 0.075) compared with leaner subjects in association with increased lipid oxidation (P < 0.05), resting energy expenditure (P = 0.046), resting oxygen consumption (P = 0.049), and plasma leptin levels (P < 0.01) in the postabsorptive condition. In conclusion, in overweight subjects, preservation of insulin sensitivity was combined with increased lipid oxidation and maintenance of normal IMCL content, suggesting that abnormalities of these factors may mutually determine the development of insulin resistance associated with weight gain.

Adult↗

PubMed2002

Amino acid kinetics during the anhepatic phase of liver transplantation.

Alanine and glutamine are interorgan nitrogen/carbon carriers for ureagenesis and gluconeogenesis, which are mainly but not necessarily only hepatic. The liver is central to alanine and glutamine metabolism, but most organs can produce and use them. We studied amino acid kinetics after liver removal to depict initial events of liver failure and to provide a model to study extrahepatic gluconeogenesis and nitrogen disposal in humans. We measured amino acid kinetics with [5,5,5-(2)H(3)]leucine and [3-(13)C]alanine or [1,2-(13)C(2)]glutamine tracers in 21 subjects during and after the anhepatic phase of liver transplantation: 12 were at 7 months posttransplantation, and 7 were healthy control subjects. Anhepatic leucine kinetics, including proteolysis, was unchanged. Alanine plasma and whole-body contents increased 3x and 2x, with a halved metabolic clearance and a doubled production, 2% greater than disposal. Free whole-body glutamine decreased 25% but increased 50% in plasma. Glutamine clearance was halved, and the production decreased by 25%, still 2% greater than disposal. Liver replacement decreased alanine and glutamine concentrations, leaving leucine unchanged. Liver removal caused doubled alanine fluxes, minor changes in glutamine, and no changes in leucine. The initial events after liver removal are an accumulation of three-carbon compounds, an acceleration of alanine turnover, and limited nitrogen storage in alanine and glutamine.

Alanine↗

PubMed2002

Fasting blood sample-based assessment of insulin sensitivity in kidney-pancreas-transplanted patients.

OBJECTIVE: To ascertain whether simple indexes of insulin sensitivity based on a fasting blood sample may be reliable measures of insulin sensitivity in combined kidney-pancreas- transplanted patients. RESEARCH DESIGN AND METHODS: Estimates of insulin sensitivity based on fasting plasma glucose, insulin (homeostasis model assessment of insulin sensitivity [HOMA-IS], Quantitative Insulin Sensitivity Check Index [QUICKI]), and free fatty acid (revised QUICKI) concentrations were compared with insulin sensitivity as assessed with the gold standard technique (euglycemic-hyperinsulinemic clamp) in 22 patients who had undergone kidney-pancreas transplantation (KP-Tx) and 18 matched healthy subjects (NOR). RESULTS: In KP-Tx patients, indexes based on the glucose-insulin product, HOMA-IS (r = 0.47, P = 0.03) and QUICKI (r = 0.47, P = 0.03), were shown to be reliable measures of insulin sensitivity. The introduction of fasting plasma free fatty acid concentration in the revised QUICKI (r = 0.76, P < 0.0001) considerably improved the power of prediction of the clamp-based measure of insulin sensitivity as observed in the healthy control subjects (r = 0.83, P < 0.0001). CONCLUSIONS: This study shows that in KP-Tx patients, HOMA-IS and QUICKI are reliable measures of insulin sensitivity; the additional incorporation of fasting plasma free fatty acid concentration into the glucose-insulin product (revised QUICKI) resulted in a considerably more powerful index.

Adult↗

PubMed2002

Energy metabolism in diabetic and nondiabetic heart transplant recipients.

OBJECTIVE: This study examined the metabolic effects of heart transplantation in patients in end-stage cardiac failure. RESEARCH DESIGN AND METHODS: A total of 18 patients after heart transplantation for end-stage heart disease (age 47 +/- 3 years; transplant age 5.5 +/- 1.5 years; BMI 25.8 +/- 0.8 kg/m(2); cyclosporin A 4.2 +/- 0.6 mg/[kg.day]; azathioprine 0.87 +/- 0.31 mg/[kg.day]), 12 patients with type 2 diabetes (D-Tx), and 6 patients without type 2 diabetes (Tx) were studied by means of 1) an oral glucose tolerance test (OGTT) to assess the beta-cell secretory response, 2) a euglycemic-hyperinsulinemic (1 mU/[kg.min]) clamp combined with indirect calorimetry and a primed continuous infusion of [6,6-2H2]glucose and [1-13C]leucine to measure postabsorptive and insulin-stimulated carbohydrate and protein metabolism, and 3) 1H-NMR spectroscopy of the calf muscles to measure intramyocellular triglyceride (IMCL) content. The patients were selected from 480 transplant patients in whom there was a 6% prevalence of type 2 diabetes. Five healthy subjects matched for anthropometric parameters served as control subjects (CON). RESULTS: Tx had postabsorptive and insulin-stimulated glucose, leucine, and free fatty acid metabolism, as well as IMCL content, similar to that of CON. D-Tx were characterized by a reduced secretory response during the OGTT and peripheral insulin resistance with respect to glucose metabolism, which was paralleled by increased plasma free fatty acid concentrations and IMCL content. A defective insulin-dependent suppression of the endogenous leucine flux (index of proteolysis) was also evident during the clamp in D-Tx. CONCLUSIONS: Heart transplantation, notwithstanding the immunosuppressive therapy, was characterized by a normal postabsorptive and insulin-stimulated glucose, leucine, and free fatty acid metabolism in Tx. In contrast, insulin resistance with respect to glucose, free fatty acids, and protein metabolism was present in D-Tx regardless of whether diabetes was preexisting or consequent to heart transplantation.

Adult↗