Adipose tissue lipolysis and circulating lipids in acute and subacute critical illness: effects of shock and treatment.

PURPOSE: The purpose of this study is to assess lipid metabolism at the tissue level in critically ill subjects. MATERIALS AND METHODS: We studied 182 patients with systemic inflammatory response syndrome/severe sepsis or shock during the acute (day 1) and subacute phase of critical illness (day 6). All subjects had a tissue microdialysis (MD) catheter placed in femoral adipose tissue upon admission to the intensive care unit (ICU). Plasma cholesterol, high-density lipoprotein, low-density lipoprotein, free fatty acids (FFAs), triglyceride, and MD glycerol (GLYC) were measured on days 1 and 6 in the ICU. RESULTS: On admission, 56% of the patients had increased levels (>200 µmol/L) of MD GLYC. Patients with shock displayed more pronounced subcutaneous tissue lipolysis and more profound derangements of circulating lipids vs patients without shock (but no appreciable differences in FFA levels). Furthermore, in patients with shock during the acute period, there were positive, albeit weak, correlations of subcutaneous tissue lipolysis (MD GLYC), plasma FFAs (r=0.260; P=.01), and norepinephrine's dose (r=0.230; P=.01), whereas during the subacute phase, MD GLY levels were higher in patients receiving glucocorticoids (344.7±276.0 µmol/L vs 252.2±158.4 µmol/L; P=.03). CONCLUSIONS: Subcutaneous tissue lipolysis is only one of the many determinants of plasma FFAs. Routinely applied therapeutic modalities in the ICU interfere with adipose tissue metabolism.

Comparing classic and newer phenotypes in Greek PCOS women: the prevalence of metabolic syndrome and their association with insulin resistance.

OBJECTIVE: Recently, it has been debated whether the new polycystic ovary syndrome (PCOS) phenotypes, according to the Rotterdam criteria, share the same metabolic risk with the classic ones (National Institutes of Health 1990). Our study sought to compare the prevalence of metabolic syndrome (MS) and glucose homeostasis disorders in Greek women with classic and new PCOS phenotypes. MATERIALS AND METHODS: Two hundred and sixty-six Greek PCOS women were recruited and divided into groups according to two of the three Rotterdam criteria that they fulfilled. Two subgroups were formed; the first represented the classic phenotypes and the second the new phenotypes. The clinical, biochemical, and ultrasound characteristics of both groups were explored. All subjects were evaluated for MS and underwent a 2-h glucose tolerance test to assess insulin resistance (IR) as measured by the homeostasis model assessment (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), and MATSUDA indices. RESULTS: 62.4% of PCOS women were classified as classic NIH phenotypes of which 32 women had MS (prevalence 19.6%). Only 4 patients categorized in the newer phenotypic groups had MS (prevalence 4.1%). Among the subjects with classic phenotypes, 11.7% exhibited impaired glucose tolerance (3-fold higher percentage compared to patients with newer phenotypes). Regarding IR indices, HOMA-IR was significantly higher and QUICKI significantly lower for classic phenotypes. CONCLUSIONS: Greek PCOS women with classic phenotypes are at increased risk for MS and impaired glucose homeostasis compared to women with newer phenotypes. A subclassification of PCOS permits the earlier recognition and closer surveillance of women whose metabolic profile indicates potential risks for adverse health outcomes.

Skeletal muscle insulin resistance in morbid obesity: the role of interleukin-6 and leptin.

BACKGROUND: Although insulin resistance in obesity is established, the link between excess body fat and skeletal muscle insulin resistance is obscure. The aim of this study was to investigate whether cytokines secreted from the subcutaneous adipose tissue are related to the sensitivity of glucose metabolism to insulin in skeletal muscle. METHODS: A meal was given to 14 obese and 10 non-obese women. Plasma samples were taken for 360 min from a forearm vein and from the radial artery for glucose and insulin measurements. Interleukin-6, leptin, TNFα, resistin and adiponectin were measured preprandially from the radial artery and from the superficial epigastric vein. Forearm blood flow was measured with plethysmography. RESULTS: (1) In obese vs non-obese: (a) Glucose uptake by skeletal muscle was decreased (AUC (0-360)369 ± 55 vs. 877 ± 146 µmol/100 g tissue, p=0.001) (b) arterial interleukin-6 (2.5 ± 0.5 vs. 1 ± 0.1 pg/ml, p=0.013) and subcutaneous venous interleukin-6 (5 ± 0.5 vs. 3.4 ± 0.5 pg/ml, p=0.027) were increased (c) arterial leptin (63 ± 7 vs. 5 ± 0.6 ng/ml, p<0.0001) and subcutaneous venous leptin 80 ± 8 vs. 6.5 ± 0.7 ng/ml, p<0.0001) were increased. (2) Arterial interleukin-6 (p=0.002) and subcutaneous venous interleukin-6 (p=0.014) were negatively associated with forearm glucose uptake in obese. (3) No association was found between leptin and forearm glucose uptake, after correcting with fat mass. CONCLUSIONS: In morbid obesity: (1) Subcutaneous adipose tissue releases interleukin-6 which could then mediate insulin resistance in skeletal muscle. (2) Although there is increased secretion of leptin by the subcutaneous adipose tissue, leptin levels are not correlated to the sensitivity of glucose metabolism to insulin in muscle.

Effects of adiponectin in TNF-α, IL-6, and IL-10 cytokine production from coronary artery disease macrophages.

Adiponectin, an adipose tissue secreted protein, exhibits anti-inflammatory and antiatherogenic properties. We examined the effects of the globular and full-length adiponectin on cytokine production in macrophages derived from Coronary Artery Disease (CAD) patients and control individuals. Adiponectin's effects in human macrophages upon lipopolysaccharide (LPS) treatment were also examined. Full length adiponectin acted differently on TNF-α and IL-6 production by upregulating TNF-α and IL-6 protein production, but not their mRNA expression. Additionally, full length adiponectin was unable to abrogate LPS proinflammatory effect in TNF-α and IL-6 mRNA expression in CAD and NON-CAD macrophages. In contrast, globular adiponectin appeared to have proinflammatory properties by potently upregulating TNF-α and IL-6 mRNA and protein secretion in human macrophages while subsequently rendered cells resistant to further proinflammatory stimuli. Moreover, both forms of adiponectin powerfully suppressed scavenger MSR-AI mRNA expression and augmented IL-10 protein release, both occurring independently of the presence of LPS or CAD. These data indicate that adiponectin could potentially protect human macrophages via the elevated IL-10 secretion and the suppression of MSR-AI expression. It can also be protective in CAD patients since the reduced adiponectin-induced IL-6 release in CAD macrophages compared to controls, could be beneficial in the development of inflammation related atherosclerosis.

Rates of lipid fluxes in adipose tissue in vivo after a mixed meal in morbid obesity.

OBJECTIVE: Although insulin resistance in obesity is established, information on insulin action on lipid fluxes, in morbid obesity, is limited. This study was undertaken in morbidly obese women to investigate insulin action on triacylglycerol fluxes and lipolysis across adipose tissue. SUBJECTS AND DESIGN: A meal was given to 26 obese (age 35+/-1 years, body mass index 46+/-1 kg m(-2)) and 11 non-obese women (age 38+/-2 years, body mass index 24+/-1 kg m(-2)). Plasma samples for glucose, insulin, triglycerides and non-esterified fatty acids (NEFAs) were taken for 360 min from a vein draining the abdominal subcutaneous adipose tissue and from the radial artery. Adipose tissue blood flow was measured with (133)Xe. RESULTS: In obese vs non-obese: (1) Arterial glucose was similar, but insulin was increased (P=0.0001). (2) Adipose tissue blood flow was decreased (P=0.0001). (3) Arterial triglycerides (P=0.0001) and NEFAs (P=0.01) were increased. (4) Lipoprotein lipase was decreased (P=0.0009), although the arteriovenous triglyceride differences were similar. (5) Veno-arterial NEFA differences across the adipose tissue were similar. (6) NEFA fluxes and hormone-sensitive lipase-derived glycerol output from 100 g adipose tissue were not different. (7) Total adipose tissue NEFA release was increased (P=0.02). CONCLUSIONS: In morbid obesity: (a) hypertriglycerinemia could be attributed to a defect in the postprandial dynamic adjustment of triglyceride clearance across the adipose tissue, partly caused by blunted BF; and (b) postprandially, there is an impairment of adipose tissue to buffer NEFA excess, despite hyperinsulinemia.

Glucose transporter expression on the plasma membrane of resting and activated white blood cells.

BACKGROUND: In white blood cells (WBC), the increase in glucose utilization is a prominent feature during immune response and this depends on the function of specific glucose transporter (GLUT) isoforms. The objective was to examine the effects of activation by Phorbol 12-myristate 13-acetate (PMA) or lipopolysaccharide (LPS) and insulin on the expression of GLUT isoforms in all subpopulations of WBC. MATERIALS AND METHODS: Blood was withdrawn from 27 healthy subjects. The expression of GLUT1, GLUT3 and GLUT4 on the plasma membrane of resting and activated monocytes, T- and B-lymphocytes and polymorphonuclear cells (PMNs) was determined in the absence and presence of physiological concentrations of insulin, by flow cytometry. RESULTS: GLUT1 did not respond to insulin in either resting or PMA/LPS activated state. In the resting state, monocytes and B-lymphocytes increased the abundance of GLUT3 and GLUT4 on their plasma membrane in response to insulin; in contrast, T-lymphocytes and PMNs were unresponsive to insulin. In the activated state, monocytes, B- and T- lymphocytes increased the expression of all three GLUT isoforms on their plasma membrane, whilst PMNs increased only GLUT1 and GLUT3; in all WBC, insulin augmented the expression of GLUT4 and GLUT3 isoforms in addition to the stimulation provided by the PMA or LPS treatment alone. CONCLUSION: Activation of WBC leads to increased expression of GLUT1, GLUT3 and GLUT4 isoforms on their plasma membrane; this process was further augmented by insulin. During infection, these mechanisms may help to redistribute glucose as a potential source of energy away from peripheral tissues and direct it towards cells that mediate the immune response and are therefore crucial to survival.

Acute nateglinide administration in subjects with type 2 diabetes: effects on postprandial metabolism, coagulation, and fibrinolysis.

BACKGROUND AND AIM: Postprandial glycaemia and lipaemia are known risk factors for atherosclerosis in type 2 diabetes. Coagulation activation in the postprandial state also contributes to acceleration of atherosclerosis. Nateglinide is effective in reducing postprandial glycaemia. Its effect on glycaemia may also be beneficial in postprandial lipaemia and coagulation. The aim of this study was to examine the potential effect of a single dose of nateglinide on postprandial triglyceridaemia, coagulation, and fibrinolysis in patients with type 2 diabetes. METHODS AND RESULTS: Ten subjects with type 2 diabetes, treated with diet alone were recruited in a crossover randomized study. In the morning, after a 12- to 14-h fast, each subject received a standard mixed meal (total energy 783 kcal), preceded by one tablet of 120 mg nateglinide or placebo. Venous blood samples were drawn prior to meal consumption and 6h afterwards for the measurement of plasma glucose, insulin, and C-peptide, lipids, coagulation, and fibrinolysis factors. As expected, there was a significant reduction in postprandial glycaemia after nateglinide administration compared to placebo (P<0.001). Plasma insulin levels were significantly higher after nateglinide than after placebo (P=0.002). Nateglinide administration resulted in a lower overall postprandial reduction of tissue-plasminogen activator than placebo (-2.9+/-1.3 vs. -8.3+/-3.7 ng/ml h, P=0.003). In addition, a significant reduction of postprandial plasminogen activator inhibitor-1 was observed in comparison with the baseline values after nateglinide (P=0.001), although the overall response was not significantly different after nateglinide and placebo (P=0.31). Plasma concentrations of C-peptide, lipids and the remaining coagulation parameters studied were not different between nateglinide and placebo. CONCLUSIONS: Acute nateglinide administration improves postprandial glycaemia and fibrinolytic activity in patients with type 2 diabetes. This combined effect, if confirmed by a long-treatment study, might reduce cardiovascular risk in type 2 diabetes.

Thyroid hormone excess increases basal and insulin-stimulated recruitment of GLUT3 glucose transporters on cell surface.

BACKGROUND: In hyperthyroidism, tissue glucose disposal is increased to adapt to high energy demand. Our aim was to examine the glucose transporter isoforms involved in this process and their regulation through insulin in monocytes from subjects with hyperthyroidism. METHODS: Blood (20 ml) was withdrawn from 12 healthy and 12 hyperthyroid subjects. The abundance of glucose transporter isoforms (GLUT) on the monocyte surface membrane was determined in the absence and presence of insulin (10-100 mU/l) using flow cytometry. Anti-CD14-PE monoclonal antibody was used for monocyte gating. GLUT isoforms were determined after staining the cells with specific antisera to GLUT1, GLUT3 and GLUT4. RESULTS: Hyperthyroidism increased basal monocyte-surface GLUT1, GLUT3 and GLUT4 transporters. In these cells, insulin had a marginal effect on GLUT4 translocation (25 %, p < 0.02) and a more significant effect on GLUT3 translocation (45 %, p < 0.001) on plasma membrane. CONCLUSIONS: In the hyperthyroid state, (1) basal abundance of GLUT1, GLUT3 and GLUT4 transporters on the cell surface is increased; (2) insulin mainly increases the recruitment of GLUT3 and, to a lesser extent, GLUT4 glucose transporters on the plasma membrane. These findings may provide a mechanism to explain the increment of glucose disposal in peripheral tissues in hyperthyroidism.

Restoration of early insulin secretion after a meal in type 2 diabetes: effects on lipid and glucose metabolism.

BACKGROUND: In type 2 diabetes (T2D) insulin secretion after a meal is delayed; this may have an impact on the development of hyperglycaemia and hyperlipidaemia. DESIGN: To investigate this, a meal was given to 15 T2D (age 52 +/- 2 years, BMI 25 +/- 0.8 kg m(-2)) on three different occasions: (1) without treatment, (2) after 120 mg of nateglinide before the meal (acute treatment), and (3) after 3 months of nateglinide (120 mg t.i.d., chronic treatment). Fifteen healthy subjects (CON, age 48 +/- 2 years, BMI 24 +/- 0.5 kg m(-2)) were also studied. Blood was withdrawn for 360 min from veins draining the anterior abdominal subcutaneous adipose tissue (AD) and from an arterialized hand vein. Blood flow (BF) in AD was measured with (133)Xe. Lipoprotein lipase activity (LPL) was calculated as the triacylglycerol (TAG) flux across AD, and hormone-sensitive lipase (HSL) as the glycerol flux minus LPL. RESULTS: (1) In T2D the increase in prandial insulin secretion was delayed; postprandial nonesterified fatty acid (NEFA) and TAG levels in blood were increased, while BF, LPL and TAG clearance were blunted vs. CON. (2) Acute or chronic nateglinide treatment induced a prompt increase in prandial insulin secretion, resulting in a decrease in blood glucose and NEFA levels owing to suppression of HSL, while BF, LPL and TAG clearance remained suppressed. CONCLUSIONS: In T2D, restoration of early phase insulin secretion improved postprandial hyperglycaemia and suppressed endogenous lipolysis, resulting in suppression of NEFA levels. These results suggest that in nonobese T2D, metabolic defects may result, to a large extent, from the delay in prandial insulin secretion.

Fusarium, a significant emerging pathogen in patients with hematologic malignancy: ten years' experience at a cancer center and implications for management.

Despite increasing reports of life-threatening Fusarium infections, little is known about its pathogenesis and management. To evaluate the epidemiology, clinicopathologic features, and outcome of invasive fusariosis in patients with hematologic cancer, we conducted a retrospective study of invasive fusarial infections in patients with hematologic malignancy treated at a referral cancer center over a 10-year period (1986 to 1995), as well as a literature review. Forty patients with disseminated and three patients with invasive lung infection were included in the analysis. All patients were immunocompromised. The infection occurred in three patients postengraftment following bone marrow transplantation. All patients were diagnosed antemortem. Thirteen patients responded to therapy, but the infection relapsed in two of them. Response was associated with granulocyte transfusions, amphotericin B lipid formulations (four patients each), and an investigational triazole (two patients). Resolution of infection was only seen in patients who ultimately recovered from myelosuppression. Portal of entry was the skin (33%), the sinopulmonary tree (30%), and unknown (37%). Fusarium causes serious morbidity and mortality, and may mimic aspergillosis. The infection seems to respond to newer therapeutic approaches, but only in patients with ultimate recovery from myelosuppression, and it may relapse if neutropenia recurs.