Association of serum adiponectin concentration to lipid and glucose metabolism in healthy humans.

BACKGROUND: Adiponectin is a recently discovered plasma protein with many associations to glucose and lipid metabolism. Due to its central role in cardiovascular diseases and insulin resistance, we studied the relationship between serum adiponectin and factors reflecting glucose and lipid metabolism. METHODS AND RESULTS: Thirty healthy participants (20M/10F, age 32.0 +/- 2.1 years, BMI 25.8 +/- 0.9 kg/m (2) and HbA (1c) 5.2 +/- 0.1 %) were studied four times at approximately one week intervals. The effects of a 4-hour euglycemic hyperinsulinemia (40 mU/m (2)/min), saline infusion (control), oral glucose, and oral fat load on serum adiponectin were studied. No significant correlation was found between serum adiponectin and insulin sensitivity before (r = 0.25) or after adjustment for age, BMI and gender (r = 0.04). Adiponectin concentration correlated inversely with HbA (1c) (r = - 0.43, p < 0.05), insulin concentration (r = - 0.38, p < 0.05) and triglyceride concentration (r = - 0.42, p < 0.05) but positively with HDL cholesterol (r = 0.38, p < 0.05). Metabolic procedures had no effect on serum adiponectin. CONCLUSIONS: Our findings favor the interpretation that adiponectin is not causally related to insulin sensitivity in healthy participants. The strongest associations of adiponectin in healthy participants are to be found to lipid metabolism. Serum levels of adiponectin are very stable and not acutely affected by hyperinsulinemia, oral glucose or fat load.     

Relationship of adiponectin with insulin sensitivity in humans, independent of lipid availability

Objective: To test in humans the hypothesis that part of the association of adiponectin with insulin sensitivity is independent of lipid availability. Research Methods and Procedures: We studied relationships among plasma adiponectin, insulin sensitivity (by hyperinsulinemic‐euglycemic clamp), total adiposity (by DXA), visceral adiposity (VAT; by magnetic resonance imaging), and indices of lipid available to muscle, including circulating and intramyocellular lipid (IMCL; by ¹H‐magnetic resonance spectroscopy). Our cohort included normal weight to obese men (n = 36). Results: Plasma adiponectin was directly associated with insulin sensitivity and high‐density lipoprotein‐cholesterol and inversely with plasma triglycerides but not IMCL. These findings are consistent with adiponectin promoting lipid uptake and subsequent oxidation in muscle and inhibiting TG synthesis in the liver. In multiple regression models that also included visceral and total fat, free fatty acids, TGs, and IMCL, either alone or in combination, adiponectin independently predicted insulin sensitivity, consistent with some of its insulin‐sensitizing effects being mediated through mechanisms other than modulation of lipid metabolism. Because VAT directly correlated with total fat and all three indices of local lipid availability, free fatty acids, and IMCL, an efficient regression model of insulin sensitivity (R² = 0.69, p < 0.0001) contained only VAT (part R² = 0.12, p < 0.002) and adiponectin (part R² = 0.41, p < 0.0001) as independent variables. Discussion: Given the broad range of total adiposity and body fat distribution in our cohort, we suggest that insulin sensitivity is robustly associated with adiponectin and VAT.     

Relationship between visceral adiposity and intramyocellular lipid content in two rat models of insulin resistance

High visceral adiposity and intramyocellular lipid levels (IMCL) are both associated with the development of type 2 diabetes. The relationship between visceral adiposity and IMCL levels was explored in diet- and glucocorticoid-induced models of insulin resistance. In the diet-induced model, lean and fa/fa Zucker rats were fed either normal or high-fat (HF) chow over 4 wk. Fat distribution, IMCL content in the tibialis anterior (TA) muscle (IMCL(TA)), and whole body insulin resistance were measured before and after the 4-wk period. The HF diet-induced increase in IMCL(TA) was strongly correlated with visceral fat accumulation and greater glucose intolerance in both groups. The increase in IMCL(TA) to visceral fat accumulation was threefold greater for fa/fa rats. In the glucocorticoid-induced model, insulin sensitivity was impaired with dexamethasone. In vivo adiposity and IMCL(TA) content measurements were combined with ex vivo analysis of plasma and muscle tissue. Dexamethasone treatment had minimal effects on visceral fat accumulation while increasing IMCL(TA) levels approximately 30% (P < 0.05) compared with controls. Dexamethasone increased plasma glucose by twofold and increased the saturated fatty acid content of plasma lipids [fatty acid (CH2)n/omegaCH3 ratio +15%, P < 0.05]. The lipid composition of the TA muscle was unchanged by dexamethasone treatment, indicating that the relative increase in IMCL(TA) observed in vivo resulted from a decrease in lipid oxidation. Visceral adiposity may influence IMCL accumulation in the context of dietary manipulations; however, a "causal" relationship still remains to be determined. Dexamethasone-induced insulin resistance likely operates under a different mechanism, i.e., independently of visceral adiposity.     

Insulin resistance,intramyocellular lipid content,and plasma adiponectin in patients with type 1 diabetes

Insulin resistance is a key pathogenic factor of type 2 diabetes (T2DM); in contrast, in type 1 diabetes (T1DM) it is considered a secondary alteration. Increased intramyocellular lipid (IMCL) content accumulation and reduced plasma adiponectin were suggested to be pathogenic events of insulin resistance in T2DM. This study was designed to assess whether IMCL content and plasma adiponectin were also associated with the severity of insulin resistance in T1DM. We studied 18 patients with T1DM, 7 older and overweight/obese patients with T2DM, and 15 nondiabetic, insulin-resistant offspring of T2DM parents (OFF) and 15 healthy individuals (NOR) as appropriate control groups matched for anthropometric features with T1DM patients by means of the euglycemic hyperinsulinemic clamp combined with the infusion of [6,6-2H2]glucose and 1H magnetic resonance spectroscopy of the calf muscles. T1DM and T2DM patients showed reduced insulin-stimulated glucose metabolic clearance rate (MCR: 5.1 +/- 0.6 and 3.2 +/- 0.8 ml x kg(-1) min(-1)) similar to OFF (5.3 +/- 0.4 ml x kg(-1) x min(-1)) compared with NOR (8.5 +/- 0.5 ml x kg(-1) min(-1), P < 0.001). Soleus IMCL content was increased in T1DM (112 +/- 15 AU), T2DM (108 +/- 10 AU) and OFF (82 +/- 13 AU) compared with NOR (52 +/- 7 AU, P < 0.05) and the result was inversely proportional to the MCR (R2 = 0.27, P < 0.001); an association between IMCL content and Hb A1c was found only in T1DM (R2 = 0.57, P < 0.001). Fasting plasma adiponectin was reduced in T2DM (7 +/- 1 microg/ml, P = 0.01) and OFF (11 +/- 1 microg/ml, P = 0.03) but not in T1DM (25 +/- 6 microg/ml), whose plasma level was increased with respect to both OFF (P = 0.03) and NOR (16 +/- 2 microg/ml, P = 0.05). In conclusion, in T1DM, T2DM, and OFF, IMCL content was associated with insulin resistance, demonstrating that IMCL accretion is a marker of insulin resistance common to both primary genetically determined and secondary metabolic (chronic hyperglycemia) alterations. The increased adiponectin levels in insulin-resistant patients with T1DM, in contrast to the reduced levels found in patients with T2DM and in OFF, demonstrated that the relationship of adiponectin to insulin resistance in humans is still unclear.     

Elevated intramyocellular lipid concentration in obese subjects is not reduced after diet and exercise training

To determine the effects of weight loss on intramyocellular energy substrates, vastus lateralis muscle biopsies were taken from six obese subjects (body mass index 34 +/- 5 kg/m(2)) before, after 15 wk of energy restriction (ER; -700 kcal/day), and after a further average 20.7 +/- 1.6 wk of endurance training plus low-fat diet (ET-LFD). Body weight fell from 100 +/- 6 to 89 +/- 6 kg during ER and to 84 +/- 4 kg after ET-LFD. Lipids and glycogen were histochemically measured in type I, IIA, and IIB fibers. Total muscle glycogen content (MGC; per 100 fibers) decreased after ER [from 72 +/- 13 to 55 +/- 8 arbitrary units (AU)]. A similar but not significant decrease was seen in total muscle lipid content (MLC; 14 +/- 5 to 9 +/- 1 AU). After ET-LFD, MGC returned to initial values (74 +/- 8 AU), and MLC approached near-initial values (12 +/- 3 AU). Individual fiber lipid concentration did not change throughout the protocol in all fiber types, whereas glycogen concentration increased after ET-LFD. The training effects of ET-LFD were measured as increasing activities of key mitochondrial enzymes. Although total muscle energy reserves can be reduced after weight loss, their concentration within individual myofibers remains elevated. Weight loss does not appear sufficient to correct the potential detrimental effects of high intracellular lipid concentrations.     

Increased intramyocellular lipid accumulation in HIV-infected women with fat redistribution.

The human immunodeficiency virus (HIV)-lipodystrophy syndrome is associated with fat redistribution and metabolic abnormalities, including insulin resistance. Increased intramyocellular lipid (IMCL) concentrations are thought to contribute to insulin resistance, being linked to metabolic and body composition variables. We examined 46 women: HIV infected with fat redistribution (n = 25), and age- and body mass index-matched HIV-negative controls (n = 21). IMCL was measured by 1H-magnetic resonance spectroscopy, and body composition was assessed with computed tomography, dual-energy X-ray absorptiometry (DEXA), and magnetic resonance imaging. Plasma lipid profile and markers of glucose homeostasis were obtained. IMCL was significantly increased in tibialis anterior [135.0 +/- 11.5 vs. 85.1 +/- 13.2 institutional units (IU); P = 0.007] and soleus [643.7 +/- 61.0 vs. 443.6 +/- 47.2 IU, P = 0.017] of HIV-infected subjects compared with controls. Among HIV-infected subjects, calf subcutaneous fat area (17.8 +/- 2.3 vs. 35.0 +/- 2.5 cm2, P < 0.0001) and extremity fat by DEXA (11.8 +/- 1.1 vs. 15.6 +/- 1.2 kg, P = 0.024) were reduced, whereas visceral abdominal fat (125.2 +/- 11.3 vs. 74.4 +/- 12.3 cm2, P = 0.004), triglycerides (131.1 +/- 11.0 vs. 66.3 +/- 12.3 mg/dl, P = 0.0003), and fasting insulin (10.8 +/- 0.9 vs. 7.0 +/- 0.9 microIU/ml, P = 0.004) were increased compared with control subjects. Triglycerides (r = 0.39, P = 0.05) and extremity fat as percentage of whole body fat by DEXA (r = -0.51, P = 0.01) correlated significantly with IMCL in the HIV but not the control group. Extremity fat (beta = -633.53, P = 0.03) remained significantly associated with IMCL among HIV-infected patients, controlling for visceral abdominal fat, abdominal subcutaneous fat, and antiretroviral medications in a regression model. These data demonstrate increased IMCL in HIV-infected women with a mixed lipodystrophy pattern, being most significantly associated with reduced extremity fat. Further studies are necessary to determine the relationship between extremity fat loss and increased IMCL in HIV-infected women.     

Relationship between serum Se concentration in dogs and incidence of some disease conditions

The aim of the study was to determine if there is a relationship between serum selenium concentration in dogs and their health, and to assess the relationship between selenium concentration and morphological parameters of blood. Mean serum selenium concentration in dogs ranged from 0.169 to 0.273 mg/ml. Dogs diagnosed with malignant neoplasm had a significantly lower mean concentration of serum selenium compared to healthy dogs and those from the groups studied. The present study showed no statistically significant differences in Se serum content according to sex, age, and food type. Dogs diagnosed with malignant neoplasm had a significantly lower mean serum selenium concentration compared to healthy dogs and those from the other groups analysed, namely with hip dysplasia, allergy and fractures and with non-malignant tumour. Healthy dogs were characterized by the highest mean serum selenium concentration, significantly higher compared to dogs with non-malignant tumour, malignant neoplasm, allergy and fractures. Low levels of selenium contribute to the incidence of neoplasms and allergies and increase the risk of bone fractures in dogs. Additional laboratory tests should be conducted when certain diseases are diagnosed to determine Se concentration in dogs, thus making it possible to take preventive measures or therapeutic action.     

Relationship between leptin concentration and insulin resistance.

Available evidences suggest that leptin has inhibitory role on insulin secretion. The aim of the work was to examine the association between plasma leptin concentrations and insulin resistance in patients with gestational diabetes mellitus. As a cross-sectional study we recruited 741 pregnant women. The universal screening was performed with an oral glucose challenge test-50 g. The recruits with plasma glucose levels of > or = 7.2 mmol/l were diagnosed as having gestational diabetes mellitus if they had an impaired oral glucose tolerance test-100 g based on Carpenter and Coustan criteria. In all pregnancies plasma insulin and leptin concentrations were measured. Gestational diabetes mellitus developed in 7% (52) of pregnancies. Elevated leptin concentrations were positively associated with insulin levels, BMI, and HOMA index while it was negatively associated with Quicky index. After adjusting for age and BMI before pregnancy, gestational diabetes mellitus had independent direct correlation with leptin concentration. Indeed, leptin level equal to or more than 20 ng/ml could help to predict the developing gestational diabetes mellitus. Measurement of leptin together with the assessment of other risk factors could help identifying women at risk of developing GDM.     

Relationship between increasing duodenal lipid doses, gastric perception, and plasma hormone levels in humans

Duodenal lipid causes gastric relaxation, CCK secretion, and nausea. Vasopressin has been implicated in motion sickness-related nausea. We hypothesized that increasing doses of lipid enhance gastric relaxation and CCK-vasopressin secretion, resulting in a dose-related exacerbation of nausea. Nine healthy subjects received isotonic saline or lipid (1, 2, or 3 kcal/min, L1, L2, L3) duodenally. Changes in gastric volume, sensations, and plasma hormone levels were assessed during infusions and isobaric gastric distensions. Lipid infusions increased gastric volume, plasma CCK (but not vasopressin) levels, and gastric compliance during distensions, compared with saline. Plasma CCK levels were related to the dose of lipid administered [CCK levels at 30 min (pmol/l), saline: 1.1 +/- 0.2, L1: 1.8 +/- 0.2, L2: 3.0 +/- 0.2, L3: 4.3 +/- 0.6]. During distensions, nausea increased in intensity with increasing doses of lipid [score (where 0 is no sensation and 100 is strongest sensation), saline: 7 +/- 4, L1: 19 +/- 7, L2: 44 +/- 7, L3: 66 +/- 8]; however, no further rise in plasma CCK occurred. Because neither lipid nor distension alone induced significant nausea, we conclude that the interaction between these stimuli together with a modulation by CCK is responsible for the effects observed. Vasopressin is not involved in lipid- and distension-induced nausea.     

Low fat adiponectin expression is associated with oxidative stress in nondiabetic humans with chronic kidney disease--impact on plasma adiponectin concentration

In spite of association between high plasma adiponectin and high metabolic and cardiovascular (CV) risk, highest adiponectin increments retain CV and metabolic protective effects in advanced chronic kidney disease (CKD). Passive accumulation can favor CKD-associated hyperadiponectinemia but potential additional regulation by adipose tissue remains undefined. Oxidative stress (OS) is associated with metabolic and CV disease and with CKD [increasing from conservative treatment (CT) to maintenance hemodialysis (MHD)], and OS can reduce adiponectin expression in experimental models. OS (in the form of plasma thiobarbituric acid-reactive substances: TBARS), subcutaneous adipose adiponectin mRNA, and plasma adiponectin were studied in CKD patients (stages 4 and 5) on CT (n = 7) or MHD (n = 11). Compared with CT and controls (C: n = 6) MHD had highest TBARS and lowest adiponectin mRNA (P < 0.05) with lower adipose adiponectin protein (P < 0.05 vs. CT). MHD also had lower plasma adiponectin than CT, although both had higher adiponectin than C (P < 0.05). In renal transplant recipients (RT: CKD stage 3; n = 5) normal TBARS were, in turn, associated with normal adiponectin mRNA (P < 0.05 vs. MHD). In all CKD (n = 23), adiponectin mRNA was associated positively with adiponectin plasma concentration (P < 0.01). In all subjects (n = 29), adiponectin mRNA was related (P < 0.05) negatively with TBARS after adjusting for plasma C-reactive protein (CRP) or CRP and creatinine. Thus altered OS, adiponectin expression, and plasma concentration represent a novel cluster of metabolic and CV risk factors in MHD that are normalized in RT. The data suggest novel roles of 1) MHD-associated OS in modulating adiponectin expression and 2) adipose tissue in contributing to circulating adiponectin in advanced CKD.     

The relationship between insulin sensitivity and serum adiponectin levels in three population groups.

Reduced plasma adiponectin levels are associated with insulin resistance. Black South Africans, like African Americans, are more insulin-resistant than BMI-matched white subjects, as are Asian Indians. We investigated whether this interethnic variation in insulin resistance is due to differences in plasma adiponectin levels. Blood and anthropometric measurements were taken from black, white and Asian-Indian subjects. Serum adiponectin, lipids, glucose and insulin were measured; insulin sensitivity was calculated using HOMA. Black (HOMA = 2.62 +/- 0.99) and Asian-Indian subjects (HOMA = 3.41 +/- 2.85) were more insulin-resistant than BMI-matched white (HOMA = 1.76 +/- 0.63) subjects (p = 0.0001). Furthermore, the white subjects had higher adiponectin levels (8.11 +/- 4.39 microg/ml) compared to black (5.71 +/- 2.50 microg/ml) and Asian Indian (5.86 +/- 2.50 microg/ml) subjects (p = 0.003). When all ethnic groups were combined, multiple regression analysis demonstrated that serum adiponectin levels corrected for BMI and ethnicity did not correlate with HOMA, but did explain 10.0 % of the variance in HDL-cholesterol levels. Within each ethnic group, adiponectin only correlated inversely with HOMA in white subjects. Adiponectin may play a role in determining serum HDL-cholesterol levels, but ethnic variation in insulin sensitivity is not dependent on serum levels of this adipokine. The relationship between adiponectin and insulin resistance varies across ethnic groups.     

Exercise training increases intramyocellular lipid and oxidative capacity in older adults

Intramyocellular lipid (IMCL) has been associated with insulin resistance. However, an association between IMCL and insulin resistance might be modulated by oxidative capacity in skeletal muscle. We examined the hypothesis that 12 wk of exercise training would increase both IMCL and the oxidative capacity of skeletal muscle in older (67.3 +/- 0.7 yr), previously sedentary subjects (n = 13; 5 men and 8 women). Maximal aerobic capacity (Vo(2 max)) increased from 1.65 +/- 0.20 to 1.85 +/- 0.14 l/min (P < 0.05), and systemic fat oxidation induced by 1 h of cycle exercise at 45% of Vo(2 max) increased (P < 0.05) from 15.03 +/- 40 to 19.29 +/- 0.80 (micromol.min(-1).kg fat-free mass(-1)). IMCL, determined by quantitative histological staining in vastus lateralis biopsies, increased (P < 0.05) from 22.9 +/- 1.9 to 25.9 +/- 2.6 arbitrary units (AU). The oxidative capacity of muscle, determined by succinate dehydrogenase staining intensity, significantly increased (P < 0.05) from 75.2 +/- 5.2 to 83.9 +/- 3.6 AU. The percentage of type I fibers significantly increased (P < 0.05) from 35.4 +/- 2.1 to 40.1 +/- 2.3%. In conclusion, exercise training increases IMCL in older persons in parallel with an enhanced capacity for fat oxidation.     

Effects of rosiglitazone on intramyocellular lipid accumulation in Psammomys obesus

Objective: To examine the effects of rosiglitazone in intramyocellular lipid (IMCL) content in diabetic Psammomys obesus using novel electron microscopy technologies. Background: P. obesus is an unique polygenic model of obesity and type 2 diabetes. Male diabetic P. obesus were treated daily with 5 mg/Kg Rosiglitazone by oral gavage for 14 days. Data were compared with a group of age-matched diabetic P. obesus treated with saline vehicle. Methods: Assessment of insulin resistance and adiposity were determine before and after the treatment period by oral glucose tolerance test (oGTT) and dual energy X-ray absorptiometry (DEXA) analysis. We used a new scanning electron microscopy technology, (WETSEM) to investigate the effects of rosiglitazone administration on IMCL content, size and distribution in red gastrocnemius muscle. Results: Rosiglitazone treatment improved glucose tolerance in P. obesus with no difference in the overall body fat content although a significant reduction in subscapular fat mass was observed. Rosiglitazone changed the distribution of lipid droplet size in skeletal muscle. Treated animals tended to have smaller lipid droplets compared with saline-treated controls. Conclusions: Since smaller IMCL droplets are associated with improvements in insulin sensitivity, we propose that this may be an important mechanism by which rosiglitazone affects glucose tolerance.     

Relationship between membrane lipid mobility and spectrin distribution in lymphocytes.

We have previously established that T and B lymphocytes in situ are remarkably heterogeneous with respect to the cytoskeletal protein spectrin. Since in erythrocytes spectrin is known to play an important role in the regulation of membrane fluidity, lipid organization and lateral mobility of membrane proteins, we have sought to determine if the heterogeneous patterns of spectrin distribution that we have observed are related to possible differences in membrane lipid organization in these various subsets. To this end, we have utilized a fluorescent pyrene-labelled phospholipid as a probe of the lipid lateral mobility and have examined two related T cell systems maintained in vitro, DO.11.10 cells and a spontaneously arising variant, DO.11.10V. In these (and other cloned in vitro systems) we have previously observed that the cells homogeneously express one of the kinds of spectrin distribution patterns observed in situ. Thus the uniformity of staining of these systems permits us to address whether the various patterns of spectrin distribution may be predictive of differences in membrane lipid properties. Here we show that in cells in which there is little or nor spectrin at the plasma membrane (DO.11.10) that the lipids in the plasma membrane are considerably less mobile than in its related variant in which spectrin is diffusely distributed within the cell and at the plasma membrane. From this and previous results, we conclude that differences in the distribution of the cytoskeletal protein spectrin among lymphocytes may be a useful parameter in helping to predict the status of membrane lipid organization.     

Relationship between quasi-static pulmonary hysteresis and maximal airway narrowing in humans.

Two groups of subjects were studied: one with (group 1: 5 healthy and 4 mildly asthmatic subjects) and another without (group 2:9 moderately and severely asthmatic subjects) a plateau of response to methacholine (MCh). We determined the effect of deep inhalation by comparing expiratory flows at 40% of forced vital capacity from maximal and partial flow-volume curves (MEF40M/P) and the quasi-static transpulmonary pressure-volume (Ptp-V) area. In group 1, MEF40M/P increased from 1.58 +/- 0.23 (SE) at baseline up to a maximum of 3.91 +/- 0.69 after MCh when forced expiratory volume in 1 s (FEV1) was decreased on plateau by 24 +/- 2%. The plateau of FEV1 was always paralleled by a plateau of MEF40M/P. In group 2, MEF40 M/P increased from 1.58 +/- 0.10 at baseline up to a maximum of 3.48 +/- 0.26 after MCh when FEV1 was decreased by 31 +/- 3% and then decreased to 2.42 +/- 0.24 when FEV1 was decreased by 46 +/- 2%. Ptp-V area was similar in the two groups at baseline yet was increased by 122 +/- 9% in group 2 and unchanged in group 1 at MCh end point. These findings suggest that the increased maximal response to MCh in asthmatic subjects is associated with an involvement of the lung periphery.