Relationship between serum adiponectin concentration and intramyocellular lipid stores in humans.

The recently identified adipocytokine adiponectin has been shown to improve insulin action and decrease triglyceride content in skeletal muscle (by stimulating lipid oxidation) in mice. In the present study, we tested the hypothesis that high serum concentrations of adiponectin are associated with lower intramyocellular (IMCL) fat content by promoting lipid oxidation in humans. IMCL-content in predominantly non-oxidative tibialis anterior muscle and oxidative soleus was determined by proton magnetic resonance spectroscopy in a cross- sectional study involving 63 healthy volunteers. In a second set of experiments, changes in IMCL in both muscles were measured after a three days dietary lipid challenge (n = 18) and after intravenous lipid challenge (n = 12) with suppressed lipid oxidation under hyperinsulinemia. Adiponectin serum concentrations were found to be negatively correlated with IMCL in the oxidative soleus muscle (IMCL [sol]) (r = - 0.46, p < 0.001) independent of measures of obesity, but not with IMCL in the non-oxidative tibialis anterior muscle (IMCL [tib]) (p = 0.40). Adiponectin serum concentrations were negatively correlated with the observed increase in IMCL load after dietary lipid challenge in the tibialis (r = 0.53, p = 0.03) but not in the soleus muscle. During suppression of lipid oxidation by hyperinsulinemia, no effect of adiponectin on IMCL was observed in either soleus or tibialis muscle. Overall, the presented findings are consistent with the hypothesis that adiponectin promotes lipid oxidation in humans resulting in lower intracellular lipid content in human muscle. These results are consistent with animal data, where adiponectin could be shown to enhance lipid oxidation and reduce muscle triglycerides.     

脂联素调节糖脂代谢相关信号通路的研究进展

脂联素是一种主要由脂肪组织分泌的脂肪细胞因子,具有调节糖脂代谢、增强胰岛素敏感性、抗炎和抗动脉粥样硬化等多种作用。在脂联素介导的信号通路中,脂联素首先与脂联素受体(AdipoR)位于膜外的羧基端结合,再通过AdipoR膜内的氨基端与信号接头蛋白结合,进而激活下游的多条信号通路,其中腺苷酸活化蛋白激酶(AMPK)是脂联素信号通路中的关键分子,活化的AMPK可以使其下游的乙酰辅酶A羧化酶(ACC)、p38丝裂原活化蛋白激酶(p38 MAPK)、磷脂酰肌醇3激酶(PI3K)等多种胞质信号分子磷酸化,介导细胞能量代谢。本文重点综述了脂联素通过AMPK调节糖脂代谢的信号通路的研究进展。     

Relations of serum interleukin 18 levels to serum lipid and glucose concentrations in an apparently healthy adult population

AIM: To investigate the associations between serum interleukin (IL) 18 concentrations and indices of lipid and carbohydrate metabolism in healthy adults. METHODS: Fasting serum concentrations of IL-18, glucose, total cholesterol, triglyceride, and high- and low-density lipoprotein cholesterols were measured in 570 apparently healthy adults. RESULTS: Univariate linear and partial regression analyses showed that the serum IL-18 concentration was positively correlated with serum triglyceride and glucose concentrations in both obese and diabetic subjects after controlling for the confounding effects of age, sex, and body mass index. CONCLUSION: IL-18 may be associated with obesity and glucose intolerance.     

Arabinoxylan-enriched meal increases serum ghrelin levels in healthy humans.

Soluble fibre like arabinoxylan (AX) is thought to have beneficial effects on metabolism. In this study, we investigated the effect of a breakfast enriched in AX fibre on glucose, insulin and ghrelin values. AX-enriched and control breakfasts were served to fifteen young volunteers (nine female, six male). Glucose, insulin and ghrelin responses were measured after the meal. To avoid effects from differences in glucose metabolism, further analysis was restricted to those subjects with known normal glucose regulation (seven female, four male). The AX fibre-enriched breakfast did not significantly change glucose levels for two hours after breakfast, but decreased insulin levels in the entire cohort (p = 0.035). Glucose response was also not significantly different in subjects with normal glucose regulation (p = 0.367), and the insulin responses after an AX-enriched breakfast showed only a tendency towards lower values (p = 0.065). Nevertheless, plasma ghrelin two hours after AX-enriched breakfast was higher than after the control meal (396.1 +/- 36.4 pg/ml vs. 328.3 +/- 32.6 pg/ml, p < 0.001). In subjects with normal glucose regulation, the AX-enriched breakfast increased ghrelin levels without any significant difference in glucose or insulin response. This effect is therefore unlikely to be mediated by insulin, but the underlying mechanism remains to be elucidated.     

Effects of macrophage-specific adiponectin expression on lipid metabolism in vivo

Epidemiological studies have associated low circulating levels of the adipokine adiponectin with multiple metabolic disorders, including metabolic syndrome, obesity, insulin resistance, type II diabetes, and cardiovascular disease. Recently, we reported that adiponectin selectively overexpressed in mouse macrophages can improve insulin sensitivity and protect against inflammation and atherosclerosis. To further investigate the role of adiponectin and macrophages on lipid and lipometabolism in vivo, we engineered the expression of adiponectin in mouse macrophages (Ad-TG mice) and examined effects on plasma lipoproteins and on the expression levels of genes involved in lipoprotein metabolism in tissues. Compared with the wild-type (WT) mice, Ad-TG mice exhibited significantly lower levels of plasma total cholesterol (-21%, P < 0.05) due to significantly decreased LDL (-34%, P < 0.05) and VLDL (-32%, P < 0.05) cholesterol concentrations together with a significant increase in HDL cholesterol (+41%, P < 0.05). Further studies investigating potential mechanisms responsible for the change in lipoprotein cholesterol profile revealed that adiponectin-producing macrophages altered expression of key genes in liver tissue, including apoA1, apoB, apoE, the LDL receptor, (P < 0.05), and ATP-binding cassette G1 (P < 0.01). In addition, Ad-TG mice also exhibited higher total and high-molecular-weight adipnection levels in plasma and increased expression of the anti-inflammatory cytokine IL-10 as well as a decrease in the proinflammatory cytokine IL-6 in adipose tissue. These results indicate that macrophages engineered to produce adiponectin can influence in vivo gene expression in adipose tissue in a manner that reduces inflammation and macrophage infiltration and in liver tissue in a manner that alters the circulating lipoprotein profile, resulting in a decrease in VLDL and LDL and an increase in HDL cholesterol. The data support further study addressing the use of genetically manipulated macrophages as a novel therapeutic approach for treatment of cardiometabolic disease.     

Dark chocolate consumption increases HDL cholesterol concentration and chocolate fatty acids may inhibit lipid peroxidation in healthy humans

Cocoa powder is rich in polyphenols and, thus, may contribute to the reduction of lipid peroxidation. Our aim was to study the effects of long-term ingestion of chocolate, with differing amounts of polyphenols, on serum lipids and lipid peroxidation ex vivo and in vivo. We conducted a 3 week clinical supplementation trial of 45 nonsmoking, healthy volunteers. Participants consumed 75 g daily of either white chocolate (white chocolate, WC group), dark chocolate (dark chocolate, DC group), or dark chocolate enriched with cocoa polyphenols (high-polyphenol chocolate, HPC group). In the DC and HPC groups, an increase in serum HDL cholesterol was observed (11.4% and 13.7%, respectively), whereas in the WC group there was a small decrease (-2.9%, p < 0.001). The concentration of serum LDL diene conjugates, a marker of lipid peroxidation in vivo, decreased 11.9% in all three study groups. No changes were seen in the total antioxidant capacity of plasma, in the oxidation susceptibility of serum lipids or VLDL + LDL, or in the concentration of plasma F2-isoprostanes or hydroxy fatty acids. Cocoa polyphenols may increase the concentration of HDL cholesterol, whereas chocolate fatty acids may modify the fatty acid composition of LDL and make it more resistant to oxidative damage.     

Interrelationships of zinc with glucose and insulin metabolism in humans

Hyperzincemia has been reported to cause alterations in the homeostasis of glycid metabolism. To determine this effect on plasma glucose and insulin levels, we studied 36 normal individuals of both sexes aged 22–26 y after a 12-h fast. The tests were initiated at 7:00am when an antecubital vein was punctured and a device for infusion was installed and maintained with physiological saline. Zinc was administered orally at 8:00am. Subjects were divided into an experimental group of 22 individuals who received doses of 25, 37.5, and 50 mg of zinc and a control group of 14 individuals. Blood samples were collected over a period of 240 min after the basal samples (−30 and 0 min). We did not detect any change in plasma glucose or insulin levels, a fact that we attribute either to the ineffectiveness of the 50 mg dose of zinc or to the lack of human response to the acute action of this trace element. The individuals who ingested zinc showed a significant fall in plasma cortisol, probably caused by the action of this trace element.     

Effect of monensin on insulin and glucose concentration in rat serum.

The effect of monensin, an electroneutral ionophore that exchanges Na+ for H+, is investigated on glucose and insulin concentration in serum of female rats. After monensin administration hyperglycemia is observed. Hyperglycemia is concentration and time dependent. In fact serum glucose starts increasing with 0.5 mg/kg b.w. of monensin and increases sharply till 2.5-3.0 mg/kg b.w. The timing of the appearance shows an increase already after few minutes and keeps increasing reaching its maximum between 30-120 minutes. Hyperglycemia is reversed by insulin; if not treated spontaneously it returns to normality in 4-5 hours. An inverse correlation is observed between insulinemia and glycemia. A significant fall in serum insulin concentration can be observed, with or without glucose-stimulation of insulin release, already after five minutes of treatment. Insulinemia returns to normal values after about two hours. The action of monensin on glycemia might therefore be a reversible inhibition of insulin secretion by the beta-cells of the pancreas.     

Stimulation of small intestinal burst activity in the postprandial state differentially affects lipid and glucose absorption in healthy adult humans

Small intestinal motor activity is important for the optimal digestion and absorption of nutrients. These motor responses to feeding are frequently abnormal during critical illness, with the persistence of migrating bursts of contractions during enteral feeding. Whether this disturbance influences nutrient absorption is not known. In this study, the effects of small intestinal burst activity on lipid and glucose absorption were evaluated in 10 healthy human adults (6 males, 4 females, 19-47 yr). Upper gastrointestinal manometry was recorded for 6 h during and shortly after a 20-min intravenous infusion of either erythromycin (1 mg/kg), to stimulate burst activity, or saline (0.9%) in a double-blind randomized fashion. Simultaneously with the start of the intravenous infusion, 60 ml liquid feed mixed with 200 microl 13C-triolein and 2 g 3-O-methylglucose (3-OMG) was infused intraduodenally for 30 min. Absorption of lipid and glucose was assessed using the [13C]triolein breath test and plasma concentrations of 3-OMG, respectively. Infusion of erythromycin was followed by a more rapid onset of burst activity following commencement of the duodenal infusion compared with saline (30 +/- 6.1 vs. 58 +/- 10.7 min; P < 0.05). Erythromycin was associated with a slower recovery of 13CO2 (P < 0.01). A positive correlation existed between the time to onset of burst activity and 13CO2 recovery (P < 0.001). Erythromycin had no effect on 3-OMG absorption. In conclusion, stimulation of small intestinal burst activity reduces the rate of lipid absorption but not glucose absorption in healthy human adults.     

Effects of fructose on hepatic glucose metabolism in humans

Hepatic and extrahepatic insulin sensitivity was assessed in six healthy humans from the insulin infusion required to maintain an 8 mmol/l glucose concentration during hyperglycemic pancreatic clamp with or without infusion of 16.7 micromol. kg(-1). min(-1) fructose. Glucose rate of disappearance (GR(d)), net endogenous glucose production (NEGP), total glucose output (TGO), and glucose cycling (GC) were measured with [6,6-(2)H(2)]- and [2-(2)H(1)]glucose. Hepatic glycogen synthesis was estimated from uridine diphosphoglucose (UDPG) kinetics as assessed with [1-(13)C]galactose and acetaminophen. Fructose infusion increased insulin requirements 2.3-fold to maintain blood glucose. Fructose infusion doubled UDPG turnover, but there was no effect on TGO, GC, NEGP, or GR(d) under hyperglycemic pancreatic clamp protocol conditions. When insulin concentrations were matched during a second hyperglycemic pancreatic clamp protocol, fructose administration was associated with an 11.1 micromol. kg(-1). min(-1) increase in TGO, a 7.8 micromol. kg(-1). min(-1) increase in NEGP, a 2.2 micromol. kg(-1). min(-1) increase in GC, and a 7.2 micromol. kg(-1). min(-1) decrease in GR(d) (P < 0. 05). These results indicate that fructose infusion induces hepatic and extrahepatic insulin resistance in humans.     

Acute hypoxia decreases plasma VEGF concentration in healthy humans

Vascular endothelial growth factor (VEGF) is known to be upregulated by hypoxia in vitro. However, in vivo data about VEGF regulation in chronic hypoxic diseases are conflicting. We investigated the effects of hypoxia on plasma VEGF concentration in healthy subjects. To control known confounders, such as insulin, glucose concentrations, or exercise, hypoxic effects on VEGF were studied during experimentally clamping glucose concentrations at rest. In a double-blind crossover study design, we induced hypoxia for 30 min by decreasing oxygen saturation to 75% (vs. normoxic control) in 14 healthy men. Plasma VEGF concentration was determined at baseline, immediately after hypoxia had ended, and after a further 150 min. Levels of its soluble (s)Flt-1 receptor were assessed at baseline and at the end of the clamp. In parallel, catecholamine and cortisol levels were monitored. To investigate potential effects of glucose administration on the release of VEGF, we performed a third session, reducing glucose infusion for 30 min while serum insulin was held stable thereby inducing hypoglycemia. Hypoxia decreased VEGF levels compared with the normoxic control (P<0.05). VEGF concentrations increased during hypoglycemia (P<0.02) but were comparable to the normoglycemic control at the end of the clamp (P>0.80). sFlt-1 receptor concentration remained unchanged during hypoxia and hypoglycemia compared with control (both P>0.4). Epinephrine concentration (P<0.01) increased upon hypoxia, whereas norepinephrine and cortisol did not change. Contrary to in vitro studies, in healthy humans hypoxia decreases plasma VEGF concentration, suggesting that systemic VEGF concentration may be differently regulated than the expression on cellular basis.     

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.