The incidence and mortality rates of diabetes with cardiovascular complications are continually rising, and diabetic cardiovascular disease is becoming a major public health issue that threatens human health. Acute endothelial dysfunction and chronic cellular damage caused by diabetes are important risk factors for diabetic cardiovascular disease and related mortality. Adiponectin is an adipocyte-derived molecule with significant cytoprotective effects, including the protection against diabetes-induced vascular endothelial injury. Here we review the mechanisms of adiponectin protective effects on acute vascular endothelial dysfunction and chronic structural damage induced by diabetes.
Adiponectin ; physiology ; Cardiovascular Diseases ; complications ; Diabetes Mellitus ; pathology ; Endothelium, Vascular ; physiopathology ; Humans

AMP-activated protein kinase (AMPK) is a key enzyme in the regulation of cellular energy homeostasis. Recent studies demonstrated that AMPK also plays an important role in the modulation of inflammation, an energy-intensive molecular response. The commonly used AMPK activators include 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) and A-769662. In addition, the biological activities of metformin and adiponectin are closely related to activation of AMPK. Numerous studies have shown that these AMPK activators play an effectively protective role in animal models of acute lung injury, asthma, colitis, hepatitis, atherosclerosis and other inflammatory diseases. Therefore, AMPK activators may have promising potential for the prevention and treatment of inflammation related diseases.
AMP-Activated Protein Kinases ; physiology ; Adiponectin ; pharmacology ; Aminoimidazole Carboxamide ; pharmacology ; Animals ; Enzyme Activation ; Inflammation ; enzymology ; Metformin ; pharmacology ; Pyrones ; pharmacology ; Thiophenes ; pharmacology

OBJECTIVE: To determine the effect of metformin and adiponectin on the proliferation of EC cells and the relationship between metformin and adiponectin. METHODS: The proliferation impact of different concentrations of metformin and adiponectin on two types of EC cells ishikawa (IK) and HEC-1B was confirmed by CCK-8 method. qRT-PCR and Western blot were used to detect the effect of different concentrations of metformin on the changes of adiponectin receptors (AdipoR1 and AdipoR2) of the EC cells both in mRNA and protein level and the role of compound C, an adenosine monophosphate-activated protein kinase (AMPK) inhibitor, on the above effects. RESULTS: (1) Both metformin and adiponectin could significantly promote the proliferation of endometrial cancer (EC) cells in a time and concentration dependent manner (P<0.05).(2)Metformin and adiponectin had synergy anti-proliferative effect on EC cells and the combination index (CI) value of IK cells was 0.906 34 and of HEC-1B cells was 0.827 65. (3)qRT-PCR was used to detect the mRNA levels of AdipoR1 and AdipoR2 after 5 mmol/L and 10 mmol/L metformin, respectively, stimulating IK and HEC-1B cells for 48 hours and the mRNA expressions of AdipoR1 and AdipoR2 were significantly increased when compared with the control group (0 mmol/L)(IK: AdipoR1 of 5 mmol/L and 10 mmol/L group: P<0.001,AdipoR2 of 5 mmol/L group: P<0.001; HEC-1B: AdipoR1 of 5 mmol/L group: P<0.001, 10 mmol/L group: P=0.023, AdipoR2 of 5 mmol/L group: P<0.001, 10 mmol/L group: P=0.024). When combined with compound C, the RNA levels of AdipoR1 and AdipoR2 were not different compared with the control group (0 mmol/L, P>0.05). (4) Western blot was used to detect the protein levels of AdipoR1 and AdipoR2 after 5 mmol/L and 10 mmol/L metformin, stimulating IK and HEC-1B cells for 48 hours and the protein level was significantly increased when compared with the control group (0 mmol/L)(IK: AdipoR1 of 5 mmol/L group: P=0.04, 10 mmol/L group: P=0.033, AdipoR2 of 5 mmol/L group: P=0.044, 10 mmol/L group: P=0.046; HEC-1B: AdipoR1 of 5 mmol/L group: P=0.04, 10 mmol/L group: P=0.049, AdipoR2 of 5 mmol/L group: P=0.043, 10 mmol/L group: P=0.035). When combined with compound C,the protein levels of AdipoR1 and AdipoR2 were not different compared with the control group (0 mmol/L, P>0.05). CONCLUSION We find that metformin and adiponectin have synergy anti-proliferative effect on EC cells. Besides, metformin can increase adiponectin receptors expressions of EC cells both in mRNA and protein levels and this effect is accomplished by the activation of AMPK signaling pathway.
Adiponectin/physiology* ; Cell Proliferation/drug effects* ; Endometrial Neoplasms/pathology* ; Female ; Humans ; Hypoglycemic Agents/pharmacology* ; Metformin/pharmacology* ; Receptors, Adiponectin ; Signal Transduction

This study was performed to evaluate the contribution of adiponectin to the production of interleukin (IL)-6, IL-8, vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)-1 and MMP-13 in human endothelial cells and osteoblasts in arthritic joints. Cultured human umbilical vascular endothelial cells (HUVECs) and osteoblasts were stimulated with adiponectin (1 or 10 mug ml-1) or IL-1beta (0.1 ng ml-1) in the presence or absence of hypoxia for 24 h. The protein expression patterns were examined by analyzing culture supernatants using the enzyme-linked immunosorbent assay (ELISA). Adiponectin significantly stimulated the production of VEGF, MMP-1 and MMP-13 in osteoblasts but not in endothelial cells, whereas it significantly stimulated the production of IL-6 and IL-8 in both endothelial cells and osteoblasts. The increase in VEGF production induced by adiponectin was significantly greater than that induced by IL-1beta. The production of IL-6 and IL-8 in adiponectin-stimulated endothelial cells was approximately 10-fold higher than that in IL-1beta-stimulated endothelial cells; in osteoblasts, adiponectin-induced IL-6 and IL-8 secretion was approximately twofold higher than that induced by IL-1beta. In addition, IL-8 production in endothelial cells was approximately sevenfold higher than in osteoblasts. However, IL-6 levels were similar between the two cell types, suggesting that adiponectin may be involved in the production of IL-8 in endothelial cells, which may have an important role in neutrophil recruitment to arthritic joints. Furthermore, the increases in protein expression induced by adiponectin were differentially regulated by hypoxia. In conclusion, adiponectin has a more important role than does IL-1beta in the production of mediators that drive synovitis and joint destruction in endothelial cells and osteoblasts at physiological concentrations.
Adiponectin/pharmacology/*physiology ; Arthritis, Rheumatoid/metabolism ; Cell Hypoxia ; Cell Line ; Human Umbilical Vein Endothelial Cells/drug effects/*metabolism ; Humans ; Interleukin-6/genetics/*metabolism ; Interleukin-8/genetics/*metabolism ; Matrix Metalloproteinase 1/genetics/*metabolism ; Osteoblasts/drug effects/*metabolism ; Vascular Endothelial Growth Factor A/genetics/*metabolism

The vascular endothelium is a dynamic structure responsible for the separation and regulated movement of biological material between circulation and interstitial fluid. Hormones and nutrients can move across the endothelium either via a transcellular or paracellular route. Transcellular endothelial transport is well understood and broadly acknowledged to play an important role in the normal and abnormal physiology of endothelial function. However, less is known about the role of the paracellular route. Although the concept of endothelial dysfunction in diabetes is now widely accepted, we suggest that alterations in paracellular transport should be studied in greater detail and incorporated into this model. In this review we provide an overview of endothelial paracellular permeability and discuss its potential importance in contributing to the development of diabetes and associated complications. Accordingly, we also contend that if better understood, altered endothelial paracellular permeability could be considered as a potential therapeutic target for diabetes.
Adherens Junctions ; Adiponectin ; Endothelium ; Endothelium, Vascular ; Extracellular Fluid ; Insulin ; Permeability ; Physiology ; Tight Junctions

OBJECTIVETo understand adiponectin, leptin, insulin and ghrelin levels in preterm colostrum and mature milk and their influence on the growth and development of the premature infant.

METHODThe study subjects were divided into two groups: preterm group and control group. Specimens of colostrum and mature milk on 42nd day after delivery were collected, the general situation of maternal and infants growth parameters at birth and at postnatal 42 days were recorded. Leptin, adiponectin, insulin and ghrelin levels in colustrum and mature milk were determined and compared.

RESULTA total of 128 mother-infant pairs were involved. There were 128 specimens of colostrums (80 from preterm group, 48 from control group) and 94 specimens of mature milk(50 from premature group, 44 from control group). The levels of colostrum, mature milk adiponectin, leptin, and insulin were not significantly different between the 2 groups; ghrelin levels in colostrum and mature milk of premature group were significantly lower than those in control group (P = 0.038), adiponectin and leptin levels in colostrum were higher than those of the mature milk (P < 0.05), colostrum ghrelin levels were lower than those of mature milk (P < 0.05). Adiponectin, leptin, and ghrelin showed no significant difference between different gestational age groups ( ≤ 34 weeks group vs. > 34 weeks group). True insulin level of mature milk in 34 weeks group was higher than that of > 34 weeks group (29.3 vs. 21.6 mU/L, P = 0.045); true insulin level in colostrums in ≤ 34 weeks group was lower than that in mature milk (21.7 vs. 29.3 mU/L, P = 0.000). Adiponectin levels in colostrum and 42 days weight gain were negatively correlated (r = -0.362, P = 0.025) . Insulin level in mature milk had a negative correlation with birth weight (r = -0.319, P = 0.029) . Ghrelin levels in colostrum and birth weight, length, head circumference, head circumference on 42(nd) day were positively correlated (r = 0.271,0.261,0.360, P < 0.05); weight, length at 42(nd) day and ghrelin levels showed borderline positive correlation (P = 0.050, 0.058).

CONCLUSIONMany bioactive hormones in milk might participate in the regulation of suitable growth after birth. Premature birth affects hormone levels in breast milk. Breast feeding is very important in preterm infants.

Adiponectin ; analysis ; Birth Weight ; physiology ; Breast Feeding ; Colostrum ; chemistry ; Female ; Gestational Age ; Ghrelin ; analysis ; Humans ; Infant ; Infant Nutritional Physiological Phenomena ; Infant, Newborn ; Infant, Premature ; growth & development ; Insulin ; analysis ; Leptin ; analysis ; Male ; Milk, Human ; chemistry ; Weight Gain ; physiology

BACKGROUNDGenioglossal dysfuntion takes an important role in pathogenesis of obstructive sleep apnea hypopnea syndrome (OSAHS) in which chronic intermittent hypoxia (CIH) is the major pathological origin. Recent studies have suggested genioglossal injury induced by CIH might be improved by adiponectin. The aim of this study was to investigate the effects of adiponectin on genioglossus contractile properties in rats exposed to CIH.

METHODSThirty-nine healthy male Wistar rats were randomly divided into three groups: normal control (NC), CIH and adiponectin supplement (CIH+Ad) with 13 rats in each. Rats in NC were kept breathing normal air, while rats in CIH and CIH+Ad experienced the same CIH environment eight hours per day for 35 successive days. Rats in CIH+Ad were given intravenous adiponectin of 10 µg twice a week for 30 successive days. Rats in the NC and CIH were injected with normal saline as a control. After 35 days' CIH exposure, the levels of serum adiponectin and genioglossus contractile properties were compared.

RESULTSSerum adiponectin level was significantly lower in CIH than in NC (1210 ng/ml vs. 2236 ng/ml). Serum adiponectin level in CIH+Ad (1844 ng/ml) was significantly higher than CIH but lower than NC. Twitch tension, time to peak tension, half relaxation time and tetanic tension were significantly lower in CIH than NC and improved in CIH+Ad. All mean tetanic fatigue indices decreased more rapidly in the first 20 seconds than during the subsequent 100 seconds. Tetanic fatigue indices in NC and CIH+Ad were significantly higher compared to CIH.

CONCLUSIONSCIH could lead to hypoadiponectinaemia, impaired genioglossus contractile properties and decreased fatigue resistance in rats. Such changes could be partially offset by supplementation of adiponectin.

Adiponectin ; blood ; therapeutic use ; Animals ; Hypoxia ; blood ; physiopathology ; Male ; Muscle Contraction ; physiology ; Rats ; Rats, Wistar ; Sleep Apnea, Obstructive ; blood ; drug therapy ; physiopathology

PURPOSE: Although the presence of cannabinoid type 1 (CB1) receptor in islets has been reported, the major contributor to the protective effect of rimonabant on islet morphology is unknown. We determined whether the protective effect of rimonabant on pancreatic islet morphology is valid in established diabetes and also whether any effect was independent of decreased food intake. MATERIALS AND METHODS: After diabetes was confirmed, Otsuka Long-Evans Tokushima Fatty rats, aged 32 weeks, were treated with rimonabant (30 mg/kg/d, rimonabant group) for 6 weeks. Metabolic profiles and islet morphology of rats treated with rimonabant were compared with those of controls without treatment (control group), a pair-fed control group, and rats treated with rosiglitazone (4 mg/kg/d, rosiglitazone group). RESULTS: Compared to the control group, rats treated with rimonabant exhibited reduced glycated albumin levels (p<0.001), islet fibrosis (p<0.01), and improved glucose tolerance (p<0.05), with no differences from the pair-fed control group. The retroperitoneal adipose tissue mass was lower in the rimonabant group than those of the pair-fed control and rosiglitazone groups (p<0.05). Rimonabant, pair-fed control, and rosiglitazone groups showed decreased insulin resistance and increased adiponectin, with no differences between the rimonabant and pair-fed control groups. CONCLUSION: Rimonabant had a protective effect on islet morphology in vivo even in established diabetes. However, the protective effect was also reproduced by pair-feeding. Thus, the results of this study did not support the significance of islet CB1 receptors in islet protection with rimonabant in established obesity-associated type 2 diabetes.
Adiponectin/metabolism ; Adiposity/drug effects ; Animals ; Cell Proliferation/drug effects ; Diabetes Mellitus, Type 2/diet therapy/*drug therapy ; Eating/*drug effects ; Glucose Intolerance/diet therapy/*drug therapy ; Insulin Resistance ; Insulin-Secreting Cells/*drug effects/pathology ; Male ; Piperidines/adverse effects/*therapeutic use ; Pyrazoles/adverse effects/*therapeutic use ; Rats ; Rats, Inbred OLETF ; Receptor, Cannabinoid, CB1/physiology ; Thiazolidinediones/*therapeutic use

PURPOSE: Plasma adiponectin concentrations are inversely related with metabolic syndrome (MetS), and MetS is associated with increased risk for heart failure (HF). However, the relationship between adiponectin and MetS in HF remains undetermined. Therefore, we tested whether MetS was associated with the degree of plasma adiponectin concentrations in HF patients. MATERIALS AND METHODS: One hundred twenty eight ambulatory HF patients with left ventricular ejection fraction of <50% (80 males, 61.8+/-11.9 years old) were enrolled for this cross-sectional study. Echocardiographic measurements were performed, and plasma concentrations of adiponectin, lipoproteins, apolipoproteins (apoB, apoA1) and high sensitive C-reactive protein (hsCRP) were measured. RESULTS: Adiponectin concentrations in HF patients with MetS (n=43) were significantly lower than those without MetS (n=85) (9.7+/-7.0 vs. 15.8+/-10.9 microg/mL, p=0.001). Higher concentrations of apoB (p=0.017), apoB/A1 ratio (p<0.001), blood urea nitrogen (p=0.034), creatinine (p=0.003), and fasting insulin (p=0.004) were observed in HF patients with MetS compared with those without MetS. In HF patients with MetS, adiponectin concentrations were negatively correlated with hsCRP (r=-0.388, p=0.015) and positively correlated with the ratio of early mitral inflow velocity to early diastolic mitral annular velocity, E/E' (r=0.399, p=0.015). There was a significant trend towards decreased adiponectin concentrations with an increasing number of components of MetS (p for trend=0.012). CONCLUSION: Our study demonstrated that adiponectin concentrations decreased in HF patients with MetS, and that relationship between adiponectin, inflammation and abnormal diastolic function, possibly leading to the progression of HF.
Adiponectin/*blood ; Aged ; Diabetes Mellitus, Type 2/epidemiology/metabolism ; Female ; Heart Failure/*epidemiology/*metabolism/ultrasonography ; Humans ; Male ; Metabolic Syndrome X/*epidemiology/*metabolism ; Middle Aged ; Risk Factors ; Ventricular Function, Left/physiology

Adiponectin may affect bone through interactions with two known receptors, adiponectin receptors (ADIPOR) 1 and 2. We examined the association between polymorphisms of ADIPOR1 and ADIPOR2 and bone mineral density (BMD) in postmenopausal Korean women. Six polymorphisms in ADIPOR1 and four polymorphisms in ADIPOR2 were selected and genotyped in all study participants (n = 1,329). BMD at the lumbar spine and femur neck were measured using dual-energy X-ray absorptiometry. Lateral thoracolumbar (T4-L4) radiographs were obtained for vertebral fracture assessment and the occurrence of non-vertebral fractures examined using self-reported data. P values were adjusted for multiple testing using Bonferroni correction (Pcorr). ADIPOR1 rs16850799 and rs34010966 polymorphisms were significantly associated with femur neck BMD (Pcorr = 0.036 in the dominant model; Pcorr = 0.024 and Pcorr = 0.006 in the additive and dominant models, respectively). Subjects with the rare allele of each polymorphism had lower BMD, and association of rs34010966 with BMD showed a gene dosage effect. However, ADIPOR2 single nucleotide polymorphisms and haplotypes were not associated with BMD at any site. Our results suggest that ADIPOR1 polymorphisms present a useful genetic marker for BMD in postmenopausal Korean women.
Base Sequence ; Bone Density/*genetics ; Female ; Femur Neck/physiology ; Genetic Association Studies ; Genetic Markers ; Genetic Predisposition to Disease ; Genotype ; Humans ; Osteoporosis, Postmenopausal/*genetics ; Polymorphism, Single Nucleotide ; Postmenopause ; Receptors, Adiponectin/*genetics ; Republic of Korea ; Sequence Analysis, DNA