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Ratiometric Measurements of Adiponectin by Mass Spectrometry in Bottlenose Dolphins (Tursiops truncatus) with Iron Overload Reveal an Association with Insulin Resistance and Glucagon  [PDF]
Benjamin A. Neely,Kevin P. Carlin,Wayne E. McFee,Michael G. Janech
Frontiers in Endocrinology , 2013, DOI: 10.3389/fendo.2013.00132
Abstract: High molecular weight (HMW) adiponectin levels are reduced in humans with type 2 diabetes and insulin resistance. Similar to humans with insulin resistance, managed bottlenose dolphins (Tursiops truncatus) diagnosed with hemochromatosis (iron overload) have higher levels of 2 h post-prandial plasma insulin than healthy controls. A parallel reaction monitoring assay for dolphin serum adiponectin was developed based on tryptic peptides identified by mass spectrometry. Using identified post-translational modifications, a differential measurement was constructed. Total and unmodified adiponectin levels were measured in sera from dolphins with (n = 4) and without (n = 5) iron overload. This measurement yielded total adiponectin levels as well as site specific percent unmodified adiponectin that may inversely correlate with HMW adiponectin. Differences in insulin levels between iron overload cases and controls were observed 2 h post-prandial, but not during the fasting state. Thus, post-prandial as well as fasting serum adiponectin levels were measured to determine whether adiponectin and insulin would follow similar patterns. There was no difference in total adiponectin or percent unmodified adiponectin from case or control fasting animals. There was no difference in post-prandial total adiponectin levels between case and control dolphins (mean ± SD) at 763 ± 298 and 727 ± 291 pmol/ml, respectively (p = 0.91); however, percent unmodified adiponectin was significantly higher in post-prandial cases compared to controls (30.0 ± 6.3 versus 17.0 ± 6.6%, respectively; p = 0.016). Interestingly, both total and percent unmodified adiponectin were correlated with glucagon levels in controls (r = 0.999, p < 0.001), but not in cases, which is possibly a reflection of insulin resistance. Although total adiponectin levels were not significantly different, the elevated percent unmodified adiponectin follows a trend similar to HMW adiponectin reported for humans with metabolic disorders.
Globular domain of adiponectin: promising target molecule for detection of atherosclerotic lesions  [cached]
Almer G,Saba-Lepek M,Haj-Yahya S,Rohde E
Biologics: Targets and Therapy , 2011,
Abstract: Gunter Almer1, Matthias Saba-Lepek2, Samih Haj-Yahya1, Eva Rohde3, Dirk Strunk4, Eleonore Fr hlich5, Ruth Prassl2, Harald Mangge11Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, 2Institute of Biophysics and Nanosystems Research, Austrian Academy of Science, 3University Clinic of Blood Group Serology and Transfusion Medicine, 4University Clinic of Hematology, 5Center for Medical Research, Medical University of Graz, Graz, AustriaBackground: Adiponectin, an adipocyte-specific plasma protein, has been shown to accumulate in injured endothelial cells during development of atherosclerotic lesions. In this study, we investigated the potential of different adiponectin subfractions with special emphasis on globular adiponectin (gAd) to recognize and visualize atherosclerotic lesions.Methods: Recombinant mouse gAd and subfractions of full-length adiponectin (ie, trimeric, hexameric, and oligomeric forms) were fluorescence-labeled. Aortas of wild-type and apoprotein E-deficient mice fed a high cholesterol diet were dissected and incubated with the labeled biomarkers. Imaging was performed using confocal laser scanning microscopy.Results: Confocal laser scanning microscopic images showed that gAd binds more strongly to atherosclerotic plaques than full-length adiponectin subfractions. Further, we showed that gAd accumulates preferentially in endothelial cells and the fibrous cap area of plaques. Here we demonstrate for the first time that gAd recognizes atherosclerotic plaques on aortic sections of apoprotein E-deficient mice.Conclusion: These results suggest that gAd, in addition to its physiological properties, is also suitable as a target molecule for prospective diagnostic strategies in imaging atherosclerotic lesions.Keywords: adiponectin subfractions, atherosclerosis, fibrous cap, globular adiponectin, vascular imaging
Incretins and the specific mechanism of action of liraglutide, the first applicable human glucagon-like peptide 1 analog in the treatment of type 2 diabetes
Edoardo Mannucci, Caterina Lamanna
Journal of Receptor, Ligand and Channel Research , 2010, DOI: http://dx.doi.org/10.2147/JRLCR.S6345
Abstract: cretins and the specific mechanism of action of liraglutide, the first applicable human glucagon-like peptide 1 analog in the treatment of type 2 diabetes Review (3412) Total Article Views Authors: Edoardo Mannucci, Caterina Lamanna Published Date September 2010 Volume 2010:3 Pages 105 - 112 DOI: http://dx.doi.org/10.2147/JRLCR.S6345 Edoardo Mannucci, Caterina Lamanna Diabetes Agency, Careggi Teaching Hospital, Florence, Italy Abstract: Liraglutide is a once-daily glucagon-like peptide 1 (GLP-1) receptor agonist, approved for use as a treatment of type 2 diabetes. Like other drugs of the same class, liraglutide stimulates insulin secretion in a glucose-dependent fashion, has the potential of preventing β-cell mass decline, and inhibits food intake. In addition, experimental studies suggest that the GLP-1 receptor agonists could protect myocardium from ischemic injury, enhancing cardiac function. In clinical trials, liraglutide (in monotherapy or as add-on to 1 or 2 oral drugs) is as effective as, or more effective than, other agents (sulfonylureas, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, insulin, and exenatide) in reducing hemoglobin A1c; induces weight loss; and has a blood pressure-lowering effect. The possible beneficial cardiovascular effects need to be confirmed by specifically designed long-term studies.
Globular domain of adiponectin: promising target molecule for detection of atherosclerotic lesions
Almer G, Saba-Lepek M, Haj-Yahya S, Rohde E, Strunk D, Fr hlich E, Prassl R, Mangge H
Biologics: Targets and Therapy , 2011, DOI: http://dx.doi.org/10.2147/BTT.S22863
Abstract: bular domain of adiponectin: promising target molecule for detection of atherosclerotic lesions Original Research (3748) Total Article Views Authors: Almer G, Saba-Lepek M, Haj-Yahya S, Rohde E, Strunk D, Fr hlich E, Prassl R, Mangge H Published Date September 2011 Volume 2011:5 Pages 95 - 105 DOI: http://dx.doi.org/10.2147/BTT.S22863 Gunter Almer1, Matthias Saba-Lepek2, Samih Haj-Yahya1, Eva Rohde3, Dirk Strunk4, Eleonore Fr hlich5, Ruth Prassl2, Harald Mangge1 1Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, 2Institute of Biophysics and Nanosystems Research, Austrian Academy of Science, 3University Clinic of Blood Group Serology and Transfusion Medicine, 4University Clinic of Hematology, 5Center for Medical Research, Medical University of Graz, Graz, Austria Background: Adiponectin, an adipocyte-specific plasma protein, has been shown to accumulate in injured endothelial cells during development of atherosclerotic lesions. In this study, we investigated the potential of different adiponectin subfractions with special emphasis on globular adiponectin (gAd) to recognize and visualize atherosclerotic lesions. Methods: Recombinant mouse gAd and subfractions of full-length adiponectin (ie, trimeric, hexameric, and oligomeric forms) were fluorescence-labeled. Aortas of wild-type and apoprotein E-deficient mice fed a high cholesterol diet were dissected and incubated with the labeled biomarkers. Imaging was performed using confocal laser scanning microscopy. Results: Confocal laser scanning microscopic images showed that gAd binds more strongly to atherosclerotic plaques than full-length adiponectin subfractions. Further, we showed that gAd accumulates preferentially in endothelial cells and the fibrous cap area of plaques. Here we demonstrate for the first time that gAd recognizes atherosclerotic plaques on aortic sections of apoprotein E-deficient mice. Conclusion: These results suggest that gAd, in addition to its physiological properties, is also suitable as a target molecule for prospective diagnostic strategies in imaging atherosclerotic lesions.
Globular Adiponectin Activates Motility and Regenerative Traits of Muscle Satellite Cells  [PDF]
Tania Fiaschi, Elisa Giannoni, Maria Letizia Taddei, Paola Chiarugi
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0034782
Abstract: Regeneration of adult injured skeletal muscle is due to activation of satellite cells, a population of stem cells resident beneath the basal lamina. Thus, information on soluble factors affecting satellite cell activation, as well as migration towards injury and fusion into new myofibers are essential. Here, we show that globular adiponectin (gAd), positively affects several features of muscle satellite cells. gAd activates satellite cells to exit quiescence and increases their recruitment towards myotubes. gAd elicits in satellite cells a specific motility program, involving activation of the small GTPase Rac1, as well as expression of Snail and Twist transcription factors driving a proteolytic motility, useful to reach the site of injury. We show that satellite cells produce autocrine full length adiponectin (fAd), which is converted to gAd by activated macrophages. In turns, gAd concurs to attract to the site of injury both satellite cells and macrophages and induces myogenesis in muscle satellite cells. Thus, these findings add a further role for gAd in skeletal muscle, including the hormone among factors participating in muscle regeneration.
Recombinant Adiponectin Does Not Lower Plasma Glucose in Animal Models of Type 2 Diabetes  [PDF]
S?ren Tullin, Anette Sams, Jakob Brandt, Kirsten Dahl, Wei Gong, Claus Bekker Jeppesen, Thomas Nylandsted Krogh, Grith Skytte Olsen, Yun Liu, Anette Amstrup Pedersen, J?rn Meidahl Petersen, Bidda Rolin, Per-Olof Wahlund, Christoph Kalthoff
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0044270
Abstract: Aims/Hypothesis Several studies have shown that adiponectin can lower blood glucose in diabetic mice. The aim of this study was to establish an effective adiponectin production process and to evaluate the anti-diabetic potential of the different adiponectin forms in diabetic mice and sand rats. Methods Human high molecular weight, mouse low molecular weight and mouse plus human globular adiponectin forms were expressed and purified from mammalian cells or yeast. The purified protein was administered at 10–30 mg/kg i.p. b.i.d. to diabetic db/db mice for 2 weeks. Furthermore, high molecular weight human and globular mouse adiponectin batches were administered at 5–15 mg/kg i.p. b.i.d. to diabetic sand rats for 12 days. Results Surprisingly, none of our batches had any effect on blood glucose, HbA1c, plasma lipids or body weight in diabetic db/db mice or sand rats. In vitro biological, biochemical and biophysical data suggest that the protein was correctly folded and biologically active. Conclusions/Interpretation Recombinant adiponectin is ineffective at lowering blood glucose in diabetic db/db mice or sand rats.
The Impact of Full-Length, Trimeric and Globular Adiponectin on Lipolysis in Subcutaneous and Visceral Adipocytes of Obese and Non-Obese Women  [PDF]
Zuzana Wedellova, Zuzana Kovacova, Michaela Tencerova, Tomas Vedral, Lenka Rossmeislova, Michaela Siklova-Vitkova, Vladimir Stich, Jan Polak
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0066783
Abstract: Contribution of individual adiponectin isoforms to lipolysis regulation remains unknown. We investigated the impact of full-length, trimeric and globular adiponectin isoforms on spontaneous lipolysis in subcutaneous abdominal (SCAAT) and visceral adipose tissues (VAT) of obese and non-obese subjects. Furthermore, we explored the role of AMPK (5'-AMP-activated protein kinase) in adiponectin-dependent lipolysis regulation and expression of adiponectin receptors type 1 and 2 (AdipoR1 and AdipoR2) in SCAAT and VAT. Primary adipocytes isolated from SCAAT and VAT of obese and non-obese women were incubated with 20 μg/ml of: A) full-length adiponectin (physiological mixture of all adiponectin isoforms), B) trimeric adiponectin isoform or C) globular adiponectin isoform. Glycerol released into media was used as a marker of lipolysis. While full-length adiponectin inhibited lipolysis by 22% in non-obese SCAAT, globular isoform inhibited lipolysis by 27% in obese SCAAT. No effect of either isoform was detected in non-obese VAT, however trimeric isoform inhibited lipolysis by 21% in obese VAT (all p<0.05). Trimeric isoform induced Thr172 p-AMPK in differentiated preadipocytes from a non-obese donor, while globular isoform induced Ser79 p-ACC by 32% (p<0.05) and Ser565 p-HSL by 52% (p = 0.08) in differentiated preadipocytes from an obese donor. AdipoR2 expression was 17% and 37% higher than AdipoR1 in SCAAT of obese and non-obese groups and by 23% higher in VAT of obese subjects (all p<0.05). In conclusion, the anti-lipolytic effect of adiponectin isoforms is modified with obesity: while full-length adiponectin exerts anti-lipolytic action in non-obese SCAAT, globular and trimeric isoforms show anti-lipolytic activity in obese SCAAT and VAT, respectively.
Serum adiponectin as a biomarker for in vivo PPARgamma activation and PPARgamma agonist-induced efficacy on insulin sensitization/lipid lowering in rats  [cached]
Yang Baichun,Brown Kathleen K,Chen Lihong,Carrick Kevin M
BMC Pharmacology , 2004, DOI: 10.1186/1471-2210-4-23
Abstract: Background PPARγ agonists ameliorate insulin resistance and dyslipidemia in type 2 diabetic patients. Adiponectin possesses insulin sensitizing properties, and predicts insulin sensitivity of both glucose and lipid metabolism. In diet-induced insulin resistant rats and ZDF rats, the current studies determined the correlation between PPARγ agonist-upregulated fatty acid binding protein(FABP3) mRNA in adipose tissue and PPARγ agonist-elevated serum adiponectin, and the correlation between PPARγ agonist-elevated serum adiponectin and PPARγ agonist-mediated efficacy in insulin sensitization and lipid lowering. Results Parallel groups of SD rats were fed a high fat/sucrose (HF) diet for 4 weeks. These rats were orally treated for the later 2 weeks with vehicle, either PPARγ agonist GI262570 (0.2–100 mg/kg, Q.D.), or GW347845 (3 mg/kg, B.I.D). Rats on HF diet showed significant increases in postprandial serum triglycerides, free fatty acids (FFA), insulin, and area under curve (AUC) of serum insulin during an oral glucose tolerance test, but showed no change in serum glucose, adiponectin, and glucose AUC. Treatment with GI262570 dose-dependently upregulated adipose FABP3 mRNA, and increased serum adiponectin. There was a positive correlation between adipose FABP3 mRNA and serum adiponectin (r = 0.7350, p < 0.01). GI262570 dose-dependently decreased the diet-induced elevations in triglycerides, FFA, insulin, and insulin AUC. Treatment with GW347845 had similar effects on serum adiponectin and the diet-induced elevations. There were negative correlations for adiponectin versus triglycerides, FFA, insulin, and insulin AUC (For GI262570, r = -0.7486, -0.4581, -0.4379, and -0.3258 respectively, all p < 0.05. For GW347845, r = -0.6370, -0.6877, -0.5512, and -0.3812 respectively, all p < 0.05). In ZDF rats treated with PPARγ agonists pioglitazone (3–30 mg/kg, B.I.D.) or GW347845 (3 mg/kg, B.I.D.), there were also negative correlations for serum adiponectin versus glucose, triglycerides, FFA (for pioglitazone, r = -0.7005, -0.8603, and -0.9288 respectively; for GW347845, r = -0.9721, -0.8483, and -0.9453 respectively, all p < 0.01). Conclusions This study demonstrated that (a) PPARγ agonists improved insulin sensitivity and ameliorated dyslipidemia in HF fed rats and ZDF rats, which were correlated with serum adiponectin; (b) Serum adiponectin was positively correlated with adipose FABP3 mRNA in GI262570-treated rats. These data suggest that serum adiponectin can serve as a biomarker for both in vivo PPARγ activation and PPARγ agonist-induced efficacy on ins
Incretins and the specific mechanism of action of liraglutide, the first applicable human glucagon-like peptide 1 analog in the treatment of type 2 diabetes  [cached]
Edoardo Mannucci,Caterina Lamanna
Journal of Receptor, Ligand and Channel Research , 2010,
Abstract: Edoardo Mannucci, Caterina LamannaDiabetes Agency, Careggi Teaching Hospital, Florence, ItalyAbstract: Liraglutide is a once-daily glucagon-like peptide 1 (GLP-1) receptor agonist, approved for use as a treatment of type 2 diabetes. Like other drugs of the same class, liraglutide stimulates insulin secretion in a glucose-dependent fashion, has the potential of preventing β-cell mass decline, and inhibits food intake. In addition, experimental studies suggest that the GLP-1 receptor agonists could protect myocardium from ischemic injury, enhancing cardiac function. In clinical trials, liraglutide (in monotherapy or as add-on to 1 or 2 oral drugs) is as effective as, or more effective than, other agents (sulfonylureas, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, insulin, and exenatide) in reducing hemoglobin A1c; induces weight loss; and has a blood pressure-lowering effect. The possible beneficial cardiovascular effects need to be confirmed by specifically designed long-term studies.Keywords: liraglutide, type 2 diabetes, GLP-1 receptor agonist
A Comparative Study on the Antioxidant and Glucose-lowering Effects of Curcumin and Bisdemethoxycurcumin Analog through in vitro Assays  [PDF]
S. Sivabalan,C.V. Anuradha
International Journal of Pharmacology , 2010,
Abstract: Type 2 diabetes has emerged as an epidemic affecting millions of people all over the world. Several research findings suggest that oxidative stress is the triggering factor for the development of type 2 diabetes. Hyperglycemia and oxidative stress go hand in hand to accelerate the disease progression in a vicious cycle. In India, the medicinal herb Curcuma longa is used as a culinary food additive and also as a therapeutic agent for diabetes. Recent research evidenced that the curcuminoids present in Curcuma longa have several medicinal properties including anti-diabetic property. However, the bioavailability of curcumin is very less compared to its derivatives and its synthetic analogs. The synthetic analog of bisdemethoxycurcumin is reported to have increased bioavailability and stability but its effect on controlling oxidative stress, glucose absorption and gluconeogenesis have not yet been explored. The aim of this study was to evaluate the anti-oxidant and glucose lowering effects of bisdemethoxycurcumin analog (BDMCA) in comparison with curcumin. Anti-oxidant activity of BDMCA and curcumin was evaluated by measuring the rate of inhibition of iron-ascorbate induced lipid peroxidation in liver homogenate in vitro. Effect of these drugs on intestinal glucose absorption in Wistar rats and on gluconeogenesis in liver homogenate in vitro was evaluated to know their glucose lowering effects. We found that both the BDMCA and curcumin lower the gluconeogenesis in the hepatocytes and function as antioxidants in vitro in a similar manner. Both BDMCA and curcumin delays the intestinal glucose absorption but BDMCA delays the intestinal glucose absorption more effectively compared to curcumin.
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