Roles of insulin and growth hormone, based on studies of forearm metabolism in man. Medicine 42 , — Richelsen, B. Growth hormone treatment of obese women for 5 wk: effect on body composition and adipose tissue LPL activity.
Krag, M. Growth hormone-induced insulin resistance is associated with increased intramyocellular triglyceride content but unaltered VLDL-triglyceride kinetics. Norrelund, H. Effects of GH on urea, glucose and lipid metabolism, and insulin sensitivity during fasting in GH-deficient patients. Jorgensen, J. Marked effects of sustained low growth hormone GH levels on day-to-day fuel metabolism: studies in GH-deficient patients and healthy untreated subjects. Growth hormone versus placebo treatment for one year in growth hormone deficient adults: increase in exercise capacity and normalization of body composition.
CAS Google Scholar. Basal- and insulin-stimulated substrate metabolism in patients with active acromegaly before and after adenomectomy. Bredella, M. Body composition and ectopic lipid changes with biochemical control of acromegaly. Krusenstjerna-Hafstrom, T.
Growth hormone GH -induced insulin resistance is rapidly reversible: an experimental study in GH-deficient adults. Shulman, G. Unraveling the cellular mechanism of insulin resistance in humans: new insights from magnetic resonance spectroscopy. Physiology 19 , — Nielsen, C. Growth hormone signaling in vivo in human muscle and adipose tissue: impact of insulin, substrate background, and growth hormone receptor blockade. Jessen, N.
Evidence against a role for insulin-signaling proteins PI 3-kinase and Akt in insulin resistance in human skeletal muscle induced by short-term GH infusion. Diabetes 56 , — Dominici, F. Influence of the crosstalk between growth hormone and insulin signalling on the modulation of insulin sensitivity. Growth Horm. IGF Res. Nellemann, B. Growth hormone-induced insulin resistance in human subjects involves reduced pyruvate dehydrogenase activity.
Acta Physiol. Mekala, K. Effects of recombinant human growth hormone therapy in obesity in adults: a meta analysis. Thankamony, A. Short-term administration of pegvisomant improves hepatic insulin sensitivity and reduces soleus muscle intramyocellular lipid content in young adults with type 1 diabetes.
Sharma, R. Growth hormone controls lipolysis by regulation of FSP27 expression. Sharma, V. Troike, K. Impact of growth hormone on regulation of adipose tissue. Brooks, A. The growth hormone receptor: mechanism of activation and clinical implications. This excellent article provides a thorough understanding of the GH—GHR interaction as a function of downstream intracellular signalling.
Rowlinson, S. An agonist-induced conformational change in the growth hormone receptor determines the choice of signalling pathway. In light of findings that GH-lipolysis and insulin resistance are primarily dependent on ERK-dependent signaling, specific and yet to be discovered ERK-dependent GH analogues might have strong therapeutic and clinical significance.
Waters, M. The growth hormone receptor. Lanning, N. Recent advances in growth hormone signaling. Herrington, J. The role of STAT proteins in growth hormone signaling. Oncogene 19 , — Wang, X. Xu, B. Growth hormone promotes the association of transcription factor STAT5 with the growth hormone receptor. Hansen, L. Identification of tyrosine residues in the intracellular domain of the growth hormone receptor required for transcriptional signaling and Stat5 activation.
Ram, P. Growth hormone activation of Stat 1, Stat 3, and Stat 5 in rat liver. Smit, L. Moriggl, R. Deletion of the carboxyl-terminal transactivation domain of MGF-Stat5 results in sustained DNA binding and a dominant negative phenotype.
Davey, H. STAT5b-deficient mice are growth hormone pulse-resistant. Role of STAT5b in sex-specific liver p expression. Kofoed, E. Growth hormone insensitivity associated with a STAT5b mutation.
Scalco, R. Growth hormone insensitivity with immune dysfunction caused by a STAT5B mutation in the south of Brazil: evidence for a founder effect. Zhu, T. GH activation of Ral and phospholipase D is Src-dependent. Ueki, K. Molecular balance between the regulatory and catalytic subunits of phosphoinositide 3-kinase regulates cell signaling and survival. GH receptor signaling in skeletal muscle and adipose tissue in human subjects following exposure to an intravenous GH bolus.
Insulin and GH signaling in human skeletal muscle in vivo following exogenous GH exposure: impact of an oral glucose load. Green, H. A dual effector theory of growth-hormone action. Differentiation 29 , — Doi, T. Glomerular lesions in mice transgenic for growth hormone and insulinlike growth factor-I. Relationship between increased glomerular size and mesangial sclerosis. Lupu, F. Roles of growth hormone and insulin-like growth factor 1 in mouse postnatal growth.
Dietz, J. Growth hormone alters lipolysis and hormone-sensitive lipase activity in 3T3-FA adipocytes. Metabolism 40 , — Regulation of lipoprotein lipase and hormone-sensitive lipase activity and gene expression in adipose and muscle tissue by growth hormone treatment during weight loss in obese patients.
Metabolism 49 , — Doris, R. Growth hormone decreases the response to anti-lipolytic agonists and decreases the levels of Gi2 in rat adipocytes. Yip, R. Growth hormone and dexamethasone stimulate lipolysis and activate adenylyl cyclase in rat adipocytes by selectively shifting Gi alpha2 to lower density membrane fractions. Ottosson, M. Growth hormone inhibits lipoprotein lipase activity in human adipose tissue.
Zhao, J. Identification of novel GH-regulated pathway of lipid metabolism in adipose tissue: a gene expression study in hypopituitary men. Cidea is associated with lipid droplets and insulin sensitivity in humans. Natl Acad. USA , — Nielsen, T. Antagonists of the glucagon receptor have been considered as glucose-lowering therapy in type 2 diabetes patients, but their clinical applicability has been questioned because of reports of therapy-induced increments in liver fat content and increased plasma concentrations of low-density lipoprotein.
Conversely, in animal models, increased glucagon receptor signaling has been linked to improved lipid metabolism. Glucagon acts primarily on the liver and by regulating hepatic lipid metabolism glucagon may reduce hepatic lipid accumulation and decrease hepatic lipid secretion.
Regarding whole-body lipid metabolism, it is controversial to what extent glucagon influences lipolysis in adipose tissue, particularly in humans. Glucagon receptor agonists combined with glucagon-like peptide 1 receptor agonists dual agonists improve dyslipidemia and reduce hepatic steatosis. Collectively, emerging data support an essential role of glucagon for lipid metabolism.
Glucagon is processed from its precursor, proglucagon, by prohormone convertase 2 and secreted from pancreatic alpha cells Rouille et al. The role of glucagon in glucose metabolism has been intensively studied, and comprehensive reviews are found elsewhere Jiang and Zhang, ; Ramnanan et al. In addition to regulating glucose metabolism, glucagon also seems important for minute-to-minute regulation of amino acid metabolism as part of the recently described liver-alpha cell axis Solloway et al.
The glucagon receptor is primarily expressed in the liver, but it is also expressed in varying amounts in the central nervous system, kidneys, gastro-intestinal tract, heart controversial , and pancreas Svoboda et al. Glucagon receptor expression has been reported in rat adipocytes Svoboda et al. As type 2 diabetic hyperglucagonaemia Faerch et al. Interestingly, potential adverse effects of this therapeutic approach include increased low-density lipoprotein LDL plasma concentrations and increased hepatic fat accumulation Guzman et al.
Furthermore, hepatocyte studies have shown that glucagon stimulates beta-oxidation Pegorier et al. PKA phosphorylates hence activates perilipins Greenberg et al. Circulating levels of FFAs and glycerol therefore reflect the rate of lipolysis Schweiger et al. For glucagon to directly influence adipocyte function, its cognate receptor must be expressed.
Glucagon receptor mRNA has been detected in rat adipocytes Svoboda et al. Specific antibodies directed against the glucagon receptor are necessary in addressing this question, but development of specific antibodies against glucagon receptors has been challenging and the antibodies available are unspecific and therefore not suitable for receptor localization van der Woning et al. As an example, one study reported localization of the glucagon receptor in rat adipocytes using a monoclonal antibody Iwanij and Vincent, whereas another using autoradiography, glucagon receptors were not found to be expressed Watanabe et al.
Clearly, future studies should investigate glucagon receptor expression using antibody and antibody-independent methods. Figure 1. Glucagon ensures energy supply by mobilizing lipids. In the fasting state, glucagon is secreted and insulin concentrations are not sufficient to inhibit lipolysis in adipocytes, where lipids are stored in lipid droplets consisting of a core of triglycerols TG and sterols esters coated with perilipins P proteins restricting access to the lipid core.
In response to an appropriate stimuli, e. The phosphorylation of P results in dissociation of the protein CGI The monoglycerols are hydrolyzed by monoacylglycerol lipase MGL , yielding free fatty acids FFAs and glycerol, which are released to the blood.
FFAs may stimulate glucagon secretion, and glucagon in turn stimulates hepatic gluconeogenesis using FFAs and glycerol as substrates , glycogenolysis, and beta-oxidation thus providing substrates for the liver to secure sufficient energy supply to metabolically active tissue.
Enzymes are written in italic and arrows indicate stimulation. Glucagon has been reported to activate HSL Vaughan et al. Glucagon has also been shown to stimulate lipolysis in birds, rabbits Richter et al. At physiological plasma concentrations 1—40 pM , a lipolytic effect of glucagon in human adipocytes has been difficult to demonstrate Mosinger et al.
One of the first human studies reporting a lipolytic effect of glucagon, demonstrated that an injection of 7. Since supra-physiological glucagon concentrations were applied, these studies may lack specificity because of interaction of glucagon with other related G protein-coupled receptors e. Pharmacological concentrations of glucagon also stimulate secretion of catecholamines and growth hormone, both of which have powerful lipolytic effects Mitchell et al. Glucagon was not found to have any lipolytic effects in clinical studies using glucagon concentrations ranging from 19 to 64 pM Wu et al.
In some clinical studies investigating the lipolytic effect of supra-physiological glucagon concentrations, the lipolytic effect of glucagon could be abolished by insulin Samols et al.
A lipolytic effect of glucagon, if any, on human adipocytes may therefore only be physiologically relevant when insulin secretion is low. However, when insulin, somatostatin, and glucagon were infused together, glucagon had no lipolytic effect Gerich et al. Furthermore, infusion with saline only gave the same increase in FFA as compared to glucagon infusion. In another study glucagon was infused at 1. In contrast, a 2-h glucagon infusion at 1. As glucagon receptors are expressed on beta cells Adriaenssens et al.
It is important to note that FFA and glycerol in plasma are not only determined by release from adipocytes, but also by rate of uptake and re-esterification in other tissues.
A lack of effect of glucagon on the free plasma pool of FFA and glycerol, does therefore not rule out that glucagon has a direct effect on lipid metabolism in adipocytes and hepatocytes Figure 1. CPT-1 enables catabolism of long-chain fatty acids by converting fatty acids to acyl-carnitines, which are transported into the mitochondria and subjected to beta-oxidation Kim et al.
During beta-oxidation the fatty acids are degraded into acetate, which ultimately enters the citric acid cycle DiMarco and Hoppel, Furthermore, through PKA-dependent phosphorylation, glucagon receptor signaling inactivates acetyl-CoA carboxylase, the enzyme catalyzing the formation of malonyl-CoA.
Periportal and perivenous hepatocytes receive different concentrations of substrates and oxygen and as a consequence periportal hepatocytes primarily mediate oxidative processes, including beta-oxidation, whereas perivenous hepatocytes preferentially mediate glucose uptake and lipogenesis Jungermann, ; Guzman and Castro, Figure 2.
The effects of glucagon receptor signaling on hepatic lipid metabolism. Glucagon activates its cognate receptor, a seven transmembrane receptor coupled to a Gs protein, resulting in AC activity and cAMP production.
Glucagon thus inhibit malonyl-CoA formation and the subsequent de novo fatty acid synthesis. When formed, the fatty acids are, after re-esterification, stored as trigycerides in and released from the hepatocytes in the form of very-low density lipoprotein VLDL. Thus, glucagon leads the free fatty acids toward beta-oxidation and decreases de novo fatty acid synthesis and VLDL release. CPT-1 catalyzes the attachment of carnitine to fatty acyl-CoA, forming acyl-carnitine.
The acyl-carnitines transverse the mitochondrial membrane mediated via the carnitine-acylcarnitine translocase CACT. Once in the mitochondrial matrix, carnitine acyl transferase-2 CPT-2 is responsible for transferring the acyl-group from the acyl-carnitine back to CoA. Carnitine leaves the mitochondria matrix through the carnitine-acylcarnitine translocase.
During beta-oxidation, the fatty acid chains are degraded into acetate. Acetate reacts with CoA to yield acetyl-CoA, which reacts with oxaloacetate to form citrate that inhibits glycolysis through inhibition of pyruvate dehydrogenase and phosphofructokinase Finally, citrate enters the citric acid cycle TCA.
Thus, glucagon increases fatty acid catabolism, inhibits glycolysis, and fuels the TCA cycle. Glucagon stimulates FoxA2 activity, which induces transcription of genes such as CPT-1, very-, and medium- long-chain acyl-CoA dehydrogenase. Enzymes and pathways inhibited by glucagon are shown in red, while enzymes and pathways stimulated by glucagon are shown in black.
Glucagon also stimulates forkhead transcription factor A2 activity FoxA2 , which induces transcription of genes involved in beta-oxidation, such as CPT-1, very-, and medium- long-chain acyl-CoA dehydrogenase Wolfrum and Stoffel, ; von Meyenn et al.
Subsequent to activating its receptors on hepatocytes, insulin suppresses most of these pathways, and the metabolic state in the hepatocytes may therefore be determined by the insulin-glucagon ratio, rather than by the hormone concentrations per se Parrilla et al. Insulin inhibits lipolysis in adipocytes and by reducing the amount of substrate FFA and glycerol reaching the liver may reduce Perry et al.
The accumulation of acetyl-CoA in the cytosol of hepatocytes results in increased lipogenesis. Supporting this, genes involved in lipogenesis, e. The hepatic gene expression profile changes markedly in response to fasting, and major differences have been reported in expression levels of genes involved in lipid metabolism between the fed and fasted state Longuet et al. Others Gelling et al. Glucagon thus seems to regulate hepatic metabolism in response to fasting by stimulating glucose-producing processes, including beta-oxidation.
In line with this, others Gelling et al. Administration of GRAs has been associated with increased hepatic fat content assessed as hepatic fat fraction measured by magnetic resonance imaging and increased plasma concentrations of LDL Guzman et al.
Furthermore, subjects with endogenous glucagon deficiency pancreatectomized subjects Dresler et al. These data suggest that inhibition of glucagon receptor signaling results in hepatic lipid accumulation. In rats, impaired glucagon action also associates with development of hepatic steatosis Charbonneau et al.
Interestingly, HFD feeding has been reported to decrease glucagon receptor expression at the plasma membrane of rat hepatocytes Charbonneau et al. These data suggest that hepatic lipid accumulation may cause impaired glucagon receptor signaling, and that this as demonstrated using GRAs may contribute to and accelerate hepatic lipid accumulation. Consistent with this, glucagon inhibited synthesis and secretion of TGs in cultured hepatocytes Longuet et al. Both of these dual agonists reduced hepatic steatosis, increased HSL activity in adipocytes, and improved dyslipidemia in DIO mice Day et al.
In addition, hepatic synthesis of VLDL and palmitate, and fatty acid esterification decreased, while beta-oxidation and LDL receptors expression increased upon co-agonist, but not liraglutide, administration More et al. The inhibitory effect on hepatic lipogenesis and stimulatory effect on beta-oxidation therefore seems to be mediated by glucagon receptor signaling. FFAs are under certain circumstances insulin secretagogs Boden and Carnell, but their ability to stimulate glucagon secretion remains debated Gerich et al.
Some clinical studies found a suppression of glucagon secretion at increased FFA concentrations Madison et al. In isolated rat pancreatic islets, palmitate stimulated glucagon secretion Gremlich et al. Others found palmitate to stimulate glucagon secretion in a glucose-dependent manner using isolated pancreatic islets; increasing at glucose concentrations of 2. FFAs may also function as metabolic substrate and stimulate alpha cell secretion through beta-oxidation Kristinsson et al.
FFAs decrease secretion of somatostatin Gromada et al. No difference in glucagon secretion was observed between subjects consuming a HFD or a low-fat diet for 2 weeks Raben et al. In contrast to this, ingestion of long—chain fatty acids olive oil and C8 fatty acids lead to increased plasma concentrations of glucagon 40 min after, whereas no increase was observed after ingestion of short-chain fatty acids C4 , however, glucose-dependent insulinotropic polypeptide GIP concentrations also increased upon ingestion of long-chain fatty acids and this may have caused an increase in glucagon secretion Mandoe et al.
Another study observed that a meal rich in mono-unsaturated fatty acids resulted in a larger glucagon response when compared to a control meal Sloth et al. Others also observed an increase in glucagon concentrations upon fat-enriched meals Radulescu et al. The glucagon response observed upon a 90 min intraduodenal infusion of linoleic, oleic, and palmitic acids were significant lower than observed upon protein infusion Ryan et al.
Studies of ability of FFAs to stimulate glucagon secretion are complex, since FFAs are found in many forms and their stimulatory effect may vary Radulescu et al. Furthermore, the increased glucagon concentrations reported in some studies may result from other proglucagon products e.
Glucagon may, aside from its physiological actions on glucose and amino acid metabolism, also be important for lipid metabolism via effects on hepatic beta-oxidation and lipogenesis, and potentially increased lipolysis in adipocytes. A direct role of glucagon on adipocytes may be of importance in rodents, as glucagon stimulates lipolysis Vaughan and Steinberg, ; Rodbell and Jones, ; Prigge and Grande, ; Manganiello and Vaughan, ; Lefebvre et al.
In both rodents and humans, glucagon is a powerful regulator of hepatic lipid metabolism Day et al. Treatment of diabetes using the current GRAs may therefore not be feasible, however, one may speculate that targeted antagonism of glucagon signaling may circumvent these unwarranted side-effects.
Currently glucagon receptor agonists, combined with GLP-1 and GIP receptor agonists, are investigated as possible therapeutic agents Gu et al. In preclinical studies, these agents improve steatosis and dyslipidemia, possibly as a consequence of regulation of hepatic lipid metabolism by glucagon agonism Day et al.
Taken together, glucagon seems to play an important physiological role in the acute regulation of lipid metabolism but clearly further studies particularly in humans are warranted. All funding sources have been submitted. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Adriaenssens, A. Transcriptomic profiling of pancreatic alpha, beta and delta cell populations identifies delta cells as a principal target for ghrelin in mouse islets.
Diabetologia 59, — Ahren, B. In Toxins. Continually high insulin levels impair Akt phosphorylation and glucose transport in human myoblasts. Insulin resistance induced by hyperinsulinemia coincides with a persistent alteration at the insulin receptor tyrosine kinase domain. Insulin resistance is a cellular antioxidant defense mechanism. Insulin resistance protects the heart from fuel overload in dysregulated metabolic states. Insulin resistance as a physiological defense against metabolic stress: implications for the management of subsets of type 2 diabetes.
Excessive caloric intake acutely causes oxidative stress, GLUT4 carbonylation, and insulin resistance in healthy men. Sci Transl Med. IRS1-independent defects define major nodes of insulin resistance. Distinct patterns of tissue-specific lipid accumulation during the induction of insulin resistance in mice by high-fat feeding. Insulin receptor isoforms in physiology and disease: an updated view. Endocr Rev. Insulin regulates the unfolded protein response in human adipose tissue.
The role of pathway-selective insulin resistance and responsiveness in diabetic dyslipoproteinemia. Curr Opin Lipidol. Postreceptor insulin resistance contributes to human dyslipidemia and hepatic steatosis.
J Clin Invest. Nat Commun. Insulin resistance is associated with diminished endoplasmic reticulum stress responses in adipose tissue of healthy and diabetic subjects. Physiol Rev.
Diabetic downregulation of Nrf2 activity via ERK contributes to oxidative stress-induced insulin resistance in cardiac cells in vitro and in vivo. Insulin mediated DNA damage in mammalian colon cells and human lymphocytes in vitro.
Mutat Res. Prolonged insulin treatment sensitizes apoptosis pathways in pancreatic beta cells. Age-related hyperinsulinemia leads to insulin resistance in neurons and cell-cycle-induced senescence. Nat Neurosci. The Fork head transcription factor DAF transduces insulin-like metabolic and longevity signals in C.
Growth signaling and longevity in mouse models. In BMB Reports. Replication of extended lifespan phenotype in mice with deletion of insulin receptor substrate 1. Extended longevity in mice lacking the insulin receptor in adipose tissue.
Reduced circulating insulin enhances insulin sensitivity in old mice and extends lifespan. Cell Rep. The critical role of metabolic pathways in aging. The mechanistic target of rapamycin: the grand ConducTOR of metabolism and aging.
Guillen C, Benito M. Front Endocrinol Lausanne. Exp Gerontol;— Insulin receptor signaling in normal and insulin-resistant states. Cold Spring Harb Perspect Biol. Adipocyte JAK2 mediates growth hormone-induced hepatic insulin resistance.
JCI Insight. Eradicating hepatitis C virus ameliorates insulin resistance without change in adipose depots. J Viral Hepat. Effect of sustained physiologic hyperinsulinaemia and hyperglycaemia on insulin secretion and insulin sensitivity in man. Kobayashi M, Olefsky JM. Effects of streptozotocin-induced diabetes on insulin binding, glucose transport, and intracellular glucose metabolism in isolated rat adipocytes.
Czech MP. Insulin action and resistance in obesity and type 2 diabetes. Nat Med. Hyperinsulinemia in individuals with obesity: role of insulin clearance. Obesity Silver Spring. Selective insulin resistance and the development of cardiovascular diseases in diabetes: the Edwin Bierman Award Lecture. Front Physiol. Br J Pharmacol. Inhibition of phosphatidylinositol 3-kinase enhances mitogenic actions of insulin in endothelial cells. Insulin potentiates cytokine-induced VCAM-1 expression in human endothelial cells.
Biochim Biophys Acta. Cellular mechanisms underlying obesity-induced arterial stiffness. Arterial stiffness in insulin resistance: the role of nitric oxide and angiotensin II receptors. Vasc Health Risk Manag. Muniyappa R, Yavuz S. Metabolic actions of angiotensin II and insulin: a microvascular endothelial balancing act. Mol Cell Endocrinol.
Mol Med. Selective insulin resistance in the kidney. Biomed Res Int. Tanaka M. Improving obesity and blood pressure. Hypertens Res. Role of hyperinsulinemia and insulin resistance in hypertension: metabolic syndrome revisited. Can J Cardiol;— Fasting insulin, insulin resistance and risk of hypertension in the general population: a meta-analysis. Clin Chim Acta. Stout RW. Insulin and atheroma. Suppression of endothelial or lipoprotein lipase in THP-1 macrophages attenuates proinflammatory cytokine secretion.
J Lipid Res. Macrophage lipoprotein lipase modulates the development of atherosclerosis but not adiposity. MicroRNA inhibits lipoprotein lipase expression and prevents atherosclerosis in apoE knockout mice. Insulin deficiency decreases lipoprotein lipase secretion by murine macrophages.
Insulin resistance is a cardiovascular risk factor in humans. Diabetes Metab Syndr. Paneni F, Luscher TF. Cardiovascular protection in the treatment of type 2 diabetes: a review of clinical trial results across drug classes. Am J Med. Insulin therapy increases cardiovascular risk in type 2 diabetes. Prog Cardiovasc Dis. Effect of metformin on all-cause and cardiovascular mortality in patients with coronary artery diseases: a systematic review and an updated meta-analysis.
Cardiovasc Diabetol. Metformin in patients with and without diabetes: a paradigm shift in cardiovascular disease management. Bailey CJ. Metformin: historical overview. Reducing cardiovascular disease risk in patients with type 2 diabetes and concomitant macrovascular disease: can insulin be too much of a good thing?
Dailey G, Wang E. A review of cardiovascular outcomes in the treatment of people with type 2 diabetes. Diabetes Ther. Sulfonylurea in combination with insulin is associated with increased mortality compared with a combination of insulin and metformin in a retrospective Danish nationwide study.
Comparative cardiovascular morbidity and mortality in patients taking different insulin regimens for type 2 diabetes: a systematic review.
BMJ Open. High daily insulin exposure in patients with type 2 diabetes is associated with increased risk of cardiovascular events. Differential cardiovascular outcomes after dipeptidyl peptidase-4 inhibitor, sulfonylurea, and pioglitazone therapy, all in combination with metformin, for type 2 diabetes: a population-based cohort study.
Heart failure considerations of antihyperglycemic medications for type 2 diabetes. Circ Res. Saper, and J. Andrews, D. Erion, R. Beiler et al. Bayliss, M. Lemus, V. Santos, M. Deo, J. Elsworth, and Z. Stievenard, M. Dickson, A. Douhan, L. Svensson, and J. Balivada, H. Pawar, S. Montgomery, and M. Soeki, K. Koshiba, T. Niki et al. Johansson, S.
Destefanis, N. Blomgren, and C. Zhang, T. Lin, Y. Gonzalez-Rey, A. Chorny, and M. Lee, E. Lim, Y. Kim, E. Li, and S. Ku, Z. Andrews, T. Barsby et al. Cheng, B. Chen, W. Xie et al. Chung, E.
Kim, D. Lee et al. Chung, J. Choi, and S. Sato, K. Nakahara, S. Goto et al. Ferrini, C. Salio, L. Lossi, and A. Talley, T. Goodsall, and M. Qin, Z. Li, Z. Masuda, T. Tanaka, N. Inomata et al. Greeley Jr. Nakazato, N. Murakami, M. Kojima, K. Kangawa, and S. Nawrot-por, J. Jaworek, A. Leja-szpak, and J. Arosio, C. Ronchi, C. Gebbia et al. Zhang, M. Chen, X. Chen, B. Segura, and M. Damjanovic, N. Lalic, P. Pesko et al. Abot, P. Cani, and C. Tack, I. Depoortere, R. Bisschops et al. Edholm, F.
Levin, P. Sakurada, S. Ro, T. Onouchi et al. Overduin, and K. Date, N. Murakami, K. Toshinai et al. Fernandez, A. Cabral, M. Cornejo et al. Shiomi, M.
Yoshimura, Y. Hori et al. Lv, T. Liang, G. Smiley, and M. Zakhari, E. Zorrilla, B. Zhou, A. Mayorov, and K. Mihalache, A. Gherasim, O. Pradhan, S. Samson, and Y. Tsubone, T. Masaki, I. Katsuragi, K. Tanaka, T. Kakuma, and H. Paul, T. Heppner et al. Yasuda, T. Masaki, T. St-pierre, A. Karelis, K. Cianflone et al. Zhang, A. Majumder, X.
Wu, and M. Giovambattista, R. Gaillard, and E. Perez-Tilve, K. Heppner, H. Kirchner et al. Cummings, D. Weigle, R. Scott, A. Patrica, and M. Ueno and M. Al-Massadi, T. Rouault, L. Rosselli-murai, C. Hernandez, L. Gimenez, G. Tall, and J. Sangiao-alvarellos, M. Va, L. Varela et al. View at: Google Scholar C. Theander-carrillo, M. Rohner-jeanrenaud et al. Vidal-puig, M. Lo, R. Lage, and C. Hu, S.
Cha, S. Chohnan, and M. Poplawski, J. Mastaitis, X. Yang, and C. Pocai, A. Arduini, L. Rossetti et al. Wolfgang, T. Kurama, Y. Dai et al. Kola, E.
Hubina, S. Tucci et al. Andrews, Z. Liu, N. Walllingford et al. Velasquez, G. Martinez, A. Romero et al. Lage, A. Saha, D. Pe et al. View at: Google Scholar Z. Walllingford, D. Erion, and J. Vazquez, A. Romero, M. Heiman and M. Qin et al. Velasco, M. Nesic, D. Stevanovic, S. Stankovic et al. Zhang, L. Zhao, T. Lin et al. Kraft, D.
Cervone, and D. Isgaard, A. Barlind, and I. Lilleness and W. Wu, W. Dong, M. Zhou, X. Cui, H. Hanksimms, and P. Nagaya, M. Kojima, M. Uematsu et al. R—R, Enomoto, N. Mao, T. Tokudome, and I. Matsumura, T. Tsuchihashi, K. Fujii, I. Abe, and M. Leite-Moreira, A. Rocha-Sousa, and T. Han, W. Huang, S. Ma et al. Cheng, G. Zhu, and A. Pei, B. Yung, S. Yip et al. Khatib, A. Shankar, R. Kirubakaran et al. Garbern and R. Iantorno, H. Chen, J. Kim et al. Rossi, A. Castelli, M. Bianco, C.
Bertone, M. Brama, and V. Okumura, N. Enomoto, E. Nakagawa, H. Oya, and K. Dimmeler, I. Fleming, B. Fisslthaler, C. Hermann, R. Busse, and A. Fulton, J. Gratton, J. Timothy, and J. Drew, N. Fidge, G. Gallon-beaumier, B. Kemp, and B. Kolb et al. Zou, X. Hou, C. Shi, D. Nagata, K.
Walsh, and R. Schlossmann, A. Ammendola, K. Ashman et al. Bolotina, S.
0コメント