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The Neuropeptide Galanin Benefits Insulin Sensitivity in Subjects with Type 2 Diabetes Penghua Fang1,2, Mei Yu3, Mingyi Shi1, Biao He1, Zhenwen Zhang1,* and Ping Bo1,* 1

Research Institute of Combined Chinese Traditional and Western Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu 225001, China; 2Department of Physiology, Hanlin College, Nanjing University of Chinese Medicine, Taizhou, Jiangsu 225300, China; 3Department of Pharmacy, Taizhou Hospital of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, Taizhou, Jiangsu 225300, China Abstract: Impaired insulin sensitivity, namely insulin resistance, is a metabolic and functional disorder that is often associated with the type 2 diabetes mellitus and/or obesity. Recent studies have provided compelling clues that the neuropeptide galanin is closely related to insulin sensitivity in skeletal muscle and adipose tissue of rats. This peptide may regulate glucose homeostasis and carbohydrate metabolism in peripheral tissues, as well as accelerate the translocation of glucose transporter 4 to the plasma membrane of various insulin-sensitive cells to reduce insulin resistance. Galanin plays a crucial role in inhibiting insulin secretion from pancreatic
cells to prevent hyperinsulinemia, which is a characteristic of type 2 diabetes mellitus. This review provides a comprehensive aggregation of the current literature available, bringing together data gleaned from our recent studies highlighting the role of galanin in regulating insulin sensitivity. This comprehensive role played by galanin and its relative agents in regulating insulin secretion and insulin sensitivity provides a new insight into the influence of this neuropeptides on the prevention and treatment of type 2 diabetes mellitus.

Keywords: Galanin, insulin, glucose transporter 4. 1. INTRODUCTION The hallmark of insulin resistance is a decreased stimulatory effect of insulin on glucose disposal in peripheral target tissues [1]. It is a fundamental and metabolic disorder that drives abnormal levels of blood pressure, lipids and glucose. Insulin resistance plays an important role in the pathogenesis of type 2 diabetes mellitus, obesity, hypertension, dyslipidemia and cardiovascular disease [2, 3]. Numerous factors are implicated in the pathogenesis of insulin resistance. An important one is that galanin may reduce insulin resistance and benefit glucose uptake in insulin-independent diabetes. Galanin, a 29 amino-acid peptide, was first isolated from pig intestine by Tatemoto and collaborators in 1983 [4]. This peptide is widely distributed throughout the central and peripheral nervous systems as well as other tissues [4, 5]. It has various biological functions in modulating depression, inflammation, pain threshold control, feeding and pituitary hormone release [6-11]. Besides, numerous studies revealed that it may inhibit insulin secretion and increase insulin sensitivity in animals [12-17]. The galanin receptor family is currently composed of three members, GalR1, GalR2 and GalR3. All are G-proteincoupled receptors and distributed in the hypothalamus, amygdala, hippocampus, paraventricular nucleus (PVN), thalamus, brainstem, spinal cord and dorsal root ganglia *Address correspondence to these authors at the Research Institute of Combined Chinese Traditional and Western Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu Province 225001, China; Tel: +86-514-87978880; Fax: +86-514-87341733; Email: [email protected]

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[18, 19]. Activated GalR1 and GalR3 both can inhibit adenylyl cyclase and decrease the cAMP level through Gi/o coupled receptors [18, 20]. Activated GalR2 may result in the hydrolysis of inositol phosphate and activation of phospholipase C (PLC) through the Gq/11 pathway to raise the intracellular Ca2+ concentration [18, 21]. These different signaling ways reflect the different functions of this peptide. As yet a variety of potential ligands have been developed to elucidate the specific roles of galanin receptors, such as the galanin antagonist M35 and galantide [19]. This review summarizes our recent studies and relevant papers concerning the effect of galanin on the regulation of insulin sensitivity, in order to deepen our understanding of the underlying mechanisms for glucose homeostasis and type 2 diabetes mellitus. 2. THE EFFECT OF GALANIN ON THE REGULATION OF INSULIN SENSITIVITY 2.1. Galanin Concentration is Positively Correlated with Blood Glucose Level In a glucose tolerance test, the galanin levels in healthy humans were significantly increased from 0 to 90 min and returned to the basal values at 180 min [22]. The fasting blood glucose contents, which were dependent on insulin sensitivity, were positively correlated with galanin levels in type 2 diabetic patients [23] and in healthy volunteers [22]. Compared with healthy controls, the plasma galanin levels were higher in subjects with type 2 diabetes mellitus [23], but were lower in women with polycystic ovary syndrome, which is characterized by hyperinsulinemia [24].

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670 Current Protein and Peptide Science, 2013, Vol. 14, No. 8

After adjusted by body mass index, the plasma galanin levels were also higher in children with type 1 diabetes mellitus than healthy controls, irrespective of sex or pubertal development [25]. In addition, there were statistically higher levels of galanin compared with controls, as well as significant positive correlations between galanin and blood glucose, galanin and body mass index in pregnant women with gestational diabetes mellitus [26]. Furthermore, oligonucleotide microarray hybridization analysis revealed that expression levels of galanin receptor 2 gene in the hippocampus and prefrontal cortex were upregulated in type 2 diabetic rats comparison to non-diabetic controls [27]. Changes in the cerebral gene expression profiles seemed to be specific for the type 2 diabetic model, as no such alterations were found in streptozotocin-treated animals. These results demonstrate that the plasma galanin contents are closely associated with blood glucose levels and insulin sensitivity in humans.

Fig. (1).

2.2. The Reciprocal Inhibition of Secretion Between Galanin and Insulin A large number of galanin-immunoreactive cells are detectable in the central and peripheral areas of the pancreatic islets in healthy rats [28, 29]. Galanin and its receptors are present in endocrine cells of the pancreas and sympathetic nerve terminals surrounded by islet cells. The coexistence of galanin and insulin in the islets provides a morphologic basis for interactions between them [30]. There is a link between galanin and insulin in the regulation of glucose homeostasis. On the one hand, galanin and its fragment galanin-(1-15)-NH2 inhibit the basal and glucosestimulated insulin secretion from isolated pancreatic islets of both normal and diabetic rats [28, 30, 31]. This inhibition may be blocked by galanin antagonists galantide and M35 [32-34]. When injected into the PVN, galanin and its active fragments, galanin (1-16) and galanin (1-11) significantly inhibit insulin secretion in mammals [35-38]. In galanin knockout (KO) mice, intravenous injection of 2-deoxyglucose causes an initial brief inhibition of insulin secretion, followed by increased insulin secretion in vivo [29]. The suppressive effect of galanin on insulin release also comes

Fang et al.

from an attenuated response of
cells to stimuli [39], and this is directly regulated by the pertussis toxin-sensitive G protein receptors in
cells [30, 40]. Tang et al. demonstrated that galanin-induced suppression of insulin secretion from
cells was via the actions of G(o)2 of the G(i/o) protein family through cell biological and electrophysiological methods [41]. In addition, intracerebroventricular administration of galanin or its overexpression in transgenic mice was implicated in the regulation of insulin-dependent pathologic processes, such as cognitive and memory disorders [27], while improvement of cognitive functions has been reported in animals treated with galanin receptor antagonists [27]. As cerebral insulin deficiency presents with similar symptoms, it is tempting to speculate that impairment of cerebral functions might be mediated at least in part by reduced insulin release induced by elevated galanin levels in diabetic subjects. These findings suggest that galanin plays a role in preventing the hyperinsulinemia induced by type 2 diabetes. Interestingly, infusion of galanin is endowed with the inhibiting effect on glucose-stimulated insulin release in animals, but not in man [42], also not L-arginine- or potassiumstimulated insulin secretion [43]. On the other hand, administration of insulin may reverse the increase in the plasma galanin contents in type 2 diabetic rats [44]. The streptozotocin (STZ)-induced diabetic rats showed a notable increase in the galanin concentration in the PVN, which was reversed by daily injections of insulin. The reciprocal inhibition of secretion between galanin and insulin in PVN suggests a physiological relevance in the control of energy balance. Besides, galanin-like immunoreactive cells were significantly reduced in the pancreatic islets in STZinduced diabetic rats compared with non-diabetic rats [30], i.e., the lack of insulin release in diabetic animals may give rise to a reduction in galanin-like immunoreactive cells as there is an extensive co-localization of galanin with insulin in the islets of rats. This suggests that diabetes mellitus results from a reduction in both insulin and galanin secretion from the islets. 2.3. Galanin and Insulin Sensitivity Accumulating evidence shows that injection with galanin may improve insulin sensitivity and glucose intolerance in animals [12-17]. First, as mentioned above, during an oral glucose tolerance test galanin secretion is positively associated with the blood glucose level, which is strongly associated with insulin sensitivity [24]. Second, animals with galanin metabolic disorder are usually vulnerable to type 2 diabetes mellitus and increased insulin resistance [45]. Third, galanin KO and GalR1 KO mice have impaired glucose disposal due to a reduction in insulin sensitivity and insulinindependent glucose elimination during the glucose tolerance tests [29, 46], while homozygous galanin transgenic C57BL/6J mice with the obese phenotype show a reduction in metabolic rate of lipids and carbohydrates as well as in insulin resistance [47]. Finally, galanin receptors have been found in skeletal muscle and adipose tissue [20, 48, 49], where are the key sites for regulating glucose disposal and insulin sensitivity [50, 51]. To date, 14 types of glucose transport protein have been discovered, each having specific functions with different distributions [52]. Of these, glucose transporter 4 (GLUT4)

Galanin Benefits Insulin Sensitivity

is particularly important one for maintaining glucose metabolism homeostasis and insulin sensitivity. Since GLUT4 is involved in glucose transport into myocytes and adipocytes in response to insulin or exercise stimuli. Insulinstimulated glucose disposal in skeletal muscle and adipose tissue predominantly depends on GLUT4 [53]. Under resting conditions, most GLUT4s are located in intracellular membrane compartments. As insulin or exercise stimulation, they are translocated to the plasma membranes of myocytes and adipocytes. Only at the cell surface can GLUT4 transport glucose into cells [54]. The maximal glucose clearance activity by skeletal muscle and adipose tissue is directly proportional to the GLUT4 protein concentration in plasma membranes, which represents and reflects insulin sensitivity [55]. Measurement of insulin resistance and GLUT4 membrane translocation provides a strong predictor of type 2 diabetes mellitus [56]. 2.3.1. Galanin and Insulin Sensitivity in Skeletal Muscle Skeletal muscle accounts for the overwhelming majority of insulin-stimulated glucose uptake and lipid oxidation. Impaired insulin-mediated glucose intake by muscles is a key feature of diabetes [48, 57]. Therefore, it is a common target for studies of glucose clearance as well as interaction between galanin and glucose intake. Previous studies reported high levels of galanin protein and galanin receptors in most spinal motor and motor endplates [20, 48]. An important question is whether galanin increases the GLUT4-mediated glucose clearance and insulin sensitivity in skeletal muscles. Our recent study demonstrated that after administration of M35, a galanin antagonist, the insulin sensitivity in skeletal muscle of both normal and type 2 diabetic rats was reduced in the hyperinsulinemiceuglycemic clamp test which directly assessed insulin sensitivity [13-16]. Quantitative densitometry in the skeletal muscle revealed that M35 treatment significantly decreased GLUT4 density and GLUT4 mRNA expression level compared with diabetic controls. Also, the ratio of GLUT4 contents in the plasma membrane fraction to the total cell membrane was lower in the M35 treatment group than in diabetic controls. These results imply that endogenous galanin elevates not only GLUT4 protein concentration and GLUT4 mRNA expression level, but also the translocation of GLUT4 from intracellular membrane compartments to plasma membranes in skeletal muscle to sustain insulin sensitivity and glucose homeostasis in healthy and type 2 diabetic rats [13, 14]. Recently Bu et al. demonstrated that i.c.v. administration of M35 reduced 2-deoxy-[3H]-D-glucose uptake into myocytes and peroxisome proliferator-activated receptor
concentration in skeletal muscles, Gal mRNA expression levels in hypothalamus, glucose infusion rates in the hyperinsulinemic-euglycemic clamp test and GLUT4 concentration in plasma membranes and total cell membranes of myocytes in both normal and type 2 diabetic rats [58]. The ratios of GLUT4 contents in M35 groups were lower in the former to the latter. These results suggest a facilitating effect of galanin on GLIT4 translocation and insulin sensitivity to accelerate glucose uptake via acting its central receptors in healthy and type 2 diabetic rats.

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Galanin influences the insulin sensitivity of skeletal muscle not only in sedentary rats [50], but also in training animals. The effect of physical exercise on insulin sensitivity of subjects is of duality. On the one hand, during physical exercise the increase in sympathetic activity and galanin secretion inhibits insulin release and insulin-signaling pathway activity [59, 60]. On the other hand, the exercise-induced increase in galanin release may upregulate GLUT4 transcription and accelerate GLUT4 translocation. The sum of both effects is to reduce insulin resistance and to transfer more glucose into cells in type 2 diabetic animals [14]. 2.3.2. Galanin and Insulin Sensitivity in Adipocytes Adipose tissue has long been considered to serve as a fat depot and an endocrine organ. However, recent research has demonstrated that it actually plays a vital role in energy balance [61]. Adipose tissue essentially contributes to the obesity-driven insulin resistance syndrome as it can buffer excess energy and control metabolic homeostasis [56]. In particular, obesity is now recognized as a risk factor for the development of insulin resistance and type 2 diabetes [62]. Though the molecular mechanism underlying increased insulin resistance by adipose tissue remains largely unknown, it has been suggested that various factors, including galanin, resistin and leptin [15, 63, 64], influence insulin sensitivity. Adipose tissue is also an important target for studying glucose clearance and diabetes. Although only 10% of insulinstimulated glucose uptake assumed by adipose tissue, this process is specifically important for controlling whole-body energy homeostasis and glucose metabolism. Impaired oxidation rates of fatty acid are associated with insulin resistance as fatty acids can interfere with insulin signaling [65]. GLUT4 in adipocytes is crucial for sustaining the energy metabolism and homeostasis. It is well documented that galanin and its receptors exist in adipocytes [49]. As the results from skeletal muscle experiments, intraperitoneal treatment of M35 significantly decreased GLUT4 mRNA expression level and GLUT4 concentration in the adipocytes of healthy and type 2 diabetic rats. Also, the ratio of GLUT4 in the plasma membranes to total cell membranes of adipocytes in the M35 groups was lower than controls [15, 16, 66]. These results imply that endogenous galanin is beneficial to the insulin sensitivity of adipocytes. Experimental evidence has shown that the GalR1selective agonist M617 increases food intake and body weight, while GalR2-selective agonists have no such effects [9, 67], Thus, GalR2 may be a valuable subtype for further exploration to reduce insulin resistance without added body weight of subjects. To date it is unknown which one of the three galanin receptor subtypes is the most effective in enhancing insulin sensitivity. These researches may open up a new avenue into the role of galanin in the regulation of insulin sensitivity, which may bring a new ideal in alleviation of type 2 diabetes mellitus. CONCLUSION Galanin plays an important role in sustaining insulin sensitivity and inhibiting insulin secretion to reduce the hyperinsulinemia in type 2 diabetes mellitus. Current research suggests decreased galanin level as a new potential plasma

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marker for insulin resistance and as a clinical measure for the risk of diabetes mellitus. However, further studies and clinical trials are needed to determine the long-term efficacy of galanin. This exploration may develop a novel therapeutic approach to prevent and treat type 2 diabetes mellitus. CONFLICT OF INTEREST

Fang et al. [14]

[15]

[16]

The author(s) confirm that this article content has no conflicts of interest. [17]

ACKNOWLEDGEMENTS This review was supported by the National Natural Scientific Foundation of China (81173392). ABBREVIATION PLC

=

Phospholipase C

GalR

=

Galanin receptor

GLUT4 =

Glucose Transporter 4

i.c.v

=

Intracerebroventricular

KO

=

Knockout

PVN

=

Paraventricular nucleus

STZ

=

Streptozotocin

REFERENCES [1]

[2] [3] [4] [5]

[6]

[7]

[8] [9]

[10]

[11] [12] [13]

Bruce, K. D.; Hanson, M. A. The developmental origins, mechanisms, and implications of metabolic syndrome. J. Nutr., 2010, 140, 648-652. Eckel, R. H.; Grundy, S. M.; Zimmet, P. Z. The metabolic syndrome. Lancet, 2005, 365, 1415-1428. Dwarakanathan, A. Diabetes update. J. Insur. Med., 2006, 38, 2030. Tatemoto, K.; Rökaeus, A.; Jörnval, H.; McDonald, T. J.; Mutt, V. Galanin-a novel biologically active peptide from porcine intestine. FEBS Lett., 1983, 164, 124-128. Merchenthaler, I.; Rotoli, G.; Grignol. G.; Dudas, B. Intimate associations between the neuropeptide Y system and the galaninimmunoreactive neurons in the human diencephalon. Neuroscience, 2010, 170, 839-845. Jaroslaw, R.; Magdalena, C.; Czeslaw, W.; Piotr, R. Effects of porcine galanin, galanin(1-15) NH2 and its new analogues on glucose-induced insulin secretion. Pol. J. Pharmacol., 2002, 54, 133141. Fang, P.; Yu, M.; Guo, L.; Bo, P.; Zhang, Z.; Shi, M. Galanin and its receptors: A novel strategy for appetite control and obesity therapy. Peptides, 2012, 36, 331-339. Rotzinger, S.; Lovejoy, D. A.; Tan, L. A. Behavioral effects of neuropeptides in rodent models of depression and anxiety. Peptides, 2010, 31, 736-756. Fang, P. H.; Yu, M.; Ma, Y. P.; Li, J.; Sui, Y. M.; Shi, M. Y. Central nervous system regulation of food intake and energy expenditure: role of galanin-mediated feeding behavior. Neurosci. Bull., 2011, 27, 407-412. Izdebska, K.; Ciosek, J. Galanin influences on vasopressin and oxytocin release: In vitro studies. Neuropeptides, 2010, 44, 341348. Lang, R.; Kofler, B. The galanin peptide family in inflammation. Neuropeptides, 2011, 45, 1-8. Fang, P.; Yu, M.; Shi, M.; Zhang, Z.; Sui, Y.; Guo, L.; Bo, P. Galanin peptide family as a modulating target for contribution to metabolic syndrome. Gen. Comp. Endocrinol., 2012, 179, 115-120. Jiang, L.; Shi, M.; Guo, L.; He, B.; Li, G.; Zhang, L.; Zhang, L.; Shao, H. Effect of M35, a neuropeptide galanin antagonist on glucose uptake translated by glucose transporter 4 in trained rat skeletal muscle. Neurosci. Lett., 2009, 467, 178-181.

[18] [19] [20]

[21]

[22] [23]

[24]

[25]

[26] [27]

[28]

[29] [30]

[31]

[32]

[33]

[34]

He, B.; Shi, M.; Zhang, L.; Li, G.; Zhang, L.; Shao, H.; Li, J.; Fang, P.; Ma, Y.; Shi, Q.; Sui, Y. Beneficial effect of galanin on insulin sensitivity in muscle of type 2 diabetic rats. Physiol. Behav., 2011, 103, 284-289. Guo, L.; Shi, M.; Zhang, L.; Li, G.; Zhang, L.; Shao, H.; Fang, P.; Ma, Y.; Li, J.; Shi, Q.; Sui, Y. Galanin antagonist increases insulin resistance by reducing glucose transporter 4 effect in adipocytes of rats. Gen. Comp. Endocrinol., 2011, 173, 159-163. Liang, Y.; Sheng, S.; Fang, P.; Ma, Y.; Li, J.; Shi, Q.; Sui, Y.; Shi, M. Exercise-induced galanin release facilitated GLUT4 translocation in adipocytes of type 2 diabetic rats. Pharmacol. Biochem. Behav., 2012, 100, 554-559. Fang, P.; Sun, J.; Wang, X.; Zhang, Z.; Bo, P.; Shi, M. Galanin participates in the functional regulation of the diabetic heart. Life Sci., 2013, 92, 628-632. Lang, R.; Gundlach, A. L.; Kofler, B. The galanin peptide family: receptor pharmacology, pleiotropic biological actions, and implications in health and disease. Pharmacol. Ther., 2007, 115, 177-207. Florén, A.; Land, T.; Langel, U. Galanin receptor subtypes and ligand binding. Neuropeptides, 2000, 34, 331-337. Wang, S.; He, C.; Maguire, M. T.; Clemmons, A. L.; Burrier, R. E.; Guzzi, M. F.; Strader, C. D.; Parker, E. M.; Bayne, M. L. Genomic organization and functional characterization of the mouse GalR1 galanin receptor. FEBS Lett., 1997, 411, 225-230. Wang, S.; Hashemi, T.; Fried, S.; Clemmons, A. L.; Hawes, B. E. Differential intracellular signaling of the GalR1 and GalR2 galanin receptor subtypes. Biochemistry, 1998, 37, 6711-6717. Legalkis, I. N.; Mantzouridis, T.; Mountokalakis, T. Positive correlation of galanin with glucose in healthy volunteers during an oral glucose tolerance test. Horm. Metab. Res., 2007, 39, 53-55. Legakis, I.; Mantzouridis, T.; Mountokalakis, T. Positive correlation of galanin with glucose in type 2 diabetes. Diabetes Care, 2005, 28, 759-760. Bidziska-Speichert, B.; Lenarcik, A.; Tworowska-Bardziska, U.; Slzak, R.; Bednarek-Tupikowska, G.; Milewicz, A. Pro12Ala PPAR 2 gene polymorphism in PCOS women: the role of compounds regulating satiety. Gynecol. Endocrinol., 2012, 28, 195198. Celi, F.; Bini, V.; Papi, F.; Santilli, E.; Ferretti, A.; Mencacci, M.; Berioli, M. G.; De Giorgi, G.; Falorni, A. Circulating acylated and total ghrelin and galanin in children with insulin-treated type 1 diabetes: relationship to insulin therapy, metabolic control and pubertal development. Clin. Endocrinol. (Oxf), 2005, 63, 139-145. Fang, P.; Bo, P.; Shi, M.; Yu, M.; Zhang, Z. Circulating galanin levels are increased in patients with gestational diabetes mellitus. Clin. Biochem., 2013, 46, 831-833. Abdul-Rahman, O.; Sasvari-Szekely, M.; Ver, A.; Rosta, K.; Szasz, B. K.; Kereszturi, E.; Keszler, G. Altered gene expression profiles in the hippocampus and prefrontal cortex of type 2 diabetic rats. BMC Genomics, 2012, 13, 81-96. Zdrojewicz, Z.; Sowiska, E. The significance of galanin in physiologic and pathologic processes in humans. Postepy. Hig. Med. Dosw., 2000, 54, 819-833. Ahrén, B.; Pacini, G.; Wynick, D.; Wierup, N.; Sundler, F. Loss-offunction mutation of the galanin gene is associated with perturbed islet function in mice. Endocrinology, 2004, 145, 3190-3196. Adeghate, E.; Ponery, A. S. Large reduction in the number of galanin-immunoreactive cells in pancreatic islets of diabetic rats. J. Neuroendocrinol., 2001, 13, 706-710. Olkowicz, M.; Ruczyski, J.; Cybal, M.; Konstaski, Z.; Petrusewicz, J.; Kamiska, B.; Rekowski, P. New galanin(1-15) analogues modified in positions 9, 10 and 11 act as galanin antagonists on glucose-induced insulin secretion. J. Physiol. Pharmacol., 2007, 58, 859-872. Gregersen, S.; Lindskog, S.; Land, T.; Langel, U.; Bartfai, T.; Ahrén, B. Blockade of galanin-induced inhibition of insulin secretion from isolated mouse islets by the non-methionine containing antagonist M35. Eur. J. Pharmacol., 1993, 232, 35-39. Lindskog, S.; Ahrén, B.; Land, T.; Langel, U.; Bartfai, T. The novel high-affinity antagonist, galantide, blocks the galaninmediated inhibition of glucose-induced insulin secretion. Eur. J. Pharmacol., 1992, 210, 183-188. Ruczyski, J.; Konstaski, Z.; Cybal, M.; Koci, I.; Rekowski, P. Aspartimide modified galanin analogue antagonizes galanin action on insulin secretion. Prot. Pept. Lett., 2010, 17, 1182-1188.

Galanin Benefits Insulin Sensitivity [35]

[36] [37]

[38]

[39]

[40]

[41]

[42]

[43] [44]

[45] [46]

[47]

[48]

[49]

[50]

Current Protein and Peptide Science, 2013, Vol. 14, No. 8

Tempel, D. L.; Leibowitz, S. F. Galanin inhibits insulin and corticosterone release after injection into the PVN. Brain Res., 1990, 536, 353-357. Kyrkouli, S. E.; Strubbe, J. H.; Scheurink, A. J. Galanin in the PVN increases nutrient intake and changes peripheral hormone levels in the rat. Physiol. Behav., 2006, 89, 103-109. Gregersen, S.; Hermansen, K.; Langel, U.; Fisone, G.; Bartfai, T.; Ahrén, B. Galanin-induced inhibition of insulin secretion from rat islets: effects of rat and pig galanin and galanin fragments and analogues. Eur. J. Pharmacol., 1991, 203, 111-114. Gregersen, S.; Langel, U.; Bartfai, T.; Ahrén, B. N-terminally elongated fragments of galanin(1-16) inhibit insulin secretion from isolated mouse islets. Regul. Pept., 1994, 53, 31-37. Drews, G.; Debuyser, A.; Henquin, J. C. Significance of membrane repolarization and cyclic AMP changes in mouse pancreatic B-cells for the inhibition of insulin release by galanin. Mol. Cell Endocrinol., 1994, 105, 97-102. Cheng, H.; Straub, S. G.; Sharp, G. W. Protein acylation in the inhibition of insulin secretion by norepinephrine, somatostatin, galanin, and PGE2. Am. J. Physiol. Endocrinol. Metab., 2003, 285, E287-E294. Tang, G.; Wang, Y.; Park, S.; Bajpayee, N. S.; Vi, D.; Nagaoka, Y.; Birnbaumer, L.; Jiang, M. Go2 G protein mediates galanin inhibitory effects on insulin release from pancreatic
cells. Proc. Natl. Acad. Sci. USA., 2012, 109, 2636-2641. Ghigo, E.; Maccario, M.; Arvat, E.; Valetto, M. R.; Valente, F.; Nicolosi, M.; Mazza, E.; Martina, V.; Cocchi, D.; Camanni, F. Interactions of galanin and arginine on growth hormone, prolactin, and insulin secretion in man. Metabolism, 1992, 41, 85-89. Yoshimura, T.; Ishizuka, J.; Greeley, G. H. Jr.; Thompson, J. C. Effect of galanin on glucose-, arginine-, or potassium-stimulated insulin release. Am. J. Physiol., 1989, 256, E619- E623. Tang, C.; Akabayashi, A.; Manitiu, A.; Leibowitz, S. F. Hypothalamic galanin gene expression and peptide levels in relation to circulating insulin: possible role in energy balance. Neuroendocrinology, 1997, 65, 265-275. Legakis, I. N. The role of galanin in metabolic disorders leading to type 2 diabetes mellitus. Drug News Perspect, 2005, 18, 173-177. Zorrilla, E. P.; Brennan, M.; Sabino, V.; Lu, X.; Bartfai, T. Galanin type 1 receptor knockout mice show altered responses to high-fat diet and glucose challenge. Physiol. Behav., 2007, 91, 479-485. Poritsanos, N. J.; Mizuno, T. M.; Lautatzis, M. E.; Vrontakis, M. Chronic increase of circulating galanin levels induces obesity and marked alterations in lipid metabolism similar to metabolic syndrome. Int. J. Obes. (Lond), 2009, 33, 1381-1389. Holmberg, K.; Kuteeva, E.; Brumovsky, P.; Kahl, U.; Karlström, H.; Lucas, G. A.; Rodriguez, J.; Westerblad, H.; Hilke, S.; Theodorsson, E.; Berge, O. G.; Lendahl, U.; Bartfai, T.; Hökfelt, T. Generation and phenotypic characterization of a galanin overexpressing mouse. Neuroscience, 2005, 133, 59-77. Li, R. Y.; Song, H. D.; Shi, W. J.; Hu, S. M.; Yang, Y. S.; Tang, J. F.; Chen, M. D.; Chen, J. L. Galanin inhibits leptin expression and secretion in rat adipose tissue and 3T3-L1 adipocytes. J. Mol. Endocrinol., 2004, 33, 11-19. Sweeney, G.; Keen, J.; Somwar, R.; Konrad, D.; Garg, R.; Klip, A. High leptin levels acutely inhibit insulin-stimulated glucose uptake

Received: October 20, 2012

Revised: June 24, 2013

Accepted: August 07, 2013

[51]

[52] [53]

[54]

[55] [56]

[57] [58]

[59]

[60]

[61] [62] [63]

[64] [65] [66]

[67]

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without affecting glucose transporter 4 translocation in L6 rat skeletal muscle. Endocrinology, 2001, 142, 4806-4812. Wood, I. S.; de Heredia, F. P.; Wang, B.; Trayhurn, P. Cellular hypoxia and adipose tissue dysfunction in obesity. Proc. Nutr. Soc., 2009, 68, 370-377. Augustin, R. The protein family of glucose transport facilitators: It's not only about glucose after all. IUBMB Life, 2010, 62, 315333. Stuart, C. A.; Yin, D.; Howell, M. E.; Dykes, R. J.; Laffan, J. J.; Ferrando, A. A. Hexose transporter mRNAs for GLUT4, GLUT5, and GLUT12 predominate in human muscle. Am. J. Physiol. Endocrinol. Metab., 2006, 291, E1067-E1073. Bogan, J. S.; Hendon, N.; McKee, A. E.; Tsao, T. S.; Lodish, H. F. Functional cloning of TUG as a regulator of GLUT4 glucose transporter trafficking. Nature, 2003, 425, 727-733. Geiger, P. C.; Han, D. H.; Wright, D. C.; Holloszy, J. O. How muscle insulin sensitivity is regulated: testing of a hypothesis. Am. J. Physiol. Endocrinol. Metab., 2006, 291, E1258- E1263. Graham, T. E.; Yang, Q.; Blüher, M.; Hammarstedt, A.; Ciaraldi, T. P.; Henry, R. R.; Wason, C. J.; Oberbach, A.; Jansson, P. A.; Smith, U.; Kahn, B. B. Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects. N. Engl. J. Med., 2006, 354, 2552-2563. DeFronzo, R. A.; Tripathy, D. Skeletal muscle insulin resistance is the primary defect in type 2 diabetes. Diabetes Care, 2009, 32, S157-S163. Bu, L.; Liu, Z.; Zou, J.; Gao, X.; Bao, Y.; Qu, S. Blocking central galanin receptors attenuates insulin sensitivity in myocytes of diabetic trained rats. J. Neurosci. Res., 2013, 91, 971-977. Murray, P. S.; Groves, J. L.; Pettett, B. J.; Britton, S. L.; Koch, L. G.; Dishman, R. K.; Holmes, P. V. Locus coeruleus galanin expression is enhanced after exercise in rats selectively bred for high capacity for aerobic activity. Peptides, 2010, 31, 2264-2268. Legakis, I. N.; Mantzouridis, T.; Saramantis, A.; Phenekos, C.; Tzioras, C.; Mountokalakis, T. Human galanin secretion is increased upon normal exercise test in middle-age individuals. Endocr. Res., 2000, 26, 357-364. Rosen, E. D.; Spiegelman, B. M. Adipocytes as regulators of energy balance and glucose homeostasis. Nature, 2006, 444, 847-853. Lazar, M. A. How obesity causes diabetes: Not a tall tale. Science, 2005, 307, 373-375. Steppan, C. M.; Bailey, S. T.; Bhat, S.; Brown, E. J.; Banerjee, R. R.; Wright, C. M.; Patel, H. R.; Ahima, R. S.; Lazar, M. A. The hormone resistin links obesity to diabetes. Nature, 2001, 409, 307312. Ceddia, R. B. Direct metabolic regulation in skeletal muscle and fat tissue by leptin: implications for glucose and fatty acids homeostasis. Int. J. Obes. (Lond), 2005, 29, 1175-1183. Bonen, A.; Dohm, G. L.; van Loon, L. J. Lipid metabolism, exercise and insulin action. Essays Biochem., 2006, 42, 47-59. Zhang, Z.; Sheng, S.; Guo, L.; Li, G.; Zhang, L.; Zhang, L.; Shi, M.; Bo, P.; Zhu, Y. Intracerebroventricular administration of galanin antagonist sustains insulin resistance in adipocytes of type 2 diabetic trained rats. Mol. Cell Endocrinol., 2012, 361, 213-218. Saar, I.; Runesson, J.; McNamara, I.; Järv, J.; Robinson, J.K.; Langel, U. Novel galanin receptor subtype specific ligands in feeding regulation. Neurochem. Int., 2011, 58, 714-720.