Diabetes The Role of Hormones in Glucose Homeostasis and ... · 4 5 Recent Advances in Diabetes...

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Recent Advances in Diabetes Treatment Recent Advances in Diabetes Treatment

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AbstractDiabetesDiabetes mellitus is a very common disorder caused

by high levels of sugar in the bloodstream. It is caused by problems with the hormone named insulin and also be affected or precipitated by other hormones. It has long been known that several peptide hormones have signifi-cant impact on the regulation of glucose homeostasis. Hormone-based therapies effectively lead to prevent or slow the progression of diabetes. Here we summarize the roles of metabolic hormones such as insulin, GLP-1, lep-tin, FGF21, adiponectin, ghrelin, nesfatin, etc. in glucose metabolism and therapies of diabetes.

IntroductionDiabetes is a metabolic disorder that human body

does not produce or properly uses insulin, a hormone that is required to convert sugar, starches, and other food into energy. Diabetes mellitus is characterized by constant high levels of blood glucose (sugar). Human body has to maintain the blood glucose level at a relatively steady range, which is related to insulin, glucagon and other hor-mones [1]. Acute, life-threatening consequences of un-controlled diabetes are hyperglycemia with ketoacidosis or the nonketotic hyperosmolar syndrome. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of different organs, espe-cially the eyes, kidneys, nerves, heart, and blood vessels. Symptoms of marked hyperglycemia include polyuria,

Chapter 3

The Role of Hormones in Glucose Homeostasis and Diabetes TreatmentHeng Zhang, Sushi Jiang, Xiaosi Hong, Jiana Huang, Danjie Li, Fenting Liu and Geyang Xu*

Department of physiology, School of Medicine, Jinan University, China

*Corresponding Author: Geyang Xu, Department of Physiology, School of Medicine, Jinan University, 601 Huangpu Avenue West, Tianhe District, Guangzhou, Guangdong 510632, China, Tel: 0086-20-85220260; Fax: 0086-20-85221343; Email: [email protected]

First Published December 16, 2015

Copyright: © 2015 Geyang Xu et al.

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source.



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polydipsia, weight loss, sometimes with polyphagia, and blurred vision. Impairment of growth and susceptibility to certain infections may also accompany chronic hyper-glycemia. Moreover, long-term complications of diabetes include retinopathy with potential loss of vision; nephrop-athy leading to renal failure; peripheral neuropathy with risk of foot ulcers, amputations, and charcot joints; and autonomic neuropathy causing gastrointestinal, genitou-rinary, and cardiovascular symptoms and sexual dysfunc-tion. Patients with diabetes have an increased incidence of atherosclerotic cardiovascular, peripheral arterial, and cerebrovascular disease. Hypertension and abnormalities of lipoprotein metabolism are also often found in people with diabetes [2].

Diabetes can be classified into the following general categories:

1. Type 1 diabetes, formerly called insulin-depend-ent diabetes or juvenile diabetes (due to β-cell destruction, usually leading to absolute insulin deficiency).

2. Type 2 diabetes (due to a progressive insulin se-cretory defect on the background of insulin resist-ance).

3. Gestational diabetes mellitus (GDM) (diabetes di-agnosed in the second or third trimester of preg-nancy that is not clearly overt diabetes).

4. Specific types of diabetes due to other causes, e.g.,

monogenic diabetes syndromes (such as neonatal diabetes and maturity-onset diabetes of the young [MODY]), diseases of the exocrine pancreas (such as cystic fibrosis), and drug- or chemical-induced diabetes (such as in the treatment of HIV/AIDS or after organ transplantation) [2-4].

Diabetes epidemic imposes a significant health bur-den on international society. There are currently 382 mil-lion people living with diabetes worldwide; by 2035 this will rise to 592 million. The number of people with type 2 diabetes is increasing in every country. 74% of people with diabetes live in low- and middle-income countries. The greatest number of people with diabetes are between 40 and 59 years of age. 179 million people with diabetes are undiagnosed. Diabetes caused 4.9 million deaths in 2014, every seven seconds a person dies from diabetes [5]. The global pandemic of diabetes induces searches for ad-junctive drugs to reinforce the basic treatment typical for the specific type of this disease. These agents are meant to stimulate insulin secretion, increase insulin sensitivity or inhibit the antagonists of the hormone. It has long been known that several peptide hormones have significant im-pact on the regulation of glucose metabolism, which have been found to increase insulin secretion, and thus hor-mone-based therapies have emerged as new modalities for the treatment of diabetes [6]. Here we summarize the roles of metabolic hormones such as insulin, GLP-1, lep-tin, FGF21, adiponectin, ghrelin, nesfatin, etc. in patho-



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genesis and treatments of diabetes.

InsulinThe Role of Insulin in Glucose MetabolismInsulin is a peptide hormone produced by beta cells

in the pancreas, which consists of A- and B-polypeptide chains, these two chains linked together by disulfide bonds [7]. It is first synthesized as a single polypeptide named preproinsulin in pancreatic β-cells. Preproinsulin contains a 24-residue signal peptide which directs the nas-cent polypeptide chain to the rough endoplasmic reticu-lum (RER). The signal peptide is cleaved as the polypep-tide which transported into lumen of the RER, forming proinsulin [8]. Insulin regulates the metabolism of carbo-hydrates and fats by promoting the absorption of glucose from the blood to skeletal muscles and fat tissue and by causing fat to be stored rather than used for energy [9].

Insulin secretionThe stimulation of insulin release, which is required

for the disposal of nutrients at the time of food intake, appears to be the result of a joint excitation of the pan-creatic β cell by metabolic, hormonal and neural stimuli [10]. Among all nutrients, glucose is the major stimulant of insulin release, insulin in turn is required for the major peripheral tissues to utilize glucose [11]. Moreover, indi-vidual amino acids also stimulate the release of insulin.

The most effective essential amino acid for insulin release is arginine, histidine is least effective [12]. Besides, free fatty acids (FFAs) provide an important energy source as nutrients, and they also act as signalling molecules in vari-ous cellular processes, including insulin secretion. FFAs are thought to promote insulin secretion in an acute phase [13,14].

When plasma glucose concentrations rise, β-cell glu-cose uptake increases mainly via insulin-independent glucose transporters. Intracellularly, glucose is metabo-lized resulting in an increase in the ATP-to-ADP ratio and the closure of ATP-sensitive potassium channels (KATP channels) [15]. As a result, the cell membrane depolar-izes, leading to the opening of voltage-dependent calcium channels and the influx of extracellular calcium. The el-evation of intracellular calcium triggers the exocytosis of insulin (and C-peptide) granules to the portal vein [16]. Although species dependent, glucose-stimulated insulin secretion (GSIS) at supraphysiological levels (ie, during a glucose tolerance test) is biphasic, with a first phase or triggering phase lasting 5 to 6 min, which represents the secretion of the readily releasable pool of insulin granules; and a second phase or amplification phase lasting over 60 min, which represents the replenishment of the readily re-leasable pool by the reserve pool of insulin granules [17].



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Insulin signalingInsulin receptor (IR) is a transmembrane dimer that

belongs to the tyrosine kinase superfamily. Biochemical-ly, the insulin receptor is encoded by a single gene INSR, from which alternate splicing during transcription results in either IR-A or IR-B isoforms [18,19]. Downstream post-translational events of either isoform result in the formation of a proteolytically cleaved α and β subunit. The α-subunit is extracellular, whereas the β-subunit compris-es extracellular, transmembrane, and intracellular regions. The latter contains the tyrosine kinase domain and regu-latory regions [19,20]. On insulin binding, the receptor is activated and undergoes autophosphorylation, which initiates a signaling cascade [21]. The current information concerning insulin signal transduction on protein ser/thr kinase cascades as signalling intermediates, and their status as participants in insulin regulation of energy me-tabolism [22]. Two canonical signaling pathways are well established: the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, responsible for insulin’s metabolic effects; and the Ras/mitogen-activated protein kinase pathway, account-able for insulin’s effects on cell growth and proliferation [23,24]. In the PI3K/Akt pathway, the activated receptor phosphorylates tyrosine residues of insulin receptor sub-strate (IRS), creating binding sites for the Src homology 2 domain of PI3K [25]. The active (phosphorylated) PI3K is translocated to the membrane where it catalyzes the

conversion of phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 3,4,5-trisphosphate. The latter acti-vates phosphatidylinositol 3,4,5-trisphosphate-dependent protein kinase, which in turn activates protein kinase B or Akt by phosphorylation of serine and threonine residues [24,25]. Activated Akt leads to the phosphorylation of multiple substrates that ultimately results in the metabolic effects of insulin, including glucose uptake, via activation of AS160 and subsequent translocation of glucose trans-porter 4 to the plasma membrane; glycogen synthesis by inactivating glycogen synthase kinase-3; protein synthe-sis by regulation of the mammalian target of rapamycin; lipolysis [26].

Major effects of insulin on glucose homeosta-sis

Insulin is the primary anabolic endocrine signal, and it plays a critical role in carbohydrate metabolism. Insu-lin increases cellular glucose uptake, stimulates glyco-lysis, and promotes the synthesis of hepatic and muscle glycogen, adipose triglycerides, and skeletal muscle pro-tein; while simultaneously preventing their degradation [27,28].

The major effects of insulin on carbohydrate metabo-lism are:

1. It increases the rate of glucose transport across the cell membrane in skeletal muscle and adipose tis-



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sue. An increase in insulin promotes glucose up-take by activating a complex cascade of signaling events. In brief, binding of insulin to the insulin receptor leads to down stream tyrosine phospho-rylation of protein substrates that then engage and activate PI3K. This leads to downstream signaling through PKB/Akt and PKC-λ/ζ, which results in GLUT4 translocation from its intracellular pool to the plasma membrane and glucose transport into the cell [28].

2. It stimulates the rate of glycolysis by increasing hexokinase and 6-phosphofructokinase activity in the liver, decreases the release of glucose from the liver by inhibiting the expression of key gluco-neogenic enzymes [29].

3. It upregulates the rate of glycogen synthesis and inhibits the rate of glycogen breakdown [29].

Treatment of DiabetesFor many decades, it has been accepted that insulin

injection is most used for diabetes therapy. Many forms of insulin treat diabetes. They’re grouped by how fast they start to work and how long their effects last [30].

Rapid-Acting insulinRapid-acting insulins such as insulin lispro and insu-

lin aspart do not self-aggregate in solution as human (reg-

ular) insulin does, and these insulins are rapidly absorbed. Insulin lispro differs from human insulin by an amino acid exchange of lysine and proline at positions 28 and 29. The substitution of aspartic acid for proline at position 28 created insulin aspart. Rapid-acting insulins peak at 40 to 60 minutes after injection. They were effective in decreas-ing the postprandial glucose concentration when admin-istered 5 min before a meal to women with GDM [31,32].

Short-Acting insulinRegular insulin has a delay to onset of action of 30 to

60 minutes. Patients are instructed to inject regular insu-lin 20 to 30 minutes prior to meals (ie, lag time is the time between injecting insulin and eating) to match insulin availability and carbohydrate absorption. Regular insu-lin acts almost immediately when injected intravenously. What is more, regular insulin has a duration of action of more than 8 h in some patients, three mealtime injections during the day can compensate for the insulin waning ef-fect of a single Neutral protamine Hagedorn injection at night [30].

Intermediate-Acting insulinThe most widely used intermediate-acting human

insulin is Neutral Protamine Hagedorn (NPH) insulin, which also has to be administered twice daily in many cases to provide a 24-h basal insulinemia. NPH insulin is slowly absorbed due to the addition of protamine to regu-



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lar insulin [30].

Long-Acting insulinA modified human insulin that forms a microprecipi-

tate in the subcutaneous tissue, is released slowly with a peakless delivery of about 20 to 24 hours in most patients. More specifically, the novel recombinant insulin analog insulin glargine is a modification of human insulin with a very long duration of action in which two arginines are added to the B-chain and glycine is substituted for aspara-gine at the A21 position of the insulin molecule [33,34]. Glargine gained approval from the United States Food and Drug Administration in April 2000, for use in treat-ing type 1 and type 2 diabetes in humans. In patients with type 2 diabetes, once-daily bedtime insulin glargine is as effective as once- or twice-daily NPH in improving and maintaining glycemic control. In addition, insulin glar-gine demonstrates a lower risk of nocturnal hypoglycemia and less weight gain compared with NPH insulin [35].

Ultra-long acting insulinInsulin degludec (IDeg) is a new-generation ultra-

long-acting basal insulin. IDeg is primarily a result of the slow release of IDeg monomers from soluble multihexam-ers that form after subcutaneous injection, resulting in a long half-life and a smooth and stable pharmacokinetic profile at steady state [36]. A clinical trial showed that IDeg, which used in combination with mealtime insulin aspart (IAsp), is a well-tolerated and efficacious treatment when used in people with type 1 diabetes, providing com-

parable glycemic control to insulin glargine at comparable doses, but with lower rates of hypoglycemia [37].

Several Adverse Effects of InsulinAlthough insulin is the most effective drugs for dia-

betes treatment, there are still some major adverse effects.

HypoglycemiaHypoglycemia is the most common adverse effect of

insulin therapy. In the type 1 DM and type 2 DM, inten-sive therapy increased the risk of severe hypoglycemia [30,37,38]. Severe hypoglycemia was reported by 26% of patients with a mean of 1.9 episodes per patient per year, and 43% of episodes occurred nocturnally in type 1 DM. While 1% to 2% more type 2 DM receiving insulin report-ed at least 1 episode of severe hypoglycemia per year than those patients receiving other therapies. Thus intensive therapy, with oral medications or insulin, has been shown to increase the risk of episodes of hypoglycemia [30,38].

Weight gainGenerally, patients receiving insulin gain weight. Pa-

tients with type 1 DM receiving intensive insulin therapy gained 4.75 kg more than patients receiving conventional therapy during the 3.5- to 9-year study period [39]. Pa-tients with type 2 DM receiving intensive insulin therapy gained significantly more weight (1.4-2.3 kg) than those patients treated with sulfonylureas or metformin [40].



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Proliferative retinopathyRapid improvement in diabetes control results in pro-

gressive worsening of retinopathy in approximately 5% of patients [41-44].

Risk of cancerCarstensen et al. pay attention that cancer is more fre-

quent among diabetes patients, but it is unknown how this excess varies with duration of diabetes and insulin use. A cohort’s analysis suggested that diabetic patients have el-evated cancer incidence rates compared with the non-di-abetic population, highest in the first year after diagnosis and the first year after initiation of insulin treatment [45].

Glucagon-like peptide 1 (GLP-1)Glucagon-like peptide 1 (GLP-1) is a 29-amino acid

peptide hormone mainly produced in the intestinal epi-thelial endocrine L-cells [46]. GLP-1 was first identified following the cloning of cDNAs and genes for progluca-gon in the early 1980s [47], which is a selective cleavage of the proglucagon molecule by PC1/3 [48]. The biologi-cally active forms of GLP-1 are: GLP-1-(7-37) and GLP-1-(7-36) amide [49, 50]. As an anorectic hormone, GLP-1 is released by the distal intestine in response to ingested nutrients [46,51], which is extremely rapidly metabo-lized and inactivated by the enzyme dipeptidyl peptidase IV even before the hormone secretion [46,52]. The main actions of GLP-1 are to enhance insulin secretion and to

inhibit glucagon secretion, thereby contributing to limit postprandial glucose excursions [46]. The insulinotropic activity of GLP-1 in type 2 diabetes mellitus therefore of-fers great potential for treatment of hyperglycemia with-out causing hypoglycemia [53,54].

Effects of GLP-1 on Islet FunctionClassically, GLP-1 is secreted from intestinal L cells

in response to nutrient ingestion, and signals through the GLP-1 receptor (GLP-1R), which is abundantly expressed in pancreatic islets [55]. The most well characterized role of GLP-1 action is its effects in pancreatic islets to lessen post-prandial glucose excursion through the glucose-sensitive stimulation of insulin release from β cells. In addition to the direct insulinotropic effects, GLP-1 also inhibits glucagon secretion from pancreatic α cells in a glucose-dependent manner. Fasting blood glucose re-duction may also be achieved via the effects of GLP-1 in the induction of satiety and gut motility delay, leading to decreased glucose absorption [54]. Furthermore, GLP-1-treatment stimulates insulin biosynthesis and secretion from pancreatic beta cells and also somatostatin release from delta cells [56].

Effects of GLP-1 on Skeletal Muscle Insulin Resistance

Approximately 80-90% of exogenous glucose infu-sion is taken up by skeletal muscle. Skeletal muscle insu-



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lin resistance is the primary defect in diabetes, preceding the failure of beta cell function and overt hyperglycemia. GLP-1 receptor has been identified in skeletal muscle tis-sue [57]. Its activation has potent effects on glycogenesis, glycolysis and glucose oxidation independent of its insu-linotropic effect [58]. In vitro studies have shown that ex-enatide, like GLP-1 and insulin, enhances glucose uptake in skeletal muscle, which is mediated by certain kinases (PI3K/PKB, p70s6k and MAPKs) through GLP-1 recep-tors in skeletal muscle [59]. In vivo expriments, the aver-age glucose uptake rates of gastrocnemius in exenatide-treated diabetic rats were approximately 65 percent of the uptake in the nondiabetic control rats and were 41 percent higher than in the vehicle-treated diabetic rats, suggest-ing skeletal muscle insulin resistance (IR) was improved by exenatide [60]. Exenatide can significantly alleviate the ultrastructural damage of cells in skeletal muscles through a protective effect on the mitochondria and myofibers of T2DM rats [60]. Therefore, exenatide remarkably increase the glucose uptake of peripheral muscle tissues to improve the IR of T2DM rats.

Effects of GLP-1 on Glucose ProductionPeripheral adipose tissue degradation is the main

source of glycerol during fasting. Because of the lack of glycerokinase in adipose tissue, the glycerol released by lipolysis cannot be resynthesized into adipose tissue, and therefore glycerol appearance rates in the blood are also a

reliable indicator for lipolysis [61]. It appears that lipolysis in the diabetic rats was partially inhibited by both GLP-1 and exenatide [62]. Gluconeogenesis is a metabolic path-way that results in the generation of glucose from non-carbohydrate carbon such as glycerol, it is one of the major sources of fasting endogenous glucose production (EGP), which maintains the body’s fasting blood glucose within normal levels [63]. However, the hepatic insulin resist-ance seen in diabetes is a major cause of the high level of gluconeogenesis in diabetes. Exenatide does significantly inhibit hepatic gluconeogenesis and increases glucose up-take in the peripheral muscle tissues to improve hepatic and extra hepatic insulin resistance in diabetic rats [57].

Incretin-based TherapiesModified gastric bypass surgery has been applied to

the treatment of the type 2 diabetes mellitus (T2DM) pa-tients in the 1990s. It is reported that Roux-en-Y gastric bypass (RYGB) rapidly reverses symptoms of diabetes via a GLP-1-mediated mechanism suggesting that GLP-1 can be used as diabetes therapy [64]. Actually, it has long been known that peptide hormones from the gastrointestinal tract have significant impact on the regulation of glucose metabolism. Among these hormones, incretins have been found to increase insulin secretion, and thus incretin-based therapies have emerged as new modalities for the treatment of type 2 diabetes [65].



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GLP-1 receptor agonistsThe development of GLP-1R agonists for the treat-

ment of type 2 diabetes with improved glycemic control combined with a sustained weight loss, is a major break-through in the medical treatment of type 2 diabetes. GLP-1 receptor agonists are effective agents for the treatment of type 2 diabetes, offering many advantages over other agents, including weight loss, potential beta-cell protec-tion, and low risks of hypoglycemia. They also have posi-tive effects on cardiovascular parameters, including re-ductions in blood pressure, lipids, and weight, although the clinical relevance of this remains to be determined. Overall, GLP-1 receptor agonists are effective and innova-tive agents for patients with type 2 diabetes. As of early 2015, there are five GLP-1 analogs either approved by the U.S. Food and Drug Administration (FDA) or the Euro-pean Commission for the treatment of type 2 diabetes: ex-enatide (Byetta), lixisenatide (Lyxumia), liraglutide (Vic-toza), dulaglutide (Trulicity), and albiglutide (Tanzeum) [66,67].

Dipeptidyl Peptidase 4 (DPP-4) inhibitorsGLP-1 is rapidly degraded by the enzyme DPP-4 and

it is no longer available in active form. Thus DPP-4 inhi-bition has the potential to be a novel, competent, accept-able approach to treat type 2 diabetes [68]. The effects of GLP-1 can also be exploited by protecting endogenous GLP-1 from degradation by the enzyme DPP-4. Oral ad-

ministration of inhibitors of this enzyme increase the cir-culating levels of active GLP-1 which is associated with anti-diabetic effects. DPP-4 inhibitors are small molecules that are active upon oral administration. They have shown a clinically significant and sustained effect on glycemic control. However, DPP-4 inhibitors have little effect on body weight, presumably because the plasma concentra-tions of active GLP-1 are not elevated sufficiently to exert this effect. Several DPP-4 inhibitors are undergoing clini-cal development. Currently four of them sitagliptin, vilda-gliptin, saxagliptin, and linagliptin have been approved a s medications for type 2 diabetes [65,68].

LeptinLeptin is a 167-amino acid peptide with a four-helix

bundle motif similar to that of a cytokine, which is pro-duced predominantly in the adipose tissue but is also ex-pressed in a variety of other tissues, including placenta, ovaries, mammary epithelium, bone marrow, and lym-phoid tissues [69,70]. In addition, it has close relationship with physiology and pathophysiology of energy homeo-stasis, reproductive, endocrinology, immune, and metab-olism [71]. Leptin binds to leptin receptors (ObRs) located throughout the central nervous system and peripheral tis-sues, with at least six receptor isoforms identified (ObRa, ObRb, ObRc, ObRd, ObRe, and ObRf) [72,73]. Studies of genetically obese mice serendipitously found in the Jackson Laboratories revealed that their phenotypes de-rive from homozygous mutations of either the obese (ob)



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or diabetic (db) genes that result in obesity and insulin resistance or diabetes as well as endocrine and immune dysfunction [74-78].

The Role of Leptin in Glucose MetabolismRegulation of islet secretion by leptinThe pancreatic beta-cell has been shown to be a key

peripheral target of leptin, with leptin suppressing insu-lin synthesis and secretion from beta-cells both in vitro and in vivo [79]. Leptin (1-100 nmol/l) also produced a dose-dependent inhibition of glucose-stimulated insulin secretion by isolated islets from ob/ob mice. In contrast, leptin at maximum effective concentration (100 nmol/l) did not inhibit glucose-stimulated insulin secretion by is-lets from db/db mice [80]. These results provide evidence that a functional leptin receptor is present in pancreatic islets and suggest that leptin overproduction, particularly from abdominal adipose tissue, may modify directly both basal and glucose-stimulated insulin secretion.

Effects of leptin on skeletal muscle metabo-lism

Skeletal muscle is a key metabolic tissue for insulin-stimulated glucose disposal and for energy metabolism. Skeletal muscle resistance to the key metabolic hormones, leptin and insulin, is an early defect in obesity. Leptin stimulates the oxidation of fatty acids and the uptake of glucose, and prevents the accumulation of lipids in non-

adipose tissues, which can lead to functional impairments known as “lipotoxicity” [81]. Leptin increases glucose uptake in skeletal muscle via the hypothalamic–sympa-thetic nervous system axis and β-adrenergic mechanism, while leptin stimulates fatty acid oxidation in muscle via AMP-activated protein kinase (AMPK) [82]. Sáinz N et al. found leptin enhances the intracellular GLUT4 transport in skeletal muscle of ob/ob animals by reducing the ex-pression and activity of the negative regulators of GLUT4 traffic TBC1D1 and TBC1D4 [83].

Effects of leptin on hepatic insulin sensitivityThe liver plays a vital role in integrating and control-

ling glucose homeostasis. Thus, it is important that the liver receive and response to signals from other tissues regarding the nutrient status of the body. Leptin appears to act as a negative regulator of insulin action in the liver. In contrast to impaired glucose homeostasis induced by a complete deficiency of leptin action, Hepatic specific deletion of leptin increases hepatic insulin sensitivity and protects against age- and diet-related glucose intolerance [84].

Leptin and DiabetesAssociation between serum leptin levels and diabetes

mellitus were restricted to specific racial/ethnic groups and were not consistent in pervious findings [85]. Some studies reported that there is no association between plas-ma leptin levels and diabetes [86-88], whereas others sug-



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gest that leptin levels are closely related to body fatness [89-91]. Higher leptin levels, conjunct with obesity and weight gain are probably involved in the subsequent de-velopment of diabetes [82]. Besides fat mass and gender, the main determinants for leptin levels in type 2 diabetic subjects as in healthy subjects is insulin secretion and the degree of insulin resistance also seem to contribute sig-nificantly to leptin levels [92].

Leptin-based TherapeuticsLeptin can correct diabetes in animal models of both

diabetes mellitus type 1 (T1DM) and type 2 (T2DM). In-terestingly, leptin exerts potent anti-diabetic actions that are independent of its effects on body weight and food intake. In addition, long-term leptin-replacement thera-py is well tolerated and dramatically improves glycemic control, insulin sensitivity, and plasma triglycerides in patients with severe insulin resistance due to lipodystro-phy. Together, these results have spurred enthusiasm for the use of leptin therapy to treat humans suffering from diabetes mellitus [93].

Type 1 diabetesLeptin suppress the apoptosis of beta cells in Kilham

rat virus induced rodent model of type 1 diabetes [94]. Leptin therapy ameliorated STZ-induced hyperglycemia and hyperketonemia in mice [95]. In nonobese diabetic mice with uncontrolled type 1 diabetes, leptin administra-tion have multiple short- and long-term advantages over

insulin monotherapy for type 1 diabetes [96]. Another new area for leptin therapeutics is its potential for achiev-ing better glucose control with lower insulin dosage in type 1 diabetes patients; a clinical trial evaluating these ef-fects is currently ongoing and is based on previous studies showing improved glucose metabolism in type 1 diabetes in rodents after combinatorial treatment with insulin and leptin [97].

Type 2 diabetesPlasma leptin is reduced in untreated type 2 diabetes

probably as a consequence of reduced insulin secretion [98]. Leptin has metabolic effects on peripheral tissues including muscle, liver, and pancreas, and it has been suc-cessfully used to treat lipodystrophic diabetes, a leptin-deficient state. Leptin administration to the type 2 diabe-tes mice (MKR mice) resulted in correction of diabetes. The main effect of leptin therapy was enhanced hepatic insulin responsiveness possibly through decreasing gluco-neogenesis without an effect that reduced food intake. In addition, the reduction of lipid stores in liver and muscle induced by enhancing fatty acid oxidation and inhibiting lipogenesis leads to an improvement of the lipotoxic con-dition. In brief, leptin could be a potent antidiabetic drug in cases of type 2 diabetes that are not leptin resistant [99].

Fibroblast Growth Factor 21 (FGF21)Tetsuya Nishimura et al. firstly isolated cDNA encod-

ing a novel FGF (210 amino acids) from mouse embryos.



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As it is the 21st documented FGF, Tetsuya Nishimura et al. tentatively termed it FGF-21 [100]. Fibroblast growth fac-tor 21 (FGF21) is an atypical member of the FGF family, which responses to the PPARα transcription factor, regu-lating lipolysis in adipose tissues, fatty acid oxidation and ketogenesis in livers. FGF21 is thought to act on its target tissues, including liver and adipose tissue, to improve in-sulin sensitivity and reduce adiposity associated with dia-betes and obesity [101,102].

The Role of FGF21 in Glucose MetabolismRegulation of islet function by FGF21Growing evidence shows that FGF21 is a potential

therapeutic agent for treatment of T2DM, obesity, and their complications [103,104]. Notably, FGF21 has also been reported to improve pancreatic β-cell function and preserve islet and β-cell mass [105]. Hyperglycemia in type 2 diabetes mellitus may lead to FGF21 resistance in pan-creatic islets, probably through reduction of PPARγ ex-pression, which provides a novel mechanism for glucose-mediated islet dysfunction [106]. In islets isolated from healthy rats, FGF-21 increased insulin mRNA and protein levels but did not potentiate glucose-induced insulin se-cretion. Islets and INS-1E cells treated with FGF-21 were partially protected from glucolipotoxicity and cytokine-induced apoptosis in islets isolated from diabetic rodents, FGF-21 treatment still increased islet insulin content and glucose-induced insulin secretion, thus preservation of

β-cell function and survival by FGF-21 may contribute to the beneficial effects of this protein on glucose homeosta-sis observed in diabetic animals [105].

Effects of FGF21 on glucose uptakeA potential role as a metabolic regulator emerged

when FGF21 was shown to increase glucose uptake in adi-pocytes. FGF21 enhances glucose uptake by inducing the expression of glucose transporter-1 (GLUT1) in adipo-cytes. Ge X et al. investigated the signaling pathways that mediate FGF21-induced GLUT1 expression and glucose uptake in vitro and in vivo, suggesting FGF21 induces GLUT1 expression and glucose uptake through sequential activation of ERK1/2 and transcription factors serum re-sponse factor (SRF) and Ets-like protein-1 (Elk-1), which in turn triggers the transcriptional activation of GLUT1 in adipocytes [107]. Moyers et al. describe the early signaling events triggered by FGF-21 treatment of 3T3-L1 adipo-cytes and reveal a functional interplay between FGF-21 and peroxisome proliferator-activated receptor gamma (PPARα) pathways that leads to a marked stimulation of glucose transport [108].

Besides as a potent regulator of glucose uptake in adi-pocytes, FGF21 also has direct effects on enhancing skel-etal muscle glucose uptake, providing additional points of regulation that may contribute to the beneficial effects of FGF21 on glucose homeostasis. FGF21 has a direct effect on skeletal muscle to enhance insulin-stimulated glucose



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uptake, which increases glucose uptake in primary hu-man myotubes and isolated adult mouse skeletal muscle. FGF21 increased glucose uptake in the absence or pres-ence of insulin, whereas the signalling mechanisms by which FGF21 regulates glucose metabolism in skeletal muscle remain to be determined [109].

Effects of FGF21 on hepatic glucose produc-tion

FGF21 functions physiologically as an insulin sensi-tizer under conditions of acute refeeding and overfeed-ing [110]. During starvation, FGF21 expression in lean rodents is strongly induced in liver by prolonged fasting through a mechanism that involves the nuclear receptor peroxisome proliferator-activated receptor α. FGF21, in turn, induces the transcriptional coactivator protein per-oxisome proliferator-activated receptor γ coactivator pro-tein 1α and stimulates hepatic gluconeogenesis, fatty acid oxidation, and ketogenesis [111]. In fed statue, rats treated with intracerebroventricular FGF21 displayed a robust increase of insulin sensitivity due to increased insulin-induced suppression of both hepatic glucose production and gluconeogenic gene expression, with no change of glucose utilization [112]. Berglund et al. also discovered that chronic FGF21 ameliorated fasting hyperglycemia in diabetic ob/ob mice via increased glucose disposal and improved hepatic insulin sensitivity [113].

FGF21 Level in Diabetic Animals and PatientsCirculating fibroblast growth factor 21 (FGF21) lev-

els are elevated in diabetic subjects and correlate directly with abnormal glucose metabolism, while pharmacologi-cally administered FGF21 can ameliorate hyperglycemia [103]. Hojman et al. found muscular FGF-21 expression was associated with hyperinsulinemia in men but not in women [114]. FGF21 expression in the liver and white adipose tissue is increased in diabetic rodents, but these increases occur in the context of impaired glucose toler-ance and increased hepatic lipid content, suggesting that the ability of endogenous FGF21 to exert beneficial effects on glucose homeostasis and lipid oxidation is impaired in the diabetic state [115,116].

Treatment of DiabetesFGF21 is a novel metabolic regulator that exerts po-

tent antidiabetic effect in animal models of type 2 diabe-tes mellitus. Positive metabolic actions of FGF21 without the presence of apparent side effects make this factor a hot candidate to treat type 2 diabetes and accompanying met-abolic diseases [117]. Metformin is widely used as a glu-cose-lowering agent in patients with type 2 diabetes (T2D), which is a potent inducer of hepatic FGF21 expression and that the effect of metformin seems to be mediated through AMPK activation. As FGF21 therapy normalizes blood glucose in animal models of type 2 diabetes, the induction of hepatic FGF21 by metformin might play an important



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role in metformin’s antidiabetic effect [118]. Moreover, treatment of obese/diabetic animals with FGF21 also re-duces blood glucose levels and increases glucose tolerance and insulin sensitivity [103,113,119]. Kharitonenkov et al. evaluated its bioactivity in diabetic nonhuman primates. When administered daily for 6 weeks to diabetic rhesus monkeys, FGF-21 caused a dramatic decline in fasting plasma glucose, fructosamine, triglycerides, insulin, and glucagon. FGF-21 administration also led to significant improvements in lipoprotein profiles, including lowering of low-density lipoprotein cholesterol and raising of high-density lipoprotein cholesterol, beneficial changes in the circulating levels of several cardiovascular risk markers/factors, and the induction of a small but significant weight loss. These data support that FGF-21 can be used for the treatment of diabetes and other metabolic diseases [120].

As an alternative to native FGF21, LY2405319 (LY), a variant of FGF21, LY treatment produced significant improvements in dyslipidemia. Favorable effects on body weight, fasting insulin, and adiponectin were also detected [121]. Another antidiabetic strategy using agonistic anti-FGFR1 (FGF receptor 1) antibodies (R1MAbs) that mimic the metabolic effects of FGF21 induced sustained amelio-ration of hyperglycemia, along with marked improvement in hyperinsulinemia, hyperlipidemia, and hepatosteatosis [122].

In sum, FGF21 is one of the most promising candi-dates given its outstanding pharmacologic benefits for

nearly each and every abnormality of a metabolic disease and lack of apparent side effects in a variety of animal models. Thus, FGF21 represents a novel and appealing therapeutic reagent for Type 2 diabetes mellitus, obesity, dyslipidemia, cardiovascular and fatty liver diseases.

AdiponectinAdiponectin is a collagen-like circulating protein se-

creted by adipocytes which can regulate energy homeo-stasis and glucose and lipid metabolism [123]. The dis-coveries of adiponectin were breakthroughs in the field of metabolic diseases because the beneficial metabolic effects of adiponectin which confer insulin-sensitizing and anti-diabetic effects are well established [124,125]. Yamauchi T et al. found that administration of adiponectin causes glu-cose-lowering effects and ameliorates insulin resistance in mice. Conversely, adiponectin-deficient mice exhibit in-sulin resistance and diabetes [126]. In addition, decreased concentrations of adiponectin are seen in patients with type 2 diabetes and in those who do not have diabetes but are resistant to insulin [127,128]. Here, we summarize the important roles of adiponectin in glucose metabolism in closely related to organs and tissues.



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The Role of Adiponectin in Glucose Homeo-stasis

Regulation of islet function by adiponectinThe effects of adiponectin on β-cell function are still

speculative. Following the discovery of adiponectin, two adiponectin receptors (AdR-1 and AdR-2) were cloned [129]. The adiponectin receptors AdR-1 and AdR-2 are expressed in pancreatic islets, specifically, on the beta cells. Although both subtypes are present, AdR-1 is the predominant form, at least in the mouse [130]. Given that globular adiponectin has a stronger affinity for AdR-1, the globular domain of adiponectin might be a potent and ef-fective fragment affecting β-cell function [131].

The direct effect of adiponectin on insulin secretion in β-cells has been examined in several studies but with variable and inconsistent results. Although adiponectin stimulates insulin secretion by enhancing exocytosis of insulin granules, expressions of the insulin gene and its transcription factors, it apparently has a dual effect on insulin secretion that is dependent on the prevailing glu-cose concentration and status of insulin resistance [131]. Beyond affecting the insulin secretion in β-cells, several investigations have demonstrated that adiponectin has anti-apoptotic effects on beta cells, both in cell culture and islet preparations [130]. The antiapoptotic properties of adiponectin are mediated by activation of PI3K-Akt and MEK-ERK1/2 pathways [132], ERK had a delayed

response to adiponectin, whereas Akt activity was en-hanced by both acute and chronic treatment. Typically, adiponectin-induced Akt phosphorylation is suggested to be downstream of AMP-activated protein kinase (AMPK) activation [133]. However, it remains unclear whether adiponectin directly activates AMPK in β-cells because experiments with isolated mouse islets report that adi-ponectin does not affect the phosphorylation of AMPK at 5.6 mmol/L of glucose [134], indicating that adiponectin may not be able to activate AMPK under basal glucose concentrations because AMPK may already be activated by glucose itself [135].

The epidemiologic evidence demonstrates a close as-sociation between adiponectin and β-cell dysfunction [136]. Considering the therapeutic potential of adiponec-tin on β-cells as well as insulin-resistant peripheral tissues, it is crucial to develop adiponectin as a new medication available for human use. Although β-cell dysfunction is by no means the sole pathophysiological feature of type 2 diabetes mellitus, studies to elucidate the mechanisms by which adiponectin improve β-cell function would provide a means to preserve β-cells in humans and thereby con-tribute toward understanding, preventing, and controlling diabetes [137].



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Effects of adiponectin on skeletal muscle me-tabolism

Being a major source of glucose uptake, skeletal mus-cle plays a key role in insulin sensitivity [130]. The anti-diabetic effects of adiponectin are well characterized and regulation of skeletal muscle metabolism is an important contributory mechanism. Early work in cultured mouse or rat skeletal muscle cells found that adiponectin increased glucose uptake and regulated the subsequent metabolic fate [138-141]. Similar findings were made in primary hu-man skeletal muscle cells [142 ] and muscle strips from human patients [143].

AdR-1 is also the major adiponectin receptor found in skeletal muscle [130]. The AdipoR isoforms and APPL1 (adaptor protein containing pleckstrin homology domain, phosphotyrosine binding domain and leucine zipper motif)-dependent downstream signaling events play a vi-tal role in adiponectin’s metabolic effects in muscle [144]. APPL1 mediates adiponectin-stimulated phosphorylation of AMPK and p38 MAPK in muscle cells. Coexpression of either kinase-inactive AMPK or kinase-inactive p38 MAPK with HA-tagged GLUT4 only partially suppressed adiponectin-stimulated GLUT4 membrane translocation. These results suggest that an AMPK and p38 MAPK-in-dependent pathway may also be involved in adiponectin-stimulated GLUT4 membrane translocation. Interaction between APPL1 and Rab5 (a small GTPase) mediates ad-

iponectin-stimulated phosphorylation of AMPK and p38 MAPK in muscle cells [127]. Therefore, when circulating adiponectin levels fall or skeletal muscle becomes resist-ant to adiponectin action, the lack of proper glucose and fatty acid homeostasis in muscle contributes to the devel-opment of diabetes [144].

Effects of adiponectin on hepatic glucose pro-duction

Adiponectin has several effects on the hepatic glucose production. One of the most prominent of these is the inhibition of hepatic glucose output, lowering systemic glucose levels. Adiponectin acts to improve the hepatic insulin sensitivity, thus glucose synthesis is significantly suppressed for any given dose of insulin in the presence of physiological doses of adiponectin [130]. On the other hand, adiponectin induces fatty acid oxidation and glucose uptake, and suppresses gluconeogenesis in muscle and liv-er, thereby improving peripheral insulin sensitivity [145]. Adiponectin acts to suppress the expression and activity of key regulators in gluconeogenesis, such as phospho-enolpyruvate carboxykinase and glucose-6-phosphatase [146]. Whereas murine euglycaemic clamp experiments have shown no difference in rates of glucose disappear-ance, glycolysis or glycogen synthesis in the presence or absence of intravenous adiponectin infusion [147], again highlighting adiponectin’s main effect, which is to lower blood sugar by suppressing hepatic glucose output rather than disposal [130,148].



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Adiponectin Level in Diabetic Animals and Patients

Recent data strongly supports that adiponectin plays a pivotal role in the pathogenesis of type 2 diabetes. The adiponectin gene is located on chromosome 3q27, which has been reported to be linked to type 2 diabetes and the metabolic syndrome [149-151]. Therefore, the aiponectin gene appears to be a promising candidate susceptibility gene for type 2 diabetes. Among the SNPs (single nu-cleotide polymorphism) in the adiponectin gene, 1 SNP located 276 bp downstream of the translational start site (SNP 276) was concomitantly associated with decreased plasma adiponectin level, greater insulin resistance, and an increased risk of type 2 diabetes [152].

For the animal model, the plasma levels of adiponec-tin were decreased in parallel to the progression of insulin resistance in obese and diabetic monkeys [153]. And also for ob/ob diabetic mice, there is a decrease in adiponec-tin levels when compared with age-matched lean animals [154]. For clinical patients, plasma adiponectin concen-trations are decreased in obese subjects and type 2 diabet-ic patients and other insulin-resistant states [155]. In sum, the decreased plasma adiponectin concentrations can be found in diabetic animals and patients.

Treatment of DiabetesThe clinical significance of our current understand-

ing of adiponectin biology have two aspects; Firstly, adi-ponectin can be regarded as a robust biomarker for iden-tifying individuals with metabolic syndrome; Secondly, adiponectin is an attractive therapeutic target because the well documented widespread beneficial physiological actions of adiponectin spanning diabetes, inflammation, cardiovascular diseases and cancer have provided much impetus for discovery and development of adiponectin-based therapeutics [156].

The discovery of adiponectin has contributed to the understanding of metabolic disorders, because substantial data have revealed its role in the development of insulin resistance, T2D, and cardiovascular disease (CVD). Cur-rently, intensive lifestyle modifications and several agents (e.g., PPAR-γ or PPAR-α agonists, some statins, angioten-sin converting enzymes inhibitors, angiotensin II recep-tor blockers, some calcium channel blockers, mineralo-corticoid receptor, new β-blockers, and several natural compounds) have been demonstrated to be effective in increasing circulating adiponectin levels to prevent meta-bolic syndrome, T2D, and CVD. In sum, identifying new agents that have adiponectin-raising properties are im-portant. Recombinant adiponectin will be a challenging therapeutic strategy for these diseases in the future despite some studies that have shown no effect of recombinant adiponectin in animals [157].



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GhrelinGhrelin is the endogenous ligand of the G protein-

coupled growth hormone secretagogue receptor, which was discovered from stomach by Masayasu Kojima and colleagues in 1999. They named it “ghrelin” for the rea-son that after the word root “ghre” in Proto-Indo-Euro-pean languages meaning “grow”, since ghrelin has potent growth hormone (GH) releasing activity [158]. Ghrelin mainly secreted from the stomach mucosa but it is also expressed widely in different tissues such as small intes-tine, brain, cerebellum, pituitary, heart, pancreas, salivary gland, adrenal, ovary and testis. It is initially produced within neurocrine cells as a 117 amino-acid preproghre-lin and then processed by preprotein convertase 1/3 to a 28-amino-acid peptide. This 28-amino-acid peptide is a peptide hormone in which the third amino acid, usually a serine but in some species a threonine, is modified by a octanoic acid; this modification is essential for ghrelin’s activity [159]. In 2008, two independent groups reported that ghrelin O-acyl transferase (GOAT) account for this acylation. Actually, majority of circulating ghrelin exists as des-acyl ghrelin, identical to acyl-ghrelin except that the third amino acid serine is not acylated [160,161].

The Functions of GhrelinOrexigenic hormone, ghrelin, which secreted from

the stomach into the bloodstream under fasting condi-tions, it transmits a hunger signal from the periphery to

the central nervous system. Ghrelin exerts wide physi-ological actions throughout the body, including growth hormone secretion, appetite and food intake, gastric se-cretion and gastrointestinal motility, glucose homeostasis, cardiovascular functions, anti-inflammatory functions, reproductive functions, and bone formation [162]. In re-cent years, many scholars focus on the research about the role of ghrelin in glucose metabolisms. However, there are with large controversies and mechanisms need further ex-plored.

The Relationship Between Ghrelin and Insu-lin Secretion

Studies show that ghrelin is highly expressed in pan-creases. Yukart Date et al. reported that ghrelin is present in pancreatic α-cells which increased the cytosolic free Ca2+ concentration in β-cells and stimulated insulin se-cretion [163]. In contrast, Wierup et al. regard that ghre-lin is expressed in a novel endocrine islet cell type named ε-cell [164]. The direct effect of ghrelin on insulin secre-tion in β-cells has been examined in several studies but with variable and inconsistent results. Martina Kvist Re-imer et al. found high does of ectogenic acylated ghrelin (150 nmol/kg ) induced a rapid rise in glucose and insu-lin levels, while lower dose of 5 nmol/kg and only slightly inhibited insulin secretion, which show that the effect of ghrelin on insulin release is dependent on the dose and elicited on distal signaling steps in islet cells [165]. Other studies demonstrated that ghrelin is able to suppress in-



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sulin secretion in several in vitro experimental models, including rodent islets, pancreatic cell lines perfused rat pancreas and human subjects [166-168]. Ghrelin recep-tor antagonism or neutralization of endogenous ghrelin significantly increases insulin release from perfused pan-creas [166]. Ghrelin attenuates glucose-induced insulin release via PTX-sensitive Gαi2-mediated activation of Kv channels and suppression of [Ca2+]i in β-cells, represent-ing the unique signaling of ghrelin distinct from that for growth hormone release [167].

The Relationship Between Ghrelin and Glu-cose Uptake

An investigation suggests that ghrelin appears to di-rectly potentiate insulin-stimulated glucose uptake in adi-pocyte. Therefore, ghrelin may plays a role in adipocyte regulation of glucose homeostasis [168]. Besides, ghrelin may also have direct insulin-sensitizing effects on skeletal muscle. Muscle expresses the putative ghrelin receptor GHS-R1b, although a function for this receptor remains to be described [169]. Wylie W Vale et al. found that ghrelin enhanced glucose uptake in C2C12 cells, induced GLUT4 translocation to the cell surface [170]. While our experi-ments show that ghrelin contributes to derangements of glucose metabolism induced by rapamycin via altering the expression and translocation of GLUT4 in muscles [171].

Effects of Ghrelin on Hepatic Glucose Pro-duction

Ghrelin was shown to activate the insulin-signaling cascade and to independently stimulate expression of glucogenic genes in cultured hepatocytes. Sustained ghre-lin treatment was associated with hyperglycemia and in-creased transcript levels of the key enzyme of the glucone-ogenic pathway, glucose-6-phosphatase, in keeping with in vitro findings [172]. Changes in phosphorylated AMP-activated protein kinase (AMPK) and total and phospho-rylated acetyl-CoA carboxylase (ACC) further support the involvement of altered AMPK signaling in hepatic effects of ghrelin treatment and indicate a link between ghrelin and AMPK in vivo [173]. In conclusion, ghrelin induced a lipogenic and glucogenic pattern of gene expression and AMP-activated protein kinase in liver [174].

In addition, ghrelin hampers insulin’s capacity to sup-press endogenous glucose production, whereas it rein-forces the action of insulin on glucose disposal, indepen-dently of food intake and body weight. These metabolic effects are unlikely to be mediated by the GHS receptor. Furthermore, simultaneous administration of des-ghrelin abolishes the inhibitory effect of ghrelin on hepatic in-sulin action. Glucose output by primary hepatocytes is time- and dose-dependently stimulated by acylated ghre-lin and inhibited by unacylated ghrelin [175]. Moreover, unacylated ghrelin counteracts the stimulatory effect of acylated ghrelin on glucose release. These actions might



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be mediated by a different receptor than GHS-R1a, and apparently, acylated ghrelin and unacylated ghrelin must be considered as separate hormones that can modify each other’s actions on glucose handling, at least in the liver [176].

Ghrelin and DiabetesShinya Ishii et al. found that plasma ghrelin concen-

trations in untreated diabetic rats were significantly high-er than in control rats and were normalized by insulin treatment, the elevated plasma ghrelin levels could con-tribute to the diabetic hyperphagia in part by increasing hypothalamic (neusopeptide Y) NPY [177]. While recent studies have shown that ghrelin concentration in the pa-tients with diabetes mellitus type 2 is lower than normal, higher BMI in subjects with lower ghrelin levels [162]. To-tal plasma ghrelin as well as unacylated ghrelin concentra-tions are lower in obese patients with metabolic syndrome compared to nonobese counterparts [178]. Furthermore, among obese subjects, plasma ghrelin levels are lower in insulin resistant persons compared to insulin sensitive persons [175]. Circulating ghrelin concentrations are also reduced in healthy offspring of type 2 diabetic patients indicating the presence of possible genetic component in the regulation of ghrelin plasma levels [179].

The ghrelin Arg51Gln mutation is associated with low plasma ghrelin concentrations. Pöykkö et al. found that the ghrelin 51Gln allele could increase the risk for Type 2

diabetes and hypertension [180].

Therapy of DiabetesIn type 1 diabetes a decreased ghrelin level can be

found, which is probably a compensating mechanism for hyperglycemia. Lowering of the ghrelin level was also seen in insulin resistant adolescents with diabetes risk factors. The hormone inhibits apoptosis and takes part in the pro-motion of the β-cells proliferation and regeneration [162]. In addition, discovery of the new cells producing ghrelin in pancreas (ε-cells) opens new perspectives in the field of the glucose metabolism control [164]. Possibly, ghre-lin producing cells or their precursors might become, in the future, a source of β-cells to transplant them to the patients with diabetes [181]. While Shin et al. found that the ghrelin agonist RM-131 accelerates gastric emptying of solids and reduces symptoms in patients with type 1 diabetes mellitus [182]. Moreover, administering the anti-bodies against ghrelin or the ghrelin receptors antagonists prevented the active energetic balance caused by this hor-mone and improved the glucose tolerance in type 2 dia-betes [162].

Nesfatin-1Nestfatin, an 82 amino acids peptide, is discovered by

Oh-I S et al. as a satiety molecule that is associated with melanocortin signalling in the hypothalamus. As an ano-rexic nucleobindin-2 (NUCB2)-derived hypothalamic peptide, nesfatin controls appetite and energy metabolism



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[183,184]. NUCB2 mRNA was predominantly expressed in the pituitary and at lower levels in the hypothalamus, spleen, thymus, heart, liver, and muscle of both male and female mice. Expression was much higher in reproduc-tive organs, such as the testis, epididymis, ovary, and uterus, than in the hypothalamus, suggesting that nes-fatin-1/NUCB2 have widespread physiological effects in endocrine and non-endocrine organs [184]. NUCB2/nesfatin-1’s physiological property is to reduce food in-take and also gave rise to an involvement in the long term regulation of body weight, especially under conditions of obesity. In addition, studies indicated the involvement of NUCB2/nesfatin-1 in other homeostatic functions as fol-low: glucose homeostasis, water intake, gastrointestinal functions, temperature regulation, cardiovascular func-tions, puberty onset and sleep. Recently, the involvement of NUCB2/nesfatin-1 in glucose homeostasis has been in-vestigated giving rise to the speculation that NUCB2/nes-fatin-1 represents a peptidergic link between eating and diabetes [185].

Regulation of islet function by NesfatinGonzalez R et al. found pronesfatin immunopositive

cells exclusively in the pancreatic islets, insulin producing beta cells colocalize pronesfatin in the islets of both mice and rats. No colocalization of glucagon and pronesfatin was found in mice, while some glucagon positive cells were positive for pronesfatin in rat islets. The abundant pres-

ence of pronesfatin immunoreactivity and its colocaliza-tion with insulin suggests a potential role for pronesfatin-derived peptides in islet biology and glucose homeostasis in rodents [186]. NUCB2/nesfatin-1 is locally released from rat pancreatic islets following stimulation with glu-cose supporting a regulatory action of nesfatin-1 secre-tion in response to increasing glucose levels [187-189]. The expression of NUCB2 in the endocrine pancreas is regulated by the glycemic state with a reduced protein ex-pression in type 2 diabetic Goto-Kakizaki rats compared to normoglycemic Wistar rats [187] and in human islets of type 2 diabetic subjects obtained from an islet transplan-tation center [190]. Functional in vitro studies using rat or mouse isolated islets or cultured MIN cells demonstrated that nesfatin-1 stimulates the expression of pre-proinsu-lin mRNA expression and increases the glucose-induced insulin release through stimulation of calcium influx involving L-type channels [188,191,192]. Whereas, an-other study using isolated mouse islets or INS-1 (832/13) cells did not observe an increase in insulin secretion but showed a stimulation of glucagon release. Matteo R et al. reported that nesfatin-1 is a novel glucagon-stimulatory peptide expressed in the beta cell and its expression is de-creased in T2D islets [190].

Nesfatin and Glucose UptakeContinuously infusing the nesfatin-1 via osmotic

pumps into twelve-week-old male C57BL/6J lean mice, high fat diet-induced obese mice, which increase insulin



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secretion and insulin sensitivity via altering AKT phos-phorylation and GLUT 4 membrane translocation in the skeletal muscle, adipose tissue and liver [193]. This obser-vation was further confirmed in diabetic animal model, intravenous injection of nesfatin-1 reduces blood glucose levels in hyperglycemic db/db mice indicating an insuli-notropic effect [194]. In vitro expriments, R. Gonzalez et al. found insulin-stimulated glucose uptake in L6 mus-cle cells was inhibited by nesfatin-1 pretreatment, basal and insulin-induced glucose uptake in adipocytes from nesfatin-1-treated rats was significantly increased [188]. Furthermore, nesfatin-1 induce glucose uptake and mo-bilize glucose transporter GLUT-4 in human and murine cardiomyocytes [195], podocytes [196].

Nesfatin and Glucose ProductionInfusion of nesfatin-1 into the third cerebral ventricle

markedly inhibited hepatic glucose production (HGP), promoted muscle glucose uptake, and was accompanied by decreases in hepatic mRNA and protein expression and enzymatic activity of phosphoenolpyruvate carboxyki-nase (PEPCK) in both standard diet- and HFD-fed rats through a neural-mediated pathway [197].

Nesfatin and DiabetesDong et al. observed that nesfatin-1 secretion was

significantly increased while expression of nesfatin-1 neurons were decreased in hypothalamus in diabetes group compared to only high-calorie diet control group;

wheras blood glucose and insulin resistance coefficient decreased with treatment of nesfatin-1 in diabetes mice [198]. Not only the mouse expriments, circulating levels of NUCB2/nesfatin-1 show an inverse relationship with circulating glucose in Goto-Kakizaki rats [186], a finding also confirmed in type 2 diabetic human subjects, fast-ing nesfatin-1 was significantly lower in T2 DM patients compared to healthy subjects, indicating the reduction in fasting nesfatin-1 may be one of the appetite-related hor-mones involved in diabetic hyperphagia [199]. Further-more, intravenous administration of nesfatin-1 decreased the blood glucose level significantly in hyperglycemic db/db mice (mimics of Type 2 diabetes model) but not in streptozotocin-mediated diabetes model, suggesting effect of nesfatin-1 is insulin-dependent [200].

In addition, nesfatin-1 levels were found lower in pa-tients with gestational diabetes mellitus (GDM) compared with control pregnant women. Maternal serum and cord blood nesfatin-1 levels correlated negatively with the ges-tational age, but there was no correlation with the birth weight [201].

In sum, most studies are consistent with lower NUCB2/nesfatin-1 levels as an underlying mechanism contributing to the glucose intolerance under conditions of diabetes. However, an investigation reported enhanced plasma NUCB2/nesfatin-1 levels in Chinese patients with newly diagnosed type 2 diabetes mellitus or impaired glu-cose tolerance compared to healthy subjects [202,203].



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The reasons for these divergent results still need further exploration and should take into account potential spe-cific racial and genetic factors [188].

Because of its effect on increasing insulin secretion, nesfatin-1 may be used as an anti-diabetic agent. Studies suggested that nesfatin-1 plays a role type 2 diabetes mel-litus (T2DM) via stimulating free acid utilization [199]. However, in another study nesfatin-1 has been described as a novel stimulatory agent for glucagon secretion in beta cells. Additionally, they showed decreased expression level of nesfatin-1 in type-2-diabetes islets which may provide a compensatory mechanism to overcome hypergluca-gonemia [190]. Therefore the precise physical and patho-physiological effects of nesfatin-1 on glucose and energy mechanism still remain unknown [198].

ConclusionThe prevalence of obesity and diabetes has grown to

epidemic proportions over the past thirty years, principal-ly as a consequence of prolonged high carbohydrate- and high fat- containing diet in combination with decreased physical activity, and with this an alarming increase in the incidence of type 2 diabetes has emerged [123,204]. Diabetes mellitus is a common and costly chronic medi-cal illness while lack of adherence to diabetic self-manage-ment regimens is associated with a high risk of diabetes complications such as loss of vision, renal failure, foot ul-cers, cardiovascular disease, stroke or even cancer, etc. [1-

4,45,205]. Diabetes actually is, in a sense, a consequence of hormonal imbalance. All of body’s hormones work to-gether and affect each other, so imbalances of other hor-mones can lead to insulin imbalances or insulin resist-ance. So far most hormones are not available to diabetes treatments, further researches are needed to investigate the safety and efficiency of hormonal basis therapy. Al-though many findings break new ground, none of the cur-rently available medications are successful as long-term monotherapy and none of them have effectively halted the continuous decline in beta-cell mass [206]. So there is still room for additional mechanisms of action and hopefully that in the next couple of years investigators will yield a more complete picture of how these hormones have func-tion on diabetes.

AcknowledgementSupported by grants from the National Natural Sci-

ence Foundation of China (31401001), the Science and Technology Planning Project of Guangdong Province, China (2014A020212210), the Guangdong Medical Sci-ence Research Foundation (A2014375), the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry (20141685) and special Grants from the Guangzhou Pearl River Young Talents of Science and Technology (201504281553023).



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