Ghrelin regulates insulin release and glycemia: physiological role and therapeutic potential

Insulin release from pancreatic islet beta-cells is stimulated by glucose. Glucose-induced insulin release is potentiated or suppressed by hormones and neural substances. Ghrelin, a novel acylated 28-amino acid peptide isolated from stomach, is the endogenous ligand for the growth hormone (GH) secretagogue-receptor (GHS-R). Circulating ghrelin is produced predominantly in stomach. Ghrelin is a potent stimulator of GH release and feeding as well as exhibiting positive cardiovascular effects. In relation to the glucose metabolism, initial studies indicated that low plasma ghrelin levels are associated with elevated fasting insulin levels, insulin resistance, and obesity. It has recently been demonstrated that ghrelin suppresses glucose-induced insulin release via G alpha(i2) subtype of GTP-binding proteins and delayed outward K(+) (Kv) channels, representing a novel signaling mechanism, and that the ghrelin originating from islets regulates insulin release and thereby glycemia. Furthermore, elimination of ghrelin enhances insulin release to prevent or ameliorate glucose intolerance in high-fat diet fed mice and ob/ob mice. This review focuses on the physiological roles of ghrelin in regulating insulin release and glycemia, the insulinostatic mechanisms of ghrelin in islet beta-cells, and the potential of ghrelin-GHS-R system as the therapeutic target to treat type 2 diabetes.     

Molecular epidemiological study of Bacillus anthracis isolated in Mongolia by multiple-locus variable-number tandem-repeat analysis for 8 loci (MLVA-8)

The incidence of anthrax, which is caused by Bacillus anthracis, in the human and animal population of Mongolia has increased recently, and control of this infection is a nationwide concern. In this study, 29 isolates obtained from animals and various regions in Mongolia from 2001 to 2007 were analyzed by performing multiple-locus variable-number tandem-repeat analysis for 8 loci (MLVA-8) to understand the genetic relationship between the Mongolian B. anthracis isolates. We found that all the Mongolian isolates can be classified into A3 cluster along with the Japanese and the Chinese B. anthracis isolates. Our data revealed that MLVA-8 is useful for studying the molecular epidemiology of the Mongolian B. anthracis isolates and would help characterize B. anthracis infections in Mongolia.     

Results of the influenza virus surveillance in wild birds in Western part of Mongolia

ObjectiveTo present results of virological study of wild birds inhabiting Western Mongolia.MethodsOver a period of 2003–2008, we isolated 13 influenza A viruses: H1N1, H3N6, H13N8 and H4N6 subtypes. We did not isolate any H5N1 subtype, that still cause epizooty in wild birds and poultry.ResultsWe revealed taxonomic and ecological heterogeneity of the birds involved in maintenance of circulation of influenza viruses in the given territory. Influenza viruses were isolated from birds of 6 orders; among them there are species preferring water and semi-aquatic biotopes, one species preferring dry plain region, and also one species which can inhabit both dry and water biotopes.ConclusionsRepresentatives of all main orders of Western Mongolia avifauna are involved in support of influenza A virus circulation, highly pathogenic H5N1 influenza viruses were registered in Mongolia thus it's necessary to continue permanent influenza virus surveillance in wild birds' populations.     

Isolation, preliminary characterization, and full-genome analyses of tick-borne encephalitis virus from Mongolia

Tick-borne encephalitis virus (TBEV) causes one of the most important inflammatory diseases of the central nervous system, namely severe encephalitis in Europe and Asia. Since the 1980s tick-borne encephalitis is known in Mongolia with increasing numbers of human cases reported during the last years. So far, however, data on TBEV strains are still sparse. We herein report the isolation of a TBEV strain from Ixodes persulcatus ticks collected in Mongolia in 2010. Phylogenetic analysis of the E-gene classified this isolate as Siberian subtype of TBEV. The Mongolian TBEV strain showed differences in virus titers, plaque sizes, and growth properties in two human neuronal cell-lines. In addition, the 10,242 nucleotide long open-reading frame and the corresponding polyprotein sequence were revealed. The isolate grouped in the genetic subclade of the Siberian subtype. The strain Zausaev (AF527415) and Vasilchenko (AF069066) had 97 and 94?% identity on the nucleotide level. In summary, we herein describe first detailed data regarding TBEV from Mongolia. Further investigations of TBEV in Mongolia and adjacent areas are needed to understand the intricate dispersal of this virus.     

Stressor-responsive central nesfatin-1 activates corticotropin-releasing hormone, noradrenaline and serotonin neurons and evokes hypothalamic-pituitary-adrenal axis

A recently discovered satiety molecule, nesfatin-1, is localized in neurons of the hypothalamus and brain stem and colocalized with stress-related substances, corticotropin-releasing hormone (CRH), oxytocin, proopiomelanocortin, noradrenaline (NA) and 5-hydroxytryptamine (5-HT). Intracerebroventricular (icv) administration of nesfatin-1 produces fear-related behaviors and potentiates stressor-induced increases in plasma adrenocorticotropic hormone (ACTH) and corticosterone levels in rats. These findings suggest a link between nesfatin-1 and stress. In the present study, we aimed to further clarify the neuronal network by which nesfatin-1 could induce stress responses in rats. Restraint stress induced c-Fos expressions in nesfatin-1-immunoreactive neurons in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus, and in the nucleus of solitary tract (NTS), locus coeruleus (LC) and dorsal raphe nucleus (DR) in the brain stem, without altering plasma nesfatin-1 levels. Icv nesfatin-1 induced c-Fos expressions in the PVN, SON, NTS, LC, DR and median raphe nucleus, including PVN-CRH, NTS-NA, LC-NA and DR-5-HT neurons. Nesfatin-1 increased cytosolic Ca2+ concentration in the CRH-immunoreactive neurons isolated from PVN. Icv nesfatin-1 increased plasma ACTH and corticosterone levels. These results indicate that the central nesfatin-1 system is stimulated by stress and activates CRH, NA and 5-HT neurons and hypothalamic-pituitary-adrenal axis, evoking both central and peripheral stress responses.     

Arsenic trioxide prevents nitric oxide production in lipopolysaccharide ‐stimulated RAW 264.7 by inhibiting a TRIF‐dependent pathway

Arsenic trioxide (ATO) is one of the most potent drugs in cancer chemotherapy, and is highly effective in treating both newly diagnosed and relapse patients with acute promyelocytic leukemia (APL). Despite a number of reports regarding the molecular mechanisms by which ATO promotes anti‐tumor or pro‐apoptotic activity in hematological and other solid malignancies, the effects of ATO on immune responses remain poorly understood. To further understand and clarify the effects of ATO on immune responses, we sought to examine whether ATO affects the production of nitric oxide (NO) in a lipopolysaccharide (LPS)‐stimulated mouse macrophage cell line, RAW 264.7. Arsenic trioxide was found to prevent NO production in a dose‐dependent manner. Arsenic trioxide significantly inhibited the increase in inducible nitric oxide synthase (iNOS) at both the mRNA and protein levels. Furthermore, our analyses revealed that the inhibitory effect of ATO on iNOS expression was ascribed to the prevention of IRF3 phosphorylation, interferon (IFN)‐β expression, and STAT1 phosphorylation, but not the prevention of the MyD88‐dependent pathway. Taken together, our results indicate that ATO prevents NO production by inhibiting the TIR‐domain‐containing adaptor protein inducing IFN‐β (TRIF)‐dependent pathway, thus highlighting an anti‐inflammatory property of ATO in innate immunity.     

Lack of TRPM2 impaired insulin secretion and glucose metabolisms in mice

OBJECTIVE

TRPM2 is a Ca²⁺-permeable nonselective cation channel activated by adenosine dinucleotides. We previously demonstrated that TRPM2 is activated by coapplication of heat and intracellular cyclic adenosine 5′-diphosphoribose, which has been suggested to be involved in intracellular Ca²⁺ increase in immunocytes and pancreatic β-cells. To clarify the involvement of TRPM2 in insulin secretion, we analyzed TRPM2 knockout (TRPM2-KO) mice.

RESEARCH DESIGN AND METHODS

Oral and intraperitoneal glucose tolerance tests (OGTT and IPGTT) were performed in TRPM2-KO and wild-type mice. We also measured cytosolic free Ca²⁺ in single pancreatic cells using fura-2 microfluorometry and insulin secretion from pancreatic islets.

RESULTS

Basal blood glucose levels were higher in TRPM2-KO mice than in wild-type mice without any difference in plasma insulin levels. The OGTT and IPGTT demonstrated that blood glucose levels in TRPM2-KO mice were higher than those in wild-type mice, which was associated with an impairment in insulin secretion. In isolated β-cells, smaller intracellular Ca²⁺ increase was observed in response to high concentrations of glucose and incretin hormone in TRPM2-KO cells than in wild-type cells. Moreover, insulin secretion from the islets of TRPM2-KO mice in response to glucose and incretin hormone treatment was impaired, whereas the response to tolbutamide, an ATP-sensitive potassium channel inhibitor, was not different between the two groups.

CONCLUSIONS

These results indicate that TRPM2 is involved in insulin secretion stimulated by glucose and that further potentiated by incretins. Thus, TRPM2 may be a new target for diabetes therapy.Under physiological conditions, blood glucose levels are kept in a narrow range despite periods of food intake and fasting. Insulin secretion from pancreatic β-cells is the only efficient means to decrease blood glucose concentration. Accordingly, insulin secretion is strictly controlled by glucose, hormones, and autonomic nervous system activity. Glucose is the principal stimulator of insulin secretion from pancreatic β-cells. The primary and best-characterized pathway involved in glucose-stimulated insulin secretion is the ATP-sensitive potassium channel (K_ATP channel)-dependent pathway. ATP closes K_ATP channels, causing depolarization, resulting in Ca²⁺ influx from the extracellular space via l-type voltage-gated Ca²⁺ channels followed by exocytosis. Glucose-stimulated insulin secretion is potentiated by incretins such as glucagon-like peptide-1 (GLP-1).Transient receptor potential melastatin 2 (TRPM2, previously named TRPC7 or LTRPC2) is a Ca²⁺-permeable nonselective cation channel, expressed predominantly in brain and also detected in bone marrow, spleen, heart, liver, lung, and immunocytes (1–3). This channel is activated by nicotinamide adenine dinucleotide (NAD), adenosine 5′-diphosphoribose (ADPR), and hydrogen peroxide (H₂O₂). Previously, we reported that TRPM2 is expressed in mouse pancreatic β-cells and is dramatically activated at body temperature by treatment with intracellular cyclic ADPR (cADPR) (4). Although some reports have shown that TRPM2 is involved in H₂O₂-mediated apoptosis in insulin-secreting cell lines (5,6), the physiological significance of TRPM2 in pancreas, especially at an in vivo level, has not been well characterized.To clarify the involvement of TRPM2 in insulin secretion, we analyzed TRPM2 knockout (TRPM2-KO) mice. We found that lack of TRPM2 impairs insulin secretion not only stimulated by glucose but also potentiated by incretins.     

Molecular characterization and phylogenetics of a reassortant H13N8 influenza virus isolated from gulls in Mongolia

Double reassortant H13N8 influenza A virus was isolated from gull in Mongolia. The basic virological characteristics were studied. Complete genome sequence analysis indicated the complicated evolutionary history. The PA gene belongs to classical Avian-like lineage and more likely originated from non-gull avian virus pool. Data confirm the state of extensive geographic mosaicism in AIV from gulls in the Northern Hemisphere.     

Rickettsia raoultii,the predominant Rickettsia found in Mongolian Dermacentor nuttalli

Since the year 2005, clinical patterns resembling tick-borne rickettsioses have been noticed in Mongolia. Epidemiological data regarding species of the aetiological agent, tick vector, prevalence, and distribution as well as incidence of human cases throughout Mongolia are still sparse to date. In order to identify Rickettsia species occurring in Mongolia, we investigated Dermacentor nuttalli (n = 179) and Ixodes persulcatus (n = 374) collected in 4 selected provinces. Rickettsia raoultii was the predominant Rickettsia (82% prevalence) found in D. nuttalli and was also detected in I. persulcatus (0.8%). The Rickettsia prevalence in D. nuttalli from different provinces varied between 70% and 97%. In addition, R. sibirica was identified in approximately 4% of D. nuttalli, but solely from Arkhanghai province. The results of this study extend the common knowledge about the geographic distribution of R. raoultii and its high prevalence in D. nuttalli. Although the pathogenicity of this Rickettsia is still unclear, it should be considered in Mongolian patients suspected of having tick-borne rickettsiosis.