Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bsk/Iyk, a murine non-receptor-tyrosine kinase which is expressed in fetal and adult islet of Langerhans was previously found to decrease NIH3T3 cell proliferation when expressed as a Y497/504F-mutant. We presently wanted to determine the effects of Bsk/Iyk on the proliferation of insulin producing cells. Cells expressing Bsk/IykY497/504F and Bsk/IykY504F display a decreased proliferation rate and express higher levels of the cell cycle inhibitor p27/Kip1 compared to control cells. These mutants also conferred diminished cell viability in response to INF-gamma and IL-1beta and contain higher levels of glucagon mRNA. Wild-type Bsk/Iyk is mainly localized at the plasma membrane whereas mutant Bsk/Iyk can enter the nucleus. In vitro kinase reactions using an exogenous substrate indicate a complicated mode of regulation of kinase activity by Y497 and Y504 with the latter being homologous to Y527 in pp60c-Src. These findings suggest that Bsk/Iyk might play a role in inhibiting cell proliferation, transducing cytokine-induced cytotoxicity and regulating hormone production of endocrine pancreatic cells.
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PMID:Role of the Bsk/Iyk non-receptor tyrosine kinase for the control of growth and hormone production in RINm5F cells. 1080 Oct 74

Feeding diabetes-prone BioBreeding (BBdp) rats a hydrolysed-casein (HC)-based semi-purified diet results in two-to-three-fold fewer diabetes cases compared with feeding cereal-based diets such as NIH-07 (NIH). We showed previously that young NIH-fed BBdp rats had decreased islet area at a time when classic insulitis was minimal. Rats fed an HC diet maintained near normal islet area followed 3-4 weeks later by a deviation of the pancreas cytokine pattern from Th1 to Th2/Th3. This finding raised the possibility that BBdp rats were more susceptible to diet-induced changes in islet homeostasis. To investigate this possibility further, BBdp rats were fed an NIH or HC diet from days 23 to 45. Bouin's fixed sections of pancreas were stained with H & E or antibodies for insulin and glucagon. Cell proliferation nuclear antigen (PCNA) was used as a marker of cell proliferation and cells were stained for putative markers of islet neogenesis, cytokeratin 20 (CK20) and Bcl-2. Apoptotic bodies were recognized by morphological features and by TUNEL-positive staining. BBdp rats fed an HC diet had a significantly higher beta-cell fraction than rats fed NIH, whereas alpha-cell fraction and beta-cell size were not affected by diet or rat type. Apoptotic bodies of beta-cells were rare and unaffected by diet. The number of PCNA(+)beta-cells was not affected by diet. CK20 expression was localized in the ductular system and at the periphery of islets in rats aged 7 and 45 days. There were more CK20(+)islets in BBdp rats fed NIH than in those fed HC but the CK20 area fraction was unaffected by diet. Bcl-2 expression was scattered among ducts and central acinar cells. The number of extra-islet insulin(+)and glucagon(+)clusters (<four cells) was significantly higher in animals fed the HC diet compared with those fed NIH. Most of the insulin(+)clusters were also homeodomain-containing transcription factor pancreas duodenum homeobox gene-1 (PDX-1) positive. Glucagon(+)/PDX-1(+)clusters were rarely found. These data are consistent with a shift in pancreas homeostasis that maintains islet cell mass by increased islet neogenesis, a process that was enhanced in animals fed a diabetes-retardant diet.
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PMID:Hydrolysed casein diet protects BB rats from developing diabetes by promoting islet neogenesis. 1109 Feb 39

Diabetes mellitus type 2 is a syndrome with different etiopathology and clinical picture. Results of clinical studies show that hyperglycaemia increases during the time of diabetes even if it is intensively treated. At the present time some new hypoglycaemic drugs have been introduced for type 2 diabetes mellitus therapy. These drugs can increase insulin secretion by the inhibition of the ATP-sensitive K+ channels (glimepyride, repaglinide) or by incretin action (glucagon-like peptide-1). Other drugs can decrease insulin resistance acting on nuclear receptors (troglitazone). Normalization of stomach motoric activity can also lead to decreasing of blood glucose concentration (pramlintid). Also other mechanisms of action are taken into consideration, like changing of cytokine activity or catabolism regulation of beta-cells of the Langerhans' islets.
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PMID:[New hypoglycemic drugs in treatment of diabetes type 2]. 1110 71

Substantial new information has accumulated on molecular mechanisms of pancreas development, regulation of beta-cell gene expression, and the role of growth factors in the differentiation, growth, and regeneration of beta-cells. The present review focuses on some recent studies on the mechanism of action of cytokines such as growth hormone (GH) and prolactin (PRL) in beta-cell proliferation and gene expression-in particular, the role of signal transducers and activators of transcription (STAT) proteins. The implication of the discovery of suppressors of cytokine signaling (SOCS) proteins for the interaction between stimulatory and inhibitory cytokines, including GH, PRL, leptin, and the proinflammatory cytokines interleukin-1 and interferon-gamma, in beta-cell survival is not yet clear. Recent studies indicate a role of cell adhesion molecules and the delta-like protein preadipocyte factor 1/fetal antigen 1 (Pref-1/FA-1) in cytokine-induced beta-cell growth and development. Surprisingly, glucagon-like peptide-1 (GLP-1) was recently found to stimulate not only insulin secretion but also beta-cell replication and differentiation, which may present a new perspective in treatment of type 2 diabetes. Together with the intriguing reports on positive effects of insulin on both beta-cell growth and function, a picture is emerging of an integrated network of signaling events acting in concert to control beta-cell mass adaptation to insulin demand.
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PMID:Regulation of beta-cell mass by hormones and growth factors. 1127 93

Glucagon-like peptide 2 (GLP-2) is a 33 amino acid peptide-encoded carboxyterminal to the sequence of GLP-1 in the proglucagon gene. Both GLP-1 and GLP-2 are secreted from gut endocrine cells and promote nutrient absorption through distinct mechanisms of action. GLP-2 regulates gastric motility, gastric acid secretion, intestinal hexose transport, and increases the barrier function of the gut epithelium. GLP-2 significantly enhances the surface area of the mucosal epithelium via stimulation of crypt cell proliferation and inhibition of apoptosis in the enterocyte and crypt compartments. The cytoprotective and reparative effects of GLP-2 are evident in rodent models of experimental intestinal injury. GLP-2 reduces mortality and decreases mucosal injury, cytokine expression, and bacterial septicemia in the setting of small and large bowel inflammation. GLP-2 also enhances nutrient absorption and gut adaptation in rodents or humans with short bowel syndrome. The actions of GLP-2 are transduced by the GLP-2 receptor, a G protein-coupled receptor expressed in gut endocrine cells of the stomach, small bowel, and colon. Activation of GLP-2 receptor signaling in heterologous cells promotes resistance to apoptotic injury in vitro. The cytoprotective, reparative, and energy-retentive properties of GLP-2 suggests that GLP-2 may potentially be useful for the treatment of human disorders characterized by injury and/or dysfunction of the intestinal mucosal epithelium.
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PMID:Glucagon-like peptide 2. 1129 14

In developmental terms, the endocrine system of neither the gut nor the pancreatic islets has been characterized fully. Little is known about the involvement of cholecystokinin (CCK), a gut hormone, involved in regulating the secretion of pancreatic hormones, and pancreatic growth. Here, we tracked CCK-expressing cells in the intestines and pancreata of normal mice (BALB/c), Non Obese Diabetic (NOD) mice and interferon (IFN)-gamma transgenic mice, which exhibit pancreatic regeneration, during embryonic development, the postnatal period and adulthood. We also questioned whether IFN-gamma influences the expression of CCK. The results from embryonic day 16 showed that all three strains had CCK in the acinar region of pancreata, and specifically in alpha cells that also expressed glucagon. However, in adulthood only BALB/c and NOD mice continued this pattern. By contrast, in IFN-gamma transgenic mice, CCK expression was suppressed from birth to 3 months of age in the pancreata but not intestines. However, by 5 months of age, CCK expression appeared in the regenerating pancreatic ductal region of IFN-gamma transgenic mice. In the intestine, CCK expression persisted from fetus to adulthood and was not influenced by IFN-gamma. Intestinal cells expressing CCK did not co-express glucagon, suggesting that these cells are phenotypically distinct from CCK-expressing cells in the pancreatic islets, and the effect of IFN-gamma on CCK varies depending upon the cytokine's specific microenvironment.
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PMID:Cholecystokinin expression in the developing and regenerating pancreas and intestine. 1131 40

Recent work has established that Kupffer cell products, including prostaglandins, can act directly on hepatocytes to modify glucose and lipid metabolism. Additionally, prostaglandins can act on Kupffer cells to modify the expression of cytokines. Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) stimulate hepatic lipogenesis following in vivo administration. To define the direct effects of these cytokines on lipogenesis in primary culture rat hepatocytes, hepatocytes were cultured in the presence of IL-6 or TNF-alpha for periods of 24--72 h. IL-6 caused an increase in hepatocyte lipogenic capacity (56% increase by 12.5 ng ml(minus sign1) IL-6 after 72 h of cytokine exposure). The increase in cellular lipogenic capacity was confirmed using (3)H2O as the radiotracer. TNF-alpha did not increase the rate of hepatocyte lipogenesis. Neither IL-6 nor TNF-alpha modified rates of lipogenesis upon acute exposure to the cytokine. Misoprostol-free acid (0.1 &mgr;M) acutely increased hepatocyte lipogenic rates by 14% in the presence of glucagon. These results demonstrate that IL-6 can act directly on hepatocytes to induce lipogenic capacity and that E-series prostaglandins can antagonize the acute inhibition of lipogenesis by glucagon. Because IL-6 is produced by Kupffer cells, and its expression is modulated by prostaglandins, the Kupffer cell is a novel target for prostaglandin therapy. Administration of prostaglandins may provide a novel strategy for pharmacologic therapy of disorders of glucose or lipid metabolism.
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PMID:Stimulation of Lipogenesis by Interleukin-6 and Misoprostol-Free Acid in Isolated Rat Hepatocytes. 1185 48

Glucagon-like peptide-1 (GLP-1) stimulates insulin secretion and augments beta cell mass via activation of beta cell proliferation and islet neogenesis. We examined whether GLP-1 receptor signaling modifies the cellular susceptibility to apoptosis. Mice administered streptozotocin (STZ), an agent known to induce beta cell apoptosis, exhibit sustained improvement in glycemic control and increased levels of plasma insulin with concomitant administration of the GLP-1 agonist exendin-4 (Ex-4). Blood glucose remained significantly lower for weeks after cessation of exendin-4. STZ induced beta cell apoptosis, which was significantly reduced by co-administration of Ex-4. Conversely, mice with a targeted disruption of the GLP-1 receptor gene exhibited increased beta cell apoptosis after STZ administration. Exendin-4 directly reduced cytokine-induced apoptosis in purified rat beta cells exposed to interleukin 1beta, tumor necrosis fator alpha, and interferon gamma in vitro. Furthermore, Ex-4-treated BHK-GLP-1R cells exhibited significantly increased cell viability, reduced caspase activity, and decreased cleavage of beta-catenin after treatment with cycloheximide in vitro. These findings demonstrate that GLP-1 receptor signaling directly modifies the susceptibility to apoptotic injury, and provides a new potential mechanism linking GLP-1 receptor activation to preservation or enhancement of beta cell mass in vivo.
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PMID:Glucagon-like peptide-1 receptor signaling modulates beta cell apoptosis. 1240 92

Glucagon-like peptide 2 (GLP-2) is a member of family of peptides derived from the proglucagon gene expressed in the intestines, pancreas and brain. Tissue-specific posttranslational processing of proglucagon leads to GLP-2 and GLP-1 secretion from the intestine and glucagon secretion from the pancreas. GLP-2 and GLP-1 are co-secreted from the enteroendocrine L-cells located in distal intestine in response to enteral nutrient ingestion, especially carbohydrate and fat. GLP-2 secretion is mediated by direct nutrient stimulation of the L-cells and indirect action from enteroendocrine and neural inputs, including GIP, gastrin-releasing peptide (GRP) and the vagus nerve. GLP-2 is secreted as a 33-amino acid peptide and is rapidly cleaved by dipeptidylpeptidase IV (DPP-IV) to a truncated peptide which acts as a weak agonist with competitive antagonistic properties. GLP-2 acts to enhance nutrient absorption by inhibiting gastric motility and secretion and stimulating nutrient transport. GLP-2 also suppresses food intake when infused centrally. The trophic actions of GLP-2 are specific for the intestine and occur via stimulation of crypt cell proliferation and suppression of apoptosis in mucosal epithelial cells. GLP-2 reduces gut permeability, bacterial translocation and proinflammatory cytokine expression under conditions of intestinal inflammation and injury. The effects of GLP-2 are mediated by a G-protein-linked receptor that is localized to the intestinal mucosa and hypothalamus. The intestinal localization of the GLP-2R to neural and endocrine cells, but not enterocytes, suggests that its actions are mediated indirectly via a secondary signaling mechanism. The implications of GLP-2 in domestic animal production are largely unexplored. However, GLP-2 may have therapeutic application in treatment of gastrointestinal injury and diarrheal diseases that occur in developing neonatal and weanling animals.
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PMID:Glucagon-like peptide 2 function in domestic animals. 1258 12

PANDER (PANcreatic DERived factor, FAM3B), a newly discovered secreted cytokine, is specifically expressed at high levels in the islets of Langerhans of the endocrine pancreas. To evaluate the role of PANDER in beta-cell function, we investigated the effects of PANDER on rat, mouse, and human pancreatic islets; the beta-TC3 cell line; and the alpha-TC cell line. PANDER protein was present in alpha- and beta-cells of pancreatic islets, insulin-secreting beta-TC3 cells, and glucagon-secreting alpha-TC cells. PANDER induced islet cell death in rat and human islets. Culture of beta-TC3 cells with recombinant PANDER had a dose-dependent inhibitory effect on cell viability. This effect was also time-dependent. PANDER caused apoptosis of beta-cells as assessed by electron microscopy, annexin V fluorescent staining, and flow-cytometric terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay. PANDER did not affect cytosolic Ca(2+) levels or nitric oxide levels. However, PANDER activated caspase-3. Hence, PANDER may have a role in the process of pancreatic beta-cell apoptosis.
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PMID:Pancreatic-derived factor (FAM3B), a novel islet cytokine, induces apoptosis of insulin-secreting beta-cells. 1294 69


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