Search Results

You are looking at 31 - 40 of 3,518 items for

  • Abstract: Diabetes x
  • Abstract: Islets x
  • Abstract: Insulin x
  • Abstract: BetaCells x
  • Abstract: Pancreas x
  • Abstract: Obesity x
  • Abstract: Glucose x
  • Abstract: Hyperglycemia x
  • Abstract: Hypoglycemia x
  • Abstract: Insulinoma x
  • Abstract: Glucagon x
  • Abstract: IGF* x
  • Abstract: Type 1 x
Clear All Modify Search
Restricted access

M L Villanueva-Peñacarrillo, E Delgado, M A Trapote, A Alcántara, F Clemente, M A Luque, A Perea and I Valverde

Abstract

We have found [125I]glucagon-like peptide (GLP)-1(7–36)amide specific binding activity in rat liver and isolated hepatocyte plasma membranes, with an Mr of approximately 63 000, estimated by cross-linking and SDS-PAGE. The specific binding was time- and membrane protein concentration-dependent, and equally displaced by unlabelled GLP-1(7–36)amide and by GLP-1(1–36)amide, achieving its ID50 at 3×10−9 m of the peptides. GLP-1(7–36)amide did not modify the basal or the glucagon (10−8 m)-stimulated adenylate cyclase in the hepatocyte plasma membranes. These data, together with our previous findings of a potent glycogenic effect of GLP-1(7–36)amide in isolated rat hepatocytes, led us to postulate that the insulin-like effects of this peptide on glucose liver metabolism could be mediated by a type of receptor probably different from that described for GLP-1 in pancreatic B-cells or, alternatively, by the same receptor which, in this tissue as well as in muscle, uses a different transduction system.

Journal of Endocrinology (1995) 146, 183–189

Free access

Paige V Bauer and Frank A Duca

The rising global rates of type 2 diabetes and obesity present a significant economic and social burden, underscoring the importance for effective and safe therapeutic options. The success of glucagon-like-peptide-1 receptor agonists in the treatment of type 2 diabetes, along with the potent glucose-lowering effects of bariatric surgery, highlight the gastrointestinal tract as a potential target for diabetes treatment. Furthermore, recent evidence suggests that the gut plays a prominent role in the ability of metformin to lower glucose levels. As such, the current review highlights some of the current and potential pathways in the gut that could be targeted to improve glucose homeostasis, such as changes in nutrient sensing, gut peptides, gut microbiota and bile acids. A better understanding of these pathways will lay the groundwork for novel gut-targeted antidiabetic therapies, some of which have already shown initial promise.

Free access

Jun-ichi Eiki, Kaori Saeki, Norihiro Nagano, Tomoharu Iino, Mari Yonemoto, Yoko Takayenoki-Iino, Satoru Ito, Teruyuki Nishimura, Yoshiyuki Sato, Makoto Bamba, Hitomi Watanabe, Kaori Sasaki, Sumika Ohyama, Akio Kanatani, Toshio Nagase and Toshihiko Yada

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that potentiates insulin secretion in a glucose-dependent manner. Selective GLP-1 secretagogue would be one of the potential therapeutic targets for type 2 diabetes. Here, we describe a newly identified small molecule compound (compound A) that stimulates secretion of GLP-1 in murine enteroendocrine cell lines, STC-1 and GLUTag cells, and in primary cultured fetal rat intestinal cells (FRIC). The underlying mechanism by which compound A stimulated GLP-1 secretion was also examined. Compound A stimulated GLP-1 secretion from STC-1 cells in a concentration-dependent manner, and also from GLUTag cells and FRIC. The action of compound A was selective against other tested endocrine functions such as secretion of insulin from rat islets, growth hormone from rat pituitary gland cells, and norepinephrine from rat PC-12 cells. In STC-1 cells, the compound A-stimulated GLP-1 secretion was neither due to cyclic AMP production nor to Ca2+ release from intracellular stores, but to extracellular Ca2+ influx. The response was inhibited by the presence of either L-type Ca2+ channel blockers or K+ ionophore. Perforated-patch clamp study revealed that compound A induces membrane depolarization. These results suggest that neither Gαs- nor Gαq-coupled signaling account for the mechanism of action, but depolarization-coupled Ca2+ influx from extracellular space is the primary cause for the GLP-1 secretion stimulated by compound A. Identifying a specific target molecule for compound A will reveal a selective regulatory pathway that leads to depolarization-mediated GLP-1 secretion.

Free access

Zhengu Liu, Violeta Stanojevic, Luke J Brindamour and Joel F Habener

Type 2 diabetes, often associated with obesity, results from a deficiency of insulin production and action manifested in increased blood levels of glucose and lipids that further promote insulin resistance and impair insulin secretion. Glucolipotoxicity caused by elevated plasma glucose and lipid levels is a major cause of impaired glucose-stimulated insulin secretion from pancreatic β-cells, due to increased oxidative stress, and insulin resistance. Glucagon-like peptide-1 (GLP1), an insulinotropic glucoincretin hormone, is known to promote β-cell survival via its actions on its G-protein-coupled receptor on β-cells. Here, we report that a nonapeptide, GLP1(28–36)amide, derived from the C-terminal domain of the insulinotropic GLP1, exerts cytoprotective actions on INS-1 β-cells and on dispersed human islet cells in vitro in conditions of glucolipotoxicity and increased oxidative stress independently of the GLP1 receptor. The nonapeptide appears to enter preferably stressed, glucolipotoxic cells compared with normal unstressed cells. It targets mitochondria and improves impaired mitochondrial membrane potential, increases cellular ATP levels, inhibits cytochrome c release, caspase activation, and apoptosis, and enhances the viability and survival of INS-1 β-cells. We propose that GLP1(28–36)amide might be useful in alleviating β-cell stress and might improve β-cell functions and survival.

Free access

Elisabet Estil.les, Noèlia Téllez, Joan Soler and Eduard Montanya

Interleukin-1β (IL1B) is an important contributor to the autoimmune destruction of β-cells in type 1 diabetes, and it has been recently related to the development of type 2 diabetes. IGF2 stimulates β-cell proliferation and survival. We have determined the effect of IL1B on β-cell replication, and the potential modulation by IGF2 and glucose. Control-uninfected and adenovirus encoding for IGF2 (Ad-IGF2)-infected rat islets were cultured at 5.5 or 22.2 mmol/l glucose with or without 1, 10, 30, and 50 U/ml of IL1B. β-Cell replication was markedly reduced by 10 U/ml of IL1B and was almost nullified with 30 or 50 U/ml of IL1B. Higher concentrations of IL1B were required to increase β-cell apoptosis. Although IGF2 overexpression had a strong mitogenic effect on β-cells, IGF2 could preserve β-cell proliferation only in islets cultured with 10 U/ml IL1B, and had no effect with 30 and 50 U/ml of IL1B. In contrast, IGF2 overexpression induced a clear protection against IL1B-induced apoptosis, and higher concentrations of the cytokine were needed to increase β-cell apoptosis in Ad-IGF2-infected islets. These results indicate that β-cell replication is highly sensitive to the deleterious effects of the IL1B as shown by the inhibition of replication by relatively low IL1B concentrations, and the almost complete suppression of β-cell replication with high IL1B concentrations. Likewise, the inhibitory effects of IL-β on β-cell replication were not modified by glucose, and were only modestly prevented by IGF2 overexpression, in contrast with the higher protection against IL1B-induced apoptosis afforded by glucose and by IGF2 overexpression.

Free access

Ronald Gonzalez, Benjamin K Reingold, Xiaodong Gao, Mandeep P Gaidhu, Robert G Tsushima and Suraj Unniappan

Nesfatin-1 is a recently discovered multifunctional metabolic hormone abundantly expressed in the pancreatic islets. The main objective of this study is to characterize the direct effects of nesfatin-1 on insulin secretion in vitro using MIN6 cells and islets isolated from C57BL/6 mice. We also examined the expression of the nesfatin-1 precursor protein, nucleobindin 2 (NUCB2) mRNA, and nesfatin-1 immunoreactivity (ir) in the islets of normal mice and in the islets from mice with streptozotocin-induced type 1 diabetes and diet-induced obese (DIO) mice with type 2 diabetes. Nesfatin-1 stimulated glucose-induced insulin release in vitro from mouse islets and MIN6 cells in a dose-dependent manner. No such stimulation in insulin secretion was found when MIN6 cells/islets were incubated with nesfatin-1 in low glucose. In addition, a fourfold increase in nesfatin-1 release from MIN6 cells was observed following incubation in high glucose (16.7 mM) compared to low glucose (2 mM). Furthermore, we observed a significant reduction in both NUCB2 mRNA expression and nesfatin-1-ir in the pancreatic islets of mice with type 1 diabetes, while a significant increase was observed in the islets of DIO mice. Together, our findings indicate that nesfatin-1 is a novel insulinotropic peptide and that the endogenous pancreatic islet NUCB2/nesfatin is altered in diabetes and diet-induced obesity.

Free access

Berit Svendsen, Ramona Pais, Maja S Engelstoft, Nikolay B Milev, Paul Richards, Charlotte B Christiansen, Kristoffer L Egerod, Signe M Jensen, Abdella M Habib, Fiona M Gribble, Thue W Schwartz, Frank Reimann and Jens J Holst

The incretin hormones glucagon-like peptide-1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted from intestinal endocrine cells, the so-called L- and K-cells. The cells are derived from a common precursor and are highly related, and co-expression of the two hormones in so-called L/K-cells has been reported. To investigate the relationship between the GLP1- and GIP-producing cells more closely, we generated a transgenic mouse model expressing a fluorescent marker in GIP-positive cells. In combination with a mouse strain with fluorescent GLP1 cells, we were able to estimate the overlap between the two cell types. Furthermore, we used primary cultured intestinal cells and isolated perfused mouse intestine to measure the secretion of GIP and GLP1 in response to different stimuli. Overlapping GLP1 and GIP cells were rare (∼5%). KCl, glucose and forskolin+IBMX increased the secretion of both GLP1 and GIP, whereas bombesin/neuromedin C only stimulated GLP1 secretion. Expression analysis showed high expression of the bombesin 2 receptor in GLP1 positive cells, but no expression in GIP-positive cells. These data indicate both expressional and functional differences between the GLP1-producing ‘L-cell’ and the GIP-producing ‘K-cell’.

Free access

Joshua A Kulas, Kendra L Puig and Colin K Combs

The amyloid precursor protein (APP) has been extensively investigated for its role in the production of amyloid beta (Aβ), a plaque-forming peptide in Alzheimer’s disease (AD). Epidemiological evidence suggests type 2 diabetes is a risk factor for AD. The pancreas is an essential regulator of blood glucose levels through the secretion of the hormones insulin and glucagon. Pancreatic dysfunction is a well-characterized consequence of type 1 and type 2 diabetes. In this study, we have examined the expression and processing of pancreatic APP to test the hypothesis that APP may play a role in pancreatic function and the pathophysiology of diabetes. Our data demonstrate the presence of APP within the pancreas, including pancreatic islets in both mouse and human samples. Additionally, we report that the APP/PS1 mouse model of AD overexpresses APP within pancreatic islets, although this did not result in detectable levels of Aβ. We compared whole pancreas and islet culture lysates by Western blot from C57BL/6 (WT), APP−/− and APP/PS1 mice and observed APP-dependent differences in the total protein levels of GLUT4, IDE and BACE2. Immunohistochemistry for BACE2 detected high levels in pancreatic α cells. Additionally, both mouse and human islets processed APP to release sAPP into cell culture media. Moreover, sAPP stimulated insulin but not glucagon secretion from islet cultures. We conclude that APP and its metabolites are capable of influencing the basic physiology of the pancreas, possibly through the release of sAPP acting in an autocrine or paracrine manner.

Full access

Olena A Fedorenko, Pawitra Pulbutr, Elin Banke, Nneoma E Akaniro-Ejim, Donna C Bentley, Charlotta S Olofsson, Sue Chan and Paul A Smith

L-type channel antagonists are of therapeutic benefit in the treatment of hyperlipidaemia and insulin resistance. Our aim was to identify L-type voltage-gated Ca2+ channels in white fat adipocytes, and determine if they affect intracellular Ca2+, lipolysis and lipogenesis. We used a multidisciplinary approach of molecular biology, confocal microscopy, Ca2+ imaging and metabolic assays to explore this problem using adipocytes isolated from adult rat epididymal fat pads. CaV1.2, CaV1.3 and CaV1.1 alpha1, beta and alpha2delta subunits were detected at the gene expression level. The CaV1.2 and CaV1.3 alpha1 subunits were identified in the plasma membrane at the protein level. Confocal microscopy with fluorescent antibodies labelled CaV1.2 in the plasma membrane. Ca2+ imaging revealed that the intracellular Ca2+ concentration, [Ca2 +]i was reversibly decreased by removal of extracellular Ca2+, an effect mimicked by verapamil, nifedipine and Co2+, all blockers of L-type channels, whereas the Ca2+ channel agonist BAY-K8644 increased [Ca2+]i. The finding that the magnitude of these effects correlated with basal [Ca2+]i suggests that adipocyte [Ca2+]i is controlled by L-type Ca2+ channels that are constitutively active at the adipocyte depolarized membrane potential. Pharmacological manipulation of L-type channel activity modulated both basal and catecholamine-stimulated lipolysis but not insulin-induced glucose uptake or lipogenesis. We conclude that white adipocytes have constitutively active L-type Ca2+ channels which explains their sensitivity of lipolysis to Ca2+ channel modulators. Our data suggest CaV1.2 as a potential novel therapeutic target in the treatment of obesity.

Full access

Kanta Kon, Hiroshi Tsuneki, Hisakatsu Ito, Yoshinori Takemura, Kiyofumi Sato, Mitsuaki Yamazaki, Yoko Ishii, Masakiyo Sasahara, Assaf Rudich, Takahiro Maeda, Tsutomu Wada and Toshiyasu Sasaoka

Disrupted sleep is associated with increased risk of type 2 diabetes. Central actions of orexin, mediated by orexin-1 and orexin-2 receptors, play a crucial role in the maintenance of wakefulness; accordingly, excessive activation of the orexin system causes insomnia. Resting-phase administration of dual orexin receptor antagonist (DORA) has been shown to improve sleep abnormalities and glucose intolerance in type 2 diabetic db/db mice, although the mechanism remains unknown. In the present study, to investigate the presence of functional link between sleep and glucose metabolism, the influences of orexin antagonists with or without sleep-promoting effects were compared on glucose metabolism in diabetic mice. In db/db mice, 2-SORA-MK1064 (an orexin-2 receptor antagonist) and DORA-12 (a DORA) acutely improved non-rapid eye movement sleep, whereas 1-SORA-1 (an orexin-1 receptor antagonist) had no effect. Chronic resting-phase administration of these drugs improved glucose intolerance, without affecting body weight, food intake, locomotor activity and energy expenditure calculated from O2 consumption and CO2 production. The expression levels of proinflammatory factors in the liver were reduced by 2-SORA-MK1064 and DORA-12, but not 1-SORA-1, whereas those in the white adipose tissue were reduced by 1-SORA-1 and DORA-12 more efficiently than 2-SORA-MK1064. When administered chronically at awake phase, these drugs caused no effect. In streptozotocin-induced type 1-like diabetic mice, neither abnormality in sleep–wake behavior nor improvement of glucose intolerance by these drugs were observed. These results suggest that both 1-SORA-type (sleep-independent) and 2-SORA-type (possibly sleep-dependent) mechanisms can provide chronotherapeutic effects against type 2 diabetes associated with sleep disturbances in db/db mice.