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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We recently reported that insulin inhibits basal and cortisone- and T3-stimulated GH secretion by GH3 rat pituitary tumor cells. The effects of purified semisynthetic human insulin were therefore tested on long-term GH secretion in normal pituitary cells. Primary monolayer cultures derived from male rat pituitaries were grown in serum-free defined medium. Insulin (7 nM) maximally inhibited basal GH secretion by almost 60% after 72 h, with 50% of maximal GH suppression occurring with 1.75 nM insulin. Insulin receptor antiserum blocked the suppression of GH by 7 nM insulin, but had no effect on the suppression of GH by IGF-I (3.25 nM). GRF (100 pM) stimulated GH two- to threefold during 48 h. Insulin (7 nM) prevented the stimulation of GH induced by up to 1 nM GRF (P less than 0.01) and this suppression was also selectively blocked by insulin receptor antiserum. The inhibition of GRF-stimulated GH required a lag period of 48 h and the dose of insulin required for 50% inhibition of GRF stimulation was 3.5 nM. Insulin did not alter the degradation rate of 125I-GH in these cultures and medium glucose concentrations were not different in control or insulin-treated wells for up to 72 h of incubation. The insulin-induced suppression of GH was also observed when cells were grown in glucose-free medium. Insulin did not nonselectively suppress cell secretion, as PRL secretion was mildly stimulated (P less than 0.01) by insulin in the same cultures. Fibroblast growth factor, epidermal growth factor, and insulin A-chain at similar doses did not alter basal or GRF-stimulated GH secretion.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1986 Apr
PMID:Effects of insulin on rat anterior pituitary cells. Inhibition of growth hormone secretion and mRNA levels. 308

Fibroblast growth factor-2 (FGF-2) is a potent mitogen and angiogenic factor normally absent from the adult circulation. We have previously shown that it appears in normal maternal serum and that circulating FGF-2 levels are elevated in pregnancies complicated by diabetes. This study was performed to determine whether serum FGF-2 is more abundant in pregnant diabetic women with retinopathy than in those without. Serum was collected monthly between 14-30 weeks gestation and every 2 weeks from then until delivery (35-38 weeks) from 36 women with type 1 diabetes. FGF-2 was extracted by heparin-Sepharose affinity chromatography and quantified by specific RIA. Patients were divided according to the White classification of diabetes. In 17 women without retinopathy (White groups B, C, and D0), immunoreactive FGF-2 was detectable at 14 weeks (mean +/- SEM, 154 +/- 39 pmol/L), was maximal after 26 weeks (306 +/- 38 pmol/L), after which values steadily declined to term (212 +/- 48 pmol/L). In 19 women with simplex or proliferative retinopathy (White groups D+ and R), circulating levels of FGF-2 were significantly greater between 22-32 weeks gestation (22 weeks, 480 +/- 102 vs. 239 +/- 38 pmol/L; P < 0.05). Serum FGF-2 was significantly correlated with hemoglobin A1c levels at 22, 30, and 34 weeks gestation. The mean birth weight of the infants did not significantly differ between groups. Macroalbuminuria was absent in all patients, and creatinine clearance and blood pressure did not significantly differ between the two groups. The results suggest that serum FGF-2 is substantially elevated in pregnant diabetic women with retinopathy in second and early third trimesters. It is unlikely that in these patients this was primarily due to altered FGF-2 clearance, but may relate to excessive production by the utero-placental compartment. The high circulating levels of FGF-2 may be causally related to the development of diabetic retinopathy.
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PMID:Increased levels of serum fibroblast growth factor-2 in diabetic pregnant women with retinopathy. 914 32

Fibroblast growth factor-2 (FGF-2) is a potent mitogen expressed widely during embryogenesis and in tissues of the human fetus. It is recognized as an endothelial cell mitogen and is angiogenic in vivo. Expression of FGF-2 mRNA has also been shown within the human term placenta, and FGF-2 isolated from placental tissue, suggesting a role in placental growth including angiogenesis. The purpose of this study was to quantify and localize the sites of expression of FGF-2 and its high-affinity receptor, FGFR1, within placentae from normal term human pregnancies (n=8, 39-42 weeks), and pregnancies complicated by pregestational, type 1 diabetes (n=8, 36-40 weeks). Tissues were collected immediately following delivery and were either snap-frozen for RNA isolation, or fixed for either in situ hybridization using a 35S-labelled cRNAs encoding human FGF-2 or FGFR1, or immunocytochemistry using antibodies against human FGF-2 or FGFR1. Northern blot hybridization showed a significantly increased abundance of mRNAs for both FGF-2 and FGFR1 in placentae from diabetic women compared to those from normal women. In normal term placenta FGF-2 mRNA was present at low abundance in fetal villous tissue, in the vascular endothelium of blood vessels, and in the syncytiotrophoblast. FGF-2 mRNA was considerably more abundant in the syncytiotrophoblast and villous tissue of placentae from diabetic patients. Messenger RNA for FGFR1 was similarly distributed to that encoding FGF-2. Immunocytochemistry revealed abundant FGF-2 and FGFR1 peptides in villous vascular endothelial cells, and associated with the cell membranes of stromal tissues in placentae from control pregnancies. Little immunoreactive FGF-2 was present in the syncytiotrophoblast at term. In pregnancies complicated by diabetes intense staining for immunoreactive FGF-2 and for FGFR1 additionally existed in syncytiotrophoblast. The results suggest that FGF-2 acting as an autocrine agent contributes to placental angiogenesis, but may be released from the syncytium into the maternal circulation. Expression is elevated in placentae from diabetic pregnancies, and is particularly associated with the syncytiotrophoblast. This suggests a placental source for the elevated circulating maternal FGF-2 previously described in diabetic pregnancy.
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PMID:Fibroblast growth factor-2 and fibroblast growth factor receptor-1 mRNA expression and peptide localization in placentae from normal and diabetic pregnancies. 954 79

Fibroblast growth factor (FGF) signalling has been implicated in patterning, proliferation and cell differentiation in many organs, including the developing pancreas. Here we show that the FGF receptors (FGFRs) 1 and 2, together with the ligands FGF1, FGF2, FGF4, FGF5, FGF7 and FGF10, are expressed in adult mouse beta-cells, indicating that FGF signalling may have a role in differentiated beta-cells. When we perturbed signalling by expressing dominant-negative forms of the receptors, FGFR1c and FGFR2b, in the pancreas, we found that that mice with attenuated FGFR1c signalling, but not those with reduced FGFR2b signalling, develop diabetes with age and exhibit a decreased number of beta-cells, impaired expression of glucose transporter 2 and increased proinsulin content in beta-cells owing to impaired expression of prohormone convertases 1/3 and 2. These defects are all characteristic of patients with type-2 diabetes. Mutations in the homeobox gene Ipf1/Pdx1 are linked to diabetes in both mouse and human. We also show that Ipf1/Pdx1 is required for the expression of FGFR1 signalling components in beta-cells, indicating that Ipf1/Pdx1 acts upstream of FGFR1 signalling in beta-cells to maintain proper glucose sensing, insulin processing and glucose homeostasis.
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PMID:Attenuation of FGF signalling in mouse beta-cells leads to diabetes. 1113 Jul 26

Fibroblast growth factor 2 (FGF-2) is normally synthesized at low levels but is elevated in various pathophysiological conditions including diabetes-associated vascular diseases. FGF-2 expression is regulated translationally through an internal ribosome entry site (IRES) located in its mRNA, which allows a nonclassical cap-independent translation. We addressed the pathophysiological regulation of the IRES in vivo by using a streptozotocin-induced hyperglycemic model known to suppress markedly overall translation. Evaluation of FGF-2 IRES-dependent translation was performed with transgenic mice expressing dual luciferase bicistronic mRNA containing the FGF-2 IRES. FGF-2 IRES-dependent reporter activity increased 240% of control in the diabetic aorta although the reporter mRNA levels significantly decreased. Expression of endogenous FGF-2 protein in the aorta closely correlated with the IRES activity but not with FGF-2 mRNA levels. Moreover, the biosynthesis of endogenous FGF-2 protein was stimulated in an IRES-dependent manner by high glucose that significantly suppressed global protein synthesis in aortic smooth muscle cells from the transgenic mice. These results suggest that IRES-dependent translational regulation could play a pathological role in FGF-2 expression in vivo, especially in the cardiovascular consequences of diabetes.
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PMID:Hyperglycemia upregulates translation of the fibroblast growth factor 2 mRNA in mouse aorta via internal ribosome entry site. 1528 45

Angiogenesis impairment in hyperglycemic patients represents a leading cause of severe vascular complications of both type-1 and -2 diabetes mellitus (DM). Angiogenesis dysfunction in DM is related to glycemic control; however, molecular mechanisms involved are still unclear. Fibroblast growth factor-2 (FGF-2) is a potent angiogenic factor and, according to previous evidence, may represent a key target of molecular modifications triggered by high-sugar exposure. Therefore, the purpose of this study was to investigate whether short incubation with hyperglycemic levels of glucose affected FGF-2 and whether glucose-modified FGF-2 was detectable in vivo. Biochemical analyses carried out with SDS-PAGE, fluorescence emission, mass-spectrometry, immunoblot, and competitive ELISA experiments demonstrated that human FGF-2 undergoes a rapid and specific glycation upon 12.5-50 mm glucose exposure. In addition, FGF-2 exposed for 30 min to 12.5 mm glucose lost mitogenic and chemotactic activity in a time- and dose-dependent manner. Under similar conditions, binding affinity to FGF receptor 1 was dramatically reduced by 20-fold, as well as FGF receptor 1 and ERK-1/2 phosphorylation, and FGF-2 lost about 45% of angiogenic activity in two different in vivo angiogenic (Matrigel and chorioallantoic-membrane) assays. Such glucose-induced modification was specific, because other angiogenic growth factors, namely platelet-derived growth factor BB and placental-derived growth factor were not significantly or markedly less modified. Finally, for the first time, glycated-FGF-2 was detected in vivo, in tissues from hyperglycemic nonobese diabetic mice, in significantly higher amounts than in normoglycemic mice. In conclusion, hyperglycemic levels of glucose may strongly affect FGF-2 structure and impair its angiogenic features, and endogenous glycated-FGF-2 is present in diabetic mice, indicating a novel pathogenetic mechanism underlying angiogenesis defects in DM.
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PMID:Glycated fibroblast growth factor-2 is quickly produced in vitro upon low-millimolar glucose treatment and detected in vivo in diabetic mice. 1684 May 37

Fibroblast growth factor-21 (FGF-21) is a recently discovered metabolic regulator. Here, we investigated the effects of FGF-21 in the pancreatic beta-cell. In rat islets and INS-1E cells, FGF-21 activated extracellular signal-regulated kinase 1/2 and Akt signaling pathways. In islets isolated from healthy rats, FGF-21 increased insulin mRNA and protein levels but did not potentiate glucose-induced insulin secretion. 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 increased islet insulin content and glucose-induced insulin secretion. Short-term treatment of normal or db/db mice with FGF-21 lowered plasma levels of insulin and improved glucose clearance compared with vehicle after oral glucose tolerance testing. Constant infusion of FGF-21 for 8 weeks in db/db mice nearly normalized fed blood glucose levels and increased plasma insulin levels. Immunohistochemistry of pancreata from db/db mice showed a substantial increase in the intensity of insulin staining in islets from FGF-21-treated animals as well as a higher number of islets per pancreas section and of insulin-positive cells per islet compared with control. No effect of FGF-21 was observed on islet cell proliferation. In conclusion, preservation of beta-cell function and survival by FGF-21 may contribute to the beneficial effects of this protein on glucose homeostasis observed in diabetic animals.
Diabetes 2006 Sep
PMID:Fibroblast growth factor-21 improves pancreatic beta-cell function and survival by activation of extracellular signal-regulated kinase 1/2 and Akt signaling pathways. 1693 95

Fibroblast growth factor (FGF)-21 is a novel regulator of insulin-independent glucose transport in 3T3-L1 adipocytes and has glucose and triglyceride lowering effects in rodent models of diabetes. The precise mechanisms whereby FGF-21 regulates metabolism remain to be determined. Here we describe the early signaling events triggered by FGF-21 treatment of 3T3-L1 adipocytes and reveal a functional interplay between FGF-21 and peroxisome proliferator-activated receptor gamma (PPARgamma) pathways that leads to a marked stimulation of glucose transport. While the early actions of FGF-21 on 3T3-L1 adipocytes involve rapid accumulation of intracellular calcium and phosphorylation of Akt, GSK-3, p70(S6K), SHP-2, MEK1/2, and Stat3, continuous treatment for 72 h induces an increase in PPARgamma protein expression. Moreover, chronic activation of the PPARgamma pathway in 3T3-L1 adipocytes with the PPARgamma agonist and anti-diabetic agent, rosiglitazone (BRL 49653), enhances FGF-21 action to induce tyrosine phosphorylation of FGF receptor-2. Strikingly, treatment of cells with FGF-21 and rosiglitazone in combination leads to a pronounced increase in expression of the GLUT1 glucose transporter and a marked synergy in stimulation of glucose transport. Together these results reveal a novel synergy between two regulators of glucose homeostasis, FGF-21 and PPARgamma, and further define FGF-21 mechanism of action.
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PMID:Molecular determinants of FGF-21 activity-synergy and cross-talk with PPARgamma signaling. 1706 60

Fibroblast growth factor (FGF)-21 has been recently characterized as a potent metabolic regulator. Systemic administration of FGF-21 reduced plasma glucose and triglycerides to near normal levels in genetically compromised diabetic rodents. Importantly, these effects were durable and did not come at the expense of weight gain, hypoglycemia, or mitogenicity. To explore the therapeutic properties of FGF-21 in a nongenetically modified primate species, and thus demonstrate the potential for efficacy in humans, we evaluated its bioactivity in diabetic nonhuman primates. When administered daily for 6 wk to diabetic rhesus monkeys, FGF-21 caused a dramatic decline in fasting plasma glucose, fructosamine, triglycerides, insulin, and glucagon. Of significant importance in regard to safety, hypoglycemia was not observed at any point during the study. 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 the development of FGF-21 for the treatment of diabetes and other metabolic diseases.
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PMID:The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21. 1706 32

Fibroblast growth factor (FGF)-21 is a unique member of the FGF family, with several molecular characteristics that differ from classical FGFs and exhibiting a pharmacologic profile that includes a variety of metabolic responses in vitro and when tested in vivo in animal models. FGF21 represents a novel and attractive therapeutic agent for type 2 diabetes mellitus, because of its ability to modulate disease phenotype in preclinical settings without inducing any apparent adverse effects. Although FGF21 was discovered relatively recently, the understanding of its biology and therapeutic utility is rapidly evolving. A number of key metabolically linked molecules and pathways have been suggested to be involved in the mechanism of action of FGF21, depending on the specific target tissue/organ. Further research into these mechanisms should lead to important advances in the understanding of FGF21 biology and pave the way for novel therapeutic strategies. The specifics of FGF21 activities both in cell culture and in vivo, its potential as a target for diabetes, and insights into the molecular mechanisms of FGF21 metabolic actions will be discussed in this review.
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PMID:Fibroblast growth factor-21 as a therapeutic agent for metabolic diseases. 1821 89


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