Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HNF4alpha (hepatocyte nuclear factor 4alpha) belongs to a complex transcription factor network that is crucial for the function of hepatocytes and pancreatic beta-cells. In these cells, it activates the expression of a very large number of genes, including genes involved in the transport and metabolism of glucose and lipids. Mutations in the HNF4alpha gene correlate with MODY1 (maturity-onset diabetes of the young 1), a form of type II diabetes characterized by an impaired glucose-induced insulin secretion. The MODY1 G115S (Gly115-->Ser) HNF4alpha mutation is located in the DNA-binding domain of this nuclear receptor. We show here that the G115S mutation failed to affect HNF4alpha-mediated transcription on apolipoprotein promoters in HepG2 cells. Conversely, in pancreatic beta-cell lines, this mutation resulted in strong impairments of HNF4alpha transcriptional activity on the promoters of LPK (liver pyruvate kinase) and HNF1alpha, with this transcription factor playing a key role in endocrine pancreas. We show as well that the G115S mutation creates a PKA (protein kinase A) phosphorylation site, and that PKA-mediated phosphorylation results in a decreased transcriptional activity of the mutant. Moreover, the G115E (Gly115-->Glu) mutation mimicking phosphorylation reduced HNF4alpha DNA-binding and transcriptional activities. Our results may account for the 100% penetrance of diabetes in human carriers of this mutation. In addition, they suggest that introduction of a phosphorylation site in the DNA-binding domain may represent a new mechanism by which a MODY1 mutation leads to loss of HNF4alpha function.
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PMID:The G115S mutation associated with maturity-onset diabetes of the young impairs hepatocyte nuclear factor 4alpha activities and introduces a PKA phosphorylation site in its DNA-binding domain. 1523 28

Little is known about the pathogenesis of adrenocortical tumors. The cAMP-dependent pathway is physiologically activated by ACTH in adrenocortical cells and different components of this cascade may be altered in some functioning adrenocortical tumors. Recently, mutations of the gene encoding the PKA type 1 A regulatory subunit (R1 A), PRKAR1A, associated with loss of heterozygosity (LOH) at PRKAR1A locus, have been demonstrated in primary pigmented nodular adrenocortical disease (PPNAD), either isolated or associated with Carney complex. Moreover, activating mutations of the Gs(alpha) gene (the gsp oncogene) have also been found in a small number of adrenocortical cortisol-secreting adenomas. Aim of this study was to investigate the presence of such genetic alterations on a series of 10 ACTH-independent Cushing syndrome due to non-PPNAD adrenocortical adenomas. The coding sequence of PRKAR1A, evaluated by PCR and direct sequencing analysis, revealed the absence of mutations while heterozygosity for at least 1 polymorphism excluded LOH in most tumors. In one single adenoma gsp mutation was detected. In conclusion, we provide additional evidence that the only mutational changes able to activate the cAMP pathway so far identified, i.e. PRKAR1A mutations and gsp oncogene, are a rare event in adrenocortical tumors.
Exp Clin Endocrinol Diabetes 2005 May
PMID:Mutational analysis of PRKAR1A and Gs(alpha) in sporadic adrenocortical tumors. 1592 8

The epsilon isoform of protein kinase C (PKCepsilon) has emerged as a critical second messenger in sensitization toward mechanical stimulation in models of neuropathic (diabetes, alcoholism, and cancer therapy) as well as acute and chronic inflammatory pain. Signaling pathways leading to activation of PKCepsilon remain unknown. Recent results indicate signaling from cAMP to PKC. A mechanism connecting cAMP and PKC, two ubiquitous, commonly considered separate pathways, remains elusive. We found that, in cultured DRG neurons, signaling from cAMP to PKCepsilon is not mediated by PKA but by the recently identified cAMP-activated guanine exchange factor Epac. Epac, in turn, was upstream of phospholipase C (PLC) and PLD, both of which were necessary for translocation and activation of PKCepsilon. This signaling pathway was specific to isolectin B4-positive [IB4(+)] nociceptors. Also, in a behavioral model, cAMP produced mechanical hyperalgesia (tenderness) through Epac, PLC/PLD, and PKCepsilon. By delineating this signaling pathway, we provide a mechanism for cAMP-to-PKC signaling, give proof of principle that the mitogen-activated protein kinase pathway-activating protein Epac also stimulates PKC, describe the first physiological function unique for the IB4(+) subpopulation of sensory neurons, and find proof of principle that G-protein-coupled receptors can activate PKC not only through the G-proteins alpha(q) and betagamma but also through alpha(s).
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PMID:Epac mediates a cAMP-to-PKC signaling in inflammatory pain: an isolectin B4(+) neuron-specific mechanism. 1614 18

3,5,3'-triiodothyronine (T3) is essential for the growth and the regulation of metabolic functions, moreover, the growth-stimulatory effect of T3 has largely been demonstrated and the pathways via which T3 promotes cell growth have been recently investigated. Type 1 diabetes (T1D) is due to the destruction of beta-cells, which occurs even through apoptosis. Aim of our study was to analyze whether T3 could have an antiapoptotic effect on cultured beta-cells undergoing apoptosis. We have demonstrated that T3 promotes cell proliferation in islet beta-cell lines (rRINm5F and hCM) provoking an increment in cell number (up to 55%: rRINm5F and 45%: hCM), cell viability, and BrdU incorporation, and regulating the cell cycle-related molecules (cyc A, D1, E, and p27(kip1)). T3 inhibited the apoptotic process induced by streptozocin, S-Nitroso-N-Acetylpenicylamine (SNAP), and H2O2 via regulation of the pro- and anti-apoptotic factors Bcl-2, Bcl-XL, Bad, Bax, and Caspase 3. The T3 protective effect was PI-3 K-, but not MAPK- or PKA-mediated, involving pAktThr308. Thus, T3 could be considered a survival factor protecting islet beta-cells from apoptosis.
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PMID:3,5,3'-triiodothyronine (T3) is a survival factor for pancreatic beta-cells undergoing apoptosis. 1602 36

We examined the effect of PGE1 on the expression of plasminogen activator inhibitor-1 (PAI-1) mRNA induced by tumor necrosis factor-alpha (TNF-alpha) in human mesangial cells, because PAI-1 is one of major factors for the progression of glomerulosclerosis. The expression of PAI-1 mRNA was increased after stimulation with TNF-alpha, and it was diminished by pre-incubation with PGE1. Next, we examined the effect of PGE1 on the phosphorylation of mitogen activated protein kinase (MAPK) family and Akt. TNF-alpha activated the phosphorylation of p44/42 MAPK, p38 MAPK, SAPK/JNK and Akt in mesangial cells. PGE1 inhibited the TNF-alpha induced phosphorylation of SAPK/JNK and Akt, but not p44/42 MAPK and p38 MAPK. The TNF-alpha induced expression of PAI-1 mRNA was not affected by PD98059, an inhibitor of MEK, SB203580, an inhibitor of p38 MAPK, nor LY294002, an inhibitor of PI3 K. However, DMAP, an inhibitor of SAPK/JNK, inhibited the expression of PAI-1 mRNA, suggesting that the TNF-alpha induced expression of PAI-1 mRNA is regulated by the SAPK/JNK dependent pathway in human mesangial cells. By the incubation with H8, an inhibitor of PKA, the inhibitory effect of PGE1 on the expression of PAI-1 mRNA was abolished, suggesting that PGE1 inhibited the PAI-1 mRNA expression via the PKA pathway. Our results suggest that the inhibition of PAI-1 synthesis by PGE1 in human mesangial cells may have therapeutic implications for glomerulosclerosis such as occurs in diabetic nephropathy.
Exp Clin Endocrinol Diabetes 2005 Jul
PMID:PGE1 inhibits the expression of PAI-1 mRNA induced by TNF-alpha in human mesangial cells. 1602 96

Among its pleiotropic actions, ghrelin modulates insulin secretion and glucose metabolism. Herein we investigated the role of ghrelin in pancreatic beta-cell proliferation and apoptosis induced by serum starvation or interferon (IFN)-gamma/TNF-alpha, whose synergism is a major cause for beta-cell destruction in type I diabetes. HIT-T15 beta-cells expressed ghrelin but not ghrelin receptor (GRLN-R), which binds acylated ghrelin (AG) only. However, both unacylated ghrelin (UAG) and AG recognized common high-affinity binding sites on these cells. Either AG or UAG stimulated cell proliferation through Galpha(s) protein and prevented serum starvation- and IFN-gamma/TNF-alpha-induced apoptosis. Antighrelin antibody enhanced apoptosis in either the presence or absence of serum but not cytokines. AG and UAG even up-regulated intracellular cAMP. Blockade of adenylyl cyclase/cAMP/protein kinase A signaling prevented the ghrelin cytoprotective effect. AG and UAG also activated phosphatidyl inositol 3-kinase (PI3K)/Akt and ERK1/2, whereas PI3K and MAPK inhibitors counteracted the ghrelin antiapoptotic effect. Furthermore, AG and UAG stimulated insulin secretion from HIT-T15 cells. In INS-1E beta-cells, which express GRLN-R, AG and UAG caused proliferation and protection against apoptosis through identical signaling pathways. Noteworthy, both peptides inhibited cytokine-induced NO increase in either HIT-T15 or INS-1E cells. Finally, they induced cell survival and protection against apoptosis in human islets of Langerhans. These expressed GRLN-R but showed also UAG and AG binding sites. Our data demonstrate that AG and UAG promote survival of both beta-cells and human islets. These effects are independent of GRLN-R, are likely mediated by AG/UAG binding sites, and involve cAMP/PKA, ERK1/2, and PI3K/Akt.
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PMID:Acylated and unacylated ghrelin promote proliferation and inhibit apoptosis of pancreatic beta-cells and human islets: involvement of 3',5'-cyclic adenosine monophosphate/protein kinase A, extracellular signal-regulated kinase 1/2, and phosphatidyl inositol 3-Kinase/Akt signaling. 1706 44

Perturbation of endoplasmic reticulum (ER) homeostasis impairs insulin biosynthesis, beta cell survival, and glucose homeostasis. We show that a murine model of diabetes is associated with the development of ER stress in beta cells and that treatment with the GLP-1R agonist exendin-4 significantly reduced biochemical markers of islet ER stress in vivo. Exendin-4 attenuated translational downregulation of insulin and improved cell survival in purified rat beta cells and in INS-1 cells following induction of ER stress in vitro. GLP-1R agonists significantly potentiated the induction of ATF-4 by ER stress and accelerated recovery from ER stress-mediated translational repression in INS-1 beta cells in a PKA-dependent manner. The effects of exendin-4 on the induction of ATF-4 were mediated via enhancement of ER stress-stimulated ATF-4 translation. Moreover, exendin-4 reduced ER stress-associated beta cell death in a PKA-dependent manner. These findings demonstrate that GLP-1R signaling directly modulates the ER stress response leading to promotion of beta cell adaptation and survival.
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PMID:GLP-1 receptor activation improves beta cell function and survival following induction of endoplasmic reticulum stress. 1708 5

It has been previously shown that diabetes-associated central nervous system abnormalities are characterized by progressive alterations of neurotransmission. In particular, recent studies from our group have demonstrated that more early diabetes is accompanied by the increased spontaneous serotonin release from isolated synaptic endings; however the mechanism is still not clear. The current study was undertaken to estimate the relative importance of membrane potential and extracellular Ca2+ in the serotonin secretion process in diabetes. With the premise that increased phosphorylation of target proteins may be responsible for the increase in transmitter release we tested whether cAMP/PKA-mediated phosphorylations as well as mono-ADP-ribosylation of effector proteins were implicated in diabetes-associated brain failures. In addition, the effects of nicotinamide, a multiple-action compound, were examined. It was shown that diabetes caused a significant increase in spontaneous release of [2-(14)C]serotonin that was accompanied by synaptic membranes depolarization. Omission of Ca2+ from the incubation medium largely inhibited serotonin release only in untreated diabetes. Exposure of diabetic synaptosomes to cAMP-dependent protein kinase inhibitor H89, similar to Ca2+ -free medium, downregulated serotonin release. The level of constitutively mono-ADP-ribosylated proteins of diabetic synaptosomes was elevated vs control. Protein mono-ADP-ribosylation induced by cholera toxin (CTX), activator of Gs-protein-coupled adenylyl cyclase, resulted in excessive 1.2-fold enhancement over basal level but to the less extent in diabetes as compared with that of control. Nevertheless, CTX as well as forskolin exerted more strong stimulating effect on serotonin release from diabetic synaptosomes as compared to control. H89 counteracted CTX-related action on this variable strongly suggesting that impaired serotonin release is, at least, dependent on Gs-protein-mediated phosphorylation. Nicotinamide treatment virtually normalized both protein mono-ADP-ribosylation and serotonin release as well as synaptosomal response to all stimuli used. The data suggest that alterations in protein mono-ADP-ribosylation may be involved as a possible mechanism responsible for the impaired neurotransmission in diabetes and nicotinamide may efficiently protect against ADP-ribosylationmediated abnormalities in brain function.
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PMID:[Mechanisms of diabetes-induced impairements of serotonin release from rat brain synaptosomes: effect of nicotinamide]. 1723 30

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily of transcription factors that respond to specific ligands by altering gene expression in a cell-, developmental- and sex-specific manner. Three subtypes of this receptor have been discovered (PPARalpha, beta and gamma), each apparently evolving to fulfill different biological niches. PPARs control a variety of target genes involved in lipid homeostasis, diabetes and cancer. Similar to other nuclear receptors, the PPARs are phosphoproteins and their transcriptional activity is affected by cross-talk with kinases and phosphatases. Phosphorylation by the mitogen-activated protein kinases (ERK- and p38-MAPK), Protein Kinase A and C (PKA, PKC), AMP Kinase (AMPK) and glycogen synthase kinase-3 (GSK3) affect their activity in a ligand-dependent or -independent manner. The effects of phosphorylation depend on the cellular context, receptor subtype and residue metabolized which can be manifested at several steps in the PPAR activation sequence including ligand affinity, DNA binding, coactivator recruitment and proteasomal degradation. The review will summarize the known PPAR kinases that directly act on these receptors, the sites affected and the result of this modification on receptor activity.
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PMID:Modulation of PPAR activity via phosphorylation. 1756 Aug 26

Tumor necrosis factor-alpha (TNF-alpha) is a cytokine that may contribute to the pathogenesis of septic shock, rheumatoid arthritis, cancer, and diabetes. Prostaglandins endogenously produced by macrophages act in an autocrine fashion to limit TNF-alpha production. We investigated the timing and signaling pathway of prostaglandin-mediated inhibition of TNF-alpha production in Raw 264.7 and J774 macrophages. TNF-alpha mRNA levels were rapidly modulated by PGE(2) or carbaprostacylin. PGE(2) or carbaprostacyclin prevented and rapidly terminated on-going TNF-alpha gene transcription within 15 min of prostaglandin treatment. Selective activation of PKA type I, but not PKA type II or Epac, with chemical analogs of cAMP was sufficient to inhibit LPS-induced TNF-alpha mRNA levels. The mechanisms by which prostaglandins limit TNF-alpha mRNA levels may underlie endogenous regulatory mechanisms that limit inflammation, and may have important implications for understanding chronic inflammatory disease pathogenesis.
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PMID:Prostaglandin E2 inhibits tumor necrosis factor-alpha RNA through PKA type I. 1806 Aug 53


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