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)

Tumor necrosis factor (TNF)-alpha causes insulin resistance on glucose uptake in fetal brown adipocytes. We explored the hypothesis that some effects of TNF-alpha could be mediated by the generation of ceramide, given that TNF-alpha treatment induced the production of ceramide in these primary cells. A short-chain ceramide analog, C2-ceramide, completely precluded insulin-stimulated glucose uptake and insulin-induced GLUT4 translocation to plasma membrane, as determined by Western blot or immunofluorescent localization of GLUT4. These effects were not produced in the presence of a biologically inactive ceramide analog, C2-dihydroceramide. Analysis of the phosphatidylinositol (PI) 3-kinase signaling pathway indicated that C2-ceramide precluded insulin stimulation of Akt kinase activity, but not of PI-3 kinase or protein kinase C-zeta activity. C2-ceramide completely abolished insulin-stimulated Akt/protein kinase B phosphorylation on regulatory residues Thr 308 and Ser 473, as did TNF-alpha, and inhibited insulin-induced mobility shift in Akt1 and Akt2 separated in PAGE. Moreover, C2-ceramide seemed to activate a protein phosphatase (PP) involved in dephosphorylating Akt because 1) PP2A activity was increased in C2-ceramide- and TNF-alpha-treated cells, 2) treatment with okadaic acid concomitantly with C2-ceramide completely restored Akt phosphorylation by insulin, and 3) transient transfection of a constitutively active form of Akt did not restore Akt activity. Our results indicate that ceramide produced by TNF-alpha induces insulin resistance in brown adipocytes by maintaining Akt in an inactive dephosphorylated state.
Diabetes 2001 Nov
PMID:Ceramide mediates insulin resistance by tumor necrosis factor-alpha in brown adipocytes by maintaining Akt in an inactive dephosphorylated state. 1167 35

1. As long-term survival improves after liver transplantation, cardiovascular complications are emerging as a major cause of late morbidity and mortality. It seems reasonable to correct the potentially reversible cardiovascular risk factors of diabetes, hyperlipidemia, and obesity, in addition to hypertension. 2. The results of liver transplantation in diabetics are acceptable in terms of morbidity, mortality, and prevalence of posttransplant diabetes, but the poor outcomes described in some series suggest that more extensive testing for macro- and microvascular disease may become necessary. 3. The management of diabetes in liver transplant recipients is not substantially different from its management in non-transplant patients, except that steroid reduction or withdrawal and minimizing doses of calcineurin inhibitors are beneficial. 4. Hyperlipidemia occurs in all solid-organ transplantation, with prevalence rates the lowest for liver transplant recipients. Following liver transplantation, between 15% and 40% of recipients on average have increased plasma cholesterol levels and about 40% have hypertriglyceridemia. Dietary changes, weight reduction, exercise and statins are the mainstays of therapy. 5. Retrospective studies suggest that long-term survival of obese recipients after liver transplantation does not differ from nonobese recipients. Posttransplant weight gain occurs in most recipients, and approximately two thirds become overweight. The management of posttransplant obesity is similar to that in non-transplant settings.
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PMID:Long-term management of the liver transplant patient: diabetes, hyperlipidemia, and obesity. 1168 72

Glycogen-targeting subunits of protein phosphatase-1 facilitate interaction of the phosphatase with enzymes of glycogen metabolism. Expression of one family member, PTG, in the liver of normal rats improves glucose tolerance without affecting other plasma variables but leaves animals unable to reduce hepatic glycogen stores in response to fasting. In the current study, we have tested whether expression of other targeting subunit isoforms, such as the liver isoform G(L), the muscle isoform G(M)/R(Gl), or a truncated version of G(M)/R(Gl) termed G(M)DeltaC in liver ameliorates glucose intolerance in rats fed on a high fat diet (HF). HF animals overexpressing G(M)DeltaC, but not G(L) or G(M)/R(Gl), exhibited a decline in blood glucose of 35-44 mg/dl relative to control HF animals during an oral glucose tolerance test (OGTT) such that levels were indistinguishable from those of normal rats fed on standard chow at all but one time point. Hepatic glycogen levels were 2.1-2.4-fold greater in G(L)- and G(M)DeltaC-overexpressing HF rats compared with control HF animals following OGTT. In a second set of studies on fed and 20-h fasted HF animals, G(M)DeltaC-overexpressing rats lowered their liver glycogen levels by 57% (from 402 +/- 54 to 173 +/- 27 microg of glycogen/mg of protein) in the fasted versus fed states compared with only 44% in G(L)-overexpressing animals (from 740 +/- 35 to 413 +/- 141 microg of glycogen/mg of protein). Since the OGTT studies were performed on 20-h fasted rats, this meant that G(M)DeltaC-overexpressing rats synthesized much more glycogen than G(L)-overexpressing HF rats during the OGTT (419 versus 117 microg of glycogen/mg of protein, respectively), helping to explain why G(M)DeltaC preferentially enhanced glucose clearance. We conclude that G(M)DeltaC has a unique combination of glycogenic potency and responsiveness to glycogenolytic signals that allows it to be used to lower blood glucose levels in diabetes.
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PMID:Reversal of diet-induced glucose intolerance by hepatic expression of a variant glycogen-targeting subunit of protein phosphatase-1. 1170 47

Recent studies have shown that vanadium salts are able to reduce blood glucose in diabetics and overcome, to some degree, insulin resistance. This paradigm has been followed to monitor the effects of diabetes and vanadyl treatment on brain calcineurin (CN), an important protein phosphatase. Male rats were rendered diabetic by a single injection of streptozotocin (STZ), resulting in an elevation of blood glucose from 108 +/- 13 to >400 mg/dl. Diabetic animals were given vanadyl sulfate trihydrate (0.5 mg/dl.) in their drinking water for 3 weeks, which led to a fall in blood glucose to 156 +/- 53 mg/ml. Brain CN activity (units/mg brain protein) in diabetic rats was 77% that of control animals, whereas vanadyl-treated diabetic animals were characterized by CN activities like that of controls. CN was purified from brains of control animals, STZ-induced diabetic animals, and STZ-induced diabetic animals receiving vanadyl, then spin-labeled with 3-maleimide-proxyl and studied via electron spin resonance spectroscopy. The rotational correlation time of CN from control animals and vanadyl-treated diabetic animals was 6.4 x 10(-11) s(-1), whereas that from STZ-induced-diabetic animals was 8 x 10(-11) s(-1). Thus, STZ-induced diabetes in rats results in an increase in the rotational correlation time of brain CN relative to control animals, yet vanadyl treatment of STZ-induced diabetic animals reduced the rotational correlation time to that of control. These data suggest that diabetes can lead to apparent conformational changes in brain CN; also, CN conformation in diabetic rats was restored by vanadyl treatment.
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PMID:Conformation changes in brain calcineurin in diabetic rats with or without treatment with vanadyl sulfate. 1175 5

5'-AMP-activated protein kinase (AMPK) functions as a metabolic switch in mammalian cells and can be artificially activated by 5-aminoimidazole-4-carboxamide (AICA)-riboside. AMPK activation during muscle contraction is dependent on muscle glycogen concentrations, but whether glycogen also modifies the activation of AMPK and its possible downstream effectors (glycogen synthase and glucose transport) by AICA-riboside in resting muscle is not known. Thus, we have altered muscle glycogen levels in rats by a combination of swimming exercise and diet and investigated the effects of AICA-riboside in the perfused rat hindlimb muscle. Two groups of rats, one with super-compensated muscle glycogen content (approximately 200-300% of normal; high glycogen [HG]) and one with moderately lowered muscle glycogen content (approximately 80% of normal; low glycogen [LG]), were generated. In both groups, the degree of activation of the alpha2 isoform of AMPK by AICA-riboside depended on muscle type (white gastrocnemius >> red gastrocnemius > soleus). Basal and AICA-riboside-induced alpha2-AMPK activity were markedly lowered in the HG group (approximately 50%) compared with the LG group. Muscle 2-deoxyglucose uptake was also increased and glycogen synthase activity decreased by AICA-riboside. Especially in white gastrocnemius, these effects, as well as the absolute activity levels of AMPK-alpha2, were markedly reduced in the HG group compared with the LG group. The inactivation of glycogen synthase by AICA-riboside was accompanied by decreased gel mobility and was eliminated by protein phosphatase treatment. We conclude that acute AICA-riboside treatment leads to phosphorylation and deactivation of glycogen synthase in skeletal muscle. Although the data do not exclude a role of other kinases/phosphatases, they suggest that glycogen synthase may be a target for AMPK in vivo. Both basal and AICA-riboside-induced AMPK-alpha2 and glycogen synthase activities, as well as glucose transport, are depressed when the glycogen stores are plentiful. Because the glycogen level did not affect adenine nucleotide concentrations, our data suggest that glycogen may directly affect the activation state of AMPK in skeletal muscle.
Diabetes 2002 Feb
PMID:Glycogen-dependent effects of 5-aminoimidazole-4-carboxamide (AICA)-riboside on AMP-activated protein kinase and glycogen synthase activities in rat skeletal muscle. 1181 34

Immunosuppressant nephrotoxicity is among the major contributors to chronic renal allograft failure, which is the primary cause of graft loss. Because of a lack of alternatives to the inherently nephrotoxic calcineurin inhibitors for maintenance immunosuppression, long-term survival rates for renal allografts have not increased in proportion to the rise in short-term graft survival. Clinical studies have shown that mammalian target of rapamycin-based immunosuppression in combination with calcineurin inhibitors, mycophenolate mofetil, or azathioprine is safe and efficacious. These data suggest that a target of rapamycin antagonist (sirolimus/everolimus) should be used initially in combination with calcineurin antagonists in order to prevent early acute rejection. After 3-6 months, a maintenance immunosuppressive regimen can then be individually tailored to each patient on the basis of their clinical and histological status. Those patients at high immunological risk should remain on full-dose triple therapy. All other patients should receive either a calcineurin inhibitor or corticosteroid-sparing regimen, with a maintenance dose of a target of rapamycin inhibitor. This regimen should result in less immunosuppressant nephrotoxicity and a reduction in the serious side effects of steroids, such as diabetes and osteoporosis. Whether the proposed individually designed immunosuppressive regimen, based on protocol biopsies and mammalian target of rapamycin inhibition, will result in prolonged graft and patient survival remains to be determined.
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PMID:The future role of target of rapamycin inhibitors in renal transplantation. 1185 56

Success in solid organ transplantation with minimal complications can now be achieved for most patients, and a remarkable rate of graft and patient survival can also be expected. However, the potential for adverse events and comorbid conditions increases with longer graft survival. Although the immunosuppressive regimen is central to the outcome of the transplant recipient and directly impacts the survival of the graft, chronic use of immunosuppressive agents is associated with metabolic disturbances such as hypertension, hyperlipidemia, loss of bone density, nephrotoxicity, and diabetes, which may contribute to other comorbid conditions. In addition, changes in appearance, gingival hyperplasia, hirsutism, alopecia, and weight gain disrupt quality of life and may lead to noncompliance with the immunosuppressive regimen. New immunosuppressive medications, including mycophenolate mofetil, sirolimus, basiliximab, and daclizumab, have allowed for experimentation with new regimens designed to reduce or allow discontinuation of corticosteroids and calcineurin inhibitors. This review highlights the impact and cost of immunosuppressive side effects and the potential for new immunosuppressive regimens to reduce this substantial clinical burden in transplantation.
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PMID:Reducing adverse effects of immunosuppressive agents in kidney transplant recipients. 1187 Dec 76

Insulin has been previously shown to regulate the expression of the hepatic glycogen-targeting subunit, G(L), of protein phosphatase 1 (PP1) and is believed to control the activity of the PP1-G(L) complex by modulation of the level of phosphorylase a, which allosterically inhibits the activity of PP1-G(L). These mechanisms contribute to the ability of insulin to increase hepatic glycogen synthesis. Human G(L) shows >88% amino acid identity to its rat and mouse homologs, with complete conservation of the phosphorylase a binding site. G(L) is highly expressed in the liver and present at appreciable levels in heart tissue of all three species. Surprisingly, G(L) is highly expressed in human skeletal muscle while only being detected at very low levels in rat, mouse, and rabbit skeletal muscle. The amino acid sequence of G(L) predicted from the cDNA is identical in human liver and skeletal muscle and encoded by a gene on chromosome 8 at p23.1. The species-specific difference in the level of expression of G(L) mRNA and protein in skeletal muscle has important implications for understanding the mechanisms by which insulin regulates glycogen synthesis in human skeletal muscle and for questions regarding whether rodents are appropriate models for this purpose.
Diabetes 2002 Mar
PMID:Human skeletal muscle expresses a glycogen-targeting subunit of PP1 that is identical to the insulin-sensitive glycogen-targeting subunit G(L) of liver. 1187 55

Currently there is intense interest to define the mechanism of action of glucagon-like peptide-1 (GLP-1) in regulating beta-cell function, including insulin gene transcription. In this study, GLP-1 (100 nmol/l), in the presence of glucose (11 mmol/l), induced a similar71-fold increase in insulin gene promoter activity in INS-1 pancreatic beta-cells, an effect that was an order of magnitude larger than with either stimulant alone. The response to GLP-1 was mimicked by forskolin and largely inhibited by the protein kinase A (PKA) inhibitors, H89 and myristoylated PKI(14--22) amide, indicating partial mediation via a cAMP/PKA pathway. Significantly, the actions of both GLP-1 and forskolin were abolished by the selective Ca(2+)/calmodulin-dependent phosphatase 2B (calcineurin) inhibitor, FK506, as well as by the chelation of intracellular Ca(2+) by BAPTA (bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetate). Glucose and GLP-1 also synergistically activated NFAT (nuclear factor of activated T-cells)-mediated transcription from a minimal promoter construct containing tandem NFAT consensus sequences. Furthermore, two-point base pair mutations in any of the three identified NFAT sites within the rat insulin I promoter resulted in a significant reduction in the combined effect of glucose and GLP-1. These data suggest that the synergistic action of glucose and GLP-1 to promote insulin gene transcription is mediated through NFAT via PKA- and calcineurin-dependent pathways in pancreatic beta-cells.
Diabetes 2002 Mar
PMID:NFAT regulates insulin gene promoter activity in response to synergistic pathways induced by glucose and glucagon-like peptide-1. 1187 68

Ongoing improvements in immunosuppression and posttransplantation care have dramatically improved patient and graft outcomes after transplantation. The frequency of graft loss due to acute rejection has declined considerably as a result of the availability of a variety of more potent immunosuppressive agents and probably also because of refined clinical care and follow-up. Complications of long-term administration of corticosteroids (steroids) and calcineurin inhibitors, however, have become increasingly apparent as patients live longer with their transplant, and attention is shifting to long-term issues. Use of both steroids and calcineurin inhibitors is associated with metabolic toxicities such as hypertension, hyperlipidemia, diabetes, bone loss, and cataracts. These contribute to posttransplantation morbidity and may negatively affect patient and allograft survival. A variety of troublesome cosmetic side effects, such as hirsutism, gingival hyperplasia, alopecia, obesity, and cushingoid appearance, also are associated with these drugs. These effects can detract from patient self-esteem and compliance with the immunosuppressive regimen. In the past 2 decades, the introduction of second-generation immunosuppressive drugs, such as tacrolimus, mycophenolate mofetil, sirolimus, and anti-interleukin-2 receptor monoclonal antibodies, has provided some alternatives to classic immunosuppressant choices. Patients experiencing undesirable adverse events now can be converted to another immunosuppressive regimen that ultimately will improve graft and patient survival rates and improve quality of life after transplantation.
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PMID:Strategies to reduce toxicities and improve outcomes in renal transplant recipients. 1189 90


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