Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin resistance, a key factor in the pathogenesis of polycystic ovary syndrome (PCOS), is associated with a reduction in activation of muscle glycogen synthase. A 5-bp insertion-deletion polymorphism in the (AU)AT-rich element (ARE) within the 3'-untranslated region of the gene encoding the muscle-specific glycogen-targeting subunit of protein phosphatase 1 (PPP1R3) has been associated with insulin resistance and type 2 diabetes. The present study was undertaken to examine the relationship of the ARE polymorphism with clinical and hormonal characteristics of women with PCOS. We studied 186 women with PCOS who had undergone a standard 75-g oral glucose tolerance test and measurement of serum androgen and SHBG levels. Among the largest cohort of nondiabetic subjects (Caucasian, n = 112), the presence of the deletion allele (ARE-2) was associated with insulin resistance and hyperandrogenemia. There was no association of the ARE polymorphism with body mass index or blood glucose concentration during the oral glucose tolerance test. Subjects who were homozygous for the insertion allele (ARE-1/1) had a mean insulin area under the curve (99,116 +/- 6,625 pmol/liter.min) that was significantly lower than that in either the heterozygous (ARE-1/2) (132,195 +/- 12,340 pmol/liter.min) or homozygous (ARE-2/2) (164,661 +/- 24,219 pmol/liter.min) deletion groups. In addition, ARE-1/1 subjects had significantly lower serum concentrations of dehydroepiandrosterone sulfate compared with ARE-2/2 subjects (4.2 +/- 0.3 vs. 6.6 +/- 0.7 micromol/liter) and a trend toward lower levels of free testosterone (78.8 +/- 6.5 vs. 114.1 +/- 30.8 pmol/liter). Studies of diabetic and nondiabetic PCOS women of other racial and ethnic backgrounds will be necessary to assess the impact of this and other variants in PPP1R3 upon the phenotype and natural history of women with PCOS.
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PMID:Association of the (AU)AT-rich element polymorphism in PPP1R3 with hormonal and metabolic features of polycystic ovary syndrome. 1518 Oct 86

Post-transplantation diabetes mellitus (PTDM) is defined as sustained hyperglycemia developing in any patient without history of diabetes before transplantation, that meets the current diagnostic criteria by the American Diabetes Association or the World Health Organization. Several risk factors have been identified: age, nonwhite ethnicity, and glucocorticoid therapy for rejection and chronic immunosuppression with cyclosporine and especially tacrolimus. The pathophysiology of this condition resembles that of type 2 diabetes mellitus: pretransplantation end-stage liver/renal and heart disease are insulin-resistant states, and after transplantation, glucocorticoids induce further peripheral insulin insensitivity. The "second hit" appears to be an acquired (yet reversible) insulin secretion defect resulting from the calcineurin inhibitors cyclosporine and tacrolimus. An international panel of experts has recently published the proceeding of a Consensus Conference proposing strategies for the screening, prevention and management of PTDM. Future directions include pre- and post-transplantation glucose load testing for high-risk individuals and pharmacological agents to decrease insulin resistance and to preserve beta-cell function.
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PMID:Post-transplantation diabetes mellitus. 1571 25

The growth and function of organs such as pancreatic islets adapt to meet physiological challenges and maintain metabolic balance, but the mechanisms controlling these facultative responses are unclear. Diabetes in patients treated with calcineurin inhibitors such as cyclosporin A indicates that calcineurin/nuclear factor of activated T-cells (NFAT) signalling might control adaptive islet responses, but the roles of this pathway in beta-cells in vivo are not understood. Here we show that mice with a beta-cell-specific deletion of the calcineurin phosphatase regulatory subunit, calcineurin b1 (Cnb1), develop age-dependent diabetes characterized by decreased beta-cell proliferation and mass, reduced pancreatic insulin content and hypoinsulinaemia. Moreover, beta-cells lacking Cnb1 have a reduced expression of established regulators of beta-cell proliferation. Conditional expression of active NFATc1 in Cnb1-deficient beta-cells rescues these defects and prevents diabetes. In normal adult beta-cells, conditional NFAT activation promotes the expression of cell-cycle regulators and increases beta-cell proliferation and mass, resulting in hyperinsulinaemia. Conditional NFAT activation also induces the expression of genes critical for beta-cell endocrine function, including all six genes mutated in hereditary forms of monogenic type 2 diabetes. Thus, calcineurin/NFAT signalling regulates multiple factors that control growth and hallmark beta-cell functions, revealing unique models for the pathogenesis and therapy of diabetes.
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PMID:Calcineurin/NFAT signalling regulates pancreatic beta-cell growth and function. 1698 14

Post-transplant diabetes mellitus (PTDM) has emerged as a major adverse effect of immunosuppressive drugs (ISD). As recipients of organ transplants survive longer, the complications of diabetes mellitus have assumed greater importance. The predominant factor for causing PTDM by corticosteroids seems to be the aggravation of insulin resistance, however several studies have displayed deleterious effects on insulin secretion and beta-cells. Calcineurin inhibitors induce PTDM by a number of mechanisms, including decreased insulin secretion and a direct toxic effect on the pancreatic beta-cells. Recent in vitro studies stress on the increased apoptosis of beta-cells when exposed to these drugs. Studies involving other immunosuppressive agents (mycophenolate mofetil [MMF], sirolimus) are scarcer and lead to conflicting results, while daclizumab seems to have a neutral effect. Clinical studies have consistently shown a greater potential of tacrolimus to induce PTDM compared with cyclosporine. Reducing PTDM incidence is a feasible goal while using corticosteroid-sparing regimens and/or lower tacrolimus trough levels. In patients developing PTDM, conversion from tacrolimus to cyclosporine could improve or reverse glucose tolerance abnormalities. In the absence of well-designed studies in this specific indication, treatment of PTDM is based on the same principles as type 2 diabetes mellitus. Thiazolidinediones do not display any pharmacological interaction with calcineurin inhibitors, but their safety and efficacy in PTDM need to be confirmed in large-scale randomized trials. Use of sulfonylureas has to be cautious regarding the suspected interaction of some of them with calcineurin inhibitors. If needed, insulin regimens have to be adapted in patients who display the particular glycaemic profile of corticosteroid-induced diabetes. Incretin-based therapies, due to their specific action on beta-cell apoptosis and proliferation, raise promises that have to be confirmed in clinical studies. Until methods for inducing specific graft tolerance become available, immunosuppressive regimens should be tailored to the individual patient on the basis of predictive criteria for the development of PTDM.
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PMID:Immunosuppressive drug-induced diabetes. 1713 Aug 15

Liver allograft recipients are at increased risk of death from cerebrovascular and cardiovascular disease. We propose the following strategy of risk-reduction, based on currently available literature. Lifestyle: standard advice should be given (avoidance of smoking, excess alcohol and obesity, adequate exercise, reduction of excess sodium intake). Hypertension: target blood pressure should be 140/90 mmHg or lower, but for those with diabetes or renal disease, 130/80 mmHg or lower. For patients without proteinuria, antihypertensive therapy should be initiated with a calcium channel blocker and for those with proteinuria, an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker. If monotherapy fails to achieve adequate response, calcium channel blockers and ACE-inhibitors or angiotensin II receptor blockers should be combined. If hypertension remains uncontrolled, an alpha-blocker may be added. Consideration should be given to changing immunosuppression and avoiding use of calcineurin inhibitors. Diabetes: recipients should be regularly screened for diabetes. For patients with new-onset diabetes after transplant, stepwise therapy should be guided by HbA1c concentrations, as with type II diabetes mellitus. Hyperlipidemia: annual screening of lipid profile should be undertaken, with treatment thresholds and targets based on those advocated for the high risk general population. Dietary intervention is appropriate for all patients. A statin should be considered as the first line treatment to achieve specified targets. In patients receiving a calcineurin inhibitor, Pravastatin should be commenced at a dose of 10 mg/day. In patients receiving other forms of immunosuppression, pravastatin may be commenced at a dose of 20 mg/day. Liver tests should be monitored and patients warned to report myalgia. If monotherapy is inadequate, ezetimibe or a fibrate may be added. Consideration may be given to change in immunosuppression if combination lipid-lowering therapy proves inadequate.
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PMID:Reducing the risks of cardiovascular disease in liver allograft recipients. 1749 26

Disrupting the interaction between glycogen phosphorylase and the glycogen targeting subunit (G(L)) of protein phosphatase 1 is emerging as a novel target for the treatment of type 2 diabetes. To elucidate the molecular basis of binding, we have determined the crystal structure of liver phosphorylase bound to a G(L)-derived peptide. The structure reveals the C terminus of G(L) binding in a hydrophobically collapsed conformation to the allosteric regulator-binding site at the phosphorylase dimer interface. G(L) mimics interactions that are otherwise employed by the activator AMP. Functional studies show that G(L) binds tighter than AMP and confirm that the C-terminal Tyr-Tyr motif is the major determinant for G(L) binding potency. Our study validates the G(L)-phosphorylase interface as a novel target for small molecule interaction.
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PMID:Molecular recognition of the protein phosphatase 1 glycogen targeting subunit by glycogen phosphorylase. 1819 82

Skeletal muscle fibers differ considerably in their metabolic and physiological properties. Skeletal muscle displays a high degree of metabolic flexibility, which allows the myofibers to adapt to various physiological demands by shifting energy substrate utilization. Transcriptional events play a pivotal role in the metabolic adaptations of skeletal muscle. The expression of genes essential for skeletal muscle glucose and lipid metabolism is tightly coordinated in support of a shift in substrate utilization. AMP-activated protein kinase (AMPK) and calcineurin (a calcium-regulated serine/threonine protein phosphatase) regulate skeletal muscle metabolic gene expression programs in response to changes in the energy status and levels of neuronal input, respectively. AMPK and calcineurin activate transcriptional regulators such as peroxisome proliferator-activated receptor-gamma coactivator-1alpha and myocyte enhancer factor as well as increase skeletal muscle oxidative capacity and mitochondrial gene expression. Activation of either the AMPK or calcineurin pathway can also enhance the glycogen storage capacity and insulin sensitivity in skeletal muscle. Characterization of pathways governing skeletal muscle metabolism offers insight into physiological and pharmacological strategies to prevent or ameliorate peripheral insulin resistance associated with metabolic disorders such as type 2 diabetes.
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PMID:Influence of AMP-activated protein kinase and calcineurin on metabolic networks in skeletal muscle. 1854 43

New-onset diabetes mellitus is a common complication of solid organ transplantation and is likely to become even more common with the current epidemic of obesity in some countries. It has become clear that both new-onset diabetes and prediabetic states (impaired fasting glucose and impaired glucose tolerance) negatively influence graft and patient survival after transplantation. This observation forms the basis for recommending meticulous screening for glucose intolerance before and after transplantation. Although a number of clinical factors including age, weight, ethnicity, family history, and infection with hepatitis C are closely associated with the new-onset diabetes mellitus, immunosuppression with corticosteroids, calcineurin inhibitors and possibly sirolimus plays a dominant role in its pathogenesis. Management of new-onset diabetes after transplantation generally conforms to the guidelines for treatment of type 2 diabetes mellitus in the general population. However, further studies are needed to determine the optimal immunosuppressive regimens for patients with this disorder.
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PMID:New-onset diabetes mellitus after solid organ transplantation. 1904 Apr 89

Chronic exposure to elevated levels of fatty acids (FAs) in conjunction with chronic hyperglycemia has been reported to contribute to the progressive deterioration of beta-cell function in patients with type 2 diabetes mellitus. The long-chain saturated free fatty acid (FFA) palmitate, unlike the unsaturated FFA oleate, is known to have an inhibitory effect on proinsulin gene expression through ceramide synthesis. This study was aimed at investigating whether this effect was exacerbated by the inhibition of ceramide degradation in pancreatic beta-cells and the molecular mechanism of intracellular ceramide-induced inhibition of proinsulin gene transcription in response to exposure to palmitate. We exposed insulin-secreting (INS-1) cells treated with low levels of palmitate to the ceramidase inhibitor n-oleoylethanolamine (NOE); this led to the generation of high levels of intracellular ceramide. We observed that the effects of ceramide accumulation in INS-1 cells were similar to the effects of the inhibition of this protein on proinsulin mRNA levels that are caused by the negative regulation of insulin promoter activity. In addition, we observed that ceramide accumulation induced by NOE leads to a significant decrease in the levels of activated extracellular signal-regulated kinase (ERK); the inactivation of the ERK cascade in response to palmitate stimuli is induced by protein phosphatase 2A (PP2A) activity. Based on these findings, we suggest that the aberrant accumulation of ceramide was caused by the inhibition of ceramide metabolism, which in turn leads to the inhibition of proinsulin gene expression; the inhibition of ERK cascades by PP2A serves as an important factor in the inhibitory effects of ceramide.
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PMID:Blockage of ceramide metabolism exacerbates palmitate inhibition of pro-insulin gene expression in pancreatic beta-cells. 2006 16

The calcineurin inhibitors-cyclosporine and tacrolimus-are the mainstay of immunosuppressive therapy in solid organ transplantation. These drugs produce severe adverse drug effects (ADEs) such as nephrotoxicity, posttransplantation diabetes mellitus, and hypertension. Accumulated evidence suggests that the development of type 2 diabetes, hypertension, and renal failure may be associated with specific DNA genotypes. In this review, the genes involved with the development of these disease processes are compared with those implicated in calcineurin inhibitor-induced ADEs. The renin-angiotensin system genes, cytokine-encoding genes, and plasminogen activator inhibitor type 1 genes have been implicated in calcineurin inhibitor-induced nephrotoxicity, as well as in development of renal failure. A number of genes are implicated in contributing to diabetes, and these include the vitamin D receptor gene, VDR; hepatocyte nuclear factor genes, HNF; transcription factor 7-like 2 gene, TCF7L2; angiotensin-converting enzyme gene, ACE; cytokines; peroxisome proliferator-activated receptor gamma gene, PPARG; and others. Studies have suggested that the VDR, PPARG, HNF1A, and adenosine 5'-triphosphate-binding cassette ABCC8 (which encodes the sulfonylurea receptor) genes are associated with calcineurin inhibitor-induced diabetes. The genes encoding for the angiotensin-converting enzyme, endothelial constitutive nitric oxide synthase, and cytochrome P450 3A isoenzyme have been involved in the development of hypertension and in calcineurin inhibitor-induced hypertension. The genetic study of disease states can be the stepping stones for thoroughly understanding the genetic basis of ADEs. Gene polymorphisms are implicated in the development of diseases and corresponding disease-like ADEs. The disease-associated genes provide candidate genes for exploring ADEs and may provide genomic biomarkers for assessing the risk for developing severe calcineurin inhibitor-related ADEs as well as for developing preventive strategies.
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PMID:Understanding the genetic basis for adverse drug effects: the calcineurin inhibitors. 2009 93


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