mia Drug-Induced Glucose Alterations Part 1: Drug-Induced Hypoglycemia By spectrum.diabetesjournals.org Published On :: 2011-08-01 Mays H. VueAug 1, 2011; 24:171-177Pharmacy and Therapeutics Full Article
mia Drug-Induced Glucose Alterations Part 2: Drug-Induced Hyperglycemia By spectrum.diabetesjournals.org Published On :: 2011-11-01 Abdur RehmanNov 1, 2011; 24:234-238Pharmacy and Therapeutics Full Article
mia Detection, Prevention, and Treatment of Hypoglycemia in the Hospital By spectrum.diabetesjournals.org Published On :: 2005-01-01 Donna TomkyJan 1, 2005; 18:39-44Articles Full Article
mia Repression of sphingosine kinase (SK)-interacting protein (SKIP) in acute myeloid leukemia diminishes SK activity and its re-expression restores SK function [Molecular Bases of Disease] By www.jbc.org Published On :: 2020-04-17T00:06:05-07:00 Previous studies have shown that sphingosine kinase interacting protein (SKIP) inhibits sphingosine kinase (SK) function in fibroblasts. SK phosphorylates sphingosine producing the potent signaling molecule sphingosine-1-phosphate (S1P). SKIP gene (SPHKAP) expression is silenced by hypermethylation of its promoter in acute myeloid leukemia (AML). However, why SKIP activity is silenced in primary AML cells is unclear. Here, we investigated the consequences of SKIP down-regulation in AML primary cells and the effects of SKIP re-expression in leukemic cell lines. Using targeted ultra-HPLC-tandem MS (UPLC-MS/MS), we measured sphingolipids (including S1P and ceramides) in AML and control cells. Primary AML cells had significantly lower SK activity and intracellular S1P concentrations than control cells, and SKIP-transfected leukemia cell lines exhibited increased SK activity. These findings show that SKIP re-expression enhances SK activity in leukemia cells. Furthermore, other bioactive sphingolipids such as ceramide were also down-regulated in primary AML cells. Of note, SKIP re-expression in leukemia cells increased ceramide levels 2-fold, inactivated the key signaling protein extracellular signal-regulated kinase, and increased apoptosis following serum deprivation or chemotherapy. These results indicate that SKIP down-regulation in AML reduces SK activity and ceramide levels, an effect that ultimately inhibits apoptosis in leukemia cells. The findings of our study contrast with previous results indicating that SKIP inhibits SK function in fibroblasts and therefore challenge the notion that SKIP always inhibits SK activity. Full Article
mia Noncatalytic Bruton's tyrosine kinase activates PLC{gamma}2 variants mediating ibrutinib resistance in human chronic lymphocytic leukemia cells [Membrane Biology] By www.jbc.org Published On :: 2020-04-24T06:08:45-07:00 Treatment of patients with chronic lymphocytic leukemia (CLL) with inhibitors of Bruton's tyrosine kinase (BTK), such as ibrutinib, is limited by primary or secondary resistance to this drug. Examinations of CLL patients with late relapses while on ibrutinib, which inhibits BTK's catalytic activity, revealed several mutations in BTK, most frequently resulting in the C481S substitution, and disclosed many mutations in PLCG2, encoding phospholipase C-γ2 (PLCγ2). The PLCγ2 variants typically do not exhibit constitutive activity in cell-free systems, leading to the suggestion that in intact cells they are hypersensitive to Rac family small GTPases or to the upstream kinases spleen-associated tyrosine kinase (SYK) and Lck/Yes-related novel tyrosine kinase (LYN). The sensitivity of the PLCγ2 variants to BTK itself has remained unknown. Here, using genetically-modified DT40 B lymphocytes, along with various biochemical assays, including analysis of PLCγ2-mediated inositol phosphate formation, inositol phospholipid assessments, fluorescence recovery after photobleaching (FRAP) static laser microscopy, and determination of intracellular calcium ([Ca2+]i), we show that various CLL-specific PLCγ2 variants such as PLCγ2S707Y are hyper-responsive to activated BTK, even in the absence of BTK's catalytic activity and independently of enhanced PLCγ2 phospholipid substrate supply. At high levels of B-cell receptor (BCR) activation, which may occur in individual CLL patients, catalytically-inactive BTK restored the ability of the BCR to mediate increases in [Ca2+]i. Because catalytically-inactive BTK is insensitive to active-site BTK inhibitors, the mechanism involving the noncatalytic BTK uncovered here may contribute to preexisting reduced sensitivity or even primary resistance of CLL to these drugs. Full Article
mia Iatrogenic Inpatient Hypoglycemia: Risk Factors, Treatment, and Prevention: Analysis of Current Practice at an Academic Medical Center With Implications for Improvement Efforts By spectrum.diabetesjournals.org Published On :: 2008-10-01 Gregory A. MaynardOct 1, 2008; 21:241-247Articles Full Article
mia Pharmacotherapy for Hyperglycemia in Noncritically Ill Hospitalized Patients By spectrum.diabetesjournals.org Published On :: 2014-08-01 Carlos E. MendezAug 1, 2014; 27:180-188From Research to Practice Full Article
mia Negotiating the Barrier of Hypoglycemia in Diabetes By spectrum.diabetesjournals.org Published On :: 2002-01-01 Philip E. CryerJan 1, 2002; 15:Articles Full Article
mia Unexplained Hyperthyroglobulinemia in Differentiated Thyroid Cancer Patients Indicates Radioiodine Adjuvant Therapy: A Prospective Multicenter Study By jnm.snmjournals.org Published On :: 2020-05-01T11:16:58-07:00 Background: The management for totally thyroidectomized differentiated thyroid cancer (TT-DTC) patients with unexplained hyperthyroglobulinemia remains indeterminate due to evidence scarcity. This multicenter study aimed at prospectively evaluating the response to radioiodine (131I) adjuvant therapy (RAT) and its potential role in risk stratification and causal clarification. Methods: TT-DTC patients with stimulated serum thyroglobulin (Tgoff) levels > 10 ng/mL but no structurally evident disease were consecutively enrolled in five tertiary care institutions. After the administration of 5.55 GBq of 131I, the risk of presence of persistent/recurrent/metastatic DTC (prmDTC) was compared to that before RAT. The causes of hyperthyroglobulinemia were explored and the response to RAT was assessed 6-12 months post RAT. The change in suppressed thyroglobulin (Tgon) level was reported. Results: A cohort of 254 subjects with a median Tgoff of 27.1 ng/mL was enrolled for the analyses. Immediately after RAT, low-, intermediate-, and high-risk were identified in 5.9%, 88.6%, and 5.5% patients, respectively, with no significant difference in risk stratification compared with that before RAT (P = 0.952). During the follow-up (median, 10.6 months), hyperthyroglobulinemia was ultimately attributed to thyroid remnant, biochemical disease, and structural/functional disease in 17.3%, 54.3%, and 28.3% of subjects, respectively. In addition, excellent, indeterminate, biochemical incomplete, and structural/functional incomplete responses were achieved in 18.1%, 27.2%, 36.2%, and 18.5% of patients, respectively. Notably, distribution for either cause of hyperthyroglobulinemia or response to RAT was comparable among the three postoperative risk groups. Tgon levels in patients who merely received RAT declined significantly over time. Conclusion: Our study demonstrated that over 90% of TT-DTC patients with unexplained hyperthyroglobulinemia are stratified as intermediate-high risk, and RAT using 5.55 GBq of 131I reveals biochemical/functional/structural disease and yields non-structural/functional incomplete response in more than 80% patients, suggesting TT-DTC patients with unexplained hyperthyroglobulinemia as explicit candidates for RAT. Full Article
mia Repression of sphingosine kinase (SK)-interacting protein (SKIP) in acute myeloid leukemia diminishes SK activity and its re-expression restores SK function [Molecular Bases of Disease] By feedproxy.google.com Published On :: 2020-04-17T00:06:05-07:00 Previous studies have shown that sphingosine kinase interacting protein (SKIP) inhibits sphingosine kinase (SK) function in fibroblasts. SK phosphorylates sphingosine producing the potent signaling molecule sphingosine-1-phosphate (S1P). SKIP gene (SPHKAP) expression is silenced by hypermethylation of its promoter in acute myeloid leukemia (AML). However, why SKIP activity is silenced in primary AML cells is unclear. Here, we investigated the consequences of SKIP down-regulation in AML primary cells and the effects of SKIP re-expression in leukemic cell lines. Using targeted ultra-HPLC-tandem MS (UPLC-MS/MS), we measured sphingolipids (including S1P and ceramides) in AML and control cells. Primary AML cells had significantly lower SK activity and intracellular S1P concentrations than control cells, and SKIP-transfected leukemia cell lines exhibited increased SK activity. These findings show that SKIP re-expression enhances SK activity in leukemia cells. Furthermore, other bioactive sphingolipids such as ceramide were also down-regulated in primary AML cells. Of note, SKIP re-expression in leukemia cells increased ceramide levels 2-fold, inactivated the key signaling protein extracellular signal-regulated kinase, and increased apoptosis following serum deprivation or chemotherapy. These results indicate that SKIP down-regulation in AML reduces SK activity and ceramide levels, an effect that ultimately inhibits apoptosis in leukemia cells. The findings of our study contrast with previous results indicating that SKIP inhibits SK function in fibroblasts and therefore challenge the notion that SKIP always inhibits SK activity. Full Article
mia LDL subclass lipidomics in atherogenic dyslipidemia:Effect of statin therapy on bioactive lipids and dense LDL By feedproxy.google.com Published On :: 2020-04-15 M John ChapmanApr 15, 2020; 0:jlr.P119000543v1-jlr.P119000543Patient-Oriented and Epidemiological Research Full Article
mia LDL subclass lipidomics in atherogenic dyslipidemia:Effect of statin therapy on bioactive lipids and dense LDL [Patient-Oriented and Epidemiological Research] By feedproxy.google.com Published On :: 2020-04-15T11:30:30-07:00 Atherogenic LDL particles are physicochemically and metabolically heterogeneous. Can bioactive lipid cargo differentiate LDL subclasses, and thus potential atherogenicity? What is the effect of statin treatment? Obese, hypertriglyceridemic, hypercholesterolemic males (n=12; Lp(a) <10 mg/dL) received pitavastatin calcium (4mg/day) for 180 days in a single-phase, unblinded study. The lipidomic profiles (23 lipid classes) of five LDL subclasses fractionated from baseline and post-statin plasmas were determined by LC-MS. At baseline and on statin treatment, very small dense LDL (LDL5) was preferentially enriched (up to 3-fold) in specific lysophospholipids (lysophosphatidylcholine (LPC); lysophosphatidylinositol (LPI); lyso-platelet activating factor (LPC(O)); 9,0.2 and 0.14 mol/mol apoB respectively; all p<0.001 versus LDL1-4), suggesting elevated inflammatory potential per particle. In contrast, lysophosphatidylethanolamine was uniformly distributed among LDL subclasses. Statin treatment markedly reduced absolute plasma concentrations of all LDL subclasses (up to 33.5%), including LPC, LPI and LPC(O) contents (up to -52%), consistent with reduction in cardiovascular risk. Despite such reductions, lipotoxic ceramide load per particle in LDL1-5 (1.5 - 3 mol/mol apoB; 3 - 7 mmol/mol phosphatidylcholine) was either conserved or elevated. Bioactive lipids may constitute biomarkers for the cardiometabolic risk associated with specific LDL subclasses in atherogenic dyslipidemia at baseline, and with residual risk on statin therapy. Full Article
mia The ProteoRed MIAPE web toolkit: A user-friendly framework to connect and share proteomics standards [Technology] By feedproxy.google.com Published On :: 2011-06-19T13:05:33-07:00 The development of the HUPO-PSI's (Proteomics Standards Initiative) standard data formats and MIAPE (Minimum Information About a Proteomics Experiment) guidelines should improve proteomics data sharing within the scientific community. Proteomics journals have encouraged the use of these standards and guidelines to improve the quality of experimental reporting and ease the evaluation and publication of manuscripts. However, there is an evident lack of bioinformatics tools specifically designed to create and edit standard file formats and reports, or embed them within proteomics workflows. In this article, we describe a new web-based software suite (The ProteoRed MIAPE web toolkit) that performs several complementary roles related to proteomic data standards. Firstly, it can verify the reports fulfill the minimum information requirements of the corresponding MIAPE modules, highlighting inconsistencies or missing information. Secondly, the toolkit can convert several XML-based data standards directly into human readable MIAPE reports stored within the ProteoRed MIAPE repository. Finally, it can also perform the reverse operation, allowing users to export from MIAPE reports into XML files for computational processing, data sharing or public database submission. The toolkit is thus the first application capable of automatically linking the PSI's MIAPE modules with the corresponding XML data exchange standards, enabling bidirectional conversions. This toolkit is freely available at http://www.proteored.org/MIAPE/. Full Article
mia Role of angiopoietin-like protein 3 in sugar-induced dyslipidemia in rhesus macaques: suppression by fish oil or RNAi [Research Articles] By feedproxy.google.com Published On :: 2020-03-01T00:06:33-08:00 Angiopoietin-like protein 3 (ANGPTL3) inhibits lipid clearance and is a promising target for managing cardiovascular disease. Here we investigated the effects of a high-sugar (high-fructose) diet on circulating ANGPTL3 concentrations in rhesus macaques. Plasma ANGPTL3 concentrations increased ~30% to 40% after 1 and 3 months of a high-fructose diet (both P < 0.001 vs. baseline). During fructose-induced metabolic dysregulation, plasma ANGPTL3 concentrations were positively correlated with circulating indices of insulin resistance [assessed with fasting insulin and the homeostatic model assessment of insulin resistance (HOMA-IR)], hypertriglyceridemia, adiposity (assessed as leptin), and systemic inflammation [C-reactive peptide (CRP)] and negatively correlated with plasma levels of the insulin-sensitizing hormone adropin. Multiple regression analyses identified a strong association between circulating APOC3 and ANGPTL3 concentrations. Higher baseline plasma levels of both ANGPTL3 and APOC3 were associated with an increased risk for fructose-induced insulin resistance. Fish oil previously shown to prevent insulin resistance and hypertriglyceridemia in this model prevented increases of ANGPTL3 without affecting systemic inflammation (increased plasma CRP and interleukin-6 concentrations). ANGPTL3 RNAi lowered plasma concentrations of ANGPTL3, triglycerides (TGs), VLDL-C, APOC3, and APOE. These decreases were consistent with a reduced risk of atherosclerosis. In summary, dietary sugar-induced increases of circulating ANGPTL3 concentrations after metabolic dysregulation correlated positively with leptin levels, HOMA-IR, and dyslipidemia. Targeting ANGPTL3 expression with RNAi inhibited dyslipidemia by lowering plasma TGs, VLDL-C, APOC3, and APOE levels in rhesus macaques. Full Article
mia ANGPTL3, PCSK9, and statin therapy drive remarkable reductions in hyperlipidemia and atherosclerosis in a mouse model [Commentary] By feedproxy.google.com Published On :: 2020-03-01T00:06:33-08:00 Full Article
mia Noncatalytic Bruton's tyrosine kinase activates PLC{gamma}2 variants mediating ibrutinib resistance in human chronic lymphocytic leukemia cells [Membrane Biology] By feedproxy.google.com Published On :: 2020-04-24T06:08:45-07:00 Treatment of patients with chronic lymphocytic leukemia (CLL) with inhibitors of Bruton's tyrosine kinase (BTK), such as ibrutinib, is limited by primary or secondary resistance to this drug. Examinations of CLL patients with late relapses while on ibrutinib, which inhibits BTK's catalytic activity, revealed several mutations in BTK, most frequently resulting in the C481S substitution, and disclosed many mutations in PLCG2, encoding phospholipase C-γ2 (PLCγ2). The PLCγ2 variants typically do not exhibit constitutive activity in cell-free systems, leading to the suggestion that in intact cells they are hypersensitive to Rac family small GTPases or to the upstream kinases spleen-associated tyrosine kinase (SYK) and Lck/Yes-related novel tyrosine kinase (LYN). The sensitivity of the PLCγ2 variants to BTK itself has remained unknown. Here, using genetically-modified DT40 B lymphocytes, along with various biochemical assays, including analysis of PLCγ2-mediated inositol phosphate formation, inositol phospholipid assessments, fluorescence recovery after photobleaching (FRAP) static laser microscopy, and determination of intracellular calcium ([Ca2+]i), we show that various CLL-specific PLCγ2 variants such as PLCγ2S707Y are hyper-responsive to activated BTK, even in the absence of BTK's catalytic activity and independently of enhanced PLCγ2 phospholipid substrate supply. At high levels of B-cell receptor (BCR) activation, which may occur in individual CLL patients, catalytically-inactive BTK restored the ability of the BCR to mediate increases in [Ca2+]i. Because catalytically-inactive BTK is insensitive to active-site BTK inhibitors, the mechanism involving the noncatalytic BTK uncovered here may contribute to preexisting reduced sensitivity or even primary resistance of CLL to these drugs. Full Article
mia Pericyte Bridges in Homeostasis and Hyperglycemia By diabetes.diabetesjournals.org Published On :: 2020-04-22T11:45:20-07:00 Diabetic retinopathy is a potentially blinding eye disease that threatens the vision of a ninth of diabetic patients. Progression of the disease has long been attributed to an initial dropout of pericytes that enwrap the retinal microvasculature. Revealed through retinal vascular digests, a subsequent increase in basement membrane bridges is observed. Using cell-specific markers, we demonstrate that pericytes rather than endothelial cells colocalize with these bridges. We show that the density of bridges transiently increases with elevation of Ang-2, PDGF-BB, and blood sugar, is rapidly reversed on a time scale of days, and often associated with a pericyte cell body located off-vessel. Cell-specific knockout of KLF4 in pericytes fully replicates this phenotype. In vivo imaging of limbal vessels demonstrates pericyte migration off-vessel, with rapid pericyte filopodial-like process formation between adjacent vessels. Accounting for off-vessel and on-vessel pericytes, we observe no pericyte loss relative to non-diabetic control retina. These findings reveal the possibility that pericyte perturbations in location and process formation may play a role in the development of pathological vascular remodeling in diabetic retinopathy. Full Article
mia Hyperuricemia Predisposes to the Onset of Diabetes via Promoting Pancreatic {beta}-Cell Death in Uricase Deficiency Male Mice By diabetes.diabetesjournals.org Published On :: 2020-04-24T13:05:31-07:00 Clinical studies have shown a link between hyperuricemia (HU) and diabetes, while the exact effect of soluble serum urate on glucose metabolism remains elusive. This study aims to characterize the glucose metabolic phenotypes and investigate the underlying molecular mechanisms using a novel spontaneous HU mouse model in which the Uricase (Uox) gene is absent. In an attempt to study the role of HU in glycometabolism, we implemented external stimulation on Uox-knockout (KO) and wild-type (WT) males with a high-fat diet (HFD) and/or injections of multiple low-dose streptozotocin (MLD-STZ) to provoke the potential role of urate. Notably, while Uox-KO mice developed glucose intolerance in the basal condition, no mice spontaneously developed diabetes, even with aging. HFD-fed Uox-KO mice manifested similar insulin sensitivity compared with WT controls. HU augmented the existing glycometabolism abnormality induced by MLD-STZ and eventually led to diabetes, as evidenced by the increased random glucose. Reduced β-cell masses and increased terminal deoxynucleotidyl TUNEL-positive β-cells suggested that HU-mediated diabetes was cell death dependent. However, urate-lowering treatment (ULT) cannot ameliorate the diabetes incidence or reverse β-cell apoptosis with significance. ULT displayed a significant therapeutic effect of HU-crystal– associated kidney injury and tubulointerstitial damage in diabetes. Moreover, we present transcriptomic analysis of isolated islets, using Uox-KO versus WT mice and streptozotocin-induced diabetic WT (STZ-WT) versus diabetic Uox-KO (STZ-KO) mice. Shared differentially expressed genes of HU primacy revealed Stk17β is a possible target gene in HU-related β-cell death. Together, this study suggests that HU accelerates but does not cause diabetes by inhibiting islet β-cell survival. Full Article
mia Acute Hyperglycemia Increases Brain Pregenual Anterior Cingulate Cortex Glutamate Concentrations in Type 1 Diabetes Mellitus By diabetes.diabetesjournals.org Published On :: 2020-04-24T14:58:49-07:00 The brain mechanisms underlying the association of hyperglycemia with depressive symptoms are unknown. We hypothesized that disrupted glutamate metabolism in pregenual anterior cingulate cortex (ACC) in type 1 diabetes (T1D) without depression affects emotional processing. Using proton magnetic resonance spectroscopy (MRS), we measured glutamate concentrations in ACC and occipital cortex (OCC) in 13 T1D without major depression (HbA1c=7.1±0.7% [54±7mmol/mol]) and 11 healthy non-diabetic controls (HbA1c=5.5±0.2% [37±3mmol/mol]) during fasting euglycemia (EU) followed by a 60-minute +5.5mmol/l hyperglycemic clamp (HG). Intrinsic neuronal activity was assessed using resting-state blood oxygen level dependent functional MRI to measure the fractional amplitude of low frequency fluctuations in slow-band 4 (fALFF4). Emotional processing and depressive symptoms were assessed using emotional tasks (Emotional-Stroop, Self-Referent-Encoding-Task SRET) and clinical ratings (HAM-D, SCL-90-R), respectively. During HG, ACC glutamate increased (1.2mmol/kg, +10%, p=0.014) while ACC fALFF4 was unchanged (-0.007, -2%, p=0.449) in T1D; in contrast, glutamate was unchanged (-0.2mmol/kg, -2%, p=0.578) while fALFF4 decreased (-0.05, -13%, p=0.002) in controls. OCC glutamate and fALFF4 were unchanged in both groups. T1D had longer SRET negative-word response-times (p=0.017) and higher depression-rating scores (HAM-D p=0.020; SCL-90-R-depression p=0.008). Higher glutamate change tended to associate with longer Emotional-Stroop response-times in T1D only. Brain glutamate must be tightly controlled during hyperglycemia due to the risk for neurotoxicity with excessive levels. Results suggest that ACC glutamate control mechanisms are disrupted in T1D, which affects glutamatergic neurotransmission related to emotional or cognitive processing. Increased prefrontal glutamate during acute hyperglycemic episodes could explain our previous findings of associations between chronic hyperglycemia, cortical thinning and depressive symptoms in T1D. Full Article
mia Repurposing Doxepin to Ameliorate Steatosis and Hyperglycemia by Activating FAM3A Signaling Pathway By diabetes.diabetesjournals.org Published On :: 2020-05-07T08:35:09-07:00 Mitochondrial protein FAM3A suppresses hepatic gluconeogenesis and lipogenesis. This study aimed to screen drug(s) that activates FAM3A expression and evaluate its effect(s) on hyperglycemia and steatosis. Drug-repurposing methodology predicted that antidepressive drug doxepin was among the drugs that potentially activated FAM3A expression. Doxepin was further validated to stimulate the translocation of transcription factor HNF4α from the cytoplasm into the nucleus, where it promoted FAM3A transcription to enhance ATP synthesis, suppress gluconeogenesis, and reduce lipid deposition in hepatocytes. HNF4α antagonism or FAM3A deficiency blunted doxepin-induced suppression on gluconeogenesis and lipid deposition in hepatocytes. Doxepin administration attenuated hyperglycemia, steatosis, and obesity in obese diabetic mice with upregulated FAM3A expression in liver and brown adipose tissues (BAT). Notably, doxepin failed to correct dysregulated glucose and lipid metabolism in FAM3A-deficient mice fed on high-fat diet. Doxepin’s effects on ATP production, Akt activation, gluconeogenesis, and lipogenesis repression were also blunted in FAM3A-deficient mouse livers. In conclusion, FAM3A is a therapeutic target for diabetes and steatosis. Antidepressive drug doxepin activates FAM3A signaling pathways in liver and BAT to improve hyperglycemia and steatosis of obese diabetic mice. Doxepin might be preferentially recommended as an antidepressive drug in potential treatment of patients with diabetes complicated with depression. Full Article
mia MANF Promotes Diabetic Corneal Epithelial Wound Healing and Nerve Regeneration by Attenuating Hyperglycemia-Induced Endoplasmic Reticulum Stress By diabetes.diabetesjournals.org Published On :: 2020-05-07T08:35:09-07:00 Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a neurotrophic factor widely expressed in mammalian tissues, and it exerts critical protective effects on neurons and other cell types in various disease models, such as those for diabetes. However, to date, the expression and roles of MANF in the cornea, with or without diabetic keratopathy (DK), remain unclear. Here, we demonstrate that MANF is abundantly expressed in normal corneal epithelial cells; however, MANF expression was significantly reduced in both unwounded and wounded corneal epithelium in streptozotocin-induced type 1 diabetic C57BL/6 mice. Recombinant human MANF significantly promoted normal and diabetic corneal epithelial wound healing and nerve regeneration. Furthermore, MANF inhibited hyperglycemia-induced endoplasmic reticulum (ER) stress and ER stress–mediated apoptosis. Attenuation of ER stress with 4-phenylbutyric acid (4-PBA) also ameliorated corneal epithelial closure and nerve regeneration. However, the beneficial effects of MANF and 4-PBA were abolished by an Akt inhibitor and Akt-specific small interfering RNA (siRNA). Finally, we reveal that the subconjunctival injection of MANF-specific siRNA prevents corneal epithelial wound healing and nerve regeneration. Our results provide important evidence that hyperglycemia-suppressed MANF expression may contribute to delayed corneal epithelial wound healing and impaired nerve regeneration by increasing ER stress, and MANF may be a useful therapeutic modality for treating DK. Full Article
mia Inhibition of glycosphingolipid biosynthesis reverts multidrug resistance by differentially modulating ABC transporters in chronic myeloid leukemias [Cell Biology] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 Multidrug resistance (MDR) in cancer arises from cross-resistance to structurally- and functionally-divergent chemotherapeutic drugs. In particular, MDR is characterized by increased expression and activity of ATP-binding cassette (ABC) superfamily transporters. Sphingolipids are substrates of ABC proteins in cell signaling, membrane biosynthesis, and inflammation, for example, and their products can favor cancer progression. Glucosylceramide (GlcCer) is a ubiquitous glycosphingolipid (GSL) generated by glucosylceramide synthase, a key regulatory enzyme encoded by the UDP-glucose ceramide glucosyltransferase (UGCG) gene. Stressed cells increase de novo biosynthesis of ceramides, which return to sub-toxic levels after UGCG mediates incorporation into GlcCer. Given that cancer cells seem to mobilize UGCG and have increased GSL content for ceramide clearance, which ultimately contributes to chemotherapy failure, here we investigated how inhibition of GSL biosynthesis affects the MDR phenotype of chronic myeloid leukemias. We found that MDR is associated with higher UGCG expression and with a complex GSL profile. UGCG inhibition with the ceramide analog d-threo-1-(3,4,-ethylenedioxy)phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol (EtDO-P4) greatly reduced GSL and monosialotetrahexosylganglioside levels, and co-treatment with standard chemotherapeutics sensitized cells to mitochondrial membrane potential loss and apoptosis. ABC subfamily B member 1 (ABCB1) expression was reduced, and ABCC-mediated efflux activity was modulated by competition with nonglycosylated ceramides. Consistently, inhibition of ABCC-mediated transport reduced the efflux of exogenous C6-ceramide. Overall, UGCG inhibition impaired the malignant glycophenotype of MDR leukemias, which typically overcomes drug resistance through distinct mechanisms. This work sheds light on the involvement of GSL in chemotherapy failure, and its findings suggest that targeted GSL modulation could help manage MDR leukemias. Full Article
mia Changes in Gut Microbiota Control Metabolic Endotoxemia-Induced Inflammation in High-Fat Diet-Induced Obesity and Diabetes in Mice By diabetes.diabetesjournals.org Published On :: 2008-06-01 Patrice D. CaniJun 1, 2008; 57:1470-1481Metabolism Full Article
mia Metabolic Endotoxemia Initiates Obesity and Insulin Resistance By diabetes.diabetesjournals.org Published On :: 2007-07-01 Patrice D. CaniJul 1, 2007; 56:1761-1772Obesity Studies Full Article
mia Trial of novel leukaemia drug is stopped for second time after two more deaths By feeds.bmj.com Published On :: Friday, November 25, 2016 - 10:46 Full Article
mia Hypoglycemia in the Diabetes Control and Complications Trial By diabetes.diabetesjournals.org Published On :: 1997-02-01 The Diabetes Control and Complications Trial Research GroupFeb 1, 1997; 46:271-286Original Article Full Article
mia Changes in Gut Microbiota Control Metabolic Endotoxemia-Induced Inflammation in High-Fat Diet-Induced Obesity and Diabetes in Mice By diabetes.diabetesjournals.org Published On :: 2008-06-01 Patrice D. CaniJun 1, 2008; 57:1470-1481Metabolism Full Article
mia Metabolic Endotoxemia Initiates Obesity and Insulin Resistance By diabetes.diabetesjournals.org Published On :: 2007-07-01 Patrice D. CaniJul 1, 2007; 56:1761-1772Obesity Studies Full Article
mia Acyl-ghrelin Is Permissive for the Normal Counterregulatory Response to Insulin-Induced Hypoglycemia By diabetes.diabetesjournals.org Published On :: 2020-01-20T12:00:26-08:00 Insulin-induced hypoglycemia leads to far-ranging negative consequences in patients with diabetes. Components of the counterregulatory response (CRR) system that help minimize and reverse hypoglycemia and coordination between those components are well studied but not yet fully characterized. Here, we tested the hypothesis that acyl-ghrelin, a hormone that defends against hypoglycemia in a preclinical starvation model, is permissive for the normal CRR to insulin-induced hypoglycemia. Ghrelin knockout (KO) mice and wild-type (WT) littermates underwent an insulin bolus-induced hypoglycemia test and a low-dose hyperinsulinemic-hypoglycemic clamp procedure. Clamps also were performed in ghrelin-KO mice and C57BL/6N mice administered the growth hormone secretagogue receptor agonist HM01 or vehicle. Results show that hypoglycemia, as induced by an insulin bolus, was more pronounced and prolonged in ghrelin-KO mice, supporting previous studies suggesting increased insulin sensitivity upon ghrelin deletion. Furthermore, during hyperinsulinemic-hypoglycemic clamps, ghrelin-KO mice required a 10-fold higher glucose infusion rate (GIR) and exhibited less robust corticosterone and growth hormone responses. Conversely, HM01 administration, which reduced the GIR required by ghrelin-KO mice during the clamps, increased plasma corticosterone and growth hormone. Thus, our data suggest that endogenously produced acyl-ghrelin not only influences insulin sensitivity but also is permissive for the normal CRR to insulin-induced hypoglycemia. Full Article
mia Case Study: Seizures and Hypoglycemia By clinical.diabetesjournals.org Published On :: 2012-01-01 Michael R. BrennanJan 1, 2012; 30:23-24Case Studies Full Article
mia Hypoglycemia in Type 1 and Type 2 Diabetes: Physiology, Pathophysiology, and Management By clinical.diabetesjournals.org Published On :: 2006-07-01 Vanessa J. BriscoeJul 1, 2006; 24:115-121Feature Articles Full Article
mia Hypoglycemia? Low Blood Glucose? Low Blood Sugar? By clinical.diabetesjournals.org Published On :: 2012-01-01 Jan 1, 2012; 30:38-38Patient Information Full Article
mia Inpatient Management of Hyperglycemia and Diabetes By clinical.diabetesjournals.org Published On :: 2011-01-01 Vasudev MagajiJan 1, 2011; 29:3-9Feature Articles Full Article
mia Severe Hypoglycemia and Cognitive Function in Older Adults With Type 1 Diabetes: The Study of Longevity in Diabetes (SOLID) By care.diabetesjournals.org Published On :: 2020-02-20T11:55:29-08:00 OBJECTIVE In children with type 1 diabetes (T1D), severe hypoglycemia (SH) is associated with poorer cognition, but the association of SH with cognitive function in late life is unknown. Given the increasing life expectancy in people with T1D, understanding the role of SH in brain health is crucial. RESEARCH DESIGN AND METHODS We examined the association between SH and cognitive function in 718 older adults with T1D from the Study of Longevity in Diabetes (SOLID). Subjects self-reported recent SH (previous 12 months) and lifetime history of SH resulting in inpatient/emergency department utilization. Global and domain-specific cognition (language, executive function, episodic memory, and simple attention) were assessed. The associations of SH with cognitive function and impaired cognition were evaluated via linear and logistic regression models, respectively. RESULTS Thirty-two percent of participants (mean age 67.2 years) reported recent SH and 50% reported lifetime SH. Compared with those with no SH, subjects with a recent SH history had significantly lower global cognition scores. Domain-specific analyses revealed significantly lower scores on language, executive function, and episodic memory with recent SH exposure and significantly lower executive function with lifetime SH exposure. Recent SH was associated with impaired global cognition (odds ratio [OR] 3.22, 95% CI 1.30, 7.94) and cognitive impairment on the language domain (OR 3.15, 95% CI 1.19, 8.29). CONCLUSIONS Among older adults with T1D, recent SH and lifetime SH were associated with worse cognition. Recent SH was associated with impaired global cognition. These findings suggest a deleterious role of SH on the brain health of older patients with T1D and highlight the importance of SH prevention. Full Article
mia Evidence-Informed Clinical Practice Recommendations for Treatment of Type 1 Diabetes Complicated by Problematic Hypoglycemia By care.diabetesjournals.org Published On :: 2015-06-01 Pratik ChoudharyJun 1, 2015; 38:1016-1029Type 1 Diabetes at a Crossroads Full Article
mia Trends in Drug Utilization, Glycemic Control, and Rates of Severe Hypoglycemia, 2006-2013 By care.diabetesjournals.org Published On :: 2017-04-01 Kasia J. LipskaApr 1, 2017; 40:468-475Emerging Science and Concepts for Management of Diabetes and Aging Full Article
mia New Insulin Glargine 300 Units/mL Versus Glargine 100 Units/mL in People With Type 2 Diabetes Using Oral Agents and Basal Insulin: Glucose Control and Hypoglycemia in a 6-Month Randomized Controlled Trial (EDITION 2) By care.diabetesjournals.org Published On :: 2014-12-01 Hannele Yki-JärvinenDec 1, 2014; 37:3235-3243Emerging Technologies and Therapeutics Full Article
mia Phase 3 Trial of Transplantation of Human Islets in Type 1 Diabetes Complicated by Severe Hypoglycemia By care.diabetesjournals.org Published On :: 2016-07-01 Bernhard J. HeringJul 1, 2016; 39:1230-1240Emerging Technologies and Therapeutics Full Article
mia Pathways to Quality Inpatient Management of Hyperglycemia and Diabetes: A Call to Action By care.diabetesjournals.org Published On :: 2013-07-01 Boris DrazninJul 1, 2013; 36:1807-1814Perspectives in Care Full Article
mia Prevalence of Hyper- and Hypoglycemia Among Inpatients With Diabetes: A national survey of 44 U.S. hospitals By care.diabetesjournals.org Published On :: 2007-02-01 Deborah J. WexlerFeb 1, 2007; 30:367-369BR Epidemiology/Health Services/Psychosocial Research Full Article
mia In-Hospital Prognosis of Ppatients With Fasting Hyperglycemia After First Myocardial Infarction By care.diabetesjournals.org Published On :: 1991-08-01 John J O'SullivanAug 1, 1991; 14:758-760Short Report Full Article
mia Personalized Management of Hyperglycemia in Type 2 Diabetes: Reflections from a Diabetes Care Editors' Expert Forum By care.diabetesjournals.org Published On :: 2013-06-01 Itamar RazJun 1, 2013; 36:1779-1788Diabetes Care Expert Forum Full Article
mia New Insulin Glargine 300 Units/mL Versus Glargine 100 Units/mL in People With Type 2 Diabetes Using Basal and Mealtime Insulin: Glucose Control and Hypoglycemia in a 6-Month Randomized Controlled Trial (EDITION 1) By care.diabetesjournals.org Published On :: 2014-10-01 Matthew C. RiddleOct 1, 2014; 37:2755-2762Emerging Technologies and Therapeutics Full Article
mia Liraglutide, a Long-Acting Human Glucagon-Like Peptide-1 Analog, Given as Monotherapy Significantly Improves Glycemic Control and Lowers Body Weight Without Risk of Hypoglycemia in Patients With Type 2 Diabetes By care.diabetesjournals.org Published On :: 2007-06-01 Tina VilsbøllJun 1, 2007; 30:1608-1610BR Emerging Treatments and Technologies Full Article
mia Consensus Development Conference on the Diagnosis of Coronary Heart Disease in People With Diabetes: 10-11 February 1998, Miami, Florida By care.diabetesjournals.org Published On :: 1998-09-01 American Diabetes AssociationSep 1, 1998; 21:1551-1559Consensus Development Conference Report Full Article
mia Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society By care.diabetesjournals.org Published On :: 2013-05-01 Elizabeth R. SeaquistMay 1, 2013; 36:1384-1395Scientific Statement Full Article
mia Blue Angels to fly over Jacksonville, Miami on Friday By www.upi.com Published On :: Thu, 07 May 2020 15:45:25 -0400 The U.S. Navy Flight Demonstration Squadron, the Blue Angels, will fly over Jacksonville and Miami, Fla., Friday as part of a nationwide tour to show appreciation for healthcare workers and frontline responders. Full Article
mia The Pathophysiology of Hyperglycemia in Older Adults: Clinical Considerations By care.diabetesjournals.org Published On :: 2017-04-01 Pearl G. LeeApr 1, 2017; 40:444-452Emerging Science and Concepts for Management of Diabetes and Aging Full Article
mia Management of Inpatient Hyperglycemia and Diabetes in Older Adults By care.diabetesjournals.org Published On :: 2017-04-01 Guillermo E. UmpierrezApr 1, 2017; 40:509-517Emerging Science and Concepts for Management of Diabetes and Aging Full Article
mia 2019 Update to: Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) By care.diabetesjournals.org Published On :: 2020-02-01 John B. BuseFeb 1, 2020; 43:487-493Consensus Report Update Full Article