News aggregator

Diabetes Induces Lysine Acetylation of Intermediary Metabolism Enzymes in the Kidney

Diabetes.org Current Issue - Tue, 06/24/2014 - 19:04

Cells in which insulin is not required for glucose uptake are susceptible to the long-term complications of diabetes. Even in these tissues, however, the major perturbations that would otherwise be engendered by the greatly increased intracellular glucose concentration are mollified by adaptive changes in the enzymes of intermediary metabolism. These include allosteric regulation, product inhibition, and covalent modification as well as alterations in gene transcription. More recently, advances in proteomic technology have shown that reversible acetylation of the -amino group of lysine provides an additional means of modulating protein function and, in particular, enzyme activity. Here, we explored the extent of protein acetylation in an organ susceptible to the long-term complications of diabetes, examining the kidneys of rats with streptozotocin-induced diabetes and kidney cells exposed to high glucose. Using high-resolution mass spectrometry coupled with immunoaffinity enrichment, we identified 47 lysine-acetylated proteins in the kidneys of diabetic rats compared with 11 in control kidneys. Bioinformatic interrogation of the acetylome from diabetic animals showed a predominance of metabolic pathway involvement including the citrate acid cycle, glycolysis/gluconeogenesis, and metabolism of branched chain amino acids. Increased lysine acetylation was also noted in mesangial and tubular cells exposed to 25 mmol/L compared with 5.6 mmol/L glucose. These findings highlight acetylation as a posttranslational modification affecting numerous proteins. Current drug discovery efforts to develop small molecule inhibitors and activators of various lysine acetylases and deacetylases offer a new potential strategy to reduce the likelihood of diabetes complications.

Categories: News Feeds

Role of Transcription Factor Acetylation in Diabetic Kidney Disease

Diabetes.org Current Issue - Tue, 06/24/2014 - 19:04

Nuclear factor (NF)-B and signal transducer and activator of transcription 3 (STAT3) play a critical role in diabetic nephropathy (DN). Sirtuin-1 (SIRT1) regulates transcriptional activation of target genes through protein deacetylation. Here, we determined the roles of Sirt1 and the effect of NF-B (p65) and STAT3 acetylation in DN. We found that acetylation of p65 and STAT3 was increased in both mouse and human diabetic kidneys. In human podocytes, advanced glycation end products (AGEs) induced p65 and STAT3 acetylation and overexpression of acetylation-incompetent mutants of p65 and STAT3 abrogated AGE-induced expression of NF-B and STAT3 target genes. Inhibition of AGE formation in db/db mice by pyridoxamine treatment attenuated proteinuria and podocyte injury, restored SIRT1 expression, and reduced p65 and STAT3 acetylation. Diabetic db/db mice with conditional deletion of SIRT1 in podocytes developed more proteinuria, kidney injury, and acetylation of p65 and STAT3 compared with db/db mice without SIRT1 deletion. Treatment of db/db mice with a bromodomain and extraterminal (BET)-specific bromodomain inhibitor (MS417) which blocks acetylation-mediated association of p65 and STAT3 with BET proteins, attenuated proteinuria, and kidney injury. Our findings strongly support a critical role for p65 and STAT3 acetylation in DN. Targeting protein acetylation could be a potential new therapy for DN.

Categories: News Feeds

Early Detection of Nerve Fiber Loss by Corneal Confocal Microscopy and Skin Biopsy in Recently Diagnosed Type 2 Diabetes

Diabetes.org Current Issue - Tue, 06/24/2014 - 19:04

We sought to determine whether early nerve damage may be detected by corneal confocal microscopy (CCM), skin biopsy, and neurophysiological tests in 86 recently diagnosed type 2 diabetic patients compared with 48 control subjects. CCM analysis using novel algorithms to reconstruct nerve fiber images was performed for all fibers and major nerve fibers (MNF) only. Intraepidermal nerve fiber density (IENFD) was assessed in skin specimens. Neurophysiological measures included nerve conduction studies (NCS), quantitative sensory testing (QST), and cardiovascular autonomic function tests (AFTs). Compared with control subjects, diabetic patients exhibited significantly reduced corneal nerve fiber length (CNFL-MNF), fiber density (CNFD-MNF), branch density (CNBD-MNF), connecting points (CNCP), IENFD, NCS, QST, and AFTs. CNFD-MNF and IENFD were reduced below the 2.5th percentile in 21% and 14% of the diabetic patients, respectively. However, the vast majority of patients with abnormal CNFD showed concomitantly normal IENFD and vice versa. In conclusion, CCM and skin biopsy both detect nerve fiber loss in recently diagnosed type 2 diabetes, but largely in different patients, suggesting a patchy manifestation pattern of small fiber neuropathy. Concomitant NCS impairment points to an early parallel involvement of small and large fibers, but the precise temporal sequence should be clarified in prospective studies.

Categories: News Feeds

Inhibition of SREBP Transcriptional Activity by a Boron-Containing Compound Improves Lipid Homeostasis in Diet-Induced Obesity

Diabetes.org Current Issue - Tue, 06/24/2014 - 19:04

Dysregulation of lipid homeostasis is intimately associated with obesity, type 2 diabetes, and cardiovascular diseases. Sterol regulatory-element binding proteins (SREBPs) are the master regulators of lipid biosynthesis. Previous studies have shown that the conserved transcriptional cofactor Mediator complex is critically required for the SREBP transcriptional activity, and recruitment of the Mediator complex to the SREBP transactivation domains (TADs) is through the MED15-KIX domain. Recently, we have synthesized several boron-containing small molecules. Among these novel compounds, BF175 can specifically block the binding of MED15-KIX to SREBP1a-TAD in vitro, resulting in an inhibition of the SREBP transcriptional activity and a decrease of SREBP target gene expression in cultured hepatocytes. Furthermore, BF175 can improve lipid homeostasis in the mouse model of diet-induced obesity. Compared with the control, BF175 treatment decreased the expression of SREBP target genes in mouse livers and decreased hepatic and blood levels of lipids. These results suggest that blocking the interaction between SREBP-TADs and the Mediator complex by small molecules may represent a novel approach for treating diseases with aberrant lipid homeostasis.

Categories: News Feeds

Impact of Acute Hyperglycemia on Myocardial Infarct Size, Area at Risk, and Salvage in Patients With STEMI and the Association With Exenatide Treatment: Results From a Randomized Study

Diabetes.org Current Issue - Tue, 06/24/2014 - 19:04

Hyperglycemia upon hospital admission in patients with ST-segment elevation myocardial infarction (STEMI) occurs frequently and is associated with adverse outcomes. It is, however, unsettled as to whether an elevated blood glucose level is the cause or consequence of increased myocardial damage. In addition, whether the cardioprotective effect of exenatide, a glucose-lowering drug, is dependent on hyperglycemia remains unknown. The objectives of this substudy were to evaluate the association between hyperglycemia and infarct size, myocardial salvage, and area at risk, and to assess the interaction between exenatide and hyperglycemia. A total of 210 STEMI patients were randomized to receive intravenous exenatide or placebo before percutaneous coronary intervention. Hyperglycemia was associated with larger area at risk and infarct size compared with patients with normoglycemia, but the salvage index and infarct size adjusting for area at risk did not differ between the groups. Treatment with exenatide resulted in increased salvage index both among patients with normoglycemia and hyperglycemia. Thus, we conclude that the association between hyperglycemia upon hospital admission and infarct size in STEMI patients is a consequence of a larger myocardial area at risk but not of a reduction in myocardial salvage. Also, cardioprotection by exenatide treatment is independent of glucose levels at hospital admission. Thus, hyperglycemia does not influence the effect of the reperfusion treatment but rather represents a surrogate marker for the severity of risk and injury to the myocardium.

Categories: News Feeds

Levemir Does Not Increase Risk of Cancer: Studies

VIENNA (Reuters) - Novo Nordisk's Levemir was not associated in any increase in incidence of cancer when compared with human insulin in studies including some 9,000 patients, according to a new analysis released on Thursday.
Categories: News Feeds

Indian Ethnicity Tied to Higher Diabetes Risk

NEW YORK (Reuters Health) - Americans of Indian descent may have a heightened risk of diabetes, even when their weight is in the normal range, research suggests.
Categories: News Feeds

Poor Math Skills May Worsen Diabetes Control

NEW YORK (Reuters Health) - A new study suggests that diabetic adults' ability to work with numbers may affect their management of the disease -- and that, in turn, may help explain racial differences in diabetes control.
Categories: News Feeds

Girl's Rare Form of Diabetes Leads to Injection-free Treatment for Some

CHICAGO - Three years after she made medical history and was freed from painful insulin injections, 9-year-old Lilly Jaffe is just beginning to understand how much her story changed the course of diabetes research and treatment.
Categories: News Feeds

People with Diabetes Hit Hard by Hurricane Katrina

NEW YORK (Reuters Health) - People with diabetes are among the hardest-hit of Hurricane Katrina's victims, and many of them are likely still feeling the effects today, new research shows.
Categories: News Feeds

Priority groups will get swine flu shots first

The federal government has decided five groups should be first in line for swine flu vaccines: .
Categories: News Feeds

Diabetes Forecast Offers "10 Tips" to Save Money and Improve Your Health

ALEXANDRIA, VA, Sep 16, 2009 (MARKETWIRE via COMTEX) -- Diabetes has so many costs -- to your health, your emotions, and of course, your wallet.
Categories: News Feeds

Diabetes Drugs Alone Do Not Ease Key Heart Risk

CHICAGO (Reuters) - Drugs used to control diabetes do not reduce signs of inflammation that are linked with heart disease, U.S.
Categories: News Feeds

Steroids Help Some with Vision-robbing Clots: Study

CHICAGO (Reuters) - Injections with a steroid improved the eyesight of more than one-quarter of patients suffering from vision-robbing blood clots, a leading cause of blindness, researchers said on Monday.
Categories: News Feeds