Time filter

Source Type

Düsseldorf, Germany

Strom A.,German Diabetes Center | Strom A.,Institute for Clinical Diabetology | Wang G.-S.,German Diabetes Center | Scott F.W.,German Diabetes Center | Scott F.W.,Ottawa Hospital Research Institute
Pancreas | Year: 2011

OBJECTIVES: We previously demonstrated that the expression of cellular prion protein (PrP) in islet β-cells is suppressed in hyperglycemic rats suggesting a major role for PrP in blood glucose regulation. To further characterize the function of PrP in glucose homeostasis, we studied glucoregulation in PrP knockout (PrP KO) mice. METHODS: Glucose tolerance, insulin secretion, and insulin sensitivity were analyzed to assess glucoregulation in Zrch I PrP KO and the C57BL/6 (control) mice. Immunohistochemistry and morphometry were used to measure β-cell mass. RESULTS: Male PrP KO mice had significantly increased blood glucose concentration 60, 120, and 180 minutes after intraperitoneal injection of glucose compared with C57BL/6 mice. Female PrP KO mice showed a less pronounced phenotype of glucose intolerance. Evaluation of β-cell mass, insulin and proinsulin deficiency, and insulin resistance in male mice revealed essentially no difference between PrP KO and control mice. The only exception was an increase in serum insulin concentration in male PrP KO mice 5 minutes after glucose injection. CONCLUSIONS: This report is the first to show that PrP in β-cells is involved in glucoregulation. A further understanding of the role of PrP in regulating β-cell function will provide valuable insight into the mechanisms of blood glucose regulation. © 2011 Lippincott Williams & Wilkins, Inc. Source

Ioacara S.,Elias Hospital | Ioacara S.,Carol Davila University of Medicine and Pharmacy | Guja C.,Carol Davila University of Medicine and Pharmacy | Ionescu-Tirgoviste C.,Carol Davila University of Medicine and Pharmacy | And 4 more authors.
PLoS ONE | Year: 2014

Aims: To test the hypothesis that cumulative exposure to insulin and long-acting insulin analogs might be associated with cancer mortality in diabetes patients. Methods: All consecutive diabetes patients aged over 40 years, residing in a major urban area were screened at their first diabetes outpatient visit between 01/01/2001-12/31/2008 (n = 79869). Exclusion criteria were insulin treatment at screening, no insulin treatment until 12/31/2008, less than 6 months of glucose-lowering treatment alone before insulin initiation, insulin prescription before glargine became available, age <40/≥80 years at first insulin prescription, and <6 months of insulin exposure. A total 4990 subjects were followed-up for death based on death certificate, until 12/31/2011. Adjusted time-dependent competing risk regression analysis, with daily updates of treatment modalities was performed. Results are expressed for every 10,000 IU of cumulative dose or one year of cumulative time exposure to insulin. Results: Mean baseline age was 62±9 years, and follow-up 4.7±1.9 years. Glargine cumulative dose was associated with lower cancer mortality risk (subhazard ratio, SHR: 0.94 (95%CI 0.89-0.99, p = 0.033)). Cumulative exposure limited to that attained one year prior to death revealed lower SHRs for cumulative time (0.94 (95%CI 0.89-0.99, p = 0.018)) and cumulative dose of glargine (0.92 (95%CI 0.86-0.98, p = 0.014)). Glargine cumulative time and cumulative dose were significant predictors for lower pancreatic and breast cancer mortality, but not for deaths from lung, colorectal, female genital, liver, and urinary tract cancer. No increased hazards were found for any other subtypes of insulins. Conclusions: The cumulative dose exposure to insulin glargine was associated with a lower risk of cancer mortality in general, and of breast and pancreatic cancer in particular. This effect remained even after additional "fixed" cohort or propensity score analyses. © 2014 Ioacara et al. Source

Ritter O.,Institute for Clinical Diabetology | Jelenik T.,Institute for Clinical Diabetology | Jelenik T.,German Center for Diabetes Research | Roden M.,Institute for Clinical Diabetology | And 2 more authors.
Journal of Molecular Medicine | Year: 2015

Increased dietary fat intake and lipolysis result in excessive lipid availability, which relates to impaired insulin sensitivity. Over the last years, several mechanisms possibly underlying lipid-mediated insulin resistance evolved. Lipid intermediates such as diacylglycerols (DAG) associate with changes in insulin sensitivity in many models. DAG activate novel protein kinase C (PKC) isoforms followed by inhibitory serine phosphorylation of insulin receptor substrate 1 (IRS1). Activation of Toll-like receptor 4 (TLR4) raises another lipid class, ceramides (CER), which induce pro-inflammatory pathways and lead to inhibition of Akt phosphorylation. Inhibition of glucosylceramide and ganglioside synthesis results in improved insulin sensitivity and increased activatory tyrosine phosphorylation of IRS1 in the muscle. Incomplete fat oxidation can increase acylcarnitines (ACC), which in turn stimulate pro-inflammatory pathways. This review analyzed the effects of lipid metabolites on insulin action in skeletal muscle of humans and rodents. Despite the evidence for the association of both DAG and CER with insulin resistance, its causal relevance may differ depending on the subcellular localization and the tested cohorts, e.g., athletes. Nevertheless, recent data indicate that individual lipid species and their degree of fatty acid saturation, particularly membrane and cytosolic C18:2 DAG, specifically activate PKCθ and induce both acute lipid-induced and chronic insulin resistance in humans. © 2015, Springer-Verlag Berlin Heidelberg. Source

Roden M.,Heinrich Heine University Dusseldorf | Roden M.,Institute for Clinical Diabetology | Weng J.,Sun Yat Sen University | Eilbracht J.,Boehringer Ingelheim | And 4 more authors.
The Lancet Diabetes and Endocrinology | Year: 2013

Background: We aimed to investigate the efficacy and tolerability of empagliflozin, an oral, potent, and selective inhibitor of sodium-glucose co-transporter 2, in patients with type 2 diabetes who had not received drug treatment in the preceding 12 weeks. Methods: In our multicentre, randomised, placebo-controlled, phase 3 trial, we enrolled adults (aged ≥18 years) who had not received oral or injected anti-diabetes treatment in the previous 12 weeks. Eligible patients had HbA1c concentrations of 7-10%. We randomly allocated patients (1:1:1:1) with a computer-generated random sequence, stratified by region, HbA1c, and estimated glomerular filtration rate at screening, to placebo, empagliflozin 10 mg, empagliflozin 25 mg, or sitagliptin 100 mg once daily for 24 weeks. Patients and investigators were masked to treatment assignment. The primary endpoint was change from baseline in HbA1c at week 24 by ANCOVA in all randomly allocated patients who were treated with at least one dose of study drug and had a baseline HbA1c value. This study is completed and registered with ClinicalTrials.gov, number NCT01177813. Findings: Between Aug 12, 2010, and March 19, 2012, we randomly allocated 228 patients to receive placebo, 224 to receive empagliflozin 10 mg, 224 to receive empagliflozin 25 mg, and 223 to receive sitagliptin. Compared with placebo, adjusted mean differences in change from baseline HbA1c at week 24 were -0·74% (95% CI -0·88 to -0·59; p<0·0001) for empagliflozin 10 mg, -0·85% (-0·99 to -0·71; p<0·0001) for empagliflozin 25 mg, and -0·73% (-0·88 to -0·59; p<0·0001) for sitagliptin. 140 (61%) patients in the placebo group reported adverse events (four [2%] severe and six [3%] serious), as did 123 (55%) patients in the empagliflozin 10 mg group (eight [4%] severe and eight [4%] serious), 135 (60%) patients in the empagliflozin 25 mg group (seven [3%] severe and five [2%] serious), and 119 (53%) patients in the sitagliptin group (five [2%] severe and six [3%] serious). Interpretation: Empagliflozin provides a tolerable and efficacious strategy to reduce HbA1c in patients with type 2 diabetes who had not previously received drug treatment. Funding: Boehringer Ingelheim and Eli Lilly. © 2013 Elsevier Ltd. Source

Jelenik T.,Institute for Clinical Diabetology | Roden M.,Institute for Clinical Diabetology | Roden M.,Heinrich Heine University Dusseldorf
Antioxidants and Redox Signaling | Year: 2013

Significance: Insulin resistance and its related diseases, obesity and type 2 diabetes mellitus (T2DM), have been linked to changes in aerobic metabolism, pointing to a possible role of mitochondria in the development of insulin resistance. Recent Advances: Refined methodology of ex vivo high-resolution respirometry and in vivo magnetic resonance spectroscopy now allows describing several features of mitochondria in humans. In addition to measuring mitochondrial function at baseline and after exercise-induced submaximal energy depletion, the response of mitochondria to endocrine and metabolic challenges, termed mitochondrial plasticity, can be assessed using hyperinsulinemic clamp tests. While insulin resistant states do not uniformly relate to baseline and post-exercise mitochondrial function, mitochondrial plasticity is typically impaired in insulin resistant relatives of T2DM, in overt T2DM and even in type 1 diabetes mellitus (T1DM). Critical Issues: The variability of baseline mitochondrial function in the main target tissue of insulin action, skeletal muscle and liver, may be attributed to inherited and acquired changes in either mitochondrial quantity or quality. In addition to certain gene polymorphisms and aging, circulating glucose and lipid concentrations correlate with both mitochondrial function and plasticity. Future Directions: Despite the associations between features of mitochondrial function and insulin sensitivity, the question of a causal relationship between compromised mitochondrial plasticity and insulin resistance in the development of obesity and T2DM remains to be resolved. Antioxid. Redox Signal. 19, 258-268. © 2013, Mary Ann Liebert, Inc. Source

Discover hidden collaborations