Institute for Clinical Diabetology

Düsseldorf, Germany

Institute for Clinical Diabetology

Düsseldorf, Germany
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Phielix E.,Institute for Clinical Diabetology | Szendroedi J.,Institute for Clinical Diabetology | Szendroedi J.,Heinrich Heine University Düsseldorf | Roden M.,Institute for Clinical Diabetology | And 2 more authors.
Trends in Pharmacological Sciences | Year: 2011

Fasting hyperglycemia in type 2 diabetes mellitus (T2DM) results from elevated endogenous glucose production (EGP), which is mostly due to augmented hepatic gluconeogenesis. Insulin-resistant humans exhibit impaired insulin-dependent suppression of EGP and excessive hepatic lipid storage (steatosis), which relates to abnormal supply of free fatty acids (FFA) and energy metabolism. Only two glucose-lowering drug classes, the biguanide metformin and the thiazolidendiones (TZDs), exert insulin- and glucagon-independent hepatic effects. Preclinical studies suggest that metformin inhibits mitochondrial complex I. TZDs, as peroxisome proliferator-activated receptor (PPAR) γ-agonists, predominantly reduce the flux of FFA and cytokines from adipose tissue to the liver, but could also directly inhibit mitochondrial complex I. Although both metformin and TZDs improve fasting hyperglycemia and EGP in clinical trials, only TZDs decrease steatosis and peripheral insulin resistance. More studies are required to address their effects on hepatocellular energy metabolism with a view to identifying novel targets for the treatment of T2DM. © 2011 Elsevier Ltd.

Roden M.,Heinrich Heine University Düsseldorf | 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, 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.

Elsen M.,Paul Langerhans Group for Integrative Physiology | Raschke S.,Paul Langerhans Group for Integrative Physiology | Tennagels N.,Sanofi S.A. | Schwahn U.,Sanofi S.A. | And 5 more authors.
American Journal of Physiology - Cell Physiology | Year: 2014

While white adipose tissue (AT is an energy storage depot, brown AT is specialized in energy dissipation. Uncoupling protein 1 (UCP1-expressing adipocytes with a different origin than classical brown adipocytes have been found in white AT. These "brite" (brown-in-white adipocytes may represent a therapeutic target to counteract obesity. Bone morphogenetic proteins (BMPs play a role in the regulation of adipogenesis. Based on studies with murine cells, BMP4 is assumed to induce stem cell commitment to the white adipocyte lineage, whereas BMP7 promotes brown adipogenesis. There is evidence for discrepancies between mouse and human AT. Therefore, we compared the effect of BMP4 and BMP7 on white-to-brown transition in primary human adipose stem cells (hASCs from subcutaneous AT. Long-term exposure of hASCs to recombinant BMP4 or BMP7 during differentiation increased adipogenesis, as determined by lipid accumulation and peroxisome proliferator-activated receptor-γ (PPARγ expression. Not only BMP7, but also BMP4, increased UCP1 expression in hASCs and decreased expression of the white-specific marker TCF21. The ability of hASCs to induce UCP1 in response to BMP4 and BMP7 markedly differed between donors and could be related to the expression of the brite marker CD137. However, mitochondrial content and oxygen consumption were not increased in hASCs challenged with BMP4 and BMP7. In conclusion, we showed for the first time that BMP4 has similar effects on white-to-brown transition as BMP7 in our human cell model. Thus the roles of BMP4 and BMP7 in adipogenesis cannot always be extrapolated from murine to human cell models. © 2014 the American Physiological Society.

Szendroedi J.,Institute for Clinical Diabetology | Szendroedi J.,Heinrich Heine University Düsseldorf | Phielix E.,Institute for Clinical Diabetology | Roden M.,Institute for Clinical Diabetology | Roden M.,Heinrich Heine University Düsseldorf
Nature Reviews Endocrinology | Year: 2012

Type 2 diabetes mellitus (T2DM) has been related to alterations of oxidative metabolism in insulin-responsive tissues. Overt T2DM can present with acquired or inherited reductions of mitochondrial oxidative phosphorylation capacity, submaximal ADP-stimulated oxidative phosphorylation and plasticity of mitochondria and/or lower mitochondrial content in skeletal muscle cells and potentially also in hepatocytes. Acquired insulin resistance is associated with reduced insulin-stimulated mitochondrial activity as the result of blunted mitochondrial plasticity. Hereditary insulin resistance is frequently associated with reduced mitochondrial activity at rest, probably due to diminished mitochondrial content. Lifestyle and pharmacological interventions can enhance the capacity for oxidative phosphorylation and mitochondrial content and improve insulin resistance in some (pre)diabetic cases. Various mitochondrial features can be abnormal but are not necessarily responsible for all forms of insulin resistance. Nevertheless, mitochondrial abnormalities might accelerate progression of insulin resistance and subsequent organ dysfunction via increased production of reactive oxygen species. This Review discusses the association between mitochondrial function and insulin sensitivity in various tissues, such as skeletal muscle, liver and heart, with a main focus on studies in humans, and addresses the effects of therapeutic strategies that affect mitochondrial function and insulin sensitivity. © 2012 Macmillan Publishers Limited. All rights reserved.

Phielix E.,Institute for Clinical Diabetology | Jelenik T.,Institute for Clinical Diabetology | Nowotny P.,Institute for Clinical Diabetology | Szendroedi J.,Institute for Clinical Diabetology | And 5 more authors.
Diabetologia | Year: 2014

Aims/hypothesis: Muscle mitochondrial function can vary during fasting, but is lower during hyperinsulinaemia in insulin-resistant humans. Ageing and hyperlipidaemia may be the culprits, but the mechanisms remain unclear. We hypothesised that (1) insulin would fail to increase mitochondrial oxidative capacity in non-diabetic insulin-resistant young obese humans and in elderly patients with type 2 diabetes and (2) reducing NEFA levels would improve insulin sensitivity by raising oxidative capacity and lowering oxidative stress. Methods: Before and after insulin (4, 40, 100 nmol/l) stimulation, mitochondrial oxidative capacity was measured in permeabilised fibres and isolated mitochondria using high-resolution respirometry, and H2O2 production was assessed fluorimetrically. Tissue-specific insulin sensitivity was measured with hyperinsulinaemic-euglycaemic clamps combined with stable isotopes. To test the second hypothesis, in a 1-day randomised, crossover study, 15 patients with type 2 diabetes recruited via local advertisement were assessed for eligibility. Nine patients fulfilled the inclusion criteria (BMI <35 kg/m2; age <65 years) and were allocated to and completed the intervention, including oral administration of 750 mg placebo or acipimox. Blinded randomisation was performed by the pharmacy; all participants, researchers performing the measurements and those assessing study outcomes were blinded. The main outcome measures were insulin sensitivity, oxidative capacity and oxidative stress. Results: Insulin sensitivity and mitochondrial oxidative capacity were ∼31% and ∼21% lower in the obese groups than in the lean group. The obese participants also exhibited blunted substrate oxidation upon insulin stimulation. In the patients with type 2 diabetes, acipimox improved insulin sensitivity by ∼27% and reduced H2O2 production by ∼45%, but did not improve basal or insulin-stimulated mitochondrial oxidative capacity. No harmful treatment side effects occurred. Conclusions/interpretation: Decreased mitochondrial oxidative capacity can also occur independently of age in insulin-resistant young obese humans. Insulin resistance is present at the muscle mitochondrial level, and is not affected by reducing circulating NEFAs in type 2 diabetes. Thus, impaired plasticity of mitochondrial function is an intrinsic phenomenon that probably occurs independently of lipotoxicity and reduced glucose uptake. Trial registration Clinical Trials NCT00943059 Funding This study was funded in part by a grant from the German Federal Ministry of Education and Research to the German Center for Diabetes Research (DZD e.V.). © 2013 Springer-Verlag Berlin Heidelberg.

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.

Jelenik T.,Institute for Clinical Diabetology | Roden M.,Institute for Clinical Diabetology | Roden M.,Heinrich Heine University Düsseldorf
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.

Karakas M.,University of Ulm | Zierer A.,Helmholtz Center for Environmental Research | Herder C.,Institute for Clinical Diabetology | Baumert J.,Helmholtz Center for Environmental Research | And 3 more authors.
Atherosclerosis | Year: 2010

Objective: Despite modulating a number of metabolic processes linked to atherosclerosis, including glucose regulation, hematopoiesis, fatty acid catabolism and angiogenesis, the potential association of adiponectin and leptin with coronary heart disease is still a matter of controversy. Methods: We conducted a population-based case-cohort study within the MONICA/KORA Augsburg studies. Serum levels of adipokines were measured in 333 case subjects with incident CHD and 1,728 non-case subjects selected from a source population of 9300 middle-aged men and women. Mean follow-up was 10.8 ± 4.6 years. We sought to analyze the association of leptin and adiponectin and their ratio with CHD. Results: After adjustment for various confounding factors the hazard ratios and 95% confidence intervals comparing tertile extremes were 0.79 (0.53-1.17) for leptin (top vs bottom tertile) and 0.87 (0. 62-1.23) for adiponectin (bottom vs top tertile), respectively. Furthermore, the ratio of leptin/adiponectin also showed no association with CHD (HR 1.01 (0.68-1.51)). Conclusions: The present study reports the association of leptin and adiponectin with incident CHD in a large population-based cohort. In contrast to fairly strong associations previously reported, our findings indicate no clinically relevant association between leptin, adiponectin and their ratio with the risk of CHD after adjustment for potential confounders. © 2009 Elsevier Ireland Ltd. All rights reserved.

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.

Marker T.,Institute for Clinical Diabetology | Kriebel J.,Institute for Clinical Diabetology | Wohlrab U.,Institute for Clinical Diabetology | Habich C.,Institute for Clinical Diabetology
Biochemical and Biophysical Research Communications | Year: 2010

Adipocyte-derived mediators contribute to chronic, diabetes-associated inflammation. We recently demonstrated, that heat shock protein 60 (Hsp60) is an effective inductor of inflammatory adipocyte activities. In the present study, we characterized the initial Hsp60 binding to adipocyte receptor structures. Analyses with preadipocytes and adipocytes from the murine 3T3-L1 line and with primary cultures from the New Zealand obese mouse, a model of human obesity, revealed comparable specific, dose-dependent and saturable Hsp60 binding, confirming the characteristics of a ligand-receptor interaction. Furthermore, we identified the N-terminal regions aa1-50 and aa91-110 of the Hsp60 molecule as relevant epitopes involved in binding to receptor structures on these cells. Our results demonstrate differentiation-independent conserved Hsp60 reactivity in permanent and primary adipocytes, strongly indicating that Hsp60 is an important regulator of inflammatory adipocyte activities. © 2010 Elsevier Inc. All rights reserved.

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