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MariettaStadler*,†,‡,AngelaStorka§,EvaAnnaTheuer†,MichaelKrebs–,ElenaVojtassakova§,PeterNowotny–,GiovanniPacini**,ThomasKa¨stenbauer†,AntonLuger–,RudolfPrager*,†,MichaelWolzt§andChristianAnderwald§,–*HietzingHospital,ThirdMedicalDepartmentofMetabolicDiseasesandNephrology,Vienna,Austria,†KarlLandsteinerInstituteofMetabolicDiseasesandNephrology,Vienna,Austria,‡MedicalUniversityVienna,DepartmentofEmergencyMedicine,Vienna,Austria,§MedicalUniversityVienna,DepartmentofClinicalPharmacology,Vienna,Austria,–MedicalUniversityVienna,DivisionofEndocrinologyandMetabolism,DepartmentofInternalMedicine3,Vienna,Austria,**MetabolicUnit,InstituteofBiomedicalEngineering,ISIB-CNR,Padua,ItalySummaryObjectiveIntype1diabetesmellitus(T1DM),thereleaseofmanyhormones, not only from beta-cells, but also from adipocytes(adipokines) may be altered. After successful pancreas–kidney-transplantation(PKTx),T1DMpatientscanreverttoanondiabeticmetabolism, but it is unclear whether alterations of adipokines arestillpresentafterPKTx.Design, patients and measurementsConcentrations ofadipokines [visfatin, retinol-binding protein-4 (RBP-4), adiponec-tin, high molecular weight (HMW) adiponectin] were measured atfasting in 10 PKTx and in 19 T1DM. Nondiabetic healthy controls(CON, n = 9) and six nondiabetic patients after kidney transplan-tation (KTx) were examined as control groups. In PKTx, KTx andCON, indices of insulin sensitivity (OGIS) and beta cell function(adaptationindex,AI)werecalculatedfrom75 goralglucosetoler-ancetest(OGTT)data.Results Fasting serum visfatin (T1DM: 56 ± 4 lg/l, PKTx:42 ± 6 lg/l, KTx: 39 ± 3 lg/l, CON: 40 ± 3 lg/l) and RBP-4(T1DM: 490 ± 26 lg/l, PKTx: 346 ± 39 lg/l, KTx: 401 ± 13 lg/l,CON: 359 ± 36 lg/l) was increased by 40% and 36%, respectively(each P

Background Angiotensin converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB) exhibit beneficial antidiabetic effects in patients with type 2 diabetes independent of their blood pressure-lowering effects. Some antidiabetic properties of ARB and ACE-I might by exerted by activation of peroxisome proliferator-activated receptor gamma (PPARgamma). However, it is not clear whether this action is drug specific. Materials and methods The binding affinity of telmisartan, valsartan, lisinopril, rosiglitazone and angiotensin II to PPARgamma was assessed in a cell-free assay system. PPARgamma signalling was studied in isolated skeletal muscle cells using Western blot analysis of phosphorylated protein kinase B (pAKT) and phosphorylated insulin like growth factor-1 receptor (pILGF-1R). Further, the ability of the drugs under study to stimulate the release of the adipocytokine visfatin was investigated in isolated human adipocytes, skeletal muscle cells, and umbilical vein endothelial cells (HUVEC). Results The binding affinity to PPARgamma was highest for telmisartan with a half-maximal effective concentration of 463 nM, followed by lisinopril (2.9 microM) and valsartan (6.2 microM). In skeletal muscle cells phosphorylation of ILGF-1R was 2-fold increased after incubation with telmisartan or valsartan and 1.7-fold with lisinopril. pAKT expression was enhanced after incubation with telmisartan, valsartan and with lisinopril. The release of visfatin from adipocytes was 1.6-fold increased after treatment with lisinopril and about 2.0-fold increased with telmisartan and valsartan. Similar results were obtained in skeletal muscle cells and HUVEC. Conclusions Our data confirm agonism of telmisartan, valsartan and lisinopril on PPARgamma. Pharmacokinetic differences may explain different potencies of PPARgamma stimulation by drugs acting on the renin-angiotensin system in clinical settings.

The insulin-mimetic adipocytokine visfatin has been associated with insulin resistance in some studies and is regulated by glucose. We hypothesized that glucose-induced changes in plasma visfatin are different in women with gestational diabetes mellitus (GDM). Plasma visfatin concentrations were studied in 10 women with GDM and 10 age-matched healthy women in pregnancy week 24-28 during a standard oral glucose tolerance test (OGTT). Women with GDM had lower systemic visfatin concentrations than controls (1.9±0.8 ng/ml vs 5.2±4.4 ng/ml, respectively, p

In type 1 diabetes mellitus (T1DM), the release of many hormones, not only from beta-cells, but also from adipocytes (adipokines) may be altered. After successful pancreas-kidney-transplantation (PKTx), T1DM patients can revert to a nondiabetic metabolism, but it is unclear whether alterations of adipokines are still present after PKTx.Concentrations of adipokines [visfatin, retinol-binding protein-4 (RBP-4), adiponectin, high molecular weight (HMW) adiponectin] were measured at fasting in 10 PKTx and in 19 T1DM. Nondiabetic healthy controls (CON, n = 9) and six nondiabetic patients after kidney transplantation (KTx) were examined as control groups. In PKTx, KTx and CON, indices of insulin sensitivity (OGIS) and beta cell function (adaptation index, AI) were calculated from 75 g oral glucose tolerance test (OGTT) data.Fasting serum visfatin (T1DM: 56 +/- 4 microg/l, PKTx: 42 +/- 6 microg/l, KTx: 39 +/- 3 microg/l, CON: 40 +/- 3 microg/l) and RBP-4 (T1DM: 490 +/- 26 microg/l, PKTx: 346 +/- 39 microg/l, KTx: 401 +/- 13 microg/l, CON: 359 +/- 36 microg/l) was increased by 40% and 36%, respectively (each P0.03) in T1DM only. Levels were positively correlated with HbA1c in all subjects (visfatin: r = 0.43, P0.004; RBP-4: r = 0.46, P0.03). Fasting plasma adiponectin was 80% higher in T1DM and in PKTx (T1DM: 18 +/- 2 mg/l, PKTx: 18 +/- 3 mg/l, KTx: 12 +/- 3 mg/l, CON: 10 +/- 1 mg/l; P0.04) and was positively correlated with diabetes duration (r = 0.37, P0.02). HMW/total adiponectin ratio was increased in T1DM (P0.02). PKTx displayed a normoglycaemic metabolism as insulin sensitive as CON, but AI was lower than in CON and KT (P0.01).T1DM after successful PKTx show normal fasting visfatin and RBP-4 levels and HMW-adiponectin/adiponectin-ratio, which are elevated in T1DM, whereas total adiponectin levels are similarly increased in T1DM and PKTx patients.