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Recent clinical practice guidelines for diabetes, obesity, cardiovascular disease (CVD) and chronic kidney disease (CKD) emphasise a holistic, person-centred approach to care. However, they do not include recommendations for the assessment of patient-reported outcomes (PROs), which would – dependent on the topic of guideline – be important for improving shared decision-making, patients’ concordance with guideline recommendations, clinical outcomes and health-related quality of life (HRQoL). The Taskforce of the Guideline Workshop discussed PROs in diabetes, obesity, CVD and CKD as well as the relevance of their inclusion in clinical practice guidelines for the management of these conditions. Highlights Patient engagement in disease management is a topic that is becoming increasingly important, also in terms of improving clinical outcomes Person-reported outcome measures (PROMs) are tools to assess person-reported outcomes (PROs) in an efficient and standardized manner Validated disease-specific measures for diabetes, obesity, CVD, and CKD as well as generic measures are available Currently underutilised in the routine care of cardio-renal-metabolic diseases, the integration of recommendations on PROs and PROMs into clinical practice guidelines may help to overcome the barriers to their implementation

In recent years, several novel agents have become available to treat individuals with type 2 diabetes (T2D), such as sodium-glucose cotransporter-2 inhibitors (SGLT-2i), tirzepatide, which is a dual glucose-dependent insulinotropic polypeptide receptor agonist (GIP RA)/glucagon-like peptide-1 receptor agonist (GLP-1 RA), and finerenone, a non-steroidal mineralocorticoid receptor antagonist (MRA) that confers significant renal and cardiovascular benefits in individuals with (CKD). New medications have the potential to improve the lives of individuals with diabetes. However, clinicians are challenged to understand the benefits and potential risks associated with these new and emerging treatment options. In this article, we discuss how use of network meta-analyses (NMA) can fill this need.

Saturated, but Not Unsaturated, Fatty Acids Induce Apoptosis of Human Coronary Artery Endothelial Cells via Nuclear Factor-κB Activation Katrin Staiger 1 , Harald Staiger 1 , Cora Weigert 1 , Carina Haas 1 , Hans-Ulrich Häring 1 and Monika Kellerer 1 2 1 Division of Endocrinology, Metabolism, and Pathobiochemistry, Department of Internal Medicine, Eberhard-Karls University Tübingen, Tübingen, Germany 2 Clinic of Diabetology, Endocrinology, Intensive Care Medicine, Vascular Medicine, and Cardiology, Center for Internal Medicine I, Marienhospital Stuttgart, Stuttgart, Germany Address correspondence and reprint requests to Dr. Monika Kellerer, Internal Medicine IV, Medical Clinic, University of Tübingen, Otfried-Müller-Str. 10, D-72076 Tübingen, Germany. E-mail: monikakellerer{at}vinzenz.de Abstract High nonesterified fatty acid (NEFA) concentrations, as observed in the metabolic syndrome, trigger apoptosis of human umbilical vein endothelial cells. Since endothelial apoptosis may contribute to atherothrombosis, we studied the apoptotic susceptibility of human coronary artery endothelial cells (HCAECs) toward selected NEFAs and the underlying mechanisms. HCAECs were treated with single or combined NEFAs. Apoptosis was quantified by flow cytometry, nuclear factor κB (NFκB) activation by electrophoretic mobility shift assay, and secreted cytokines by enzyme-linked immunosorbent assay. Treatment of HCAECs with saturated NEFAs (palmitate and stearate) increased apoptosis up to fivefold ( P < 0.05; n = 4). Unsaturated NEFAs (palmitoleate, oleate, and linoleate) did not promote apoptosis but prevented stearate-induced apoptosis ( P < 0.05; n = 4). Saturated NEFA-induced apoptosis neither depended on ceramide formation nor on oxidative NEFA catabolism. However, NEFA activation via acyl-CoA formation was essential. Stearate activated NFκB and linoleate impaired stearate-induced NFκB activation. Pharmacological inhibition of NFκB and inhibitor of κB kinase (IKK) also blocked stearate-induced apoptosis. Finally, the saturated NEFA effect on NFκB was not attributable to NEFA-induced cytokine production. In conclusion, NEFAs display differential effects on HCAEC survival; saturated NEFAs (palmitate and stearate) are proapoptotic, and unsaturated NEFAs (palmitoleate, oleate, and linoleate) are antilipoapoptotic. Mechanistically, promotion of HCAEC apoptosis by saturated NEFA requires acyl-CoA formation, IKK, and NFκB activation. HCAEC, human coronary artery endothelial cell HUVEC, human umbilical vein endothelial cell IKK, inhibitor of κB kinase IL, interleukin NEFA, nonesterified fatty acid NFκB, nuclear factor κB TNF, tumor necrosis factor Footnotes K.S. and H.S. contributed equally to this work. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted August 15, 2006. Received February 9, 2006. DIABETES

Palmitate-Induced Interleukin-6 Expression in Human Coronary Artery Endothelial Cells Harald Staiger 1 , Katrin Staiger 1 , Norbert Stefan 1 , Hans Günther Wahl 2 , Fausto Machicao 1 , Monika Kellerer 1 3 and Hans-Ulrich Häring 1 1 Department of Endocrinology, Metabolism, and Pathobiochemistry, Medical Clinic, Eberhard-Karls-University, Tübingen, Germany 2 Department of Clinical Chemistry and Molecular Diagnostics, Philipps-University, Marburg, Germany 3 Department of Internal Medicine I, Marienhospital, Stuttgart, Germany Address correspondence and reprint requests to Prof. Dr. med. Hans-Ulrich Häring, Department of Internal Medicine IV, Medical Clinic Tübingen, Otfried-Müller-Str. 10, D-72076 Tübingen, Germany. E-mail: hans-ulrich.haering{at}med.uni-tuebingen.de Abstract Obesity-linked insulin resistance is associated with chronic inflammation and cardiovascular complications. Free fatty acids (FFAs) are prominent candidates for the molecular link between these disorders. In this study, we determined whether FFAs contribute to vascular inflammation via induction of interleukin (IL)-6 in coronary artery endothelial cells (CAECs) and coronary artery smooth muscle cells (CASMCs) and whether this is reflected in vivo. In contrast to our findings regarding IL-6 and gp130 (the glycoprotein of 130 kDa) expression, IL-6 receptor mRNA expression was very low in these cells. Palmitate, but not linoleate, induced a significant increase in IL-6 mRNA expression in CAECs ( P < 0.001) and, to a less relevant extent, in CASMCs ( P < 0.01). gp130 remained unaffected. As to potency, palmitate was comparable with the IL-6−inducer IL-1β. To substantiate our in vitro data, we examined the plasma FFA pattern in 54 healthy human subjects and studied the relation of individual FFAs with plasma IL-6. IL-6 levels correlated with palmitate, but not with other abundant FFAs, even after adjusting for body fat ( r = 0.33, P < 0.05) and total FFAs ( r = 0.29, P < 0.05). We show here that the common plasma FFA palmitate induces high levels of IL-6 in CAECs. Furthermore, palmitate correlates with IL-6 in vivo. This points to a potential contribution of palmitate to vascular inflammation. CAEC, coronary artery endothelial cell CASMC, coronary artery smooth muscle cell ELISA, enzyme-linked immunosorbent assay FFA, free fatty acid gp130, glycoprotein of 130 kDa IL, interleukin IL-6R, interleukin-6 receptor PPAR, peroxisome proliferator−activated receptor TNF-α, tumor necrosis factor-α Footnotes H.S. and K.S. contributed equally to this article. Accepted August 25, 2004. Received January 23, 2004. DIABETES

National and international medical societies have published guidelines and recommendations pertaining to the diagnostics and monitoring of chronic kidney disease in patients with type 2 diabetes mellitus. Consistency and implementation in daily clinical practice are rarely reported.BACKGROUNDNational and international medical societies have published guidelines and recommendations pertaining to the diagnostics and monitoring of chronic kidney disease in patients with type 2 diabetes mellitus. Consistency and implementation in daily clinical practice are rarely reported.This article provides an overview on recommendations as a reflection of the global state of the art and assesses the implementation in daily practice in Germany, which was collected via a representative questionnaire.OBJECTIVEThis article provides an overview on recommendations as a reflection of the global state of the art and assesses the implementation in daily practice in Germany, which was collected via a representative questionnaire.The current guidelines were compared with respect to the consistency of parameters, frequency of testing and recommendations for nephrological referrals. The results were then compared with the survey responses to estimate the level of their implementation in daily practice in Germany.MATERIAL AND METHODSThe current guidelines were compared with respect to the consistency of parameters, frequency of testing and recommendations for nephrological referrals. The results were then compared with the survey responses to estimate the level of their implementation in daily practice in Germany.According to the recommendations the estimated glomerular filtration rate (eGFR) and the urine albumin to creatinine ratio (UACR) should be tested at least once per year in all patients with type 2 diabetes. In cases of more severe kidney impairment (above Kidney Disease:Improving Global Outcomes, KDIGO, stage 3b with eGFR < 45 ml/min/1,73 m2) or albuminuria (from stage A2), more frequent measurements and nephrological referrals are recommended; however, different threshold values and frequencies are recommended. The responses from the questionnaires indicate that eGFR is tested annually in 96.5% of all cases and albuminuria is tested in 77.2% of cases. An eGRF triggered referral to a nephrologist is implemented by 19.6% of all nonnephrological practitioners, albuminuria triggered referrals are implemented in the majority of cases.RESULTSAccording to the recommendations the estimated glomerular filtration rate (eGFR) and the urine albumin to creatinine ratio (UACR) should be tested at least once per year in all patients with type 2 diabetes. In cases of more severe kidney impairment (above Kidney Disease:Improving Global Outcomes, KDIGO, stage 3b with eGFR < 45 ml/min/1,73 m2) or albuminuria (from stage A2), more frequent measurements and nephrological referrals are recommended; however, different threshold values and frequencies are recommended. The responses from the questionnaires indicate that eGFR is tested annually in 96.5% of all cases and albuminuria is tested in 77.2% of cases. An eGRF triggered referral to a nephrologist is implemented by 19.6% of all nonnephrological practitioners, albuminuria triggered referrals are implemented in the majority of cases.Measurement of eGFR is the established standard in Germany. Potential improvement was found in albumin measurement, the frequency of testing and the time point for nephrological consultation. All guidelines emphasize the benefits of interdisciplinary cooperation.CONCLUSIONMeasurement of eGFR is the established standard in Germany. Potential improvement was found in albumin measurement, the frequency of testing and the time point for nephrological consultation. All guidelines emphasize the benefits of interdisciplinary cooperation.

Protein Kinase C δ Activation and Translocation to the Nucleus Are Required for Fatty Acid-Induced Apoptosis of Insulin-Secreting Cells Katrin Eitel 1 , Harald Staiger 1 , Johannes Rieger 2 , Harald Mischak 3 , Heide Brandhorst 4 , Mathias D. Brendel 4 , Reinhard G. Bretzel 4 , Hans-Ulrich Häring 1 and Monika Kellerer 1 1 Internal Medicine IV, University of Tübingen, Tübingen, Germany 2 Department of Neurology, University of Tübingen, Tübingen, Germany 3 Department of Nephrology, University of Hannover, Hannover, Germany 4 Internal Medicine III, University of Giessen, Giessen, Germany Abstract Insulin resistance as well as pancreatic β-cell failure can be induced by elevated free fatty acid (FFA) levels. We studied the mechanisms of FFA-induced apoptosis in rat and human β-cells. Chronic treatment with high physiological levels of saturated fatty acids (palmitate and stearate), but not with monounsaturated (palmitoleate and oleate) or polyunsaturated fatty acids (linoleate), triggers apoptosis in ∼20% of cultured RIN1046-38 cells. Apoptosis restricted to saturated FFAs was also observed in primary cultured human β-cells, suggesting that this mechanism is potentially relevant in vivo in humans. To further analyze FFA-induced signaling pathways leading to apoptosis, we used RIN1046-38 cells. Apoptosis was accompanied by a rapid (within 15 min) nuclear translocation of protein kinase C (PKC)-δ and subsequent lamin B1 disassembly. This translocation was impaired by the phospholipase C inhibitor U-73122, which also substantially reduced apoptosis. Furthermore, lamin B1 disassembly and apoptosis were decreased by cell transfection with a dominant-negative mutant form of PKC-δ. These data suggest that nuclear translocation and kinase activity of PKC-δ are both necessary for saturated fatty acid-induced apoptosis. Footnotes Address correspondence and reprint requests to PD Dr. Monika Kellerer, University of Tübingen, Internal Medicine IV, Otfried-Müller-Str. 10, D-72076 Tübingen, Germany. E-mail: monika.kellerer{at}med.uni-tuebingen.de . Received for publication 9 July 2002 and accepted in revised form 2 January 2003 FFA, free fatty acid; PKC, protein kinase C; PLC, phospholipase C; TUNEL, transferase-mediated dUTP nick-end labeling. DIABETES

Zusammenfassung Hintergrund Nationale und internationale Fachgesellschaften publizieren Leitlinien zur Diagnostik und Verlaufsbeobachtung einer chronischen Nierenerkrankung bei Menschen mit Diabetes mellitus Typ 2. Über die Kongruenz und Implementierung dieser Publikationen im klinischen Alltag wird jedoch selten berichtet. Ziel der Arbeit Diese Arbeit bietet einen Überblick über die Empfehlungen als Ausdruck des globalen Wissensstands und eruiert deren Umsetzung im deutschen Praxisalltag. Dazu wurde eine repräsentative Befragung erhoben. Material und Methoden Aktuelle Leitlinien wurden in Bezug auf Kongruenz der folgenden Aspekte verglichen: diagnostische Parameter, Testfrequenz und Empfehlungen zur nephrologischen Mitbetreuung. Die Ergebnisse wurden im nächsten Schritt mit den Antworten aus der Befragung verglichen. So war es möglich, die Umsetzung im deutschen Praxisalltag einzuschätzen. Ergebnisse Laut Empfehlungen sollten die geschätzte glomeruläre Filtrationsrate (eGFR) und das Albumin-Kreatinin-Verhältnis im Urin mindestens 1‑mal pro Jahr bei allen Menschen mit Diabetes mellitus Typ 2 bestimmt werden. Bei höhergradiger Niereninsuffizienz (ab Kidney-Disease:Improving-Global-Outcomes[KDIGO]-Stadium 3b mit eGFR < 45 ml/min/1,73 m 2 ) bzw. Albuminurie (ab Stadium A2) sind eine häufigere Bestimmung sowie die nephrologische Mitbetreuung empfehlenswert; hier werden jedoch unterschiedliche Schwellenwerte und Frequenzen empfohlen. In der Auswertung der Fragebögen wurde die jährliche Bestimmung der eGFR in 96,5 % aller Fragebögen positiv beantwortet, die Bestimmung der Albuminurie in 77,2 %. Eine eGFR-getriggerte nephrologische Mitbetreuung wird von 19,6 % der nichtnephrologischen Praxen umgesetzt; die Albuminurie-getriggerte Mitbetreuung erfolgt in der Mehrzahl der Fälle. Schlussfolgerungen Die Messung der eGFR ist als Standard in Deutschland etabliert. Verbesserungspotenzial ergibt sich bei Albuminuriemessung, Häufigkeit der Testung und Zeitpunkt der nephrologischen Konsultation. Die interdisziplinäre Zusammenarbeit wird von allen Leitlinien betont.

HintergrundNationale und internationale Fachgesellschaften publizieren Leitlinien zur Diagnostik und Verlaufsbeobachtung einer chronischen Nierenerkrankung bei Menschen mit Diabetes mellitus Typ 2. Über die Kongruenz und Implementierung dieser Publikationen im klinischen Alltag wird jedoch selten berichtet.Ziel der ArbeitDiese Arbeit bietet einen Überblick über die Empfehlungen als Ausdruck des globalen Wissensstands und eruiert deren Umsetzung im deutschen Praxisalltag. Dazu wurde eine repräsentative Befragung erhoben.Material und MethodenAktuelle Leitlinien wurden in Bezug auf Kongruenz der folgenden Aspekte verglichen: diagnostische Parameter, Testfrequenz und Empfehlungen zur nephrologischen Mitbetreuung. Die Ergebnisse wurden im nächsten Schritt mit den Antworten aus der Befragung verglichen. So war es möglich, die Umsetzung im deutschen Praxisalltag einzuschätzen.ErgebnisseLaut Empfehlungen sollten die geschätzte glomeruläre Filtrationsrate (eGFR) und das Albumin-Kreatinin-Verhältnis im Urin mindestens 1‑mal pro Jahr bei allen Menschen mit Diabetes mellitus Typ 2 bestimmt werden. Bei höhergradiger Niereninsuffizienz (ab Kidney-Disease:Improving-Global-Outcomes[KDIGO]-Stadium 3b mit eGFR < 45 ml/min/1,73 m2) bzw. Albuminurie (ab Stadium A2) sind eine häufigere Bestimmung sowie die nephrologische Mitbetreuung empfehlenswert; hier werden jedoch unterschiedliche Schwellenwerte und Frequenzen empfohlen. In der Auswertung der Fragebögen wurde die jährliche Bestimmung der eGFR in 96,5 % aller Fragebögen positiv beantwortet, die Bestimmung der Albuminurie in 77,2 %. Eine eGFR-getriggerte nephrologische Mitbetreuung wird von 19,6 % der nichtnephrologischen Praxen umgesetzt; die Albuminurie-getriggerte Mitbetreuung erfolgt in der Mehrzahl der Fälle.SchlussfolgerungenDie Messung der eGFR ist als Standard in Deutschland etabliert. Verbesserungspotenzial ergibt sich bei Albuminuriemessung, Häufigkeit der Testung und Zeitpunkt der nephrologischen Konsultation. Die interdisziplinäre Zusammenarbeit wird von allen Leitlinien betont.

The interplay between type 1 diabetes (T1D) and concomitant autoimmune diseases (AID) is both clinically and scientifically relevant. In this review, we delineate the epidemiological, pathophysiological and practical aspects underlying polyautoimmunity with a focus on T1D. A comprehensive review of literature on T1D and associated AID was conducted, with the aim of drawing informed conclusions relevant to clinical practice. It draws on a targeted PubMed search conducted March-May 2025, emphasising recent peer-reviewed articles in English. Epidemiological data consistently indicate that individuals with T1D exhibit a significantly increased prevalence of additional AID. Familial aggregation of discordant AID and the concept of polyglandular autoimmune syndromes (PAS) or autoimmune polyendocrinopathy highlight that multiple AID can cluster and occur in a sequential and overlapping fashion, with T1D frequently acting as either an early or a subsequent manifestation. Thereby, genetic susceptibility, environmental triggers and epigenetic factors are pivotal in the initiation and progression of autoimmunity. Clinically, the coexistence of T1D with other AID poses significant challenges in disease management, often necessitating adjustments in therapeutic regimens and careful monitoring to mitigate complications. Early detection via stratified autoantibody testing is important for timely intervention and improved long-term outcomes. Accordingly, screening for T1D-associated autoantibodies in individuals with a personal or family history of AIDs, and vice versa, should be implemented in clinical practice.