Diabetes beeinträchtigt unverändert relevant Lebensqualität und -zeit mit atherosklerotischen Ereignissen als Hauptursache für vorzeitige Mortalität. Natrium-Glukose-Transporter-2-Inhibitoren (SGLT2i) und Glucagon-like-Peptide-1-Rezeptoragonisten (GLP1RA) haben eine neue Ära der Diabetestherapie mit Fokus auf Organprotektion eingeleitet. Darstellung von Strategie, Zielen, Nutzen und Nebenwirkungen eingesetzter neuerer Antidiabetika. Narrative Übersichtsarbeit der aktuellen Empfehlungen und Literatur. GLP1RA und SGLT2i werden zur Organprotektion bei Menschen mit Diabetes (MmD) und atherosklerotischer Erkrankung, Herzinsuffizienz und Nierenerkrankung empfohlen. Während sie vergleichbar effektiv das Risiko für kardiovaskuläre Ereignisse reduzieren, werden SGLT2i zur Protektion vor Hospitalisation aufgrund von Herzinsuffizienz und bevorzugt vor GLP1RA zur Nierenprotektion empfohlen. Inkretinagonisten sollen zum Schutz vor einer metabolisch-assoziierten steatotischen Dysfunktion und bei atherosklerotischer Grunderkrankung eingesetzt werden. GLP1RA und SGLT2i unterscheiden sich in ihrer glukosesenkenden und gewichtsreduzierenden Effektivität mit einem Vorteil bestimmter Inkretinagonisten gegenüber den SGLT2i. Nebenwirkungen wie gastrointestinale Intoleranz unter den GLP1RA sowie Urogenitalinfektionen und die seltene, aber potenziell fatale (euglykäme) diabetische Ketoazidose unter SGLT2i sollten auch bei gefäßchirurgischen Interventionen beachtet werden. Insbesondere Personen mit hohem Risiko profitieren in Anbetracht komplementärer Effekte von einer GLP1RA/SGLT2i-Kombinationstherapie. Die Entwicklungen in der Diabetes-Pharmakotherapie verspricht zukünftig neue Substanzen und eine weiterführende Organprotektion.

Das polyzystische Ovarsyndrom (PCOS) ist die häufigste Endokrinopathie prämenopausaler Frauen. Neben reproduktiven Beeinträchtigungen ist das PCOS mit einem erhöhten Risiko für kardiometabolische Folgeerkrankungen verbunden. Dies umfasst nicht nur das Vorhandensein einer Insulinresistenz und klassischer kardiovaskulärer Risiken wie Typ 2 Diabetes, Adipositas, Dyslipidämie und arterielle Hypertonie, sondern auch die frühe Manifestation kardiovaskulärer Ereignisse sowie eine erhöhte kardiovaskuläre Mortalität. Aus diesem Risiko leiten sich zwei zentrale Aufgaben für die internistisch-diabetologische PCOS-Versorgung ab. Zum einen bedarf es einer strukturierten Sensibilisierung der betroffenen Frauen für dieses spezielle mit PCOS assoziierte kardiometabolische Risiko, um Eigenfürsorge zu ermöglichen. Zum anderen sind die frühzeitige Einleitung eines systematischen Screenings und die individuelle Risikostratifizierung der von PCOS-betroffenen Frauen essenziell, um in Konsequenz identifizierte kardiometabolische Risiken und Erkrankungen rechtzeitig systematisch therapeutisch zu adressieren und das Präventionspotenzial zu nutzen. Ein interdisziplinäres Management, das verschiedene medizinische Fachrichtungen einbezieht, sowie ein stärkeres Bewusstsein um die systemischen Aspekte dieser häufig unterschätzten Erkrankung können dazu beitragen, die kardiometabolische Gesundheit betroffener Frauen entscheidend zu verbessern. Die Empfehlungen der in Kürze erscheinenden nationalen Leitlinie zur Diagnostik und Therapie des PCOS werden bei der Umsetzung einer PCOS-Behandlungsstrategie unterstützen.

Die Pharmakotherapie des polzystischen Ovarsyndroms (PCOS) als Teil eines multimodalen Behandlungskonzeptes ist bedingt durch einige Aspekte, wie dem Off-label-Use, herausfordernd. Die Wahl der Medikation von oralen Kontrazeptiva, Metformin, Antiandrogenen bis zu Folgen- und Komorbiditäten-adressierenden Therapeutika wird in partizipativer Entscheidungsfindung mit der Betroffenen und in Abwägung von substanzspezifischem Nutzen und Nebenwirkungen getroffen. Die Festlegung des Therapiezieles erfolgt unter Berücksichtigung von Symptomausprägung, Leidensdruck und Präferenzen der von PCOS betroffenen Frau, aber auch langfristiger Risiken für Folge- und Begleiterkrankungen wie Adipositas, Diabetes, atherosklerotisch-kardiovaskuläre Erkrankungen und metabolische Dysfunktion assoziierte Lebererkrankung. Im Sinne eines holistischen Ansatzes sollte das gewählte Therapiekonzept dabei in interprofessioneller Abstimmung sowohl gynäkologische als auch internistische Aspekte des PCOS adressieren.

The prevalence of heart failure with preserved ejection fraction (HFpEF) is increasing, while treatment options are inadequate. Hypertension and obesity-related metabolic dysfunction contribute to HFpEF. Nitro-oleic acid (NO2-OA) impacts metabolic syndromes by improving glucose tolerance and adipocyte function. Here we show that treatment with NO2-OA ameliorates diastolic dysfunction and heart failure symptoms in a HFpEF mouse model induced by high-fat diet and inhibition of the endothelial nitric oxide synthase. Proteomic analysis of left ventricular tissue reveals that one-third of identified proteins, predominantly mitochondrial, are upregulated in hearts of NO2-OA-treated HFpEF mice compared to naïve and vehicle-treated HFpEF mice. Increased mitochondrial mass and numbers, and enhanced mitochondrial respiration are linked with this response, as assessed by transmission electron microscopy and high-resolution respirometry. Activation of the 5'-adenosine-monophosphate-activated-protein-kinase (AMPK) signaling pathway mediates the enhancement of mitochondrial dynamics in hearts of NO2-OA-treated HFpEF mice. These findings suggest that targeting mitochondrial function with NO2-OA may represent a promising therapeutic strategy for HFpEF.

BACKGROUND:Glucose overload drives diabetic cardiomyopathy by affecting the tricarboxylic acid pathway. However, it is still unknown how cells could overcome massive chronic glucose influx on cellular and structural level. METHODS/MATERIALS:Expression profiles of hyperglycemic, glucose transporter-4 (GLUT4) overexpressing H9C2 (KE2) cardiomyoblasts loaded with 30 mM glucose (KE230L) and wild type (WT) cardiomyoblasts loaded with 30 mM glucose (WT30L) were compared using proteomics, real-time polymerase quantitative chain reaction analysis, or Western blotting, and immunocytochemistry. RESULTS:The findings suggest that hyperglycemic insulin-sensitive cells at the onset of diabetic cardiomyopathy present complex changes in levels of structural cell-related proteins like tissue inhibitor of metalloproteases-1 (1.3 fold), intercellular adhesion molecule 1 (1.8 fold), type-IV-collagen (3.2 fold), chaperones (Glucose-Regulated Protein 78: 1.8 fold), autophagy (Autophagosome Proteins LC3A, LC3B: 1.3 fold), and in unfolded protein response (UPR; activating transcription factor 6α expression: 2.3 fold and processing: 2.4 fold). Increased f-actin levels were detectable with glucose overload by immnocytochemistry. Effects on energy balance (1.6 fold), sirtuin expression profile (Sirtuin 1: 0.7 fold, sirtuin 3: 1.9 fold, and sirtuin 6: 4.2 fold), and antioxidant enzymes (Catalase: 0.8 fold and Superoxide dismutase 2: 1.5 fold) were detected. CONCLUSION:In conclusion, these findings implicate induction of chronic cell distress by sustained glucose accumulation with a non-compensatory repair reaction not preventing final cell death. This might explain the chronic long lasting pathogenesis observed in developing heart failure in diabetes mellitus.

Islet amyloid polypeptide (IAPP) is co-secreted with insulin from pancreatic ß-cells. Its oligomerisation is regarded as disease driving force in type 2 diabetes (T2D) pathology. Up to now, IAPP oligomers have been detected in affected tissues. IAPP oligomer concentrations in blood have not been analysed so far. Using the IAPP single-oligomer-sensitive and monomer-insensitive surface-based fluorescence intensity distribution analysis (sFIDA) technology, levels of IAPP oligomers in blood plasma from healthy controls and people with T2D in different disease stages where determined. Subsequently, the level of IAPP oligomerisation was introduced as the ratio between the IAPP oligomers determined with sFIDA and the total IAPP concentration determined with ELISA. Highest oligomerisation levels were detected in plasma of people with T2D without late complication and without insulin therapy. Their levels stand out significantly from the control group. Healthy controls presented with the lowest oligomerisation levels in plasma. In people with T2D without complications, IAPP oligomerisation levels correlated with disease duration. The results clearly demonstrate that IAPP oligomerisation in insulin-naïve patients correlates with duration of T2D. Although a correlation per se does not identify, which is cause and what is consequence, this result supports the hypothesis that IAPP aggregation is the driving factor of T2D development and progression. The alternative and conventional hypothesis explains development of T2D with increasing insulin resistance causing exhaustion of pancreatic ß-cells due to over-secretion of insulin, and thus IAPP, too, resulting in subsequent IAPP aggregation and fibril deposition in the pancreas. Further experiments and comparative analyses with primary tissues are warranted.

Osteomyelitis in Zusammenhang mit dem Diabetisches Fußsyndrom stellt in der derzeitigen klinischen Praxis ein komplexes Problem dar. Nach angiologischer Intervention wird oftmals ein chirurgischer Eingriff empfohlen. Ein möglicher Abheilungsversuch unter konservativem Procedere mit Gliedmaßenerhalt wird somit oftmals umgangen, was die Zahl von Major-Amputationen erhöht.

Multimorbidity, polypharmacy and malnutrition are special challenges in the care of geriatric patients with diabetes mellitus and must be considered in perioperative management. The metabolic response to anesthesia, surgical intervention and the postoperative course is markedly different from that of a metabolically healthy person of similar age. Optimal glucose management in the perioperative phase is controversial. Moderate and individual blood glucose control before surgery is recommended. Close correction of hyperglycemia by intraoperative insulin administration reduces the complication rate. The risk of postoperative complications and increased mortality depends on the quality of acute and chronic glycemic control. The prevalence, diagnosis and pathophysiology of perioperative hyperglycemia form the basis of this article, which also aims to provide a practical overview of the management of geriatric surgical patients with diabetes mellitus and hyperglycemia.

Aims Cold atmospheric plasma (CAP) has been proven to enhance wound healing in superficial, chronically infected, diabetic foot ulcers. We aimed to investigate the molecular drivers responsible for this macroscopically observed improvement in diabetic wound healing. Methods Wound exudate was available from each change of dressing within a prospective, randomised, patient-blinded clinical trial. Specific protein level analyses were conducted via multiplex ELISA for wound samples of a representative subcohort (placebo: n = 13; CAP: n = 14). Expression of fibroblast growth factor 2 (FGF-2), vascular endothelial growth factor A (VEGF-A), cytokines and matrix metalloproteinases (MMPs) were evaluated over a treatment period of about 14 days. Results Analysis revealed increased levels of the growth factors FGF-2 (placebo: median 46.9 range [32.0-168.6] AU vs. CAP: 113.7[55.8-208.1] AU) and VEGF-A (placebo: 79.7 [52.4-162.7] AU vs. CAP: 120.8 [51.1-198.1] AU) throughout the treatment period and in head-to-head comparison in a daily assessment. CAP-treated wounds showed increased levels of tumour necrosis factor-alpha, interleukins 1 alpha and 8. However, the total protein amounts were not significantly elevated. The total protein amounts of MMPs were not altered by CAP. Conclusions Induction of crucial growth factors, like FGF-2 and VEGF-A, and interleukins appears to be an important component of CAP-mediated promotion of granulation, vascularisation and reepithelialisation in the diabetic foot. These findings demonstrate for the first time that CAP-mediated growth factor induction also occurs in persons with diabetes, as previously described only in several in vitro and rodent experiments.

The assessment of the corneal nerve fibre plexus with corneal confocal microscopy (CCM) is an upcoming but still experimental method in the diagnosis of early stage diabetic peripheral neuropathy (DPN). Using an innovative imaging technique—Heidelberg Retina Tomograph equipped with the Rostock Cornea Module (HRT-RCM) and EyeGuidance module (EG)—we were able to look at greater areas of subbasal nerve plexus (SNP) in order to increase the diagnostic accuracy. The aim of our study was to evaluate the usefulness of EG instead of single image analysis in diagnosis of early stage DPN. This prospective study was performed on 60 patients with type 2 diabetes mellitus, classified equally into two subgroups based on neuropathy deficient score (NDS): patients without DPN (group 1) or with mild DPN (group 2). The following parameters were analysed in the two subgroups: corneal nerve fibre length (CNFL; mm/mm2), corneal nerve fibre density (CNFD; no./mm2), corneal nerve branch density (CNBD; no./mm2). Furthermore, we compared the data calculated with the novel mosaic, EG-based method with those received from single image analysis using different quantification tools. Using EG we did not find a significant difference between group 1 and group 2: CNFL (16.81 ± 5.87 mm/mm2 vs. 17.19 ± 7.19 mm/mm2, p = 0.895), CNFD (254.05 ± 115.36 no./mm2 vs. 265.91 ± 161.63 no./mm2, p = 0.732) and CNBD (102.68 ± 62.28 no./mm2 vs. 115.38 ± 96.91 no./mm2, p = 0.541). No significant difference between the EG method of analysing the SNP and the single image analysis of 10 images per patient was detected. On the basis of our results it was not possible to differentiate between early stages of large nerve fibre DPN in patients with type 2 diabetes mellitus via SNP analysis. To improve sensitivity and specificity of this method newer technologies are under current evaluation. ClinicalTrials.gov Identifier NCT05326958.

Late vascular complications play a prominent role in the diabetes-induced increase in morbidity and mortality. Diabetes mellitus is recognised as a risk factor driving atherosclerosis and cardiovascular mortality; even after the normalisation of blood glucose concentration, the event risk is amplified-an effect called "glycolytic memory". The hallmark of this glycolytic memory and diabetic pathology are advanced glycation end products (AGEs) and reactive glucose metabolites such as methylglyoxal (MGO), a highly reactive dicarbonyl compound derived mainly from glycolysis. MGO and AGEs have an impact on vascular and organ structure and function, contributing to organ damage. As MGO is not only associated with hyperglycaemia in diabetes but also with other risk factors for diabetic vascular complications such as obesity, dyslipidaemia and hypertension, MGO is identified as a major player in the development of vascular complications in diabetes both on micro- as well as macrovascular level. In diabetes mellitus, the detoxifying system for MGO, the glyoxalase system, is diminished, accounting for the increased MGO concentration and glycotoxic load. This overview will summarise current knowledge on the effect of MGO and AGEs on vascular function.

Kardiovaskuläre Erkrankungen sind bei Patienten mit Diabetes mellitus Typ 1 hauptursächlich für deren erhöhte Morbidität und Mortalität, auch in jüngeren Lebensjahren. Dieses erhöhte Risiko bleibt auch nach einer therapeutischen Normalisierung des Stoffwechsels bestehen. Die klassischen, aus dem Typ-2-Diabetes bekannten Risikomechanismen können nicht immer für eine Vorhersage des Risikos bei Typ-1-Diabetes herangezogen werden, sodass weiterhin viele Fragen offen bleiben. Insbesondere ist die nach dem optimalen Beginn und der Aggressivität des Risikofaktorenmanagements noch nicht beantwortet. Unbestritten ist aber die Abhängigkeit eines kardiovaskulären Risikos von der Güte der Stoffwechseleinstellung und der Dauer des Diabetes. Ziel des vorliegenden Beitrags ist, das kardiovaskuläre Risiko in der 4.–6. Lebensdekade eines Patienten mit Diabetes mellitus Typ 1 zu erarbeiten und zu bewerten.

Cardiovascular disease is the main cause of increased morbidity and mortality in patients with type 1 Diabetes mellitus, even in younger age groups. This increased risk remains even after metabolic normalization. The classical risk mechanisms known from type 2 diabetes events are not always effective in predicting the risk in type 1 diabetes, so that many open questions remain. In particular, the question of optimal onset and aggressiveness of risk factor management has not yet been answered. However, the dependence of cardiovascular risk on the quality of metabolic control and the duration of diabetes is undisputed. In the following, the aim is to work out and evaluate the cardiovascular risk in the 4th-6th decade of life of a patient with type 1 diabetes mellitus.

Einleitung Die diabetische Kardiomyopathie ist gekennzeichnet durch den Verlust der metabolischen Flexibilität bei gleichzeitigem Überangebot der einzelnen Nahrungskomponenten. Durch die verminderte Aktivität der Stoffwechselwege erfährt das diabetische Herz eine Energieverarmung. Hohe Glukosegehalte bremsen die Fettsäureoxidation, hohe Fettsäurekonzentrationen hemmen die Glykolyse. Zur Untersuchung dieser Effekte wurde basierend auf der Zelllinie H9C2 eine GLUT4-überexprimierende Zelllinie (H9C2KE2) entwickelt. Diese zeigt bei Hyperglykämie wesentliche Charakteristika der diabetischen Kardiomyopathie.

An oversupply of nutrients with a loss of metabolic flexibility and subsequent cardiac dysfunction are hallmarks of diabetic cardiomyopathy. Even if excess substrate is offered, the heart suffers energy depletion as metabolic fluxes are diminished. To study the effects of a high glucose supply, a stably glucose transporter type 4 (GLUT4)-overexpressing cell line presenting an onset of diabetic cardiomyopathy-like phenotype was established. Long-term hyperglycaemia effects were analysed. Rat cardiomyoblasts overexpressing GLUT4 (H9C2KE2) were cultured under normo- and hyperglycaemic conditions for long-term. Expression profiles of several proteins were compared to non-transfected H9C2 cells (H9C2) using RT-qPCR, proteomics-based analysis, or Western blotting. GLUT4 surface analysis, glucose uptake, and cell morphology changes as well as apoptosis/necrosis measurements were performed using flow cytometry. Additionally, brain natriuretic peptide (BNP) levels, reactive oxygen species (ROS) formation, glucose consumption, and lactate production were quantified. Long-term hyperglycaemia in H9C2KE2 cells induced increased GLUT4 presence on the cell surface and was associated with exaggerated glucose influx and lactate production. On the metabolic level, hyperglycaemia affected the tricarboxylic acid (TCA) cycle with accumulation of fumarate. This was associated with increased BNP-levels, oxidative stress, and lower antioxidant response, resulting in pronounced apoptosis and necrosis. Chronic glucose overload in cardiomyoblasts induced by GLUT4 overexpression and hyperglycaemia resulted in metabolically stimulated proteome profile changes and metabolic alterations on the TCA level.