Sex hormones differently regulate lipid metabolism genes in primary human hepatocytes.

Background: Prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is higher in men than in women. Hormonal and genetic causes may account for the sex differences in MASLD. Current human in vitro liver models do not sufficiently take the influence of biological sex and sex hormones into consideration.

Cell atlas of the regenerating human liver after portal vein embolization.

The liver has the remarkable capacity to regenerate. In the clinic, regeneration is induced by portal vein embolization, which redirects portal blood flow, resulting in liver hypertrophy in locations with increased blood supply, and atrophy of embolized segments. Here, we apply single-cell and single-nucleus transcriptomics on healthy, hypertrophied, and atrophied patient-derived liver samples to explore cell states in the regenerating liver.

Positive allosteric GABA receptor modulation counteracts lipotoxicity-induced gene expression changes in hepatocytes .

We have previously shown that the novel positive allosteric modulator of the GABA receptor, HK4, exerts hepatoprotective effects against lipotoxicity-induced apoptosis, DNA damage, inflammation and ER stress This might be mediated by downregulated phosphorylation of the transcription factors NF-κB and STAT3. The current study aimed to investigate the effect of HK4 on lipotoxicity-induced hepatocyte injury at the transcriptional level. HepG2 cells were treated with palmitate (200 μM) in the presence or absence of HK4 (10 μM) for 7 h.

Selective ablation of P53 in pancreatic beta cells fails to ameliorate glucose metabolism in genetic, dietary and pharmacological models of diabetes mellitus.

Objective: Beta cell dysfunction and death are critical steps in the development of both type 1 and type 2 diabetes (T1D and T2D), but the underlying mechanisms are incompletely understood. Activation of the essential tumor suppressor and transcription factor P53 (also known as TP53 and Trp53 in mice) was linked to beta cell death in vitro and has been reported in several diabetes mouse models and beta cells of humans with T2D. In this article, we set out to determine the beta cell specific role of P53 in beta cell dysfunction, cell death and development of diabetes in vivo.

Positive allosteric γ-aminobutyric acid type A receptor modulation prevents lipotoxicity-induced injury in hepatocytes in vitro.

Aim: To determine if a novel positive allosteric modulator of the γ-aminobutyric acid type A (GABA ) receptor, the thioacrylamide-derivative HK4, which does not penetrate the blood-brain barrier, protects human hepatocytes against lipotoxicity-induced injury.

Materials And Methods: Allosteric modulation of the GABA receptor by HK4 was determined by patch clamp in HEK-293 cells, calcium influx in INS-1E cells and by using the specific GABA channel blockers picrotoxin and tert-butylbicyclophosphorothionate (TBPS) in HepG2 cells. Apoptosis was analysed using caspase 3/7, terminal deoxynucleotidyl transferase-dUTP nick end labelling (TUNEL) and array assays in HepG2 cells and/or human primary hepatocytes.

Genetic Etiologies for Chronic Kidney Disease Revealed through Next-Generation Renal Gene Panel.

Introduction: Chronic kidney disease (CKD) is a major public health issue in the USA. Identification of monogenic causes of CKD, which are present in ∼10% of adult cases, can impact prognosis and patient management. Broad gene panels can provide unbiased testing approaches, which are advantageous in phenotypically heterogeneous diseases.

Polymorphism Is Associated With Physical Activity-Mediated Metabolic Changes in Type 2 Diabetes.

Unlabelled: The rs540467 SNP in the gene, encoding a mitochondrial complex I subunit, has been shown to modulate adaptations to exercise training. Interaction effects with diabetes mellitus remain unclear. We assessed associations of habitual physical activity (PA) levels with metabolic variables and examined a possible modifying effect of the rs540467 SNP.

Organ Crosstalk and the Modulation of Insulin Signaling.

A highly complex network of organ communication plays a key role in regulating metabolic homeostasis, specifically due to the modulation of the insulin signaling machinery. As a paradigm, the role of adipose tissue in organ crosstalk has been extensively investigated, but tissues such as muscles and the liver are equally important players in this scenario. Perturbation of organ crosstalk is a hallmark of insulin resistance, emphasizing the importance of crosstalk molecules in the modulation of insulin signaling, potentially leading to defects in insulin action.

Cannabinoid Receptors in Metabolic Regulation and Diabetes.

There is an urgent need for developing effective drugs to combat the obesity and Type 2 diabetes mellitus epidemics. The endocannabinoid system plays a major role in energy homeostasis. It comprises the cannabinoid receptors 1 and 2 (CB and CB), endogenous ligands called endocannabinoids and their metabolizing enzymes.

DPP4 and ACE2 in Diabetes and COVID-19: Therapeutic Targets for Cardiovascular Complications?

COVID-19 outbreak, caused by severe acute respiratory syndrome (SARS)-CoV-2 coronavirus has become an urgent health and economic challenge. Diabetes is a risk factor for severity and mortality of COVID-19. Recent studies support that COVID-19 has effects beyond the respiratory tract, with vascular complications arising as relevant factors worsening its prognosis, then making patients with previous vascular disease more prone to severity or fatal outcome.

DPP4 deletion in adipose tissue improves hepatic insulin sensitivity in diet-induced obesity.

Besides a therapeutic target for type 2 diabetes, dipeptidyl peptidase 4 (DPP4) is an adipokine potentially upregulated in human obesity. We aimed to explore the role of adipocyte-derived DPP4 in diet-induced obesity and insulin resistance with an adipose tissue-specific knockout (AT-DPP4-KO) mouse. Wild-type and AT-DPP4-KO mice were fed for 24 wk with a high fat diet (HFD) and characterized for body weight, glucose tolerance, insulin sensitivity by hyperinsulinemic-euglycemic clamp, and body composition and hepatic fat content.

An explorative vs. traditional practical course: how to inspire scientific thinking in medical students.

Recently, medical students' scientific thinking skills have been identified as an important issue in medical education. Scientific thinking cannot be imparted in conventional lectures, but rather requires actively involving students. We modified a practical course in physiology.

Myokines in metabolic homeostasis and diabetes.

Physical activity exerts multiple beneficial effects and the myokine concept provides a framework for understanding the molecular pathways that integrate contracting muscle in the complex network of organ communication. This network includes multiple distinct and distal organs; however, the autocrine and paracrine effects of myokines within skeletal muscle (in which they are produced) also need specific attention. In humans, the functional allocation of myokines remains limited and recent findings on fibre type-specific myokine signatures point to an additional level of complexity.

Adipokines and inflammatory markers in elderly subjects with high risk of type 2 diabetes and cardiovascular disease.

Inflammation plays a significant role in pathogenesis of diabetes and atherosclerosis. Increased adiposity with an upregulation of cytokines in prediabetes has been associated with vascular inflammation and considered a leading causal factor for type 2 diabetes (T2D). Information on adipokines and inflammatory markers in prediabetes, defined by hemoglobin A1C (HbA1c) 5.

Heat Shock Protein 60 in Obesity: Effect of Bariatric Surgery and its Relation to Inflammation and Cardiovascular Risk.

Objective: Heat shock protein 60 (Hsp60) is an adipokine, and its serum concentrations are higher in patients with obesity compared to lean patients. This study aimed to analyze the effect of bariatric surgery on circulating concentrations of Hsp60 in morbid obesity and their correlation with inflammation and metabolic and cardiovascular risk.

Methods: Fifty-three females with morbid obesity undergoing bariatric surgery were enrolled.

Hypoxia in Combination With Muscle Contraction Improves Insulin Action and Glucose Metabolism in Human Skeletal Muscle via the HIF-1α Pathway.

Skeletal muscle insulin resistance is the hallmark of type 2 diabetes and develops long before the onset of the disease. It is well accepted that physical activity improves glycemic control, but the knowledge on underlying mechanisms mediating the beneficial effects remains incomplete. Exercise is accompanied by a decrease in intramuscular oxygen levels, resulting in induction of HIF-1α.

The inventory as a core element in the further development of the science curriculum in the Mannheim Reformed Curriculum of Medicine.

The German Council of Science and Humanities as well as a number of medical professional associations support the strengthening of scientific competences by developing longitudinal curricula for teaching scientific competences in the undergraduate medical education. The National Competence Based Catalogue of Learning Objectives for Undergraduate Medical Education (NKLM) has also defined medical scientific skills as learning objectives in addition to the role of the scholar. The development of the Mannheim science curriculum started with a systematic inventory of the teaching of scientific competences in the Mannheim Reformed Curriculum of Medicine (MaReCuM).

Insulin115: A novel ultra-long-acting basal insulin with a unique action profile.

Aims: To conduct a comprehensive pre-clinical study of the novel ultra-long acting insulin analogue Insulin115.

Methods: Pharmacokinetic/pharmacodynamic studies comparing Insulin115 with other basal insulins were conducted in genetically diabetic (db/db) mice. Insulin signalling in the major target organs was analysed using Western blot after single subcutaneous injection in wild-type male Wistar rats.

Protease-Activated Receptor 2 Promotes Pro-Atherogenic Effects through Transactivation of the VEGF Receptor 2 in Human Vascular Smooth Muscle Cells.

Obesity is associated with impaired vascular function. In the cardiovascular system, protease-activated receptor 2 (PAR2) exerts multiple functions such as the control of the vascular tone. In pathological conditions, PAR2 is related to vascular inflammation.

Electrical pulse stimulation of cultured skeletal muscle cells as a model for in vitro exercise - possibilities and limitations.

The beneficial health-related effects of exercise are well recognized, and numerous studies have investigated underlying mechanism using various in vivo and in vitro models. Although electrical pulse stimulation (EPS) for the induction of muscle contraction has been used for quite some time, its application on cultured skeletal muscle cells of animal or human origin as a model of in vitro exercise is a more recent development. In this review, we compare in vivo exercise and in vitro EPS with regard to effects on signalling, expression level and metabolism.

Effect of the long-acting insulin analogues glargine and degludec on cardiomyocyte cell signalling and function.

Background: The effects of insulin on cardiomyocytes, such as positive inotropic action and glucose uptake are well described. However, in vitro studies comparing long-acting insulin analogues with regard to cardiomyocyte signalling and function have not been systematically conducted.

Methods: Insulin receptor (IR) binding was assessed using membrane embedded and solubilised IR preparations.

Eicosapentaenoic acid and arachidonic acid differentially regulate adipogenesis, acquisition of a brite phenotype and mitochondrial function in primary human adipocytes.

Scope: n-3 and n-6 PUFAs have several opposing biological effects and influence white adipose tissue (WAT) function. The recent discovery of thermogenic UCP1-expressing brite adipocytes within WAT raised the question whether n-3 and n-6 PUFAs exert differential effects on brite adipocyte formation and mitochondrial function.

Methods And Results: Primary human preadipocytes were treated with n-3 PUFAs (eicosapentaenoic acid, EPA; docosahexaenoic acid, DHA) or n-6 PUFA (arachidonic acid, ARA) during differentiation, and adipogenesis, white and brite gene expression markers, mitochondrial content and function were analyzed at day 12 of differentiation.

Soluble dipeptidyl peptidase-4 induces microvascular endothelial dysfunction through proteinase-activated receptor-2 and thromboxane A2 release.

Background: Dipeptidyl peptidase-4 (DPP4) is a key protein in glucose homeostasis and a pharmacological target in type 2 diabetes mellitus. This study explored whether the novel adipokine soluble DPP4 (sDPP4) can cause endothelial dysfunction, an early marker of impaired vascular reactivity.

Method: Reactivity was studied in mesenteric arteries from 3-month-old female mice, using a small vessel myograph.