Loci for insulin processing and secretion provide insight into type 2 diabetes risk.

Insulin secretion is critical for glucose homeostasis, and increased levels of the precursor proinsulin relative to insulin indicate pancreatic islet beta-cell stress and insufficient insulin secretory capacity in the setting of insulin resistance. We conducted meta-analyses of genome-wide association results for fasting proinsulin from 16 European-ancestry studies in 45,861 individuals. We found 36 independent signals at 30 loci (p value < 5 × 10-8), which validated 12 previously reported loci for proinsulin and ten additional loci previously identified for another glycemic trait. Half of the alleles associated with higher proinsulin showed higher rather than lower effects on glucose levels, corresponding to different mechanisms. Proinsulin loci included genes that affect prohormone convertases, beta-cell dysfunction, vesicle trafficking, beta-cell transcriptional regulation, and lysosomes/autophagy processes. We colocalized 11 proinsulin signals with islet expression quantitative trait locus (eQTL) data, suggesting candidate genes, including ARSG, WIPI1, SLC7A14, and SIX3. The NKX6-3/ANK1 proinsulin signal colocalized with a T2D signal and an adipose ANK1 eQTL signal but not the islet NKX6-3 eQTL. Signals were enriched for islet enhancers, and we showed a plausible islet regulatory mechanism for the lead signal in the MADD locus. These results show how detailed genetic studies of an intermediate phenotype can elucidate mechanisms that may predispose one to disease.

vPIF-1 is an insulin-like antiferroptotic viral peptide.

Iridoviridae, such as the lymphocystis disease virus-1 (LCDV-1) and other viruses, encode viral insulin-like peptides (VILPs) which are capable of triggering insulin receptors (IRs) and insulin-like growth factor receptors. The homology of VILPs includes highly conserved disulfide bridges. However, the binding affinities to IRs were reported to be 200- to 500-fold less effective compared to the endogenous ligands. We therefore speculated that these peptides also have noninsulin functions. Here, we report that the LCDV-1 VILP can function as a potent and highly specific inhibitor of ferroptosis. Induction of cell death by the ferroptosis inducers erastin, RSL3, FIN56, and FINO2 and nonferroptotic necrosis produced by the thioredoxin-reductase inhibitor ferroptocide were potently prevented by LCDV-1, while human insulin had no effect. Fas-induced apoptosis, necroptosis, mitotane-induced cell death and growth hormone-releasing hormone antagonist-induced necrosis were unaffected, suggesting the specificity to ferroptosis inhibition by the LCDV-1 VILP. Mechanistically, we identified the viral C-peptide to be required for inhibition of lipid peroxidation and ferroptosis inhibition, while the human C-peptide exhibited no antiferroptotic properties. In addition, the deletion of the viral C-peptide abolishes radical trapping activity in cell-free systems. We conclude that iridoviridae, through the expression of insulin-like viral peptides, are capable of preventing ferroptosis. In analogy to the viral mitochondrial inhibitor of apoptosis and the viral inhibitor of RIP activation (vIRA) that prevents necroptosis, we rename the LCDV-1 VILP a viral peptide inhibitor of ferroptosis-1. Finally, our findings indicate that ferroptosis may function as a viral defense mechanism in lower organisms.

Bariatric-metabolic surgery versus lifestyle intervention plus best medical care in non-alcoholic steatohepatitis (BRAVES): a multicentre, open-label, randomised trial.

BACKGROUND: Observational studies suggest that bariatric-metabolic surgery might greatly improve non-alcoholic steatohepatitis (NASH). However, the efficacy of surgery on NASH has not yet been compared with the effects of lifestyle interventions and medical therapy in a randomised trial. METHODS: We did a multicentre, open-label, randomised trial at three major hospitals in Rome, Italy. We included participants aged 25-70 years with obesity (BMI 30-55 kg/m2), with or without type 2 diabetes, with histologically confirmed NASH. We randomly assigned (1:1:1) participants to lifestyle modification plus best medical care, Roux-en-Y gastric bypass, or sleeve gastrectomy. The primary endpoint of the study was histological resolution of NASH without worsening of fibrosis at 1-year follow-up. This study is registered at ClinicalTrials.gov, NCT03524365. FINDINGS: Between April 15, 2019, and June 21, 2021, we biopsy screened 431 participants; of these, 103 (24%) did not have histological NASH and 40 (9%) declined to participate. We randomly assigned 288 (67%) participants with biopsy-proven NASH to lifestyle modification plus best medical care (n=96 [33%]), Roux-en-Y gastric bypass (n=96 [33%]), or sleeve gastrectomy (n=96 [33%]). In the intention-to-treat analysis, the percentage of participants who met the primary endpoint was significantly higher in the Roux-en-Y gastric bypass group (54 [56%]) and sleeve gastrectomy group (55 [57%]) compared with lifestyle modification (15 [16%]; p<0·0001). The calculated probability of NASH resolution was 3·60 times greater (95% CI 2·19-5·92; p<0·0001) in the Roux-en-Y gastric bypass group and 3·67 times greater (2·23-6·02; p<0·0001) in the sleeve gastrectomy group compared with in the lifestyle modification group. In the per protocol analysis (236 [82%] participants who completed the trial), the primary endpoint was met in 54 (70%) of 77 participants in the Roux-en-Y gastric bypass group and 55 (70%) of 79 participants in the sleeve gastrectomy group, compared with 15 (19%) of 80 in the lifestyle modification group (p<0·0001). No deaths or life-threatening complications were reported in this study. Severe adverse events occurred in ten (6%) participants who had bariatric-metabolic surgery, but these participants did not require re-operations and severe adverse events were resolved with medical or endoscopic management. INTERPRETATION: Bariatric-metabolic surgery is more effective than lifestyle interventions and optimised medical therapy in the treatment of NASH. FUNDING: Fondazione Policlinico Universitario A Gemelli, Policlinico Universitario Umberto I and S Camillo Hospital, Rome, Italy.

Clinical improvement of Long-COVID is associated with reduction in autoantibodies, lipids, and inflammation following therapeutic apheresis.

In the aftermath of the COVID-19 pandemic, we are witnessing an unprecedented wave of post-infectious complications. Most prominently, millions of patients with Long-Covid complain about chronic fatigue and severe post-exertional malaise. Therapeutic apheresis has been suggested as an efficient treatment option for alleviating and mitigating symptoms in this desperate group of patients. However, little is known about the mechanisms and biomarkers correlating with treatment outcomes. Here, we have analyzed in different cohorts of Long-Covid patients specific biomarkers before and after therapeutic apheresis. In patients that reported a significant improvement following two cycles of therapeutic apheresis, there was a significant reduction in neurotransmitter autoantibodies, lipids, and inflammatory markers. Furthermore, we observed a 70% reduction in fibrinogen, and following apheresis, erythrocyte rouleaux formation and fibrin fibers largely disappeared as demonstrated by dark field microscopy. This is the first study demonstrating a pattern of specific biomarkers with clinical symptoms in this patient group. It may therefore form the basis for a more objective monitoring and a clinical score for the treatment of Long-Covid and other postinfectious syndromes.

Sensitivity of the Neuroendocrine Stress Axis in Metabolic Diseases.

Metabolic diseases are prevalent in modern society and have reached pandemic proportions. Metabolic diseases have systemic effects on the body and can lead to changes in the neuroendocrine stress axis, the critical regulator of the body's stress response. These changes may be attributed to rising insulin levels and the release of adipokines and inflammatory cytokines by adipose tissue, which affect hormone production by the neuroendocrine stress axis. Chronic stress due to inflammation may exacerbate these effects. The increased sensitivity of the neuroendocrine stress axis may be responsible for the development of metabolic syndrome, providing a possible explanation for the high prevalence of severe comorbidities such as heart disease and stroke associated with metabolic disease. In this review, we address current knowledge of the neuroendocrine stress axis in response to metabolic disease and discuss its role in developing metabolic syndrome.

International Roadshow: New Advances in Endocrinology and Metabolic Diseases.

Dear Readers,Currently, there is a myriad of new developments in the field of endocrinology. In particular, significant strides have been made in the development of poly-agonists for the treatment of type 2 diabetes and obesity 1 2. Poly-agonists represent a novel therapeutic approach by combining multiple actions within a single molecule, targeting multiple receptors simultaneously to achieve enhanced efficacy. These innovative compounds aim to address the complex interplay of hormonal pathways involved in glucose regulation and metabolism, offering potential breakthroughs in the management of diabetes and obesity.

Marine Sponge-Derived Secondary Metabolites Modulate SARS-CoV-2 Entry Mechanisms.

The emergence of SARS-CoV 2 caused the COVID-19 pandemic, resulting in numerous global infections and deaths. In particular, people with metabolic diseases display an increased risk of severe COVID 19 and a fatal outcome. Treatment options for severe cases are limited, and the appearance of new virus variants complicates the development of novel therapies. To better manage viral infections like COVID 19, new therapeutic approaches are needed. Marine sponges offer a natural and renewable source of unique bioactive agents. These sponges produce secondary metabolites with various effects, including anti-viral, anti-inflammatory, and anti-tumorigenic properties. In the current study, we investigated the effect of five different marine sponge-derived secondary metabolites (four bromotyrosines and one sesquiterpenoid hydroquinone). Two of these, Avarol and Acetyl-dibromoverongiaquinol reduced the expression of ACE2, the main receptor for SARS-CoV 2, and the alternative receptor NRP1. Moreover, these substances derived from sponges demonstrated the ability to diminish the virus titer in SARS-CoV 2-infected cells, especially concerning the Omicron lineage. However, the reduction was not substantial enough to expect a significant impact on infected humans. Consequently, the investigated sponge-derived secondary metabolites are not likely to be effective to treat COVID 19 as a stand-alone therapy.

The Adrenal Gland and Pancreatic Islets - A Beneficial Endocrine Alliance.

Intraportal islet transplantation in patients with type 1 diabetes enables restoration of glucose-regulated insulin secretion. However, several factors hamper a widespread application and long-term success: chronic hypoxia, an inappropriate microenvironment and suppression of regenerative and proliferative potential by high local levels of immunosuppressive agents. Therefore, the identification of alternative and superior transplant sites is of major scientific and clinical interest. Here, we aim to evaluate the adrenal as an alternative transplantation site. The adrenal features a particular microenvironment with extensive vascularization, anti-apoptotic and pro-proliferative, anti-inflammatory and immunosuppressive effects. To validate this novel transplantation site, an in vitro co-culture system of adrenal cells and pancreatic islets was established and viability, islet survival, functional potency and antioxidative defense capacity were evaluated. For in vivo validation, an immune-deficient diabetic mouse model for intra-adrenal islet transplantation was applied. The functional capacity of intra-adrenally grafted islets to reverse diabetes was compared to a standard islet transplant model and measures of engraftment such as vascular integration were evaluated. The presence of adrenal cells positively impacted on cell metabolism and oxidative stress. Following transplantation, we could demonstrate enhanced islet function in comparison to standard models with improved engraftment and superior re-vascularization. This experimental approach allows for novel insights into the interaction of endocrine systems and may open up novel strategies for islet transplantation augmented through the bystander effect of other endocrine cells or the active factors secreted by adrenal cells modulating the microenvironment.

Mechanistic Insights into Ferroptotic Cell Death in Pancreatic Islets.

Ferroptosis was recently identified as a non-apoptotic, iron-dependent cell death mechanism that is involved in various pathologic conditions. There is first evidence for its significance also in the context of islet isolation and transplantation. Transplantation of pancreatic human islets is a viable treatment strategy for patients with complicated diabetes mellitus type 1 (T1D) that suffer from severe hypoglycemia. A major determinant for functional outcome is the initial islet mass transplanted. Efficient islet isolation procedures and measures to minimize islet loss are therefore of high relevance. To this end, better understanding and subsequent targeted inhibition of cell death during islet isolation and transplantation is an effective approach. In this study, we aimed to elucidate the mechanism of ferroptosis in pancreatic islets. Using a rodent model, isolated islets were characterized relating to the effects of experimental induction (RSL3) and inhibition (Fer1) of ferroptotic pathways. Besides viability, survival, and function, the study focused on characteristic ferroptosis-associated intracellular changes such as MDA level, iron concentration and the expression of ACSL4. The study demonstrates that pharmaceutical induction of ferroptosis by RSL3 causes enhancement of oxidative stress and leads to an increase of intracellular iron, zinc and MDA concentration, as well as the expression of ACSL4 protein. Consequently, a massive reduction of islet function, viability, and survival was found. Fer1 has the potential to inhibit and attenuate these cellular changes and thereby protect the islets from cell death.

Unawareness of Primary Aldosteronism as a Common Cause of Hypokalemia - Insights from the IPAHK+ Trial (Incidence of Primary Aldosteronism in Patients with Hypokalemia).

Hypokalemia plays an important role in the diagnosis and management of primary aldosteronism (PA). While the hypokalemic variant of the disease accounts for about one third of all cases, little is known about the incidence of PA in hypokalemic populations. The IPAHK+ study is an epidemiological, cross-sectional trial to provide evidence on the incidence of PA in hypokalemic patients from a university hospital outpatient population. Recruitment of outpatients with hypokalemia≤3 mmol/l is carried out on a continuous referral-basis through an automated data delivery system. Up to an interim data closure, 66 patients underwent the study protocol. The mean age of the participants was 52.9±1.5 years with an equal sex ratio of 1:1 women to men, a mean potassium value of 2.78±0.31 mmol/l [1.8;3.0] and a prevalence of arterial hypertension of 72.7%. PA was diagnosed in 46.6% of all participants, all of whom had a history of hypertension. Incidence of PA increased continuously with decreasing potassium levels with proportions of 26.7%, 50% and 57.1% in the subgroups of 3.0 mmol/l (n=15), 2.8-2.9 mmol/l (n=22) and≤2.7 mmol/l (n=21), respectively. Prior to testing, 59.1% of all patients presented at least with one plausible other cause of hypokalemia. The incidence of PA in the investigated outpatient population was more than 4 out of 10 and inversely correlated with baseline potassium levels. Moderate or severe hypokalemia, regardless of its cause, should therefore prompt evaluation for PA in hypertensive individuals. Normotensive hypokalemic PA was not observed in this cohort.

Aldosterone synthase inhibitor (BI 690517) therapy for people with diabetes and albuminuric chronic kidney disease: A multicentre, randomized, double-blind, placebo-controlled, Phase I trial.

AIM: This Phase I study evaluated the safety and early efficacy of an aldosterone synthase inhibitor (BI 690517) in people with diabetes and albuminuric chronic kidney disease. METHODS: Double-blind, placebo-controlled study (NCT03165240) at 40 sites across Europe. Eligible participants [estimated glomerular filtration rate ≥20 and <75 ml/min/1.73 m2; urine albumin/creatinine ratio (UACR) ≥200 and <3500 mg/g] were randomized 6:1 to receive once-daily oral BI 690517 3, 10 or 40 mg, or eplerenone 25-50 mg, or placebo, for 28 days. The primary endpoint was the proportion of participants with drug-related adverse events (AEs). Secondary endpoints included changes from baseline in the UACR. RESULTS: Fifty-eight participants were randomized and treated from 27 November 2017 to 16 April 2020 (BI 690517: 3 mg, n = 18; 10 mg, n = 13; 40 mg, n = 14; eplerenone, n = 4; placebo, n = 9) for 28 days. Eight (13.8%) participants experienced drug-related AEs [BI 690517: 3 mg (two of 18); 10 mg (four of 13); 40 mg (two of 14)], most frequently constipation [10 mg (one of 13); 40 mg (one of 14)] and hyperkalaemia [3 mg (one of 18); 10 mg (one of 13)]. Most AEs were mild to moderate; one participant experienced severe hyperkalaemia (serum potassium 6.9 mmol/L; BI 690517 10 mg). UACR responses [≥20% decrease from baseline (first morning void urine) after 28 days] were observed for 80.0% receiving BI 690517 40 mg (eight of 10) versus 37.5% receiving placebo (three of eight). Aldosterone levels were suppressed by BI 690517, but not eplerenone or placebo. CONCLUSIONS: BI 690517 was generally well tolerated, reduced plasma aldosterone and may decrease albuminuria in participants with diabetes and albuminuric chronic kidney disease.

Efficacy of finerenone in patients with type 2 diabetes, chronic kidney disease and altered markers of liver steatosis and fibrosis: A FIDELITY subgroup analysis.

AIM: Investigating the effect of finerenone on liver function, cardiovascular and kidney composite outcomes in patients with chronic kidney disease and type 2 diabetes, stratified by their risk of liver steatosis, inflammation and fibrosis. MATERIALS AND METHODS: Post hoc analysis stratified patients (N = 13 026) by liver fibrosis and enzymes: high risk of steatosis (hepatic steatosis index >36); elevated transaminases [alanine transaminase (ALT) >33 (males) and >25 IU/L (females)]; and fibrosis-4 (FIB-4) index scores >3.25, >2.67 and >1.30. Liver enzymes were assessed by changes in ALT, aspartate aminotransferase and gamma-glutamyl transferase. Composite kidney outcome was defined as onset of kidney failure, sustained estimated glomerular filtration rate decline ≥57% from baseline over ≥4 weeks or kidney death. Composite cardiovascular outcome was defined as cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for heart failure. RESULTS: ALT, aspartate aminotransferase and gamma-glutamyl transferase levels were consistent between treatment groups and remained stable throughout. Finerenone consistently reduced the risk of composite kidney outcome, irrespective of altered liver tests. Higher FIB-4 score was associated with higher incidence rates of composite cardiovascular outcome. Finerenone reduced the risk of composite cardiovascular outcome versus placebo in FIB-4 subgroups by 52% (>3.25), 39% (>2.67) and 24% (>1.30) (p values for interaction = .01, .13 and .03, respectively). CONCLUSIONS: Finerenone has neutral effects on liver parameters in patients with chronic kidney disease and type 2 diabetes. Finerenone showed robust and consistent kidney benefits in patients with altered liver tests, and profound cardiovascular benefits even in patients with higher FIB-4 scores who were at high risk of developing cardiovascular complications.

Accurate liquid biopsy for the diagnosis of non-alcoholic steatohepatitis and liver fibrosis.

OBJECTIVE: Clinical diagnosis and approval of new medications for non-alcoholic steatohepatitis (NASH) require invasive liver biopsies. The aim of our study was to identify non-invasive biomarkers of NASH and/or liver fibrosis. DESIGN: This multicentre study includes 250 patients (discovery cohort, n=100 subjects (Bariatric Surgery Versus Non-alcoholic Steato-hepatitis - BRAVES trial); validation cohort, n=150 (Liquid Biopsy for NASH and Liver Fibrosis - LIBRA trial)) with histologically proven non-alcoholic fatty liver (NAFL) or NASH with or without fibrosis. Proteomics was performed in monocytes and hepatic stellate cells (HSCs) with iTRAQ-nano- Liquid Chromatography - Mass Spectrometry/Mass Spectrometry (LC-MS/MS), while flow cytometry measured perilipin-2 (PLIN2) and RAB14 in peripheral blood CD14+CD16- monocytes. Neural network classifiers were used to predict presence/absence of NASH and NASH stages. Logistic bootstrap-based regression was used to measure the accuracy of predicting liver fibrosis. RESULTS: The algorithm for NASH using PLIN2 mean florescence intensity (MFI) combined with waist circumference, triglyceride, alanine aminotransferase (ALT) and presence/absence of diabetes as covariates had an accuracy of 93% in the discovery cohort and of 92% in the validation cohort. Sensitivity and specificity were 95% and 90% in the discovery cohort and 88% and 100% in the validation cohort, respectively.The area under the receiver operating characteristic (AUROC) for NAS level prediction ranged from 83.7% (CI 75.6% to 91.8%) in the discovery cohort to 97.8% (CI 95.8% to 99.8%) in the validation cohort.The algorithm including RAB14 MFI, age, waist circumference, high-density lipoprotein cholesterol, plasma glucose and ALT levels as covariates to predict the presence of liver fibrosis yielded an AUROC of 95.9% (CI 87.9% to 100%) in the discovery cohort and 99.3% (CI 98.1% to 100%) in the validation cohort, respectively. Accuracy was 99.25%, sensitivity 100% and specificity 95.8% in the discovery cohort and 97.6%, 99% and 89.6% in the validation cohort. This novel biomarker was superior to currently used FIB4, non-alcoholic fatty liver disease fibrosis score and aspartate aminotransferase (AST)-to-platelet ratio and was comparable to ultrasound two-dimensional shear wave elastography. CONCLUSIONS: The proposed novel liquid biopsy is accurate, sensitive and specific in diagnosing the presence and severity of NASH or liver fibrosis and is more reliable than currently used biomarkers. CLINICAL TRIALS: Discovery multicentre cohort: Bariatric Surgery versus Non-Alcoholic Steatohepatitis, BRAVES, ClinicalTrials.gov identifier: NCT03524365.Validation multicentre cohort: Liquid Biopsy for NASH and Fibrosis, LIBRA, ClinicalTrials.gov identifier: NCT04677101.

Activation of ß-adrenergic receptor signaling prevents glucocorticoid-induced obesity and adipose tissue dysfunction in male mice.

Elevated serum concentrations of glucocorticoids (GCs) result in excessive lipid accumulation in white adipose tissue (WAT) as well as dysfunction of thermogenic brown adipose tissue (BAT), ultimately leading to the development of obesity and metabolic disease. Here, we hypothesized that activation of the sympathetic nervous system either via cold exposure or the use of a selective ß3-adrenergic receptor (ß3-AR) agonist alleviates the adverse metabolic effects of chronic GC exposure in rodents. To this end, male 10-wk-old C57BL/6NRj mice were treated with corticosterone via drinking water or placebo for 4 wk while being maintained at 29°C (thermoneutrality), 22°C (room temperature), or 13°C (cold temperature); in a follow-up study mice received a selective ß3-AR agonist or placebo with and without corticosterone while being maintained at room temperature. Body weight and food intake were monitored throughout the study. Histological and molecular analyses were performed on white and brown adipose depots. Cold exposure not only preserved the thermogenic function of brown adipose tissue but also reversed GC-induced lipid accumulation in white adipose tissue and corrected GC-driven obesity, hyperinsulinemia, and hyperglycemia. The metabolic benefits of cold exposure were associated with enhanced sympathetic activity in adipose tissue, thus potentially linking an increase in sympathetic signaling to the observed metabolic benefits. In line with this concept, chronic administration of a selective ß3-AR agonist reproduced the beneficial metabolic effects of cold adaption during exposure to exogenous GCs. This preclinical study demonstrates the potential of ß3-AR as a therapeutic target in the management and prevention of GC-induced metabolic disease.NEW & NOTEWORTHY This preclinical study in mice shows that the ß3-adrenergic receptor can be a potential therapeutic approach to counteracting glucocorticoid (GC)-induced obesity and metabolic dysfunction. Both cold acclimation and ß3-adrenergic receptor stimulation in a mouse model of excess glucocorticoids were adequate in not only preventing obesity, adiposity, and adipose tissue dysfunction but also correcting hyperinsulinemia, hyperleptinemia, and dyslipidemia.

Chronic post-COVID-19 syndrome and chronic fatigue syndrome: Is there a role for extracorporeal apheresis?

As millions of patients have been infected by SARS-CoV-2 virus a vast number of individuals complain about continuing breathlessness and fatigue even months after the onset of the disease. This overwhelming phenomenon has not been well defined and has been called "post-COVID syndrome" or "long-COVID" [1]. There are striking similarities to myalgic encephalomyelitis also called chronic fatigue syndrome linked to a viral and autoimmune pathogenesis. In both disorders neurotransmitter receptor antibodies against ß-adrenergic and muscarinic receptors may play a key role. We found similar elevation of these autoantibodies in both patient groups. Extracorporeal apheresis using a special filter seems to be effective in reducing these antibodies in a significant way clearly improving the debilitating symptoms of patients with chronic fatigue syndrome. Therefore, such a form of neuropheresis may provide a promising therapeutic option for patients with post-COVID-19 syndrome. This method will also be effective when other hitherto unknown antibodies and inflammatory mediators are involved.

Transplantation of porcine adrenal spheroids for the treatment of adrenal insufficiency.

Primary adrenal insufficiency is a life-threatening disorder, which requires lifelong hormone replacement therapy. Transplantation of xenogeneic adrenal cells is a potential alternative approach for the treatment of adrenal insufficiency. For a successful outcome of this replacement therapy, transplanted cells should provide adequate hormone secretion and respond to adrenal physiological stimuli. Here, we describe the generation and characterization of primary porcine adrenal spheroids capable of replacing the function of adrenal glands in vivo. Cells within the spheroids morphologically resembled adult adrenocortical cells and synthesized and secreted adrenal steroid hormones in a regulated manner. Moreover, the embedding of the spheroids in alginate led to the formation of cellular elongations of steroidogenic cells migrating centripetally towards the inner part of the slab, similar to zona Fasciculata cells in the intact organ. Finally, transplantation of adrenal spheroids in adrenalectomized SCID mice reversed the adrenal insufficiency phenotype, which significantly improved animals' survival. Overall, such adrenal models could be employed for disease modeling and drug testing, and represent the first step toward potential clinical trials in the future.

On the Mechanical Properties of Microfibre-Based 3D Chitinous Scaffolds from Selected Verongiida Sponges.

Skeletal constructs of diverse marine sponges remain to be a sustainable source of biocompatible porous biopolymer-based 3D scaffolds for tissue engineering and technology, especially structures isolated from cultivated demosponges, which belong to the Verongiida order, due to the renewability of their chitinous, fibre-containing architecture focused attention. These chitinous scaffolds have already shown excellent and promising results in biomimetics and tissue engineering with respect to their broad diversity of cells. However, the mechanical features of these constructs have been poorly studied before. For the first time, the elastic moduli characterising the chitinous samples have been determined. Moreover, nanoindentation of the selected bromotyrosine-containing as well as pigment-free chitinous scaffolds isolated from selected verongiids was used in the study for comparative purposes. It was shown that the removal of bromotyrosines from chitin scaffolds results in a reduced elastic modulus; however, their hardness was relatively unaffected.

Solute Carrier Transporters as Potential Targets for the Treatment of Metabolic Disease.

The solute carrier (SLC) superfamily comprises more than 400 transport proteins mediating the influx and efflux of substances such as ions, nucleotides, and sugars across biological membranes. Over 80 SLC transporters have been linked to human diseases, including obesity and type 2 diabetes (T2D). This observation highlights the importance of SLCs for human (patho)physiology. Yet, only a small number of SLC proteins are validated drug targets. The most recent drug class approved for the treatment of T2D targets sodium-glucose cotransporter 2, product of the SLC5A2 gene. There is great interest in identifying other SLC transporters as potential targets for the treatment of metabolic diseases. Finding better treatments will prove essential in future years, given the enormous personal and socioeconomic burden posed by more than 500 million patients with T2D by 2040 worldwide. In this review, we summarize the evidence for SLC transporters as target structures in metabolic disease. To this end, we identified SLC13A5/sodium-coupled citrate transporter, and recent proof-of-concept studies confirm its therapeutic potential in T2D and nonalcoholic fatty liver disease. Further SLC transporters were linked in multiple genome-wide association studies to T2D or related metabolic disorders. In addition to presenting better-characterized potential therapeutic targets, we discuss the likely unnoticed link between other SLC transporters and metabolic disease. Recognition of their potential may promote research on these proteins for future medical management of human metabolic diseases such as obesity, fatty liver disease, and T2D. SIGNIFICANCE STATEMENT: Given the fact that the prevalence of human metabolic diseases such as obesity and type 2 diabetes has dramatically risen, pharmacological intervention will be a key future approach to managing their burden and reducing mortality. In this review, we present the evidence for solute carrier (SLC) genes associated with human metabolic diseases and discuss the potential of SLC transporters as therapeutic target structures.

Beyond the Paradigm: Novel Functions of Renin-Producing Cells.

The juxtaglomerular renin-producing cells (RPC) of the kidney are referred to as the major source of circulating renin. Renin is the limiting factor in renin-angiotensin system (RAS), which represents a proteolytic cascade in blood plasma that plays a central role in the regulation of blood pressure. Further cells disseminated in the entire organism express renin at a low level as part of tissue RASs, which are thought to locally modulate the effects of systemic RAS. In recent years, it became increasingly clear that the renal RPC are involved in developmental, physiological, and pathophysiological processes outside RAS. Based on recent experimental evidence, a novel concept emerges postulating that next to their traditional role, the RPC have non-canonical RAS-independent progenitor and renoprotective functions. Moreover, the RPC are part of a widespread renin lineage population, which may act as a global stem cell pool coordinating homeostatic, stress, and regenerative responses throughout the organism. This review focuses on the RAS-unrelated functions of RPC - a dynamic research area that increasingly attracts attention.

Metabolic surgery versus conventional medical therapy in patients with type 2 diabetes: 10-year follow-up of an open-label, single-centre, randomised controlled trial.

BACKGROUND: No data from randomised controlled trials of metabolic surgery for diabetes are available beyond 5 years of follow-up. We aimed to assess 10-year follow-up after surgery compared with medical therapy for the treatment of type 2 diabetes. METHODS: We did a 10-year follow-up study of an open-label, single-centre (tertiary hospital in Rome, Italy), randomised controlled trial, in which patients with type 2 diabetes (baseline duration >5 years; glycated haemoglobin [HbA1c] >7·0%, and body-mass index ≥35 kg/m2) were randomly assigned (1:1:1) to medical therapy, Roux-en-Y gastric bypass (RYGB), or biliopancreatic diversion (BPD) by a computerised system. The primary endpoint of the study was diabetes remission at 2 years (HbA1c <6·5% and fasting glycaemia <5·55 mmol/L without ongoing medication for at least 1 year). In the 10-year analysis, durability of diabetes remission was analysed by intention to treat (ITT). This study is registered with ClinicalTrials.gov, NCT00888836. FINDINGS: Between April 30, 2009, and Oct 31, 2011, of 72 patients assessed for eligibility, 60 were included. The 10-year follow-up rate was 95·0% (57 of 60). Of all patients who were surgically treated, 15 (37·5%) maintained diabetes remission throughout the 10-year period. Specifically, 10-year remission rates in the ITT population were 5·5% for medical therapy (95% CI 1·0-25·7; one participant went into remission after crossover to surgery), 50·0% for BPD (29·9-70·1), and 25·0% for RYGB (11·2-46·9; p=0·0082). 20 (58·8%) of 34 participants who were observed to be in remission at 2 years had a relapse of hyperglycaemia during the follow-up period (BPD 52·6% [95% CI 31·7-72·7]; RYGB 66·7% [41·7-84·8]). All individuals with relapse, however, maintained adequate glycaemic control at 10 years (mean HbA1c 6·7% [SD 0·2]). Participants in the RYGB and BPD groups had fewer diabetes-related complications than those in the medical therapy group (relative risk 0·07 [95% CI 0·01-0·48] for both comparisons). Serious adverse events occurred more frequently among participants in the BPD group (odds ratio [OR] for BPD vs medical therapy 2·7 [95% CI 1·3-5·6]; OR for RYGB vs medical therapy 0·7 [0·3-1·9]). INTERPRETATION: Metabolic surgery is more effective than conventional medical therapy in the long-term control of type 2 diabetes. Clinicians and policy makers should ensure that metabolic surgery is appropriately considered in the management of patients with obesity and type 2 diabetes. FUNDING: Fondazione Policlinico Universitario Agostino Gemelli IRCCS.