Showing papers by "Andreas L. Birkenfeld published in 2022"

Finerenone in Patients With Chronic Kidney Disease and Type 2 Diabetes by Sodium–Glucose Cotransporter 2 Inhibitor Treatment: The FIDELITY Analysis

Abstract: OBJECTIVE Finerenone reduced the risk of kidney and cardiovascular events in people with chronic kidney disease (CKD) and type 2 diabetes in the FIDELIO-DKD and FIGARO-DKD phase 3 studies. Effects of finerenone on outcomes in patients taking sodium–glucose cotransporter 2 inhibitors (SGLT2is) were evaluated in a prespecified pooled analysis of these studies. RESEARCH DESIGN AND METHODS Patients with type 2 diabetes and urine albumin-to-creatinine ratio (UACR) ≥30 to ≤5,000 mg/g and estimated glomerular filtration rate (eGFR) ≥25 mL/min/1.73 m2 were randomly assigned to finerenone or placebo; SGLT2is were permitted at any time. Outcomes included cardiovascular composite (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) and kidney composite (kidney failure, sustained ≥57% eGFR decline, or renal death) end points, changes in UACR and eGFR, and safety outcomes. RESULTS Among 13,026 patients, 877 (6.7%) received an SGLT2i at baseline and 1,113 (8.5%) initiated one during the trial. For the cardiovascular composite, the hazard ratios (HRs) were 0.87 (95% CI 0.79–0.96) without SGLT2i and 0.67 (95% CI 0.42–1.07) with SGLT2i. For the kidney composite, the HRs were 0.80 (95% CI 0.69–0.92) without SGLT2i and 0.42 (95% CI 0.16–1.08) with SGLT2i. Baseline SGLT2i use did not affect risk reduction for the cardiovascular or kidney composites with finerenone (Pinteraction = 0.46 and 0.29, respectively); neither did SGLT2i use concomitant with study treatment. CONCLUSIONS Benefits of finerenone compared with placebo on cardiorenal outcomes in patients with CKD and type 2 diabetes were observed irrespective of SGLT2i use.

Obesity and Impaired Metabolic Health Increase Risk of COVID-19-Related Mortality in Young and Middle-Aged Adults to the Level Observed in Older People: The LEOSS Registry

Abstract: Advanced age, followed by male sex, by far poses the greatest risk for severe COVID-19. An unresolved question is the extent to which modifiable comorbidities increase the risk of COVID-19-related mortality among younger patients, in whom COVID-19-related hospitalization strongly increased in 2021. A total of 3,163 patients with SARS-COV-2 diagnosis in the Lean European Open Survey on SARS-CoV-2-Infected Patients (LEOSS) cohort were studied. LEOSS is a European non-interventional multi-center cohort study established in March 2020 to investigate the epidemiology and clinical course of SARS-CoV-2 infection. Data from hospitalized patients and those who received ambulatory care, with a positive SARS-CoV-2 test, were included in the study. An additive effect of obesity, diabetes and hypertension on the risk of mortality was observed, which was particularly strong in young and middle-aged patients. Compared to young and middle-aged (18–55 years) patients without obesity, diabetes and hypertension (non-obese and metabolically healthy; n = 593), young and middle-aged adult patients with all three risk parameters (obese and metabolically unhealthy; n = 31) had a similar adjusted increased risk of mortality [OR 7.42 (95% CI 1.55–27.3)] as older (56–75 years) non-obese and metabolically healthy patients [n = 339; OR 8.21 (95% CI 4.10–18.3)]. Furthermore, increased CRP levels explained part of the elevated risk of COVID-19-related mortality with age, specifically in the absence of obesity and impaired metabolic health. In conclusion, the modifiable risk factors obesity, diabetes and hypertension increase the risk of COVID-19-related mortality in young and middle-aged patients to the level of risk observed in advanced age.

Fat-distribution Patterns and Future Type-2 Diabetes.

Abstract: Fat accumulation in the liver, pancreas, skeletal muscle, and visceral bed relates to type-2 diabetes (T2D). However, the distribution of fat among these compartments is heterogenous and it is unclear whether specific distribution patterns indicate high T2D risk. We therefore investigated fat-distribution patterns and their link to future T2D. From 2168 individuals without diabetes who underwent computed tomography in Japan, this case-cohort study included 658 randomly selected individuals and 146 incident cases of T2D over 6 years of follow-up. Using data-driven analysis (k-means) based on fat content in the liver, pancreas, muscle, and visceral bed, we identified four fat-distribution clusters: Hepatic steatosis, Pancreatic steatosis, Trunk myosteatosis, and Steatopenia. Compared with the Steatopenia cluster, the adjusted hazard ratios (95% CIs) for incident T2D were 4.02 (2.27-7.12) for the Hepatic steatosis cluster, 3.38 (1.65-6.91) for the Pancreatic steatosis cluster, and 1.95 (1.07-3.54) for the Trunk myosteatosis cluster. The clusters were replicated in 319 German individuals without diabetes who underwent magnetic resonance imaging and metabolic phenotyping. The distribution of AUC-glucose across the four clusters found in Germany was similar to the distribution of T2D risk across the four clusters in Japan. Insulin sensitivity and insulin secretion differed across the four clusters. Thus, we identified patterns of fat distribution with different T2D risks presumably due to differences in insulin sensitivity and insulin secretion.

Sex differences in central insulin action: Effect of intranasal insulin on neural food cue reactivity in adults with normal weight and overweight

Abstract: Abstract Background/Objectives Central insulin action influences cognitive processes, peripheral metabolism, and eating behavior. However, the contribution of obesity and sex on central insulin-mediated neural food cue processing still remains unclear. Subjects/Methods In a randomized within-participant design, including two visits, 60 participants (30 women, BMI 18–32 kg/m 2 , age 21–69 years) underwent a functional MRI task measuring blood oxygen level-dependent (BOLD) signal in response to visual food cues after intranasal insulin or placebo spray administration. Central insulin action was defined as the neural BOLD response to food cues after insulin compared to placebo administration. Afterwards, participants were asked to rate the food cues for desire to eat (i.e., wanting rating). For statistical analyses, participants were grouped according to BMI and sex. Results Food cue reactivity in the amygdala showed higher BOLD activation in response to central insulin compared to placebo. Furthermore, women with overweight and obesity and men of normal weight showed higher BOLD neural food cue responsivity to central insulin compared to placebo. Higher central insulin action in the insular cortex was associated with better peripheral insulin sensitivity and higher cognitive control. Moreover, central insulin action in the dorsolateral prefrontal cortex (DLPFC) revealed significant sex differences. In response to central insulin compared to placebo, men showed lower DLPFC BOLD activity, whereas women showed higher DLPFC activity in response to highly desired food cues. On behavioral level, central insulin action significantly reduced hunger, whereas the desire to eat, especially for low caloric food cues was significantly higher with central insulin than with placebo. Conclusions Obesity and sex influenced the central insulin-mediated neural BOLD activity to visual food cues in brain regions implicated in reward and cognitive control. These findings show that central insulin action regulates food response differentially in men and women, which may have consequences for metabolism and eating behavior.

Sodium retention in nephrotic syndrome is independent of the activation of the membrane-anchored serine protease prostasin (CAP1/PRSS8) and its enzymatic activity

Abstract: Experimental nephrotic syndrome leads to activation of the epithelial sodium channel (ENaC) by proteolysis and promotes renal sodium retention. The membrane-anchored serine protease prostasin (CAP1/PRSS8) is expressed in the distal nephron and participates in proteolytic ENaC regulation by serving as a scaffold for other serine proteases. However, it is unknown whether prostasin is also involved in ENaC-mediated sodium retention of experimental nephrotic syndrome. In this study, we used genetically modified knock-in mice with Prss8 mutations abolishing its proteolytic activity (Prss8-S238A) or prostasin activation (Prss8-R44Q) to investigate the development of sodium retention in doxorubicin-induced nephrotic syndrome. Healthy Prss8-S238A and Prss8-R44Q mice had normal ENaC activity as reflected by the natriuretic response to the ENaC blocker triamterene. After doxorubicin injection, all genotypes developed similar proteinuria. In all genotypes, urinary prostasin excretion increased while renal expression was not altered. In nephrotic mice of all genotypes, triamterene response was similarly increased, consistent with ENaC activation. As a consequence, urinary sodium excretion dropped in all genotypes and mice similarly gained body weight by + 25 ± 3% in Prss8-wt, + 20 ± 2% in Prss8-S238A and + 28 ± 3% in Prss8-R44Q mice (p = 0.16). In Western blots, expression of fully cleaved α- and γ-ENaC was similarly increased in nephrotic mice of all genotypes. In conclusion, proteolytic ENaC activation and sodium retention in experimental nephrotic syndrome are independent of the activation of prostasin and its enzymatic activity and are consistent with the action of aberrantly filtered serine proteases or proteasuria.

Trip13 Depletion in Liver Cancer Induces a Lipogenic Response Contributing to Plin2‐Dependent Mitotic Cell Death

Abstract: Aberrant energy metabolism and cell cycle regulation both critically contribute to malignant cell growth and both processes represent targets for anticancer therapy. It is shown here that depletion of the AAA+‐ATPase thyroid hormone receptor interacting protein 13 (Trip13) results in mitotic cell death through a combined mechanism linking lipid metabolism to aberrant mitosis. Diminished Trip13 levels in hepatocellular carcinoma cells result in insulin‐receptor‐/Akt‐pathway‐dependent accumulation of lipid droplets, which act as functional acentriolar microtubule organizing centers disturbing mitotic spindle polarity. Specifically, the lipid‐droplet‐coating protein perilipin 2 (Plin2) is required for multipolar spindle formation, induction of DNA damage, and mitotic cell death. Plin2 expression in different tumor cells confers susceptibility to cell death induced by Trip13 depletion as well as treatment with paclitaxel, a spindle‐interfering drug commonly used against different cancers. Thus, assessment of Plin2 levels enables the stratification of tumor responsiveness to mitosis‐targeting drugs, including clinically approved paclitaxel and Trip13 inhibitors currently under development.

The German Gestational Diabetes Study (PREG), a prospective multicentre cohort study: rationale, methodology and design

Abstract: Introduction Even well-treated gestational diabetes mellitus (GDM) might still have impact on long-term health of the mother and her offspring, although this relationship has not yet been conclusively studied. Using in-depth phenotyping of the mother and her offspring, we aim to elucidate the relationship of maternal hyperglycaemia during pregnancy and adequate treatment, and its impact on the long-term health of both mother and child. Methods The multicentre PREG study, a prospective cohort study, is designed to metabolically and phenotypically characterise women with a 75-g five-point oral glucose tolerance test (OGTT) during, and repeatedly after pregnancy. Outcome measures are maternal glycaemia during OGTTs, birth outcome and the health and growth development of the offspring. The children of the study participants are followed up until adulthood with developmental tests and metabolic and epigenetic phenotyping in the PREG Offspring study. A total of 800 women (600 with GDM, 200 controls) will be recruited. Ethics and dissemination The study protocol has been approved by all local ethics committees. Results will be disseminated via conference presentations and peer-reviewed publications. Trial registration number The PREG study and the PREG Offspring study are registered with Clinical Trials (ClinicalTrials.gov identifiers: NCT04270578, NCT04722900).

Lower Hepatic Fat Is Associated With Improved Insulin Secretion in a High-Risk Prediabetes Subphenotype During Lifestyle Intervention

Abstract: The objective of this work was to investigate whether impaired insulin secretion can be restored by lifestyle intervention in specific subphenotypes of prediabetes. We assigned 1,045 participants from the Prediabetes Lifestyle Intervention Study (PLIS) to six recently established prediabetes clusters. Insulin secretion was assessed by a C-peptide–based index derived from oral glucose tolerance tests and modeled from three time points during a 1-year intervention. We also analyzed the change of glycemia, insulin sensitivity, and liver fat. All prediabetes high-risk clusters (cluster 3, 5, and 6) had improved glycemic traits during the lifestyle intervention, whereas insulin secretion only increased in clusters 3 and 5 (P < 0.001); however, high liver fat in cluster 5 was associated with a failure to improve insulin secretion (Pinteraction < 0.001). Thus, interventions to reduce liver fat have the potential to improve insulin secretion in a defined subgroup of prediabetes.

Endoplasmic reticulum stress and the unfolded protein response in skeletal muscle of subjects suffering from peritoneal sepsis

Abstract: We provide a descriptive characterization of the unfolded protein response (UPR) in skeletal muscle of human patients with peritoneal sepsis and a sepsis model of C57BL/6J mice. Patients undergoing open surgery were included in a cross-sectional study and blood and skeletal muscle samples were taken. Key markers of the UPR and cluster of differentiation 68 (CD68) as surrogate of inflammatory injury were evaluated by real-time PCR and histochemical staining. CD68 mRNA increased with sepsis in skeletal muscle of patients and animals (p < 0.05). Mainly the inositol-requiring enzyme 1α branch of the UPR was upregulated as shown by elevated X-box binding-protein 1 (XBP1u) and its spliced isoform (XBP1s) mRNA (p < 0.05, respectively). Increased expression of Gadd34 indicated activation of PRKR-Like Endoplasmic Reticulum Kinase (PERK) branch of the UPR, and was only observed in mice (p < 0.001) but not human study subjects. Selected cell death signals were upregulated in human and murine muscle, demonstrated by increased bcl-2 associated X protein mRNA and TUNEL staining (p < 0.05). In conclusion we provide a first characterization of the UPR in skeletal muscle in human sepsis.

Endoplasmic reticulum stress and the unfolded protein response in skeletal muscle of subjects suffering from peritoneal sepsis

Abstract: We provide a descriptive characterization of the unfolded protein response (UPR) in skeletal muscle of human patients with peritoneal sepsis and a sepsis model of C57BL/6J mice. Patients undergoing open surgery were included in a cross-sectional study and blood and skeletal muscle samples were taken. Key markers of the UPR and cluster of differentiation 68 (CD68) as surrogate of inflammatory injury were evaluated by real-time PCR and histochemical staining. CD68 mRNA increased with sepsis in skeletal muscle of patients and animals (p < 0.05). Mainly the inositol-requiring enzyme 1α branch of the UPR was upregulated as shown by elevated X-box binding-protein 1 (XBP1u) and its spliced isoform (XBP1s) mRNA (p < 0.05, respectively). Increased expression of Gadd34 indicated activation of PRKR-Like Endoplasmic Reticulum Kinase (PERK) branch of the UPR, and was only observed in mice (p < 0.001) but not human study subjects. Selected cell death signals were upregulated in human and murine muscle, demonstrated by increased bcl-2 associated X protein mRNA and TUNEL staining (p < 0.05). In conclusion we provide a first characterization of the UPR in skeletal muscle in human sepsis.

A Novel and Cross-Species Active Mammalian INDY (NaCT) Inhibitor Ameliorates Hepatic Steatosis in Mice with Diet-Induced Obesity

Abstract: Mammalian INDY (mINDY, NaCT, gene symbol SLC13A5) is a potential target for the treatment of metabolically associated fatty liver disease (MAFLD). This study evaluated the effects of a selective, cross-species active, non-competitive, non-substrate-like inhibitor of NaCT. First, the small molecule inhibitor ETG-5773 was evaluated for citrate and succinate uptake and fatty acid synthesis in cell lines expressing both human NaCT and mouse Nact. Once its suitability was established, the inhibitor was evaluated in a diet-induced obesity (DIO) mouse model. DIO mice treated with 15 mg/kg compound ETG-5773 twice daily for 28 days had reduced body weight, fasting blood glucose, and insulin, and improved glucose tolerance. Liver triglycerides were significantly reduced, and body composition was improved by reducing fat mass, supported by a significant reduction in the expression of genes for lipogenesis such as SREBF1 and SCD1. Most of these effects were also evident after a seven-day treatment with the same dose. Further mechanistic investigation in the seven-day study showed increased plasma β-hydroxybutyrate and activated hepatic adenosine monophosphate-activated protein kinase (AMPK), reflecting findings from Indy (−/−) knockout mice. These results suggest that the inhibitor ETG-5773 blocked citrate uptake mediated by mouse and human NaCT to reduce liver steatosis and body fat and improve glucose regulation, proving the concept of NaCT inhibition as a future liver treatment for MAFLD.

Eight weeks of empagliflozin does not affect pancreatic fat content and insulin secretion in people with prediabetes

Abstract: Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center, Munich at the University of Tübingen, Tübingen, Germany German Center for Diabetes Research (DZD), Neuherberg, Germany Department of Radiology, Section on Experimental Radiology, Eberhard Karls University Tübingen, Tübingen, Germany Department of Internal Medicine, Division of Diabetology, Endocrinology and Nephrology, Eberhard Karls University Tübingen, Tübingen, Germany Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, Eberhard Karls University Tübingen, Tübingen, Germany Department of Endocrinology and Diabetology, University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany German Diabetes Center (Deutsches Diabetes-Zentrum/DDZ), Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany Department of Internal Medicine I, University of Ulm, Ulm, Germany

Exercise restores brain insulin sensitivity in sedentary adults who are overweight and obese

Abstract: BACKGROUND Insulin resistance of the brain can unfavorably affect long-term weight maintenance and body fat distribution. Little is known if and how brain insulin sensitivity can be restored in humans. We aimed to evaluate the effects of an exercise intervention on insulin sensitivity of the brain and how this relates to exercise-induced changes in whole-body metabolism and behavior. METHODS In this clinical trial, sedentary participants who were overweight and obese underwent an 8-week supervised aerobic training intervention. Brain insulin sensitivity was assessed in 21 participants (14 women, 7 men; age range 21–59 years; BMI range 27.5–45.5 kg/m2) using functional MRI, combined with intranasal administration of insulin, before and after the intervention. RESULTS The exercise program resulted in enhanced brain insulin action to the level of a person of healthy weight, demonstrated by increased insulin-induced striatal activity and strengthened hippocampal functional connectivity. Improved brain insulin action correlated with increased mitochondrial respiration in skeletal muscle, reductions in visceral fat and hunger, as well as improved cognition. Mediation analyses suggest that improved brain insulin responsiveness helps mediate the peripheral exercise effects leading to healthier body fat distribution and reduced perception of hunger. CONCLUSION Our study demonstrates that an 8-week exercise intervention in sedentary individuals can restore insulin action in the brain. Hence, the ameliorating benefits of exercise toward brain insulin resistance may provide an objective therapeutic target in humans in the challenge to reduce diabetes risk factors. TRIAL REGISTRATION ClinicalTrials.gov (NCT03151590). FUNDING BMBF/DZD 01GI0925.

IKCa channels control breast cancer metabolism including AMPK-driven autophagy

Abstract: Abstract Ca 2+ -activated K + channels of intermediate conductance (IK) are frequently overexpressed in breast cancer (BC) cells, while IK channel depletion reduces BC cell proliferation and tumorigenesis. This raises the question, of whether and mechanistically how IK activity interferes with the metabolic activity and energy consumption rates, which are fundamental for rapidly growing cells. Using BC cells obtained from MMTV-PyMT tumor-bearing mice, we show that both, glycolysis and mitochondrial ATP-production are reduced in cells derived from IK-deficient breast tumors. Loss of IK altered the sub-/cellular K + - and Ca 2+ - homeostasis and mitochondrial membrane potential, ultimately resulting in reduced ATP-production and metabolic activity. Consequently, we find that BC cells lacking IK upregulate AMP-activated protein kinase activity to induce autophagy compensating the glycolytic and mitochondrial energy shortage. Our results emphasize that IK by modulating cellular Ca 2+ - and K + -dynamics contributes to the remodeling of metabolic pathways in cancer. Thus, targeting IK channel might disturb the metabolic activity of BC cells and reduce malignancy.

Positionspapier Herzinsuffizienz und Diabetes

Abstract: Diabetes mellitus (DM) stellt eine wichtige Komorbidität bei Patienten mit Herzinsuffizienz dar, die maßgeblich die Prognose determiniert. Von entscheidender Bedeutung zur Verbesserung der Prognose dieser Hochrisikopatienten ist daher eine frühzeitige Diagnostik und differenzierte medikamentöse Therapie mit Ausschöpfung aller möglichen Therapieoptionen und Absetzen potenziell schädlicher Substanzen. Das gemeinsame Positionspapier der Deutschen Gesellschaft für Kardiologie (DGK) und der Deutschen Diabetes Gesellschaft (DDG) fasst die vorhandene wissenschaftliche Evidenz zusammen und gibt Empfehlungen, was bei der Diagnose und Therapie der Herzinsuffizienz und des DM zu beachten ist, um die Prognose zu verbessern.

Therapy of Type 2 Diabetes.

Abstract: The Clinical Practice Guidelines of the German Diabetes Society/Deutsche Diabetes Gesellschaft (DDG) together with the German Society for Internal Medicine/Deutschen Gesellschaft für Innere Medizin (DGIM) are based on the contents of the National Treatment Guideline (Nationale Versorgungsleitlinie (NVL)) “Type 2 Diabetes” [1]. The modifications in therapy and their justifications made in the present Clinical Practice Guidelines were updated on the basis of new randomized controlled trials (RCTs) and meta-analyses.

Comprehensive validation of fasting-based and oral glucose tolerance test–based indices of insulin secretion against gold standard measures

Abstract: Introduction With pre-diabetes and diabetes increasingly recognized as heterogeneous conditions, assessment of beta-cell function is gaining clinical importance to identify disease subphenotypes. Our study aims to comprehensively validate all types of surrogate indices based on oral glucose tolerance test (OGTT) and fasting measurements in comparison with gold standard methods. Research design and methods The hyperglycemic clamp extended with glucagon-like peptide 1 (GLP-1) infusion and intravenous glucose tolerance test (IVGTT), as well as OGTT, was performed in two well-phenotyped cohorts. The gold standard–derived indices were compared with surrogate insulin secretion markers, derived from fasting state and OGTT, using both Pearson’s and Spearman’s correlation coefficients. The insulin-based and C-peptide-based indices were analyzed separately in different groups of glucose tolerance and the entire cohorts. Results The highest correlation coefficients were found for area under curve (AUC) (I0-30)/AUC (G0-30), I30/G30, first-phase Stumvoll and Kadowaki model. These indices have high correlation coefficients with measures obtained from both insulin and C-peptide levels from IVGTT and hyperglycemic clamp. AUC (I0-120)/AUC (G0-120), BIGTT-AIR0-60-120, I30/G30, first-phase Stumvoll and AUC (I0-30)/AUC (G0-30) demonstrated the strongest association with incretin-stimulated insulin response. Conclusions We have identified glucose-stimulated and GLP-1-stimulated insulin secretion indices, derived from OGTT and fasting state, that have the strongest correlation with gold standard measures and could be potentially used in future researches and clinical practice.

Impaired Metabolic Health and low Cardiorespiratory Fitness independently associate with Subclinical Atherosclerosis in Obesity.

Abstract: BACKGROUND For a given body-mass index (BMI), both, impaired metabolic health (MH) and reduced cardiorespiratory fitness (CRF), associate with an increased risk of cardiovascular disease (CVD). It is still unknown whether both risk phenotypes relate to CVD independently of each other, and whether these relationships differ in normal weight, overweight and obese subjects. METHODS Data from 421 participants from the Tübingen Diabetes Family Study, who had measurements of anthropometrics, metabolic parameters, CRF (maximal aerobic capacity [VO2max]) and carotid intima-media thickness (cIMT), an early marker of atherosclerosis, were analysed. Subjects were divided by BMI and MH status into 6 phenotypes. RESULTS In univariate analyses higher age, increased BMI and a metabolic risk profile correlated positively, while insulin sensitivity and VO2max negatively with cIMT. In multivariable analyses in obese subjects, higher age, male sex, lower VO2max (std. ß -0.21, p=0.002) and impaired MH (std. ß 0.13, p=0.02) were independent determinants of increased cIMT. After adjustment for age and sex, subjects with metabolically healthy obesity (MHO) had higher cIMT than subjects with metabolically healthy normal weight (MHNW; 0.59±0.009 mm vs 0.52±0.01 mm, p<0.05). When VO2max was additionally included in this model, the difference in cIMT between the MHO and MHNW groups became statistically non-significant (0.58 ±0.009 mm vs 0.56 ±0.02 mm, p>0.05). CONCLUSIONS These data suggest that impaired MH and low CRF independently determine increased cIMT in obese subjects and that a low CRF may explain part of the increased CVD risk observed in subjects with MHO, when compared to subjects with MHNW.

Novel Insights into the Management of Patients with Very High Cardiovascular Risk Eligible for PCSK9 Inhibitor Treatment: Baseline Findings from the PERI-DYS Study.

Abstract: The PERI-DYS study aims to characterize two groups of patients with dyslipidaemia at very high CV risk: PCSK9i receivers and patients qualifying for but not receiving PCSK9i.This is an observational study by office-based and clinic-based physicians, mainly cardiologists and other internists in Germany, with data extracted from patient charts.gov identifier NCT03110432.A total of 1659 patients were enrolled across 70 sites. The majority of patients (91.0%) were reported as having mixed dyslipidaemia or non-familial or heterozygous familial hypercholesterolemia. At enrolment, 794 (47.9%) of patients were PCSK9i receivers (of these 65.9% ongoing, and 34.1% newly treated within 30 days before their baseline visit). Among PCSK9i receivers, the majority had evolocumab 140 mg (n = 632, 38.1% of total). PCSK9i receivers compared to non-receivers were about 2 years younger and had a lower proportion of males. In terms of comorbidities, they had (statistically significantly) more often CAD, and less often PAD, diabetes mellitus, arterial hypertension and chronic renal disease. The calculated untreated median LDL-C was 187 mg/dl (IQR 127; 270) in ongoing PCSK9i receivers, 212 mg/dl (IQR 132; 277) in newly treated PCSK9i receivers, and 179 mg/dl (IQR 129; 257) in non-receivers. Physician-reported statin intolerance was much more common in the two PCSK9i receiver groups as compared to non-receivers (67.3% versus 15.3%). Consequently, patients in the PCSK9i groups received fewer concomitant statins. Mean total cholesterol (143 vs. 172 mg/dl) and LDL-C (69 vs. 99 mg/dl) were considerably lower in ongoing PCSK9i receivers compared to non-receivers.PCSK9i receivers are characterized by higher baseline LDL-C and a higher portion of statin intolerance compared to those qualified for but not-receiving PCSK9i treatment. On-treatment, LDL-C was lower in PCSK9i receivers. Ongoing follow-up will determine the prognostic importance of these findings.

Two cases of severe vitamin D3 intoxication treated with therapeutic plasma exchange and high cut-off hemodialysis

Abstract: Abstract We report on a 53-year-old female patient and a 33-year-old male patient presenting with life-threatening hypercalcemic crisis caused by self-induced vitamin-D intoxication. Both patients took high doses of vitamin D 3 supplements, cumulatively up to 2,500,000–10,000,000 I.U. over several months. Accordingly, serum 25-OH-vitamin D concentrations were increased to 663 and 1289 nmol/L (reference 50–175 nmol/L), respectively. As forced diuresis and bisphosphonates failed to correct recurrent hypercalcemia, we hypothesized that add-on extracorporeal treatments might help overcome the refractory situation. Considering the binding of vitamin D 3 metabolites to vitamin D-binding protein (VDBP, 59 kDa), we started extracorporeal treatments involving total plasma exchange with replacement by human albumin and by fresh frozen plasma, online hemodiafiltration and high cut-off hemodialysis. We found that in the former case, total plasma exchange with albumin and fresh frozen plasma and high cut-off hemodialysis lowered both 25-OH-vitamin D 3 and 1,25-OH-vitamin D 3, whereas in the latter case total plasma exchange with albumin was found to more effectively remove vitamin D metabolites compared to high cut-off hemodialysis. In contrast, the amount of total plasma calcium removed by high cut-off hemodialysis was higher compared to total plasma exchange with albumin. During follow up, patients 1 and 2 achieved almost normal total plasma calcium and vitamin D concentrations after 355 and 109 days, respectively. These two cases suggest that extracorporeal treatments with high cut-off hemodialysis and total plasma exchange with albumin may be considered as add-on treatment in refractory cases of vitamin D 3 -induced hypercalcemia to lower plasma 25-OH-vitamin D 3 concentrations.

NIK/MAP3K14 in hepatocytes orchestrates NASH to hepatocellular carcinoma progression via JAK2/STAT5 inhibition

Abstract: Nonalcoholic fatty liver disease (NAFLD) ranges from steatosis to nonalcoholic steatohepatitis (NASH), which often progresses to hepatocellular carcinoma (HCC) through a largely undefined mechanism. NASH and HCC depend on inflammatory signaling, whose master regulator is the NFκB transcription factor family, activated by canonical and non-canonical pathways.Here, we investigated non-canonical NFκB-inducing kinase (NIK/MAP3K14) in metabolic NASH, NASH to HCC transition, and DEN-induced HCC. To this end, we performed dietary and chemical interventions in mice that were analyzed via single nucleus sequencing, gene expression and histochemical methods. Ultimately, we verified our mouse results in human patient samples.We revealed that hepatocyte-specific NIK deficiency (NIKLKO) ameliorated metabolic NASH complications and reduced hepatocarcinogenesis, independent of its role in the NFκB pathway. Instead, hepatic NIK attenuated hepatoprotective JAK2/STAT5 signaling that is a prerequisite for NASH and NASH to HCC progression in mice and humans.Our data suggest NIK-mediated inhibitory JAK2 phosphorylation at serine 633 that might be amenable for future therapeutic interventions in patients.

Effects of adrenergic-stimulated lipolysis and cytokine production on in vitro mouse adipose tissue–islet interactions

Abstract: Abstract Inflammatory cytokines and non-esterified fatty acids (NEFAs) are obesity-linked factors that disturb insulin secretion. The aim of this study was to investigate whether pancreatic adipose tissue (pWAT) is able to generate a NEFA/cytokine overload within the pancreatic environment and as consequence to impact on insulin secretion. Pancreatic fat is a minor fat depot, therefore we used high-fat diet (HFD) feeding to induce pancreatic steatosis in mice. Relative Adipoq and Lep mRNA levels were higher in pWAT of HFD compared to chow diet mice. Regardless of HFD, Adipoq and Lep mRNA levels of pWAT were at least 10-times lower than those of epididymal fat (eWAT). Lipolysis stimulating receptors Adrb3 and Npr1 were expressed in pWAT and eWAT, and HFD reduced their expression in eWAT only. In accordance, HFD impaired lipolysis in eWAT but not in pWAT. Despite expression of Npr mRNA, lipolysis was stimulated solely by the adrenergic agonists, isoproterenol and adrenaline. Short term co-incubation of islets with CD/HFD pWAT did not alter insulin secretion. In the presence of CD/HFD eWAT, glucose stimulated insulin secretion only upon isoproterenol-induced lipolysis, i.e. in the presence of elevated NEFA. Isoproterenol augmented Il1b and Il6 mRNA levels both in pWAT and eWAT. These results suggest that an increased sympathetic activity enhances NEFA and cytokine load of the adipose microenvironment, including that of pancreatic fat, and by doing so it may alter beta-cell function.

Diabetes Mellitus and the Heart.

Abstract: Patients with diabetes mellitus (DM) have a significantly increased risk of developing cardiovascular diseases with their sequelae of acute myocardial infarction, stroke and cardiovascular death. For example, even today a 60-year-old male patient with diabetes has 6 years less life expectancy compared to a metabolically healthy male of the same age, and a 60-year-old patient with diabetes and a previous history of a heart attack has 12 years less [1]. These data highlight the need for targeted risk stratification of patients with diabetes and the consistent treatment of diabetes, associated risk factors and cardiovascular disease.

The Acute Cytokine Response to 30-Minute Exercise Bouts Before and After 8-Week Endurance Training in Individuals With Obesity

Abstract: Abstract Context One acute bout of exercise leads to a rapid increase in the systemic cytokine concentration. Regular exercise might alter the cytokine response, in particular in beforehand untrained and obese individuals. Objective Using a proximity extension assay, we studied the effects of acute exercise as well as endurance training on a panel of 92 cytokines related to inflammation. Methods A total of 22 individuals (30 ± 9 years; peak oxygen uptake [VO2peak] 25.2 ± 4.2 mL/[kg × min]; body mass index [BMI] 31.7 ± 4.4) participated in an 8-week endurance exercise intervention. Blood samples were collected before and immediately after 30 minutes’ ergometer exercise at 80% VO2peak. Results Before and after the training intervention, 40 and 37 cytokines, respectively, were acutely increased more than 1.2-fold (Benjamini-Hochberg [BH]-adjusted P < .05). The exercise intervention did not change the acute increase in cytokines nor the resting cytokine levels, whereas fitness was improved and adiposity reduced. The increase in fitness led to a slight increase in power output when exercising at the same heart rate, which might explain the comparable increase in cytokines before and after the intervention. The largest acute increase was found for OSM, TGFA, CXCL1 and 5, and TNFSF14 (≥ 1.9-fold, BH-adjusted P < .001). The transcript levels of these proteins in whole blood were also elevated, particularly in the trained state. Only the acute increase in IL6 (1.3-fold) was related to the increase in lactate, confirming the lactate-driven secretion of IL6. Conclusion Our comprehensive proteomics approach detected several underexplored serum exerkines with up to now less understood function in the adaptation to exercise.

Bezafibrate Reduces Elevated Hepatic Fumarate in Insulin-Deficient Mice

Abstract: Glucotoxic metabolites and pathways play a crucial role in diabetic complications, and new treatment options which improve glucotoxicity are highly warranted. In this study, we analyzed bezafibrate (BEZ) treated, streptozotocin (STZ) injected mice, which showed an improved glucose metabolism compared to untreated STZ animals. In order to identify key molecules and pathways which participate in the beneficial effects of BEZ, we studied plasma, skeletal muscle, white adipose tissue (WAT) and liver samples using non-targeted metabolomics (NMR spectroscopy), targeted metabolomics (mass spectrometry), microarrays and mitochondrial enzyme activity measurements, with a particular focus on the liver. The analysis of muscle and WAT demonstrated that STZ treatment elevated inflammatory pathways and reduced insulin signaling and lipid pathways, whereas BEZ decreased inflammatory pathways and increased insulin signaling and lipid pathways, which can partly explain the beneficial effects of BEZ on glucose metabolism. Furthermore, lysophosphatidylcholine levels were lower in the liver and skeletal muscle of STZ mice, which were reverted in BEZ-treated animals. BEZ also improved circulating and hepatic glucose levels as well as lipid profiles. In the liver, BEZ treatment reduced elevated fumarate levels in STZ mice, which was probably due to a decreased expression of urea cycle genes. Since fumarate has been shown to participate in glucotoxic pathways, our data suggests that BEZ treatment attenuates the urea cycle in the liver, decreases fumarate levels and, in turn, ameliorates glucotoxicity and reduces insulin resistance in STZ mice.

Low IGF-1 and high IGFBP-1 predict diabetes onset in prediabetic patients.

Abstract: Some individuals develop T2DM despite significant metabolic improvements through lifestyle intervention. We tested the hypotheses that IGF1 and its binding proteins 1 and 2 a) predict the onset of T2DM in prediabetes patients, b) determine the capacity for metabolic regeneration. Design We measured fasting serum IGF1, IGFBP1 and IGFBP2 in 3 randomized controlled lifestyle intervention trials, covering at least 1 year of intervention period and 1 year of additional follow-up. Methods Within a sample of 414 high-risk prediabetes patients (58% women; 28-80 years), we analyzed fasting serum concentrations of IGF1, IGFBP1 and IGFBP2 in relation to diabetes incidence and metabolic parameters over 2 years. 345 subjects finished the first year of intervention. Results The interventions significantly improved body weight (BMI: -3.24%, p<0.001), liver fat (-36.8%, p<0.001), IS (HOMA-IR: -6.3%, p<0.001) and insulin secretion (Disposition index: +35%, p <0.001) in the cohort. 14 % developed T2DM within 2 years. Mean IGFBP1 levels at baseline were lower in prediabetes compared to a healthy population. Also, prediabetes patients with obesity and NAFLD had lower IGFBP1. Those with impaired glucose tolerance had higher IGFBP1 compared to those with only impaired fasting glucose. Baseline IGF1 was lower (122.5 vs. 146.6 µg/L) and IGFBP1 higher (3.32 vs. 2.09 µg/L) in subjects who developed T2DM (n=57), resulting in a significant prediction of diabetes incidence (HR IGF1 0.991 µg/L, p=0.003; HR IGFBP1 1.061 µg/L, p=0.002). This translates into a 20% and 9% difference in T2DM incidence for IGF1 and IGFBP1, respectively. Despite reduced weight, visceral and hepatic fat as response to one year of lifestyle intervention, those who developed T2DM had not improved insulin sensitivity, glucose tolerance or IGFBP1. Conclusions Lower IGF1 and higher IGFBP1 in prediabetes predicted the incidence of T2DM, indicating an impairment of beta-cell function, which explains the unresponsiveness to lifestyle intervention.

16-LB: Effects of Finerenone in Patients with CKD and T2D Are Independent of HbA1c at Baseline, HbA1c Variability, and Duration of Diabetes

Abstract: Introduction: Finerenone reduced the risk of cardiovascular (CV) and kidney outcomes, without affecting HbA1c, in CKD and T2D patients in the FIDELITY prespecified pooled analysis of the FIDELIO-DKD and FIGARO-DKD studies. Here, we evaluate the effect of finerenone by baseline HbA1c, HbA1c variability, and diabetes duration. Methods: Patients with T2D and CKD (UACR ≥30-≤5000 mg/g and eGFR ≥25 mL/min/1.73 m2) were randomized to finerenone or placebo. Effects of finerenone vs. placebo on CV (CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) and kidney (kidney failure, sustained ≥57% eGFR decline from baseline, or renal death) composite outcomes were analyzed by baseline HbA1c quartiles, HbA1c variability (first year of treatment) , and diabetes duration quartiles. Results: In 13,026 patients included in the analysis, mean baseline HbA1c was 7.7% and diabetes duration was 15.4 years. Higher baseline HbA1c quartiles had longer diabetes duration and more diabetes-related complications. Risk reductions in the CV and kidney composite outcomes with finerenone vs. placebo were consistent across HbA1c (p-interaction 0.52 and 0.09, respectively) and diabetes duration (p-interaction 0.12 and 0.75) quartiles. HbA1c variability in the first year of treatment was associated with higher cardiorenal risks; each 1 unit increase in mean absolute residual of HbA1c was associated with a 20% increased risk of a CV event (HR 1.20; 95% CI 1.07-1.35; p=0.0016) and a 36% increased risk of a kidney event (HR 1.36; 95% CI 1.21-1.52; p<0.001) . The CV and kidney benefits of finerenone were not modified by HbA1c variability (p-interaction 0.48 and 0.09, respectively) . Conclusion: Greater variability in HbA1c was associated with increased risks of cardiorenal outcomes. Risk reductions in the CV and kidney outcomes with finerenone in patients with CKD and T2D were not modified by baseline HbA1c, HbA1c variability, or duration of diabetes. J. B. Mcgill: Advisory Panel; Gilead Sciences, Inc., Lilly Diabetes, MannKind Corporation, Novo Nordisk A/S, Provention Bio, Inc., Salix Pharmaceuticals, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; Dexcom, Inc., Novo Nordisk. M. Brinker: Employee; Bayer AG. A. Joseph: Employee; Bayer AG. A. Z. Lage: None. R. Lawatscheck: None. C. Scott: Employee; Bayer AG. P. Rossing: Consultant; Astellas Pharma Inc., AstraZeneca, Bayer AG, Gilead Sciences, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Speaker’s Bureau; Eli Lilly and Company. R. Agarwal: Advisory Panel; Akebia Therapeutics, Inc., Bayer AG, Board Member; Chinook Therapeutics Inc., DiaMedica Therapeutics, Inc., Vertex Pharmaceuticals Incorporated, Consultant; Boehringer Ingelheim International GmbH, Reata Pharmaceuticals, Inc., Vifor Pharma Management Ltd. S. Anker: Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Novartis AG, Novo Nordisk, Vifor Pharma Management Ltd., Research Support; Abbott. G. Bakris: Consultant; Alnylam Pharmaceuticals, Inc., AstraZeneca, DiaMedica Therapeutics, Inc., Horizon Therapeutics plc, Ionis Pharmaceuticals, Merck & Co., Inc., Other Relationship; Novo Nordisk. G. Filippatos: Other Relationship; Amgen Inc., Amgen Inc., Bayer AG, Boehringer Ingelheim International GmbH, Medtronic, Novartis AG, Servier Laboratories, Vifor Pharma Management Ltd. B. Pitt: Advisory Panel; Merck & Co., Inc., Consultant; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Lexicon Pharmaceuticals, Inc., Vifor Pharma Management Ltd. L. M. Ruilope: Consultant; Bayer AG. A. L. Birkenfeld: None. L. Caramori: Advisory Panel; Bayer AG, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk, Research Support; Bayer AG, Novartis AG.

254-OR: Glucose Response Patterns Based on 75g OGTTS during Pregnancy and Their Association with the Risk of Macrosomia: A Latent Class Analysis of TWO Cohort Studies

Abstract: Background and Aims: People with different glucose response patterns during the 2-h oral glucose tolerance test (OGTT) have substantially different clinical characteristics and risk for long-term outcomes in the general population. We aimed to identify comparable glucose response patterns in pregnancy and their association with maternal and fetal outcomes. Materials and Methods: We used latent class trajectory modelling to identify glucose response patterns using 5-point 75g OGTT in 470 pregnant women at 27.3±2.2 weeks of gestation. We assessed these classes and investigated pregnancy outcomes in an independent cohort of 7073 pregnant women with 3-point OGTTs. Results: We identified five different glucose response patterns (classes) . Rate of gestational diabetes (GDM) was lowest in class 1 (< 7%) and highest in class 5 (100%) for both cohorts. Class 3 was characterized by transient hyperinsulinemia at 30 minutes but the prevalence of GDM was only 25-36%. Compared to class 1, women in class 3 had an increased gestational weight gain (GWG, β=0.85 SE: 0.31kg, p=0.0065, adjusted for age, gestational age, pre-gestational BMI, GDM treatment and AUCGlucose) . New-borns in class 3 had the highest risk of macrosomia (OR 1.47 95% CI: [1.12, 1.93] vs. class 1) after adjustment for maternal age, parity and smoking, but this was attenuated by additional adjustment for pre-pregnancy BMI and GWG. Conclusion: We found an easily identifiable group of pregnant women who have an increased risk of macrosomia without formally meeting GDM diagnosis. These women would most likely benefit from a therapy (e.g. nutritional counselling) aiming at preventing excessive glucose excursions and GWG. Note: LF and AH contributed equally to this work. L.Fritsche: None. R.Wagner: Advisory Panel; Akcea Therapeutics, Daiichi Sankyo, Sanofi-Aventis Deutschland GmbH, Speaker's Bureau; Lilly, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. A.Hulman: None. K.Prystupa: None. M.Heni: Advisory Panel; Boehringer Ingelheim International GmbH, Research Support; Boehringer Ingelheim International GmbH, Sanofi, Speaker's Bureau; Amryt Pharma Plc, Boehringer Ingelheim International GmbH, Novo Nordisk. A.L.Birkenfeld: None. A.Peter: None. A.Fritsche: Advisory Panel; Boehringer Ingelheim International GmbH, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. A.Kun: None. A.Tabak: Consultant; 77 Elektronika Kft., Boehringer Ingelheim International GmbH, Speaker's Bureau; 77 Elektronika Kft., AstraZeneca, Sanofi_aventis Zrt. The PREG study is supported in part by a grant from the Federal Ministry of Education and Research (BMBF) (01GI0925) to the German Center for Diabetes Research (DZD)