TY - JOUR AB - INTRODUCTION: Maturity-onset Diabetes of the Young (MODY) is a rare form of diabetes and arises from mutations in key regulatory genes of the pancreatic beta cell, leading to their functional impairment and early-onset diabetes. Research into PDX1-MODY, a form of MODY caused by mutations in the PDX1 gene, enhances understanding of gene-specific mechanisms underlying glucose dysregulation and provides insights into possible approaches to restore normal metabolic function. However, no currently published mouse model accurately depicts the genetic cause of PDX1-MODY in human patients. METHODS: Using CRISPR-Cas9 technology, we generated the first mouse model carrying one of the most prevalent pathological PDX1 point mutation found in human patients, P33T, and conducted an 18-week in vivo phenotyping experiment assessing homozygous PDX1P33T and wild-type littermates on both chow and high fat diet (HFD). Additionally, transcriptomic and proteomic analyses were performed on isolated pancreatic islets. Islet architecture was investigated via fluorescent microscopy. RESULT: Contrary to expectations, our comprehensive phenotypic analysis of the mouse model carrying the homozygous PDX1P33T mutation revealed no significant differences in metabolic parameters compared to wild-type controls, and no pathological outcomes were observed as seen in human patients. Notably, male PDX1P33T mice exhibited an increase in islet size and number on chow diet, with omics analyses suggesting reprogramming toward stress resilience, but failed to adapt respectively on HFD. DISCUSSION: Our work indicates substantial differences between mouse and human PDX1 function in the pancreas. Further refinement of animal models is necessary to better elucidate the pathophysiology of PDX1-MODY. AU - Harten, A. AU - Schmidtke, M. AU - Giesert, F. AU - Skerrett-Byrne, D.A. AU - Teperino, R. AU - Przemeck, G.K.H. AU - Hrabě de Angelis, M. C1 - 75974 C2 - 58302 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - MODY PDX1P33T: A mouse model reveals phenotypic divergence from human disease. JO - Front. Endocrin. VL - 16 PB - Frontiers Media Sa PY - 2025 SN - 1664-2392 ER - TY - JOUR AB - Males suffer more often from profibrotic changes in liver than females. The underlying mechanism for this sex difference in the prevalence and manifestation of Metabolic dysfunction-associated Steatotic Liver Disease (MASLD) is not yet completely known. We studied male and female mice that were induced to develop MASLD by consuming a "fast food" diet (FFD) and assessed metabolic phenotype as well as liver histology and compared them with mice fed with a matched control diet (CD). Our aim was to check for sex-specific differences in MASLD development in a mouse model of diet-induced profibrotic changes in the liver. Our results demonstrate a clear difference in body weight, fat distribution and changes in liver tissue for male and female mice fed with FFD. We found that female mice stored lipids mainly in subcutaneous and visceral adipose tissue while males increased ectopic lipid accumulation in the liver which resulted in hepatomegaly and increased transforming growth factor β 1 (Tgfb1) and collagen I (Col1a1) expression concomitant to fibrosis development. This was absent in female mice. Analysis of estrogen receptor -α (Esr1) and -β (Esr2) expression revealed an upregulation of Esr2 in livers of male FFD-fed mice whereas in female liver tissue a higher expression in Esr1 could be observed. This study supports Esr1 and Esr2 as potential targets to reverse negative effects of diet-induced profibrotic changes in the liver. AU - Meyer, J.* AU - Teixeira, A.M.* AU - Richter, S.* AU - Larner, D.P.* AU - Syed, A.* AU - Klöting, N. AU - Matz-Soja, M.* AU - Gaul, S.* AU - Barnikol-Oettler, A.* AU - Kiess, W.* AU - Le Duc, D.* AU - Penke, M.* AU - Garten, A.* C1 - 73927 C2 - 57245 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Sex differences in diet-induced MASLD - are female mice naturally protected? JO - Front. Endocrin. VL - 16 PB - Frontiers Media Sa PY - 2025 SN - 1664-2392 ER - TY - JOUR AU - Prince, A.* AU - Kushwaha, P.P.* AU - Blüher, M. AU - Müller-Wieland, D.* AU - Kiss, R.* C1 - 75608 C2 - 57903 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Editorial: Endocrinology, lipids, and disease: unraveling the links. JO - Front. Endocrin. VL - 16 PB - Frontiers Media Sa PY - 2025 SN - 1664-2392 ER - TY - JOUR AB - BACKGROUND: Obesity is a global health burden and recent evidence indicates that epitranscriptomic regulation is potentially involved in its etiology. The epitranscriptomic mark 5-methylcytosine (m5C) is implicated in cancer and recent data linked the gene expression of m5C writers, erasers and readers to diabetes, a well-known co-morbidity of obesity. Here, we tested whether gene expression of m5C regulators in paired samples of human visceral and subcutaneous adipose tissue is (i) adipose tissue depot-specific and (ii) correlates with important clinical variables of obesity. METHODS: Intra-individually paired adipose tissue samples from human subcutaneous adipose tissue (SAT) and omental visceral adipose tissue (OVAT) were utilized from three different cohorts from the Leipzig Obesity Biobank including a large cross-sectional cohort, a two-step bariatric surgery cohort and a cohort of metabolically healthy vs unhealthy individuals (LOBB, total N=962). Data analysis on intra-individual samples was performed by using the paired Wilcoxon signed-rank test, while in comparisons on independent groups the unpaired Wilcoxon rank-sum test was employed. Bonferroni correction method was used to adjust multiple testing of p-values and Spearman's rank correlation was used to assess associations. RESULTS: We observed that multiple m5C regulators were differentially expressed between human subcutaneous and visceral adipose tissue depots. Interestingly, we found that for several regulators the effects were less pronounced after weight loss, whilst stronger in individuals with insulin resistance compared to their healthy counterparts. A strong correlation of m5C regulator expression with macrophages was observed in OVAT compared to its SAT counterpart. Correlations between m5C regulators with important clinical variables related to obesity were observed in all three cohorts. CONCLUSION: Our findings provide evidence for adipose tissue depot-specific gene expression of m5C regulators that correlate with clinical variables of obesity. AU - Svensson, S.I.A.* AU - Hoffmann, A. AU - Hagemann, T. AU - Cayir, A.* AU - Saeed, S.* AU - Ghosh, A.* AU - Wolfrum, C.* AU - Blüher, M. AU - Böttcher, Y.* C1 - 75680 C2 - 58275 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Regulators of RNA m5C methylation are adipose tissue depot-specific expressed and correlate with clinical variables of obesity in humans. JO - Front. Endocrin. VL - 16 PB - Frontiers Media Sa PY - 2025 SN - 1664-2392 ER - TY - JOUR AU - Amado, I.R.* AU - Romaní-Pérez, M.* AU - Fuciños, P.* AU - Gil Lozano, M. C1 - 70643 C2 - 55678 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Editorial: Novel and emerging therapies for the treatment of obesity and related disorders. JO - Front. Endocrin. VL - 15 PB - Frontiers Media Sa PY - 2024 SN - 1664-2392 ER - TY - JOUR AU - Ansarullah* AU - Migliorini, A.* AU - Bakhti, M. C1 - 70789 C2 - 55674 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Editorial: Islet cell development, heterogeneity and regeneration. JO - Front. Endocrin. VL - 15 PB - Frontiers Media Sa PY - 2024 SN - 1664-2392 ER - TY - JOUR AU - Lorza-Gil, E. AU - Ekim Üstünel, B. AU - Sancar, G. C1 - 70171 C2 - 55437 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Editorial: Organ crosstalk in the pathophysiology and treatment of type-2 diabetes. JO - Front. Endocrin. VL - 15 PB - Frontiers Media Sa PY - 2024 SN - 1664-2392 ER - TY - JOUR AU - Ali, H.* AU - Abu-Farha, M.* AU - Hofmann, S.M. C1 - 67397 C2 - 54168 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Editorial: COVID-19 and diabetes, volume II. JO - Front. Endocrin. VL - 14 PB - Frontiers Media Sa PY - 2023 SN - 1664-2392 ER - TY - JOUR AB - BACKGROUND: Fasting morning cortisol (FMC) stress hormone levels, are suggested to reflect increased cardiometabolic risk. Acute response to weight loss diet could elevate FMC. Richer Polyphenols and lower carbohydrates diets could favor FMC levels. We aimed to explore the effect of long-term high polyphenol Mediterranean diet (green-MED) on FMC and its relation to metabolic health. METHODS: We randomized 294 participants into one of three dietary interventions for 18-months: healthy dietary guidelines (HDG), Mediterranean (MED) diet, and Green-MED diet. Both MED diets were similarly hypocaloric and lower in carbohydrates and included walnuts (28 g/day). The high-polyphenols/low-meat Green-MED group further included green tea (3-4 cups/day) and a Wolffia-globosa Mankai plant 1-cup green shakeFMC was obtained between 07:00-07:30AM at baseline, six, and eighteen-months. RESULTS: Participants (age=51.1years, 88% men) had a mean BMI of 31.3kg/m2, FMC=304.07nmol\L, and glycated-hemoglobin-A1c (HbA1c)=5.5%; 11% had type 2 diabetes and 38% were prediabetes. Baseline FMC was higher among men (308.6 ± 90.05nmol\L) than women (269.6± 83.9nmol\L;p=0.02). Higher baseline FMC was directly associated with age, dysglycemia, MRI-assessed visceral adiposity, fasting plasma glucose (FPG), high-sensitivity C-reactive-protein (hsCRP), testosterone, Progesterone and TSH levels (p ≤ 0.05 for all). The 18-month retention was 89%. After 6 months, there were no significant changes in FMC among all intervention groups. However, after 18-months, both MED groups significantly reduced FMC (MED=-1.6%[-21.45 nmol/L]; Green-MED=-1.8%[-26.67 nmol/L]; p<0.05 vs. baseline), as opposed to HDG dieters (+4%[-12 nmol/L], p=0.28 vs. baseline), whereas Green-MED diet FMC change was significant as compared to HDG diet group (p=0.048 multivariable models). Overall, 18-month decrease in FMC levels was associated with favorable changes in FPG, HbA1c, hsCRP, TSH, testosterone and MRI-assessed hepatosteatosis, and with unfavorable changes of HDLc (p<0.05 for all, weight loss adjusted, multivariable models). CONCLUSION: Long-term adherence to MED diets, and mainly green-MED/high polyphenols diet, may lower FMC, stress hormone, levels,. Lifestyle-induced FMC decrease may have potential benefits related to cardiometabolic health, irrespective of weight loss. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier NCT03020186. AU - Alufer, L.* AU - Tsaban, G.* AU - Rinott, E.* AU - Kaplan, A.* AU - Meir, A.Y.* AU - Zelicha, H.* AU - Ceglarek, U.* AU - Isermann, B.* AU - Blüher, M. AU - Stumvoll, M. AU - Stampfer, M.J.* AU - Shai, I.* C1 - 68890 C2 - 53746 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Long-term green-Mediterranean diet may favor fasting morning cortisol stress hormone; the DIRECT-PLUS clinical trial. JO - Front. Endocrin. VL - 14 PB - Frontiers Media Sa PY - 2023 SN - 1664-2392 ER - TY - JOUR AB - Over the past 50 years, the number of overweight/obese people increased significantly, making obesity a global public health challenge. Apart from rare monogenic forms, obesity is a multifactorial disease, most likely resulting from a concerted interaction of genetic, epigenetic and environmental factors. Although recent studies opened new avenues in elucidating the complex genetics behind obesity, the biological mechanisms contributing to individual's risk to become obese are not yet fully understood. Non-genetic factors such as eating behaviour or physical activity are strong contributing factors for the onset of obesity. These factors may interact with genetic predispositions most likely via epigenetic mechanisms. Epigenome-wide association studies or methylome-wide association studies are measuring DNA methylation at single CpGs across thousands of genes and capture associations to obesity phenotypes such as BMI. However, they only represent a snapshot in the complex biological network and cannot distinguish between causes and consequences. Intervention studies are therefore a suitable method to control for confounding factors and to avoid possible sources of bias. In particular, intervention studies documenting changes in obesity-associated epigenetic markers during lifestyle driven weight loss, make an important contribution to a better understanding of epigenetic reprogramming in obesity. To investigate the impact of lifestyle in obesity state specific DNA methylation, especially concerning the development of new strategies for prevention and individual therapy, we reviewed 19 most recent human intervention studies. In summary, this review highlights the huge potential of targeted interventions to alter disease-associated epigenetic patterns. However, there is an urgent need for further robust and larger studies to identify the specific DNA methylation biomarkers which influence obesity. AU - Aurich, S. AU - Müller, L.* AU - Kovacs, P.* AU - Keller, M. C1 - 67962 C2 - 54440 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Implication of DNA methylation during lifestyle mediated weight loss. JO - Front. Endocrin. VL - 14 PB - Frontiers Media Sa PY - 2023 SN - 1664-2392 ER - TY - JOUR AU - Barlier, A.* AU - Romanet, P.* AU - Pellegata, N.S. C1 - 67937 C2 - 54415 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Editorial: New insights into multiple endocrine neoplasia type 1. JO - Front. Endocrin. VL - 14 PB - Frontiers Media Sa PY - 2023 SN - 1664-2392 ER - TY - JOUR AB - BACKGROUND: Sex hormones and sex hormone-binding globulin (SHBG) may play a role in fatty liver development. We sought to examine the association of various endogenous sex hormones, including testosterone (T), and SHBG with liver fat using complementary observational and Mendelian randomization (MR) analyses. METHODS: The observational analysis included a total of 2,239 participants (mean age 60 years; 35% postmenopausal women) from the population-based KORA study (average follow-up time: 6.5 years). We conducted linear regression analysis to investigate the sex-specific associations of sex hormones and SHBG with liver fat, estimated by fatty liver index (FLI). For MR analyses, we selected genetic variants associated with sex hormones and SHBG and extracted their associations with magnetic resonance imaging measured liver fat from the largest up to date European genome-wide associations studies. RESULTS: In the observational analysis, T, dihydrotestosterone (DHT), progesterone and 17α-hydroxyprogesterone (17-OHP) were inversely associated with FLI in men, with beta estimates ranging from -4.23 to -2.30 [p-value <0.001 to 0.003]. Whereas in women, a positive association of free T with FLI (β = 4.17, 95%CI: 1.35, 6.98) was observed. SHBG was inversely associated with FLI across sexes [men: -3.45 (-5.13, -1.78); women: -9.23 (-12.19, -6.28)]. No causal association was found between genetically determined sex hormones and liver fat, but higher genetically determined SHBG was associated with lower liver fat in women (β = -0.36, 95% CI: -0.61, -0.12). CONCLUSION: Our results provide suggestive evidence for a causal association between SHBG and liver fat in women, implicating the protective role of SHBG against liver fat accumulation. AU - Cai, X. AU - Thorand, B. AU - Hohenester, S.* AU - Prehn, C. AU - Cecil, A. AU - Adamski, J. AU - Zeller, T.* AU - Dennis, A.* AU - Banerjee, R.* AU - Peters, A. AU - Yaghootkar, H.* AU - Nano, J. C1 - 68743 C2 - 54953 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Association of sex hormones and sex hormone-binding globulin with liver fat in men and women: An observational and Mendelian randomization study. JO - Front. Endocrin. VL - 14 PB - Frontiers Media Sa PY - 2023 SN - 1664-2392 ER - TY - JOUR AB - INTRODUCTION: The molecular programs regulating human pancreatic endocrine cell induction and fate allocation are not well deciphered. Here, we investigated the spatiotemporal expression pattern and the function of the neurogenic differentiation factor 2 (NEUROD2) during human endocrinogenesis. METHODS: Using Crispr-Cas9 gene editing, we generated a reporter knock-in transcription factor (TF) knock-out human inducible pluripotent stem cell (iPSC) line in which the open reading frame of both NEUROD2 alleles are replaced by a nuclear histone 2B-Venus reporter (NEUROD2nVenus/nVenus). RESULTS: We identified a transient expression of NEUROD2 mRNA and its nuclear Venus reporter activity at the stage of human endocrine progenitor formation in an iPSC differentiation model. This expression profile is similar to what was previously reported in mice, uncovering an evolutionarily conserved gene expression pattern of NEUROD2 during endocrinogenesis. In vitro differentiation of the generated homozygous NEUROD2nVenus/nVenus iPSC line towards human endocrine lineages uncovered no significant impact upon the loss of NEUROD2 on endocrine cell induction. Moreover, analysis of endocrine cell specification revealed no striking changes in the generation of insulin-producing b cells and glucagon-secreting a cells upon lack of NEUROD2. DISCUSSION: Overall, our results suggest that NEUROD2 is expendable for human b cell formation in vitro. AU - Cota, P. AU - Saber, L. AU - Taskin, D. AU - Jing, C. AU - Bastidas-Ponce, A. AU - Vanheusden, M. AU - Shahryari, A. AU - Sterr, M. AU - Burtscher, I. AU - Bakhti, M. AU - Lickert, H. C1 - 68752 C2 - 54962 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - NEUROD2 function is dispensable for human pancreatic β cell specification. JO - Front. Endocrin. VL - 14 PB - Frontiers Media Sa PY - 2023 SN - 1664-2392 ER - TY - JOUR AB - INTRODUCTION: Atrial natriuretic peptide (ANP), a hormone secreted from the heart, controls cardiovascular and renal functions including arterial blood pressure and natriuresis. ANP also exerts metabolic effects in adipose tissue, liver and skeletal muscle, and interacts with the secretion of adipokines. We tested the hypothesis that ANP lowers concentrations of the anorexigenic adipokine leptin in healthy humans in vivo. METHODS: Human ANP or matching placebo was infused intravenously (iv) into healthy men in a controlled clinical trial. RESULTS: Within 135 minutes of iv ANP infusion, we observed an acute decrease in plasma leptin levels compared to controls. Free fatty acids markedly increased with ANP infusion in vivo, indicating activated lipolysis. In human SGBS adipocytes, ANP suppressed leptin release. DISCUSSION: The study shows that the cardiac hormone ANP reduces the levels of the anorexigenic adipokine leptin in healthy humans, providing further support for ANP as a cardiomyokine in a heart - adipose tissue axis. (registered in the German Clinical Trials Register and the WHO International Clinical Trials Registry Platform was granted under DRKS00024559). AU - Daniels, M. AU - Fischer-Posovszky, P.* AU - Boschmann, M.* AU - Jumpertz von Schwartzenberg, R. AU - Müller, T.D. AU - Sandforth, L. AU - Frank-Podlech, S. AU - Hülskämper, S. AU - Peter, A. AU - Wabitsch, M.* AU - Jordan, J.* AU - Birkenfeld, A.L. C1 - 68096 C2 - 54574 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Atrial natriuretic peptide and leptin interactions in healthy men. JO - Front. Endocrin. VL - 14 PB - Frontiers Media Sa PY - 2023 SN - 1664-2392 ER - TY - JOUR AB - BACKGROUND: Diabetic sensorimotor polyneuropathy (DSPN) is one of the most prevalent and poorly understood diabetic microvascular complications. Recent studies have found that fractional anisotropy (FA), a marker for microstructural nerve integrity, is a sensitive parameter for the structural and functional nerve damage in DSPN. The aim of this study was to investigate the significance of proximal sciatic nerve's FA on different distal nerve fiber deficits of the upper and lower limbs and its correlation with the neuroaxonal biomarker, neurofilament light chain protein (NfL). MATERIALS AND METHODS: Sixty-nine patients with type 2 diabetes (T2DM) and 30 healthy controls underwent detailed clinical and electrophysiological assessments, complete quantitative sensory testing (QST), and diffusion-weighted magnetic resonance neurography of the sciatic nerve. NfL was measured in the serum of healthy controls and patients with T2DM. Multivariate models were used to adjust for confounders of microvascular damage. RESULTS: Patients with DSPN showed a 17% lower sciatic microstructural integrity compared to healthy controls (p<0.001). FA correlated with tibial and peroneal motor nerve conduction velocity (NCV) (r=0.6; p<0.001 and r=0.6; p<0.001) and sural sensory NCV (r=0.50; p<0.001). Participants with reduced sciatic nerve´s FA showed a loss of function of mechanical and thermal sensation of upper (r=0.3; p<0.01 and r=0.3; p<0.01) and lower (r=0.5; p<0.001 and r=0.3; p=<0.01) limbs and reduced functional performance of upper limbs (Purdue Pegboard Test for dominant hand; r=0.4; p<0.001). Increased levels of NfL and urinary albumin-creatinine ratio (ACR) were associated with loss of sciatic nerve´s FA (r=-0.5; p<0.001 and r= -0.3, p= 0.001). Of note, there was no correlation between sciatic FA and neuropathic symptoms or pain. CONCLUSION: This is the first study showing that microstructural nerve integrity is associated with damage of different nerve fiber types and a neuroaxonal biomarker in DSPN. Furthermore, these findings show that proximal nerve damage is related to distal nerve function even before clinical symptoms occur. The microstructure of the proximal sciatic nerve and is also associated with functional nerve fiber deficits of the upper and lower limbs, suggesting that diabetic neuropathy involves structural changes of peripheral nerves of upper limbs too. AU - Kender, Z.* AU - Jende, J.M.E.* AU - Kurz, F.T.* AU - Tsilingiris, D.* AU - Schimpfle, L.* AU - Sulaj, A.* AU - von Rauchhaupt, E.* AU - Bartl, H.* AU - Mooshage, C.* AU - Göpfert, J.* AU - Nawroth, P.* AU - Herzig, S. AU - Szendroedi, J.* AU - Bendszus, M.* AU - Kopf, S.* C1 - 67633 C2 - 53940 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Sciatic nerve fractional anisotropy and neurofilament light chain protein are related to sensorimotor deficit of the upper and lower limbs in patients with type 2 diabetes. JO - Front. Endocrin. VL - 14 PB - Frontiers Media Sa PY - 2023 SN - 1664-2392 ER - TY - JOUR AB - BACKGROUND AND AIM: Current strategies for preventing diabetic sensorimotor polyneuropathy (DSPN) are limited mainly to glucose control but rapid decrease of glycemia can lead to acute onset or worsening of DSPN. The aim of this study was to examine the effects of periodic fasting on somatosensory nerve function in patients with type 2 diabetes (T2D). STUDY DESIGN AND METHODS: Somatosensory nerve function was assessed in thirty-one patients with T2D (HbA1c 7.8 ± 1.3% [61.4 ± 14.3 mmol/mol]) before and after a six-month fasting-mimicking diet (FMD; n=14) or a control Mediterranean diet (M-diet; n=17). Neuropathy disability score (NDS), neuropathy symptoms score (NSS), nerve conduction velocity and quantitative sensory testing (QST) were analyzed. 6 participants of the M-Diet group and 7 of the FMD group underwent diffusion-weighted high-resolution magnetic resonance neurography (MRN) of the right leg before and after the diet intervention. RESULTS: Clinical neuropathy scores did not differ between study groups at baseline (64% in the M-Diet group and 47% in the FMD group had DSPN) and no change was found after intervention. The differences in sensory NCV and sensory nerve action potential (SNAP) of sural nerve were comparable between study groups. Motor NCV of tibial nerve decreased by 12% in the M-Diet group (P=0.04), but did not change in the FMD group (P=0.39). Compound motor action potential (CMAP) of tibial nerve did not change in M-Diet group (P=0.8) and increased in the FMD group by 18% (P=0.02). Motor NCV and CMAP of peroneal nerve remained unchanged in both groups. In QST M-diet-group showed a decrease by 45% in heat pain threshold (P=0.02), FMD group showed no change (P=0.50). Changes in thermal detection, mechanical detection and mechanical pain did not differ between groups. MRN analysis showed stable fascicular nerve lesions irrespective of the degree of structural pathology. Fractional anisotropy and T2-time did not change in both study groups, while a correlation with the clinical degree of DSPN could be confirmed for both. CONCLUSIONS: Our study shows that six-month periodic fasting was safe in preserving nerve function and had no detrimental effects on somatosensory nerve function in T2D patients. CLINICAL TRIAL REGISTRATION: https://drks.de/search/en/trial/DRKS00014287, identifier DRKS00014287. AU - Kender, Z.* AU - von Rauchhaupt, E.* AU - Schwarz, D.* AU - Tsilingiris, D.* AU - Schimpfle, L.* AU - Bartl, H.* AU - Longo, V.D.* AU - Bendszus, M.* AU - Kopf, S.* AU - Herzig, S. AU - Heiland, S.* AU - Szendroedi, J. AU - Sulaj, A.* C1 - 67871 C2 - 54349 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Six-month periodic fasting does not affect somatosensory nerve function in type 2 diabetes patients. JO - Front. Endocrin. VL - 14 PB - Frontiers Media Sa PY - 2023 SN - 1664-2392 ER - TY - JOUR AB - INTRODUCTION: Brown adipocytes produce heat through non shivering thermogenesis (NST). To adapt to temperature cues, they possess a remarkably dynamic metabolism and undergo substantial cellular remodeling. The proteasome plays a central role in proteostasis and adaptive proteasome activity is required for sustained NST. Proteasome activators (PAs) are a class of proteasome regulators but the role of PAs in brown adipocytes is unknown. Here, we studied the roles of PA28α (encoded by Psme1) and PA200 (encoded by Psme4) in brown adipocyte differentiation and function. METHODS: We measured gene expression in mouse brown adipose tissue. In cultured brown adipocytes, we silenced Psme1 and/or Psme4 expression through siRNA transfection. We then assessed impact on the ubiquitin proteasome system, brown adipocyte differentiation and function. RESULTS: We found that Psme1 and Psme4 are expressed in brown adipocytes in vivo and in vitro. Through silencing of Psme1 and/or Psme4 expression in cultured brown adipocytes, we found that loss of PAs did not impair proteasome assembly or activity, and that PAs were not required for proteostasis in this model. Loss of Psme1 and/or Psme4 did not impair brown adipocyte development or activation, suggesting that PAs are neither required for brown adipogenesis nor NST. DISCUSSION: In summary, we found no role for Psme1 and Psme4 in brown adipocyte proteostasis, differentiation, or function. These findings contribute to our basic understanding of proteasome biology and the roles of proteasome activators in brown adipocytes. AU - Koçberber, Z.* AU - Willemsen, N.* AU - Bartelt, A. C1 - 67921 C2 - 54399 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - The role of proteasome activators PA28αβ and PA200 in brown adipocyte differentiation and function. JO - Front. Endocrin. VL - 14 PB - Frontiers Media Sa PY - 2023 SN - 1664-2392 ER - TY - JOUR AB - Adipose tissue inflammation and insulin resistance are hallmarks in the development of metabolic diseases resulting from overweight and obesity, such as type 2 diabetes and non-alcoholic fatty liver disease. In obesity, adipocytes predominantly secrete proinflammatory adipokines that further promote adipose tissue dysfunction with negative effects on local and systemic insulin sensitivity. Expression of the serpin vaspin (SERPINA12) is also increased in obesity and type 2 diabetes, but exhibits compensatory roles in inflammation and insulin resistance. This has in part been demonstrated using vaspin-transgenic mice. We here report a new mouse line (h-vaspinTG) with transgenic expression of human vaspin in adipose tissue that reaches vaspin concentrations three orders of magnitude higher than wild type controls (>200 ng/ml). Phenotyping under chow and high-fat diet conditions included glucose-tolerance tests, measurements of energy expenditure and circulating parameters, adipose tissue and liver histology. Also, ex vivo glucose uptake in isolated adipocytes and skeletal muscle was analyzed in h-vaspinTG and littermate controls. The results confirmed previous findings, revealing a strong reduction in diet-induced weight gain, fat mass, hyperinsulinemia, -glycemia and -cholesterolemia as well as fatty liver. Insulin sensitivity in adipose tissue and muscle was not altered. The h-vaspinTG mice showed increased energy expenditure under high fat diet conditions, that may explain reduced weight gain and overall metabolic improvements. In conclusion, this novel human vaspin-transgenic mouse line will be a valuable research tool to delineate whole-body, tissue- and cell-specific effects of vaspin in health and disease. AU - Rapöhn, I. AU - Elias, I.* AU - Weiner, J.* AU - Pujol, A.* AU - Kehr, S.* AU - Chadt, A.* AU - Al-Hasani, H.* AU - Burkhardt, R.* AU - Klöting, N. AU - Stumvoll, M. AU - Bosch, F.* AU - Kovacs, P.* AU - Heiker, J.T. AU - Breitfeld, J.* C1 - 67766 C2 - 54244 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Overexpressing high levels of human vaspin limits high fat diet-induced obesity and enhances energy expenditure in a transgenic mouse. JO - Front. Endocrin. VL - 14 PB - Frontiers Media Sa PY - 2023 SN - 1664-2392 ER - TY - JOUR AB - OBJECTIVE: Acyl-CoA-binding protein (ACBP)/diazepam-binding inhibitor has lately been described as an endocrine factor affecting food intake and lipid metabolism. ACBP is dysregulated in catabolic/malnutrition states like sepsis or systemic inflammation. However, regulation of ACBP has not been investigated in conditions with impaired kidney function, so far. DESIGN/METHODS: Serum ACBP concentrations were investigated by enzyme-linked immunosorbent assay i) in a cohort of 60 individuals with kidney failure (KF) on chronic haemodialysis and compared to 60 individuals with a preserved kidney function; and ii) in a human model of acute kidney dysfunction (AKD). In addition, mACBP mRNA expression was assessed in two CKD mouse models and in two distinct groups of non-CKD mice. Further, mRNA expression of mACBP was measured in vitro in isolated, differentiated mouse adipocytes - brown and white - after exposure to the uremic agent indoxyl sulfate. RESULTS: Median [interquartile range] serum ACBP was almost 20-fold increased in KF (514.0 [339.3] µg/l) compared to subjects without KF (26.1 [39.1] µg/l) (p<0.001). eGFR was the most important, inverse predictor of circulating ACBP in multivariate analysis (standardized β=-0.839; p<0.001). Furthermore, AKD increased ACBP concentrations almost 3-fold (p<0.001). Increased ACBP levels were not caused by augmented mACBP mRNA expression in different tissues of CKD mice in vivo or in indoxyl sulfate-treated adipocytes in vitro. CONCLUSIONS: Circulating ACBP inversely associates with renal function, most likely through renal retention of the cytokine. Future studies need to investigate ACBP physiology in malnutrition-related disease states, such as CKD, and to adjust for markers of renal function. AU - Schürfeld, R.* AU - Sandner, B.* AU - Hoffmann, A.* AU - Klöting, N. AU - Baratashvili, E.* AU - Nowicki, M.* AU - Paeschke, S.* AU - Kosacka, J.* AU - Kralisch, S.* AU - Bachmann, A.* AU - Frille, A.* AU - Dietel, A.* AU - Stolzenburg, J.U.* AU - Blüher, M. AU - Zhang, M.Z.* AU - Harris, R.C.* AU - Isermann, B.* AU - Stumvoll, M.* AU - Tönjes, A.* AU - Ebert, T.* C1 - 67844 C2 - 54322 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Renal function is a major predictor of circulating acyl-CoA-binding protein/diazepam-binding inhibitor. JO - Front. Endocrin. VL - 14 PB - Frontiers Media Sa PY - 2023 SN - 1664-2392 ER - TY - JOUR AB - Introduction: Progression to type 1 diabetes has emerged as a complex process with metabolic alterations proposed to be a significant driver of disease. Monitoring products of altered metabolism is a promising tool for determining the risk of type 1 diabetes progression and to supplement existing predictive biomarkers. Methylglyoxal (MG) is a reactive product produced from protein, lipid, and sugar metabolism, providing a more comprehensive measure of metabolic changes compared to hyperglycemia alone. MG forms covalent adducts on nucleic and amino acids, termed MG-advanced glycation end products (AGEs) that associate with type 1 diabetes. Methods: We tested their ability to predict risk of disease and discriminate which individuals with autoimmunity will progress to type 1 diabetes. We measured serum MG-AGEs from 141 individuals without type 1 diabetes and 271 individuals with type 1 diabetes enrolled in the Fr1da cohort. Individuals with type 1 diabetes were at stages 1, 2, and 3. Results: We examined the association of MG-AGEs with type 1 diabetes. MG-AGEs did not correlate with HbA1c or differ between stages 1, 2, and 3 type 1 diabetes. Yet, RNA MG-AGEs were significantly associated with the rate of progression to stage 3 type 1 diabetes, with lower serum levels increasing risk of progression. Discussion: MG-AGEs were able to discriminate which individuals with autoantibodies would progress at a faster rate to stage 3 type 1 diabetes providing a potential new clinical biomarker for determining rate of disease progression and pointing to contributing metabolic pathways. AU - Shuck, S.C.* AU - Achenbach, P. AU - Roep, B.O.* AU - Termini, J.S.* AU - Hernandez-Castillo, C.* AU - Winkler, C. AU - Weiss, A. AU - Ziegler, A.-G. C1 - 67401 C2 - 54156 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Methylglyoxal products in pre-symptomatic type 1 diabetes. JO - Front. Endocrin. VL - 14 PB - Frontiers Media Sa PY - 2023 SN - 1664-2392 ER - TY - JOUR AB - Bi-allelic variants in ASCC1 cause the ultrarare bone fragility disorder "spinal muscular atrophy with congenital bone fractures-2" (SMABF2). However, the mechanism by which ASCC1 dysfunction leads to this musculoskeletal condition and the nature of the associated bone defect are poorly understood. By exome sequencing, we identified a novel homozygous deletion in ASCC1 in a female infant. She was born with severe muscular hypotonia, inability to breathe and swallow, and virtual absence of spontaneous movements; showed progressive brain atrophy, gracile long bones, very slender ribs, and a femur fracture; and died from respiratory failure aged 3 months. A transiliac bone sample taken postmortem revealed a distinct microstructural bone phenotype with low trabecular bone volume, low bone remodeling, disordered collagen organization, and an abnormally high bone marrow adiposity. Proteomics, RNA sequencing, and qPCR in patient-derived skin fibroblasts confirmed that ASCC1 was hardly expressed on protein and RNA levels compared with healthy controls. Furthermore, we demonstrate that mutated ASCC1 is associated with a downregulation of RUNX2, the master regulator of osteoblastogenesis, and SERPINF1, which is involved in osteoblast and adipocyte differentiation. It also exerts an inhibitory effect on TGF-β/SMAD signaling, which is important for bone development. Additionally, knockdown of ASCC1 in human mesenchymal stromal cells (hMSCs) suppressed their differentiation capacity into osteoblasts while increasing their differentiation into adipocytes. This resulted in reduced mineralization and elevated formation of lipid droplets. These findings shed light onto the pathophysiologic mechanisms underlying SMABF2 and assign a new biological role to ASCC1 acting as an important pro-osteoblastogenic and anti-adipogenic regulator. AU - Voraberger, B.* AU - Mayr, J.A.* AU - Fratzl-Zelman, N.* AU - Blouin, S.* AU - Uday, S.* AU - Kopajtich, R. AU - Koedam, M.* AU - Hödlmayr, H.* AU - Wortmann, S.B.* AU - Csillag, B.* AU - Prokisch, H. AU - van der Eerden, B.C.J.* AU - El-Gazzar, A.* AU - Högler, W.* C1 - 68095 C2 - 54573 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Investigating the role of ASCC1 in the causation of bone fragility. JO - Front. Endocrin. VL - 14 PB - Frontiers Media Sa PY - 2023 SN - 1664-2392 ER - TY - JOUR AB - PURPOSE: E47 has been identified as a modulating transcription factor of glucocorticoid receptor target genes, its loss protecting mice from metabolic adverse effects of glucocorticoids. We aimed to analyze the role of E47 in patients with endogenous glucocorticoid excess [Cushing's syndrome (CS)] and its association with disorders of lipid and glucose metabolism. METHODS: This is a prospective cohort study including 120 female patients with CS (ACTH-dependent = 79; ACTH-independent = 41) and 26 healthy female controls. Morning whole blood samples after an overnight fast were used to determine E47 mRNA expression levels in patients with overt CS before and 6-12 months after curative surgery. Expression levels were correlated with the clinical phenotype of the patients. Control subjects underwent ACTH stimulation tests and dexamethasone suppression tests to analyze short-term regulation of E47. RESULTS: E47 gene expression showed significant differences in patient cohorts with overt CS vs. patients in remission (p = 0.0474) and in direct intraindividual comparisons pre- vs. post-surgery (p = 0.0353). ACTH stimulation of controls resulted in a significant decrease of E47 mRNA expression 30 min after i.v. injection compared to baseline measurements. Administration of 1 mg of dexamethasone overnight in controls did not change E47 mRNA expression. E47 gene expression showed a positive correlation with total serum cholesterol (p = 0.0036), low-density lipoprotein cholesterol (p = 0.0157), and waist-arm ratio (p = 0.0138) in patients with CS in remission. CONCLUSION: E47 is a GC-dependent gene that is upregulated in GC excess potentially aiming at reducing metabolic glucocorticoid side effects such as dyslipidemia. AU - Zhang, W.* AU - Nowotny, H.* AU - Theodoropoulou, M.* AU - Simon, J.* AU - Hemmer, C.M. AU - Bidlingmaier, M.* AU - Auer, M.K.* AU - Reincke, M.* AU - Uhlenhaut, N.H. AU - Reisch, N.* C1 - 68875 C2 - 53733 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - E47 as a novel glucocorticoid-dependent gene mediating lipid metabolism in patients with endogenous glucocorticoid excess. JO - Front. Endocrin. VL - 14 PB - Frontiers Media Sa PY - 2023 SN - 1664-2392 ER - TY - JOUR AU - Abu-Farha, M.* AU - Hofmann, S.M. AU - Ali, H.* C1 - 65600 C2 - 52380 TI - Editorial: Covid-19 and diabetes. JO - Front. Endocrin. VL - 13 PY - 2022 SN - 1664-2392 ER - TY - JOUR AB - Aims/hypothesis: Advanced glycation end-products (AGEs) may contribute to the development of diabetic neuropathy. In young adults with type 1 diabetes, we aimed to investigate the association between AGEs and cardiovascular autonomic neuropathy (CAN) and distal symmetric polyneuropathy (DSPN). Methods: This cross-sectional study comprised 151 young adults. CAN was assessed by cardiovascular autonomic reflex tests; lying-to-standing test, deep breathing test (E/I), Valsalva manoeuvre, and heart rate variability indices; and the mean square of the sum of the squares of differences between consecutive R-R intervals and standard deviation of normal-to-normal intervals (SDNN), high- (HF) and low-frequency (LF) power, total frequency power, and the LF/HF ratio. DSPN was assessed by light touch, pain and vibration perception threshold (VPT), neuropathy questionnaires, and objective measures. AGEs were analysed in four groups using z-scores adjusted for relevant confounders and multiple testing: i) "glycolytic dysfunction", ii) "lipid peroxidation", iii) "oxidative stress", and iv) "glucotoxicity". Results: A higher z-score of "glycolytic dysfunction" was associated with higher VPT (4.14% (95% CI 1.31; 7.04), p = 0.004) and E/I (0.03% (95% CI 0.01; 0.05), p = 0.005), "lipid peroxidation" was associated with higher LF/HF ratio (37.72% (95% CI 1.12; 87.57), p = 0.044), and "glucotoxicity" was associated with lower SDNN (-4.20% (95% CI -8.1416; -0.0896), p = 0.047). No significance remained after adjustment for multiple testing. Conclusions/interpretations: In young adults with type 1 diabetes, increased levels of AGEs involving different metabolic pathways were associated with several measures of CAN and DSPN, suggesting that AGEs may play a diverse role in the pathogeneses of diabetic neuropathy. AU - Al-Saoudi, E.* AU - Christensen, M.M.B.* AU - Nawroth, P.P. AU - Fleming, T.* AU - Hommel, E.E.* AU - Jørgensen, M.E.* AU - Fleischer, J.* AU - Hansen, C.S.* C1 - 66627 C2 - 53251 TI - Advanced glycation end-products are associated with diabetic neuropathy in young adults with type 1 diabetes. JO - Front. Endocrin. VL - 13 PY - 2022 SN - 1664-2392 ER - TY - JOUR AB - Adipose tissue is essential for energy storage and endocrine regulation of metabolism. Imbalance in energy intake and expenditure result in obesity causing adipose tissue dysfunction. This alters cellular composition of the stromal cell populations and their function. Moreover, the individual cellular composition of each adipose tissue depot, regulated by environmental factors and genetics, determines the ability of the depots to expand and maintain its endocrine and storage function. Thus, stromal cells modulate adipocyte function and vice versa. In this mini-review we discuss heterogeneity in terms of composition and fate of adipose progenitor subtypes and their interactions with and regulation by different immune cell populations. Immune cells are the most diverse cell populations in adipose tissue and play essential roles in regulating adipose tissue function via interaction with adipocytes but also with adipocyte progenitors. We specifically discuss the role of macrophages, mast cells, innate lymphoid cells and T cells in the regulation of adipocyte progenitor proliferation, differentiation and lineage commitment. Understanding the factors and cellular interactions regulating preadipocyte expansion and fate decision will allow the identification of novel mechanisms and therapeutic strategies to promote healthy adipose tissue expansion without systemic metabolic impairment. AU - Altun, I. AU - Yan, X. AU - Ussar, S. C1 - 64790 C2 - 52486 TI - Immune cell regulation of white adipose progenitor cell fate. JO - Front. Endocrin. VL - 13 PY - 2022 SN - 1664-2392 ER - TY - JOUR AU - Blüher, M. AU - Mueller-Wieland, D.* C1 - 66098 C2 - 52648 TI - Editorial: Adipose tissue dysfunction. JO - Front. Endocrin. VL - 13 PY - 2022 SN - 1664-2392 ER - TY - JOUR AB - Introduction: The role of endogenous androgens in kidney function and disease has not been extensively explored in men and women. Research design and methods: We analyzed data from the observational KORA F4 study and its follow-up examination KORA FF4 (median follow-up time 6.5 years) including 1293 men and 650 peri- and postmenopausal women, not using exogenous sex hormones. We examined the associations between endogenous androgens (testosterone [T], dihydrotestosterone [DHT], free T [fT], free DHT [fDHT], and T/DHT), with estimated glomerular filtration rate (eGFR) at baseline and follow-up, prevalent, and incident chronic kidney disease (CKD) adjusting for common CKD risk factors. Results: At baseline, 73 men (5.7%) and 54 women (8.4%) had prevalent CKD. Cross-sectionally, no significant associations between androgens and kidney function were observed among men. In women, elevated T (β=-1.305, [95% CI -2.290; -0.320]) and fT (β=-1.423, [95% CI -2.449; -0.397]) were associated with lower eGFR. Prospectively, 81 men (8.8%) and 60 women (15.2%) developed incident CKD. In women, a reverse J-shaped associations was observed between DHT and incident CKD (Pnon-linear=0.029), while higher fDHT was associated with lower incident CKD risk (odds ratio per 1 standard deviation=0.613, [95% CI 0.369; 0.971]. Among men, T/DHT (β=-0.819, [95% CI -1.413; -0.226]) and SHBG (Pnon-linear=0.011) were associated with eGFR at follow-up but not with incident CKD. Some associations appeared to be modified by type 2 diabetes (T2D). Conclusion: Suggestive associations are observed of androgens and SHBG with kidney impairment among men and women. However, larger well-phenotyped prospective studies are required to further elucidate the potential of androgens, SHBG, and T2D as modifiable risk factors for kidney function and CKD. AU - Lau, L.H.Y. AU - Nano, J. AU - Prehn, C. AU - Cecil, A. AU - Rathmann, W.* AU - Zeller, T.* AU - Lechner, A.* AU - Adamski, J. AU - Peters, A. AU - Thorand, B. C1 - 67151 C2 - 53428 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Associations of endogenous androgens and sex hormone-binding globulin with kidney function and chronic kidney disease. JO - Front. Endocrin. VL - 13 PB - Frontiers Media Sa PY - 2022 SN - 1664-2392 ER - TY - JOUR AB - Aims/Hypothesis: Large-scale prediabetes screening is still a challenge since fasting blood glucose and HbA1c as the long-standing, recommended analytes have only moderate diagnostic sensitivity, and the practicability of the oral glucose tolerance test for population-based strategies is limited. To tackle this issue and to identify reliable diagnostic patterns, we developed an innovative metabolomics-based strategy deviating from common concepts by employing urine instead of blood samples, searching for sex-specific biomarkers, and focusing on modified metabolites. Methods: Non-targeted, modification group-assisted metabolomics by liquid chromatography–mass spectrometry (LC-MS) was applied to second morning urine samples of 340 individuals from a prediabetes cohort. Normal (n = 208) and impaired glucose-tolerant (IGT; n = 132) individuals, matched for age and BMI, were randomly divided in discovery and validation cohorts. ReliefF, a feature selection algorithm, was used to extract sex-specific diagnostic patterns of modified metabolites for the detection of IGT. The diagnostic performance was compared with conventional screening parameters fasting plasma glucose (FPG), HbA1c, and fasting insulin. Results: Female- and male-specific diagnostic patterns were identified in urine. Only three biomarkers were identical in both. The patterns showed better AUC and diagnostic sensitivity for prediabetes screening of IGT than FPG, HbA1c, insulin, or a combination of FPG and HbA1c. The AUC of the male-specific pattern in the validation cohort was 0.889 with a diagnostic sensitivity of 92.6% and increased to an AUC of 0.977 in combination with HbA1c. In comparison, the AUCs of FPG, HbA1c, and insulin alone reached 0.573, 0.668, and 0.571, respectively. Validation of the diagnostic pattern of female subjects showed an AUC of 0.722, which still exceeded the AUCs of FPG, HbA1c, and insulin (0.595, 0.604, and 0.634, respectively). Modified metabolites in the urinary patterns include advanced glycation end products (pentosidine-glucuronide and glutamyl-lysine-sulfate) and microbiota-associated compounds (indoxyl sulfate and dihydroxyphenyl-gamma-valerolactone-glucuronide). Conclusions/Interpretation: Our results demonstrate that the sex-specific search for diagnostic metabolite biomarkers can be superior to common metabolomics strategies. The diagnostic performance for IGT detection was significantly better than routinely applied blood parameters. Together with recently developed fully automatic LC-MS systems, this opens up future perspectives for the application of sex-specific diagnostic patterns for prediabetes screening in urine. AU - Li, Z.* AU - Zhang, Y.* AU - Hoene, M.* AU - Fritsche, L. AU - Zheng, S.* AU - Birkenfeld, A.L. AU - Fritsche, A. AU - Peter, A. AU - Liu, X.* AU - Zhao, X.* AU - Zhou, L.* AU - Luo, P.* AU - Weigert, C. AU - Lin, X.* AU - Xu, G.* AU - Lehmann, R. C1 - 65823 C2 - 52923 TI - Diagnostic performance of sex-specific modified metabolite patterns in urine for screening of prediabetes. JO - Front. Endocrin. VL - 13 PY - 2022 SN - 1664-2392 ER - TY - JOUR AB - Lipedema may be considered a model for healthy expandability of subcutaneous adipose tissue (SAT). This condition is characterized by the disproportional and symmetrical SAT accumulation in the lower-body parts and extremities, avoiding the abdominal area. There are no circulating biomarkers facilitating the diagnosis of lipedema. We tested the hypothesis that women living with lipedema present a distinct pattern of circulating parameters compared to age- and BMI-matched women. In 26 women (Age 48.3 ± 13.9 years, BMI 32.6 ± 5.8 kg/m2; lipedema group: n=13; control group: n=13), we assessed circulating parameters of glucose and lipid metabolism, inflammation, oxidative stress, sex hormones and a proteomics panel. We find that women with lipedema have better glucose metabolism regulation represented by lower HbA1c (5.55 ± 0.62%) compared to controls (6.73 ± 0.85%; p<0.001); and higher adiponectin levels (lipedema: 4.69 ± 1.99 mmol/l; control: 3.28 ± 1.00 mmol/l; p=0.038). Despite normal glycemic parameters, women with lipedema have significantly higher levels of total cholesterol (5.84 ± 0.70 mmol/L vs 4.55 ± 0.77 mmol/L in control; p<0.001), LDL-C (3.38 ± 0.68 mmol/L vs 2.38 ± 0.66 mmol/L in control; p=0.002), as well as higher circulating inflammation (top 6 based on p-values: TNFSF14, CASP8, EN-RAGE, EIF4EBP1, ADA, MCP-1) and oxidative stress markers (malondialdehyde, superoxide dismutase and catalase). Our findings suggest that the expected association between activation of inflammatory and oxidative stress pathways and impaired glucose metabolism are counterbalanced by protective factors in lipedema. AU - Nono Nankam, P.A. AU - Cornely, M.* AU - Klöting, N. AU - Blüher, M. C1 - 66735 C2 - 53286 TI - Is subcutaneous adipose tissue expansion in people living with lipedema healthier and reflected by circulating parameters? JO - Front. Endocrin. VL - 13 PY - 2022 SN - 1664-2392 ER - TY - JOUR AB - The incretin hormone glucagon-like peptide-1 (GLP-1) has received enormous attention during the past three decades as a therapeutic target for the treatment of obesity and type 2 diabetes. Continuous improvement of the pharmacokinetic profile of GLP-1R agonists, starting from native hormone with a half-life of ~2-3 min to the development of twice daily, daily and even once-weekly drugs highlight the pharmaceutical evolution of GLP-1-based medicines. In contrast to GLP-1, the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) received little attention as a pharmacological target, because of conflicting observations that argue activation or inhibition of the GIP receptor (GIPR) provides beneficial effects on systemic metabolism. Interest in GIPR agonism for the treatment of obesity and diabetes was recently propelled by the clinical success of unimolecular dual-agonists targeting the receptors for GIP and GLP-1, with reported significantly improved body weight and glucose control in patients with obesity and type II diabetes. Here we review the biology and pharmacology of GLP-1 and GIP and discuss recent advances in incretin-based pharmacotherapies. AU - Tan, Q.* AU - Akindehin, S.E. AU - Orsso, C.E.* AU - Waldner, R.C.* AU - DiMarchi, R.D.* AU - Müller, T.D. AU - Haqq, A.M.* C1 - 64632 C2 - 52360 TI - Recent advances in incretin-based pharmacotherapies for the treatment of obesity and diabetes. JO - Front. Endocrin. VL - 13 PY - 2022 SN - 1664-2392 ER - TY - JOUR AB - Introduction: While oral glucose ingestion typically leads to a decrease in circulating glucagon levels, a substantial number of persons display stable or rising glucagon concentrations when assessed by radioimmunoassay (RIA). However, these assays show cross-reactivity to other proglucagon cleavage products. Recently, more specific assays became available, therefore we systematically assessed glucagon and other proglucagon cleavage products and their relation to metabolic health. Research Design and Methods: We used samples from 52 oral glucose tolerance tests (OGTT) that were randomly selected from persons with different categories of glucose tolerance in an extensively phenotyped study cohort. Results: Glucagon concentrations quantified with RIA were non-suppressed at 2 hours of the OGTT in 36% of the samples. Non-suppressors showed lower fasting glucagon levels compared to suppressors (p=0.011). Similar to RIA measurements, ELISA-derived fasting glucagon was lower in non-suppressors (p<0.001). Glucagon 1-61 as well as glicentin and GLP-1 kinetics were significantly different between suppressors and non-suppressors (p=0.004, p=0.002, p=0.008 respectively) with higher concentrations of all three hormones in non-suppressors. Levels of insulin, C-peptide, and free fatty acids were comparable between groups. Non-suppressors were leaner and had lower plasma glucose concentrations (p=0.03 and p=0.047, respectively). Despite comparable liver fat content and insulin sensitivity (p≥0.3), they had lower 2-hour post-challenge glucose (p=0.01). Conclusions: Glucagon 1-61, glicentin and GLP-1 partially account for RIA-derived glucagon measurements due to cross-reactivity of the assay. However, this contribution is small, since the investigated proglucagon cleavage products contribute less than 10% to the variation in RIA measured glucagon. Altered glucagon levels and higher post-challenge incretins are associated with a healthier metabolic phenotype. AU - Wagner, R. AU - Eckstein, S.S. AU - Fritsche, L. AU - Hörber, S. AU - Häring, H.-U. AU - Birkenfeld, A.L. AU - Fritsche, A. AU - Heni, M. C1 - 65753 C2 - 52895 TI - Postprandial dynamics of proglucagon cleavage products and their relation to metabolic health. JO - Front. Endocrin. VL - 13 PY - 2022 SN - 1664-2392 ER - TY - JOUR AU - Brusko, T.M.* AU - Mallone, R.* AU - Rodriguez-Calvo, T. C1 - 63407 C2 - 51312 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Editorial: Footprints of immune cells in the type 1 diabetic pancreas. JO - Front. Endocrin. VL - 12 PB - Frontiers Media Sa PY - 2021 SN - 1664-2392 ER - TY - JOUR AU - Chondronikola, M.* AU - Bartelt, A. AU - Vidal-Puig, A.* AU - Virtanen, K.A.* C1 - 62800 C2 - 50992 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Editorial: Brown adipose tissue: From heat production in rodents to metabolic health in humans. JO - Front. Endocrin. VL - 12 PB - Frontiers Media Sa PY - 2021 SN - 1664-2392 ER - TY - JOUR AU - Di Franco, S.* AU - Pellegata, N.S. AU - Luconi, M.* AU - Stassi, G.* C1 - 62572 C2 - 50815 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Editorial: Stem cells in endocrine tumors. JO - Front. Endocrin. VL - 12 PB - Frontiers Media Sa PY - 2021 SN - 1664-2392 ER - TY - JOUR AU - Fritsche, A. AU - Szendrödi, J.* AU - Schürmann, A.* C1 - 63185 C2 - 51182 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Editorial: Intermittent fasting - mechanisms and clinical usefulness. JO - Front. Endocrin. VL - 12 PB - Frontiers Media Sa PY - 2021 SN - 1664-2392 ER - TY - JOUR AB - Patients with diabetes are over-represented among the total cases reported with "idiopathic" pulmonary fibrosis (IPF). This raises the question, whether this is an association only or whether diabetes itself can cause pulmonary fibrosis. Recent studies in mouse models of type 1 and type 2 diabetes demonstrated that diabetes causes pulmonary fibrosis. Both types of diabetes trigger a cascade, starting with increased DNA damage, an impaired DNA repair, and leading to persistent DNA damage signaling. This response, in turn, induces senescence, a senescence-associated-secretory phenotype (SASP), marked by the release of pro-inflammatory cytokines and growth factors, finally resulting in fibrosis. Restoring DNA repair drives fibrosis into remission, thus proving causality. These data can be translated clinically to patients with type 2 diabetes, characterized by long-term diabetes and albuminuria. Hence there are several arguments, to substitute the term "idiopathic" pulmonary fibrosis (IPF) in patients with diabetes (and exclusion of other causes of lung diseases) by the term "diabetes-induced pulmonary fibrosis" (DiPF). However, future studies are required to establish this term and to study whether patients with diabetes respond to the established therapies similar to non-diabetic patients. AU - Kopf, S.* AU - Kumar, V.* AU - Kender, Z.* AU - Han, Z.* AU - Fleming, T.* AU - Herzig, S. AU - Nawroth, P.P. C1 - 63772 C2 - 51752 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Diabetic pneumopathy-a new diabetes-associated complication: Mechanisms, consequences and treatment considerations. JO - Front. Endocrin. VL - 12 PB - Frontiers Media Sa PY - 2021 SN - 1664-2392 ER - TY - JOUR AB - Context: Pheochromocytomas and paragangliomas (PPGL) cause catecholamine excess leading to a characteristic clinical phenotype. Intra-individual changes at metabolome level have been described after surgical PPGL removal. The value of metabolomics for the diagnosis of PPGL has not been studied yet. Objective: Evaluation of quantitative metabolomics as a diagnostic tool for PPGL. Design: Targeted metabolomics by liquid chromatography-tandem mass spectrometry of plasma specimens and statistical modeling using ML-based feature selection approaches in a clinically well characterized cohort study. Patients: Prospectively enrolled patients (n=36, 17 female) from the Prospective Monoamine-producing Tumor Study (PMT) with hormonally active PPGL and 36 matched controls in whom PPGL was rigorously excluded. Results: Among 188 measured metabolites, only without considering false discovery rate, 4 exhibited statistically significant differences between patients with PPGL and controls (histidine p=0.004, threonine p=0.008, lyso PC a C28:0 p=0.044, sum of hexoses p=0.018). Weak, but significant correlations for histidine, threonine and lyso PC a C28:0 with total urine catecholamine levels were identified. Only the sum of hexoses (reflecting glucose) showed significant correlations with plasma metanephrines.By using ML-based feature selection approaches, we identified diagnostic signatures which all exhibited low accuracy and sensitivity. The best predictive value (sensitivity 87.5%, accuracy 67.3%) was obtained by using Gradient Boosting Machine Modelling. Conclusions: The diabetogenic effect of catecholamine excess dominates the plasma metabolome in PPGL patients. While curative surgery for PPGL led to normalization of catecholamine-induced alterations of metabolomics in individual patients, plasma metabolomics are not useful for diagnostic purposes, most likely due to inter-individual variability. AU - März, J.* AU - Kurlbaum, M.* AU - Roche-Lancaster, O.* AU - Deutschbein, T.* AU - Peitzsch, M.* AU - Prehn, C. AU - Weismann, D.* AU - Robledo, M.* AU - Adamski, J. AU - Fassnacht, M.* AU - Kunz, M.* AU - Kroiss, M.* C1 - 63117 C2 - 51328 TI - Plasma metabolome profiling for the diagnosis of catecholamine producing tumors. JO - Front. Endocrin. VL - 12 PY - 2021 SN - 1664-2392 ER - TY - JOUR AB - An intact intestinal barrier, representing the interface between inner and outer environments, is an integral regulator of health. Among several factors, bacteria and their products have been evidenced to contribute to gut barrier impairment and its increased permeability. Alterations of tight junction integrity - caused by both external factors and host metabolic state - are important for gut barrier, since they can lead to increased influx of bacteria or bacterial components (endotoxin, bacterial DNA, metabolites) into the host circulation. Increased systemic levels of bacterial endotoxins and DNA have been associated with an impaired metabolic host status, manifested in obesity, insulin resistance, and associated cardiovascular complications. Bacterial components and cells are distributed to peripheral tissues via the blood stream, possibly contributing to metabolic diseases by increasing chronic pro-inflammatory signals at both tissue and systemic levels. This response is, along with other yet unknown mechanisms, mediated by toll like receptor (TLR) transduction and increased expression of pro-inflammatory cytokines, which in turn can further increase intestinal permeability leading to a detrimental positive feedback loop. The modulation of gut barrier function through nutritional and other interventions, including manipulation of gut microbiota, may represent a potential prevention and treatment target for metabolic diseases. AU - Massier, L.* AU - Blüher, M. AU - Kovacs, P.* AU - Chakaroun, R.M.* C1 - 61659 C2 - 50370 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Impaired intestinal barrier and tissue bacteria: Pathomechanisms for metabolic diseases. JO - Front. Endocrin. VL - 12 PB - Frontiers Media Sa PY - 2021 SN - 1664-2392 ER - TY - JOUR AB - The acclimatization of brown adipose tissue (BAT) to sustained cold exposure requires an adaptive increase in proteasomal protein quality control. Ubiquilins represent a recently identified family of shuttle proteins with versatile functions in protein degradation, such as facilitating substrate targeting and proteasomal degradation. However, whether ubiquilins participate in brown adipocyte function has not been investigated so far. Here, we determine the role of ubiquilins for proteostasis and non-shivering thermogenesis in brown adipocytes. We found that Ubqln1, 2 and 4 are highly expressed in BAT and their expression was induced by cold and proteasomal inhibition. Surprisingly, silencing of ubiquilin gene expression (one or multiple in combinations) did not lead to aggravated ER stress or inflammation. Moreover, ubiquitin level and proteasomal activity under basal conditions were not impacted by loss of ubiquilins. Also, non-shivering thermogenesis measured by norepinephrine-induced respiration remained intact after loss of ubiquilins. In conclusion, ubiquilin proteins are highly abundant in BAT and regulated by cold, but they are dispensable for brown adipocyte proteostasis and thermogenesis. AU - Muley, C.* AU - Kotschi, S.* AU - Bartelt, A. C1 - 63262 C2 - 51444 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Role of ubiquilins for brown adipocyte proteostasis and thermogenesis. JO - Front. Endocrin. VL - 12 PB - Frontiers Media Sa PY - 2021 SN - 1664-2392 ER - TY - JOUR AB - Background: N6-methyladenosine (m6A) is one of the most abundant post-transcriptional modifications on mRNA influencing mRNA metabolism. There is emerging evidence for its implication in metabolic disease. No comprehensive analyses on gene expression of m6A regulators in human adipose tissue, especially in paired adipose tissue depots, and its correlation with clinical variables were reported so far. We hypothesized that inter-depot specific gene expression of m6A regulators may differentially correlate with clinical variables related to obesity and fat distribution. Methods: We extracted intra-individually paired gene expression data (omental visceral adipose tissue (OVAT) N=48; subcutaneous adipose tissue (SAT) N=56) of m6A regulators from an existing microarray dataset. We also measured gene expression in another sample set of paired OVAT and SAT (N=46) using RT-qPCR. Finally, we extracted existing gene expression data from peripheral mononuclear blood cells (PBMCs) and single nucleotide polymorphisms (SNPs) in METTL3 and YTHDF3 from genome wide data from the Sorbs population (N=1049). The data were analysed for differential gene expression between OVAT and SAT; and for association with obesity and clinical variables. We further tested for association of SNP markers with gene expression and clinical traits. Results: In adipose tissue we observed that several m6A regulators (WTAP, VIRMA, YTHDC1 and ALKBH5) correlate with obesity and clinical variables. Moreover, we found adipose tissue depot specific gene expression for METTL3, WTAP, VIRMA, FTO and YTHDC1. In PBMCs, we identified ALKBH5 and YTHDF3 correlated with obesity. Genetic markers in METTL3 associate with BMI whilst SNPs in YTHDF3 are associated with its gene expression. Conclusions: Our data show that expression of m6A regulators correlates with obesity, is adipose tissue depot-specific and related to clinical traits. Genetic variation in m6A regulators adds an additional layer of variability to the functional consequences. AU - Rønningen, T.* AU - Dahl, M.B.* AU - Valderhaug, T.G.* AU - Cayir, A.* AU - Keller, M. AU - Tönjes, A.* AU - Blüher, M. AU - Böttcher, Y. C1 - 63874 C2 - 51658 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - m6A regulators in human adipose tissue - depot-specificity and correlation with obesity. JO - Front. Endocrin. VL - 12 PB - Frontiers Media Sa PY - 2021 SN - 1664-2392 ER - TY - JOUR AB - In all forms of diabetes, β cell mass or function is reduced and therefore the capacity of the pancreatic cells for regeneration or replenishment is a critical need. Diverse lines of research have shown the capacity of endocrine as well as acinar, ductal and centroacinar cells to generate new β cells. Several experimental approaches using injury models, pharmacological or genetic interventions, isolation and in vitro expansion of putative progenitors followed by transplantations or a combination thereof have suggested several pathways for β cell neogenesis or regeneration. The experimental results have also generated controversy related to the limitations and interpretation of the experimental approaches and ultimately their physiological relevance, particularly when considering differences between mouse, the primary animal model, and human. As a result, consensus is lacking regarding the relative importance of islet cell proliferation or progenitor differentiation and transdifferentiation of other pancreatic cell types in generating new β cells. In this review we summarize and evaluate recent experimental approaches and findings related to islet regeneration and address their relevance and potential clinical application in the fight against diabetes. AU - Spears, E.* AU - Serafimidis, I.* AU - Powers, A.C.* AU - Gavalas, A. C1 - 62852 C2 - 51104 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Debates in pancreatic beta cell biology: Proliferation versus progenitor differentiation and transdifferentiation in restoring β cell mass. JO - Front. Endocrin. VL - 12 PB - Frontiers Media Sa PY - 2021 SN - 1664-2392 ER - TY - JOUR AB - The important role of microRNAs as major modulators of various physiological processes, including immune regulation and homeostasis, has been increasingly recognized. Consequently, aberrant miRNA expression contributes to the defective regulation of T cell development, differentiation, and function. This can result in immune activation and impaired tolerance mechanisms, which exert a cardinal function for the onset of islet autoimmunity and the progression to T1D. The specific impact of miRNAs for immune regulation and how miRNAs and their downstream targets are involved in the pathogenesis of islet autoimmunity and T1D has been investigated recently. These studies revealed that increased expression of individual miRNAs is involved in several layers of tolerance impairments, such as inefficient Treg induction and Treg instability. The targeted modulation of miRNAs using specific inhibitors, resulting in improved immune homeostasis, as well as improved methods for the targeting of miRNAs, suggest that miRNAs, especially in T cells, are a promising target for the reestablishment of immune tolerance. AU - Scherm, M.G. AU - Daniel, C. C1 - 60828 C2 - 49607 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - miRNA-mediated immune regulation in islet autoimmunity and type 1 diabetes. JO - Front. Endocrin. VL - 11 PB - Frontiers Media Sa PY - 2020 SN - 1664-2392 ER - TY - JOUR AB - Introduction: Genetic polymorphisms in TCF7L2 are the strongest common risk variants for type 2 diabetes mellitus (T2D). We and others have shown that genetic variation in TCF7L2 and WFS1 affect incretin-stimulated insulin secretion. A recent genome-wide association study discovered genetic variants associated with incretin levels. We hypothesized that these SNPs (single nucleotide polymorphisms) interact with the well-known TCF7L2 variant rs7903146 on insulin secretion due to their incretin altering effect. Methods: In this retrospective analysis, we used data from the cross-sectional TUEF-cohort (n = 2929) and a hyperglycemic clamp study using additional GLP-1 infusion at the end of the clamp (n = 76). Insulin secretion was measured by evaluating OGTT-derived indexes of insulin secretion and insulin/C-peptide levels during clamp. We genotyped rs7903146 in TCF7L2, rs10010131 in WFS1, and six SNPs associated with GLP-1 and GIP levels. Results: One of the six incretin-associated SNPs, rs17681684 in GLP2R, exhibited significant SNP x SNP interactions with rs7903146 in TCF7L2 on insulin secretion (p = 0.0024) after correction for multiple testing. Three further SNP‘s showed nominally significant interactions (p < 0.05). In the hyperglycemic clamp study, rs7903146 in TCF7L2 also interacted with rs17681684 on AUC C-peptide during the GLP-1 stimulation phase, thereby replicating the above finding. Conclusion: The findings exemplify the role of SNP x SNP interactions in the genetics of type 2 diabetes mellitus and corroborate the existence of clinically relevant differences in incretin sensitivity. AU - Jaghutriz, B.A. AU - Heni, M. AU - Lutz, S.Z. AU - Fritsche, L. AU - Machicao, F. AU - Staiger, H. AU - Peter, A. AU - Häring, H.-U. AU - Fritsche, A. AU - Wagner, R. C1 - 55617 C2 - 46427 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Gene X gene interactions highlight the role of incretin resistance for insulin secretion. JO - Front. Endocrin. VL - 10 PB - Frontiers Media Sa PY - 2019 SN - 1664-2392 ER - TY - JOUR AB - Background: Testosterone levels are differentially linked with diabetes risk in men and women: lower testosterone levels in men and higher testosterone levels in women are associated with type 2 diabetes, though, the mechanisms are not fully clear. We addressed sex-specific links between testosterone and major pathogenetic mechanisms of diabetes. Methods: We analyzed data of 623 subjects (202 male, 345 female without, and 76 female with oral contraceptive therapy [OCT]) for whom insulin sensitivity and insulin secretion were assessed by oral glucose tolerance test. Body fat percentage was assessed by bioelectrical impedance. Testosterone was measured by enzyme-linked immunoassay; free testosterone and Framingham risk score were calculated. Results: There were significant interactions between testosterone and sex for all tested metabolic traits. Increasing testosterone was associated with less body fat, elevated insulin sensitivity, and reduced glycemia, independent of adiposity in men. In women without OCT, testosterone correlated with more body fat, insulin resistance, and higher glucose concentrations. Testosterone was not associated with insulin secretion in either sex, but with lower Framingham risk score in men and higher Framingham risk score in women. Conclusions: Similar to diabetes risk, insulin resistance has different association directions with testosterone levels in males and females. Insulin resistance could therefore constitute the best biological candidate linking testosterone levels and diabetes prevalence. The question of antiandrogen therapy being able to improve metabolism, glucose tolerance and cardiovascular risk in women was not clarified in our study but should be reviewed with higher numbers in a carefully matched study to reduce the influence of confounding variables. AU - Lutz, S.Z. AU - Wagner, R. AU - Fritsche, L. AU - Peter, A. AU - Rettig, I.* AU - Willmann, C. AU - Fehlert, E. AU - Martus, P.* AU - Todenhoefer, T.* AU - Stefan, N. AU - Fritsche, A. AU - Häring, H.-U. AU - Heni, M. C1 - 55759 C2 - 46536 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Sex-specific associations of testosterone with metabolic traits. JO - Front. Endocrin. VL - 10 PB - Frontiers Media Sa PY - 2019 SN - 1664-2392 ER - TY - JOUR AB - Background: Adrenocortical carcinoma (ACC) is a rare tumor entity with restricted therapeutic opportunities. HSP90 (Heat Shock Protein 90) chaperone activity is fundamental for cell survival and contributes to different oncogenic signaling pathways. Indeed, agents targeting HSP90 function have shown therapeutic efficacy in several cancer types. We have examined the expression of HSP90 in different adrenal tumors and evaluated the use of HSP90 inhibitors in vitro as possible therapy for ACC.Methods: Immunohistochemical expression of HSP90 isoforms was investigated in different adrenocortical tumors and associated with clinical features. Additionally, a panel of N-terminal (17-allylamino-17-demethoxygeldanamycin (17-AAG), luminespib, and ganetespib) and C-terminal (novobiocin and silibinin) HSP90 inhibitors were tested on various ACC cell lines.Results: Within adrenocortical tumors, ACC samples exhibited the highest expression of HSP90 beta. Within a cohort of ACC patients, HSP90 beta expression levels were inversely correlated with recurrence-free and overall survival. In functional assays, among five different compounds tested luminespib and ganetespib induced a significant decrease in cell viability in single as well as in combined treatments with compounds of the clinically used EDP-M scheme (etoposide, doxorubicin, cisplatin, mitotane). Inhibition of cell viability correlated furthermore with a decrease in proliferation, in cell migration and an increase in apoptosis. Moreover, analysis of cancer pathways indicated a modulation of the ERK1/2-and AKT-pathways by luminespib and ganetespib treatment.Conclusions: Our findings emphasize HSP90 as a marker with prognostic impact and promising target with N-terminal HSP90 inhibitors as drugs with potential therapeutic efficacy toward ACC. AU - Siebert, C.* AU - Ciato, D.* AU - Murakami, M.* AU - Frei-Stuber, L.* AU - Perez-Rivas, L.G.* AU - Monteserin-Garcia, J.L.* AU - Noelting, S.* AU - Maurer, J.* AU - Feuchtinger, A. AU - Walch, A.K. AU - Haak, H.R.* AU - Bertherat, J.* AU - Mannelli, M.* AU - Fassnacht, M.* AU - Korpershoek, E.* AU - Reincke, M.* AU - Stalla, G.K.* AU - Hantel, C.* AU - Beuschlein, F.* C1 - 56723 C2 - 47224 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Heat shock protein 90 as a prognostic marker and therapeutic target for adrenocortical carcinoma. JO - Front. Endocrin. VL - 10 PB - Frontiers Media Sa PY - 2019 SN - 1664-2392 ER - TY - JOUR AB - Introduction: Impaired glucose tolerance (IGT) is diagnosed by a standardized oral glucose tolerance test (OGTT). However, the OGTT is laborious, and when not performed, glucose tolerance cannot be determined from fasting samples retrospectively. We tested if glucose tolerance status is reasonably predictable from a combination of demographic, anthropometric, and laboratory data assessed at one time point in a fasting state. Methods: Given a set of 22 variables selected upon clinical feasibility such as sex, age, height, weight, waist circumference, blood pressure, fasting glucose, HbA1c, hemoglobin, mean corpuscular volume, serum potassium, fasting levels of insulin, C-peptide, triglyceride, non-esterified fatty acids (NEFA), proinsulin, prolactin, cholesterol, low-density lipoprotein, HDL, uric acid, liver transaminases, and ferritin, we used supervised machine learning to estimate glucose tolerance status in 2,337 participants of the TUEF study who were recruited before 2012. We tested the performance of 10 different machine learning classifiers on data from 929 participants in the test set who were recruited after 2012. In addition, reproducibility of IGT was analyzed in 78 participants who had 2 repeated OGTTs within 1 year. Results: The most accurate prediction of IGT was reached with the recursive partitioning method (accuracy = 0.78). For all classifiers, mean accuracy was 0.73 +/- 0.04. The most important model variable was fasting glucose in all models. Using mean variable importance across all models, fasting glucose was followed by NEFA, triglycerides, HbA1c, and C-peptide. The accuracy of predicting IGT from a previous OGTT was 0.77. Conclusion: Machine learning methods yield moderate accuracy in predicting glucose tolerance from a wide set of clinical and laboratory variables. A substitution of OGTT does not currently seem to be feasible. An important constraint could be the limited reproducibility of glucose tolerance status during a subsequent OGTT. AU - Babbar, R.* AU - Heni, M. AU - Peter, A. AU - Hrabě de Angelis, M. AU - Häring, H.-U. AU - Fritsche, A. AU - Preissl, H. AU - Schölkopf, B.* AU - Wagner, R. C1 - 53277 C2 - 44472 CY - Lausanne TI - Prediction of glucose tolerance without an oral glucose tolerance test. JO - Front. Endocrin. VL - 9 PB - Frontiers Media Sa PY - 2018 SN - 1664-2392 ER - TY - JOUR AB - Glucose sensing is pursued extensively in biomedical research and clinical practice for assessment of the carbohydrate and fat metabolism as well as in the context of an array of disorders, including diabetes, morbid obesity, and cancer. Currently used methods for real-time glucose measurements are invasive and require access to body fluids, with novel tools and methods for non-invasive sensing of the glucose levels highly desired. In this study, we introduce a near-infrared (NIR) optoacoustic spectrometer for sensing physiological concentrations of glucose within aqueous media and describe the glucose spectra within 850-1,900 nm and various concentration ranges. We apply the ratiometric and dictionary learning methods with a training set of data and validate their utility for glucose concentration measurements with optoacoustics in the probe dataset. We demonstrate the superior signal-to-noise ratio (factor of ~3.9) achieved with dictionary learning over the ratiometric approach across the wide glucose concentration range. Our data show a linear relationship between the optoacoustic signal intensity and physiological glucose concentration, in line with the results of optical spectroscopy. Thus, the feasibility of detecting physiological glucose concentrations using NIR optoacoustic spectroscopy is demonstrated, enabling the sensing glucose with ±10 mg/dl precision. AU - Ghazaryan, A. AU - Ovsepian, S.V. AU - Ntziachristos, V. C1 - 53283 C2 - 44498 CY - Lausanne TI - Extended near-infrared optoacoustic spectrometry for sensing physiological concentrations of glucose. JO - Front. Endocrin. VL - 9 IS - MAR PB - Frontiers Media Sa PY - 2018 SN - 1664-2392 ER - TY - JOUR AB - Insulin acts in the brain to limit food intake and improve memory function. We have previously shown that 8 weeks of intranasal insulin delivered in four daily doses of 40 IU decrease body weight and enhance word list recall. In the present study, we investigated the effect on body composition, endocrine parameters, and memory performance of 8 weeks of once-daily administration of 160 IU in healthy men. We assumed that intranasal insulin administered before nocturnal sleep, a period of relative metabolic inactivity that moreover benefits memory formation, would be superior to insulin delivery in the morning and placebo administration. After a 2-week baseline period, healthy male normal-weight subjects (mean age, 27.1 +/- 0.9 years) received either placebo, 160 IU intranasal insulin in the morning, or 160 IU in the evening (n = 12 per group) for 8 consecutive weeks. Throughout the experiment, we measured body weight and body composition as well as circulating concentrations of glucose, insulin, adrenocorticotropin, cortisol, growth hormone, insulin-like growth-factor 1, adiponectin, and leptin. Declarative and procedural memory function was repeatedly assessed by means of, respectively, word list recall and word-stem priming. We found that neither morning nor evening insulin compared to placebo administration induced discernible changes in body weight and body composition. Delayed recall of words showed slight improvements by insulin administration in the evening, and serum cortisol concentrations were reduced after 2 weeks of insulin administration in the morning compared to the other groups. Results indicate that catabolic long-term effects of central nervous insulin delivery necessitate repetitive, presumably pre-meal delivery schedules. The observed memory improvements, although generally weaker than previously found effects, suggest that sleep after intranasal insulin administration may support its beneficial cognitive impact. AU - Ritze, Y.* AU - Kern, W.* AU - Ebner, E.* AU - Jahn, S.* AU - Benedict, C.* AU - Hallschmid, M. C1 - 54801 C2 - 45839 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Metabolic and cognitive outcomes of subchronic once-daily intranasal insulin administration in healthy men. JO - Front. Endocrin. VL - 9 PB - Frontiers Media Sa PY - 2018 SN - 1664-2392 ER - TY - JOUR AB - Introduction: We have previously shown that fetuses of mothers with gestational diabetes mellitus (GDM) and insulin resistance exhibit a prolongation of fetal auditory event-related brain responses (fAER) compared to fetuses of normal glucose tolerant women during an oral glucose tolerance test (oGTT). This implies that maternal metabolism may program the developing fetal brain. We now asked whether a family history of type 2 diabetes without metabolic programing also impacts fetal brain activity. We therefore investigated brain activity in fetuses of normal glucose tolerant mothers with and without family history of type 2 diabetes (FHD+ and FHD-).Methods: A 75 g oGTT was performed in healthy pregnant women. Plasma glucose and insulin levels were measured after 0, 60, and 120 min. Each blood draw was preceded by fetal magnetoencephalographic (fMEG) recordings of fAER. From a group of 167 participants, a subsample of 52 metabolically healthy women, 37 with a negative, and 15 with a positive FHD (at least one first- or second-degree relative) was carefully selected based on the following inclusion criteria: inconspicuous pregnancy, no GDM, BMI 18.5-30 kg/m(2), no preterm birth and at least two fMEG with detectable fetal responses during oGTT.Results: An ANOVA showed a significant interaction between fMEG measurement time during the oGTT and FHD on fAER latency [F-(2) = 4.163, p = 0.018]. Fetuses of mothers with FHD+ had a prolonged fAER (273 +/- 113 ms) compared to fetuses of mothers with FHD- (219 +/- 69 ms) at 60 min during the oGTT [F-(1() )= 4.902, p = 0.032]. There were no significant differences in age, BMI before pregnancy, weight gain during pregnancy and gestational age between the groups. Maternal glucose levels and insulin sensitivity were also not significantly different.Discussion: In addition to the previously shown influence of maternal metabolism on fetal brain activity, maternal family history of diabetes (FHD) is also linked to fetal postprandial brain activity. This indicates that genetic and/or epigenetic factors modulate the postprandial brain response of the developing fetus. AU - Schleger, F. AU - Linder, K. AU - Walter, L.* AU - Heni, M. AU - Braendle, J.* AU - Brucker, S.* AU - Pauluschke-Froehlich, J.* AU - Weiss, M.* AU - Häring, H.-U. AU - Preissl, H. AU - Fritsche, A. C1 - 54824 C2 - 45847 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Family history of diabetes is associated with delayed fetal postprandial brain activity. JO - Front. Endocrin. VL - 9 PB - Frontiers Media Sa PY - 2018 SN - 1664-2392 ER - TY - JOUR AB - The hypothalamus is a key brain region in the regulation of energy balance as it controls food intake and both energy storage and expenditure through integration of humoral, neural, and nutrient-related signals and cues. Many years of research have focused on the regulation of energy balance by hypothalamic neurons, but the most recent findings suggest that neurons and glial cells, such as microglia and astrocytes, in the hypothalamus actually orchestrate together several metabolic functions. Because glial cells have been described as mediators of inflammatory processes in the brain, the existence of a causal link between hypothalamic inflammation and the deregulations of feeding behavior, leading to involuntary weight loss or obesity for example, has been suggested. Several inflammatory pathways that could impair the hypothalamic control of energy balance have been studied over the years such as, among others, toll-like receptors and canonical cytokines. Yet, less studied so far, chemokines also represent interesting candidates that could link the aforementioned pathways and the activity of hypothalamic neurons. Indeed, chemokines, in addition to their role in attracting immune cells to the inflamed site, have been suggested to be capable of neuromodulation. Thus, they could disrupt cellular activity together with synthesis and/or secretion of multiple neurotransmitters/mediators involved in the maintenance of energy balance. This review discusses the different inflammatory pathways that have been identified so far in the hypothalamus in the context of feeding behavior and body weight control impairments, with a particular focus on chemokines signaling that opens a new avenue in the understanding of the major role played by inflammation in obesity. AU - Le Thuc, O. AU - Stobbe, K.* AU - Cansell, C.* AU - Nahon, J.L.* AU - Blondeau, N.* AU - Rovère, C.* C1 - 51751 C2 - 43334 CY - Lausanne TI - Hypothalamic inflammation and energy balance disruptions: Spotlight on chemokines. JO - Front. Endocrin. VL - 8 IS - AUG PB - Frontiers Media Sa PY - 2017 SN - 1664-2392 ER - TY - JOUR AB - Steroid hormones regulate physiological processes in species ranging from plants to humans. A wide range of steroid hormones exist, and their contributions to processes, such as growth, reproduction, development, and aging, is almost always complex. Understanding the biosynthetic pathways that generate steroid hormones and the signaling pathways that mediate their effects is thus of fundamental importance. In this work, we review recent advances in (i) the biological role of steroid hormones in the roundworm Caenorhabditis elegans and (ii) the development of novel methods to facilitate the detection and identification of these molecules. Our current understanding of steroid signaling in this simple organism serves to illustrate the challenges we face moving forward. First, it seems clear that we have not yet identified all of the enzymes responsible for steroid biosynthesis and/or degradation. Second, perturbation of steroid signaling affects a wide range of phenotypes, and subtly different steroid molecules can have distinct effects. Finally, steroid hormone levels are critically important, and minute variations in quantity can profoundly impact a phenotype. Thus, it is imperative that we develop innovative analytical tools and combine them with cutting-edge approaches including comprehensive and highly selective liquid chromatography coupled to mass spectrometry based on new methods such as supercritical fluid chromatography coupled to mass spectrometry (SFC-MS) if we are to obtain a better understanding of the biological functions of steroid signaling. AU - Aguilaniu, H.* AU - Fabrizio, P.* AU - Witting, M. C1 - 47713 C2 - 39630 CY - Lausanne TI - The role of dafachronic acid signaling in development and longevity in Caenorhabditis elegans: Digging deeper using cutting edge analytical chemistry. JO - Front. Endocrin. VL - 7 PB - Frontiers Media Sa PY - 2016 SN - 1664-2392 ER - TY - JOUR AB - Intact melanocortin signaling via the G protein-coupled receptors (GPCRs), melanocortin receptor 4 (MC4R), and melanocortin receptor 3 (MC3R) is crucial for body weight maintenance. So far, no connection between melanocortin signaling and hypothalamic inflammation has been reported. Using a bimolecular fluorescence complementation library screen, we identified a new interaction partner for these receptors, ring finger protein 11 (RNF11). RNF11 participates in the constitution of the A20 complex that is involved in reduction of tumor necrosis factor α (TNFα)-induced NFκB signaling, an important pathway in hypothalamic inflammation. Mice treated with high-fat diet (HFD) for 3 days demonstrated a trend toward an increase in hypothalamic Rnf11 expression, as shown for other inflammatory markers under HFD. Furthermore, Gs-mediated signaling of MC3/4R was demonstrated to be strongly reduced to 20-40% by co-expression of RNF11 despite unchanged total receptor expression. Cell surface expression was not affected for MC3R but resulted in a significant reduction of MC4R to 61% by co-expression with RNF11. Mechanisms linking HFD, inflammation, and metabolism remain partially understood. In this study, a new axis between signaling of specific body weight regulating GPCRs and factors involved in hypothalamic inflammation is suggested. AU - Müller, A.* AU - Niederstadt, L.* AU - Jonas, W.* AU - Yi, C.X.* AU - Meyer, F.* AU - Wiedmer, P.* AU - Fischer, J.* AU - Grötzinger, C.* AU - Schürmann, A.* AU - Tschöp, M.H. AU - Kleinau, G.* AU - Grüters, A.* AU - Krude, H.* AU - Biebermann, H.* C1 - 49316 C2 - 41737 CY - Lausanne TI - Ring finger protein 11 inhibits melanocortin 3 and 4 receptor signaling. JO - Front. Endocrin. VL - 7 PB - Frontiers Media Sa PY - 2016 SN - 1664-2392 ER - TY - JOUR AB - De novo formation of beige/brite adipocytes from progenitor cells contributes to the thermogenic adaptation of adipose tissue and holds great potential for the therapeutic remodeling of fat as a treatment for obesity. Despite the recent identification of several factors regulating browning of white fat, there is a lack of physiological cell models for the mechanistic investigation of progenitor-mediated beige/brite differentiation. We have previously revealed prostacyclin (PGI2) as one of the few known endogenous extracellular mediators promoting de novo beige/brite formation by relaying β-adrenergic stimulation to the progenitor level. Here, we present a cell model based on murine primary progenitor cells defined by markers previously shown to be relevant for in vivo browning, including a simplified isolation procedure. We demonstrate the specific and broad induction of thermogenic gene expression by PGI2 signaling in the absence of lineage conversion, and reveal the previously unidentified nuclear relocalization of the Ucp1 gene locus in association with transcriptional activation. By profiling the time course of the progenitor response, we show that PGI2 signaling promoted progenitor cell activation through cell cycle and adhesion pathways prior to metabolic maturation toward an oxidative cell phenotype. Our results highlight the importance of core progenitor activation pathways for the recruitment of thermogenic cells and provide a resource for further mechanistic investigation. AU - Bayindir, I.* AU - Babaeikelishomi, R.* AU - Kocanova, S.* AU - Sousa, I.S.* AU - Lerch, S.* AU - Hardt, O.* AU - Wild, S.* AU - Bosio, A.* AU - Bystricky, K.* AU - Herzig, S. AU - Vegiopoulos, A.* C1 - 46762 C2 - 37787 CY - Lausanne TI - Transcriptional pathways in cPGI2-induced adipocyte progenitor activation for browning. JO - Front. Endocrin. VL - 6 PB - Frontiers Media Sa PY - 2015 SN - 1664-2392 ER - TY - JOUR AB - The increase of life expectancy has led to the increase of age-related diseases such as osteoporosis. Osteoporosis is characterized by bone weakening promoting the occurrence of fractures with defective bone regeneration. Men aged over 50 have a prevalence for osteoporosis of 20%, which is related to a decline in sex hormones occurring during andropause or surgical orchidectomy. As we previously demonstrated in a mouse model for menopause in women that treatment with the neurohypophyseal peptide hormone oxytocin (OT) normalizes body weight and prevents the development of osteoporosis, herein we addressed the effects of OT in male osteoporosis. Thus, we treated orchidectomized mice, an animal model suitable for the study of male osteoporosis, for 8 weeks with OT and then analyzed trabecular and cortical bone parameters as well as fat mass using micro-computed tomography. Orchidectomized mice displayed severe bone loss, muscle atrophy accompanied by fat mass gain as expected in andropause. Interestingly, OT treatment in male mice normalized fat mass as it did in female mice. However, although OT treatment led to a normalization of bone parameters in ovariectomized mice, this did not happen in orchidectomized mice. Moreover, loss of muscle mass was not reversed in orchidectomized mice upon OT treatment. All of these observations indicate that OT acts on fat physiology in both sexes, but in a sex specific manner with regard to bone physiology. AU - Beranger, G.E.* AU - Djedaini, M.* AU - Battaglia, S.* AU - Roux, C.H.* AU - Scheideler, M. AU - Heymann, D.* AU - Amri, E.Z.* AU - Pisani, D.F.* C1 - 45113 C2 - 37213 TI - Oxytocin reverses osteoporosis in a sex-dependent manner. JO - Front. Endocrin. VL - 6 PY - 2015 SN - 1664-2392 ER - TY - JOUR AB - Objective: Ghrelin, a stomach-derived, secreted peptide, and its receptor (growth hormone secretagogue receptor, GHSR) are known to modulate food intake and energy homeostasis. The ghrelin system is also expressed broadly in cardiovascular tissues. Since ghrelin has been associated with anti-inflammatory and anti-atherogenic properties, but is also well known to promote obesity and impair glucose metabolism, we investigated whether ghrelin has any impact on the development of atherosclerosis. The hypothesis that endogenous ghrelin signaling may be involved in atherosclerosis has not been tested previously. Methods and Results: We crossed ghrelin receptor knockout mice (GHSr(-/-)) into a low-density lipoprotein receptor-null (Ldlr(-/-)) mouse line. In this model, atherosclerotic lesions were promoted by feeding a high-fat, high-cholesterol Western-type diet for 13 months, following a standard protocol. Body composition and glucose homeostasis were similar between Ldlr(-/-) and Ldlr/GHSR(-/-)ko mice throughout the study. Absence or presence of GHSr did not alter the apolipoprotein profile changes in response to diet exposure on an LDLRko background. Atherosclerotic plaque volume in the aortic arch and thoracic aorta were also not affected differentially in mice without ghrelin signaling due to GHSR gene disruption as compared to control LDLRko littermates. In light of the associations reported for ghrelin with cardiovascular disease in humans, the lack of a phenotype in these loss-of-function studies in mice suggests no direct role for endogenous ghrelin in either the inhibition or the promotion of diet-induced atherosclerosis. Conclusion: These data indicate that, surprisingly, the complex and multifaceted actions of endogenous ghrelin receptor mediated signaling on the cardiovascular system have minimal direct impact on atherosclerotic plaque progression as based on a loss-of-function mouse model of the disease. AU - Habegger, K.M.* AU - Grant, E.* AU - Pfluger, P.T. AU - Perez-Tilve, D.* AU - Daugherty, A.* AU - Bruemmer, D.* AU - Tschöp, M.H. AU - Hofmann, S.M. C1 - 11127 C2 - 30510 TI - Ghrelin receptor deficiency does not affect diet-induced atherosclerosis in low-density lipoprotein receptor-null mice. JO - Front. Endocrin. VL - 2 PB - Frontiers Research Foundation PY - 2011 SN - 1664-2392 ER -