The transCampus Metabolic Training Programme Explores the Link of SARS-CoV-2 Virus to Metabolic Disease.

Currently, we are experiencing a true pandemic of a communicable disease by the virus SARS-CoV-2 holding the whole world firmly in its grasp. Amazingly and unfortunately, this virus uses a metabolic and endocrine pathway via ACE2 to enter our cells causing damage and disease. Our international research training programme funded by the German Research Foundation has a clear mission to train the best students wherever they may come from to learn to tackle the enormous challenges of diabetes and its complications for our society. A modern training programme in diabetes and metabolism does not only involve a thorough understanding of classical physiology, biology and clinical diabetology but has to bring together an interdisciplinary team. With the arrival of the coronavirus pandemic, this prestigious and unique metabolic training programme is facing new challenges but also new opportunities. The consortium of the training programme has recognized early on the need for a guidance and for practical recommendations to cope with the COVID-19 pandemic for the community of patients with metabolic disease, obesity and diabetes. This involves the optimal management from surgical obesity programmes to medications and insulin replacement. We also established a global registry analyzing the dimension and role of metabolic disease including new onset diabetes potentially triggered by the virus. We have involved experts of infectious disease and virology to our faculty with this metabolic training programme to offer the full breadth and scope of expertise needed to meet these scientific challenges. We have all learned that this pandemic does not respect or heed any national borders and that we have to work together as a global community. We believe that this transCampus metabolic training programme provides a prime example how an international team of established experts in the field of metabolism can work together with students from all over the world to address a new pandemic.

Urinary Lipidomics: evidence for multiple sources and sexual dimorphism in healthy individuals.

Urinary lipidomics may add new valuable biomarkers to the diagnostic armamentarium for early detection of metabolic and kidney diseases. Sources and composition of urinary lipids in healthy individuals, however, have not been investigated in detail. Shotgun lipidomics was used to quantify lipidomic profiles in native urine samples from 16 individuals (eight men, eight women) collected in five fractions over 24 h. All probands were comprehensively characterized by urinary and clinical indices. The mean total urinary lipid concentration per sample was 0.84 µM in men and 1.03 µM in women. We observed significant intra- and interindividual variations of lipid concentrations over time, but failed to detect a clear circadian pattern. Based on quantity and subclass composition it seems very unlikely that plasma serves as major source for the urinary lipidome. Considering lipid metabolites occurring in at least 20% of all samples 38 lipid species from 7 lipid classes were identified. Four phosphatidylserine and one phosphatidylethanolamine ether species (PE-O 36:5) were detectable in almost all urine samples. Sexual dimorphism has been found mainly for phosphatidylcholines and phosphatidylethanolamines. In men and in women urinary lipid species were highly correlated with urinary creatinine and albumin excretion, reflecting glomerular filtration and tubular transport processes. In women, however, lipid species deriving from urinary cells and cellular constituents of the lower genitourinary tract considerably contributed to the urinary lipidome. In conclusion, our study revealed the potential of urinary lipidomics but also the complexity of methodological challenges which have to be overcome for its implementation as a routine diagnostic tool for renal, urological and metabolic diseases.

Characteristics of high- and low-risk individuals in the PRIORITY study: urinary proteomics and mineralocorticoid receptor antagonism for prevention of diabetic nephropathy in Type 2 diabetes.

AIM: To compare clinical baseline data in individuals with Type 2 diabetes and normoalbuminuria, who are at high or low risk of diabetic kidney disease based on the urinary proteomics classifier CKD273. METHODS: We conducted a prospective, randomized, double-blind, placebo-controlled international multicentre clinical trial and observational study in participants with Type 2 diabetes and normoalbuminuria, stratified into high- or low-risk groups based on CKD273 score. Clinical baseline data for the whole cohort and stratified by risk groups are reported. The associations between CKD273 and traditional risk factors for diabetic kidney disease were evaluated using univariate and logistic regression analysis. RESULTS: A total of 1777 participants from 15 centres were included, with 12.3% of these having a high-risk proteomic pattern. Participants in the high-risk group (n=218), were more likely to be men, were older, had longer diabetes duration, a lower estimated GFR and a higher urinary albumin:creatinine ratio than those in the low-risk group (n=1559, P<0.02). Numerical differences were small and univariate regression analyses showed weak associations (R2 < 0.04) of CKD273 with each baseline variable. In a logistic regression model including clinical variables known to be associated with diabetic kidney disease, estimated GFR, gender, log urinary albumin:creatinine ratio and use of renin-angiotensin system-blocking agents remained significant determinants of the CKD273 high-risk group: area under the curve 0.72 (95% CI 0.68-0.75; P<0.01). CONCLUSIONS: In this population of individuals with Type 2 diabetes and normoalbuminuria, traditional diabetic kidney disease risk factors differed slightly between participants at high risk and those at low risk of diabetic kidney disease, based on CKD273. These data suggest that CKD273 may provide additional prognostic information over and above the variables routinely available in the clinic. Testing the added value will be subject to our ongoing study. (European Union Clinical Trials Register: EudraCT 2012-000452-34 and Clinicaltrials.gov: NCT02040441).

Pharmacogenomics in type 2 diabetes: oral antidiabetic drugs.

Type 2 diabetes mellitus (T2DM) is a fast progressing disease reaching pandemic proportions. T2DM is specifically harmful because of its severe secondary complications. In the course of the disease, most patients require treatment with oral antidiabetic drugs (OADs), for which a relatively large number of different options are available. The growing number of individuals affected by T2DM as well as marked interindividual differences in the response to treatment call for individualized therapeutic regimens that can maximize treatment efficacy and thus reduce side effects and costs. A large number of genetic polymorphisms have been described affecting the response to treatment with OADs; in this review, we summarize the most recent advances in this area of research. Extensive evidence exists for polymorphisms affecting pharmacokinetics and pharmacodynamics of biguanides and sulfonylureas. Data on incretin-based medications as well as the new class of sodium/glucose cotransporter 2 (SGLT2) inhibitors are just starting to emerge. With diabetes being a known comorbidity of several psychiatric disorders, we also review genetic polymorphisms possibly responsible for a common treatment response in both conditions. For all drug classes reviewed here, large prospective trials are necessary in order to consolidate the existing evidence and derive treatment schemes based on individual genetic traits.

Serum and Plasma Levels of Vascular Endothelial Growth Factors in Relation to Quality of Glucose Control, Biomarkers of Inflammation, and Diabetic Nephropathy.

Levels of vascular endothelial growth factors (VEGF) are regulated in a complex network of adipokines, glucose control, and low grade inflammation together with activated platelets, leucocytes, and endothelial dysfunction. Increased levels of VEGF are associated with enhanced angiogenesis and impaired repair mechanisms of vascular lesions in endorgans. Little is known about the interaction of systemic VEGF levels with quality of diabetes control, biomarkers of inflammation, and diabetic nephropathy. Moreover, it is unclear, whether serum and plasma VEGF levels are similarly suited to reflect risk associated with VEGF.In this case control study, we analyzed these parameters in serum and plasma of age and sex matched controls without diabetes (n=99) and type 2 diabetes (n=302). Serum VEGF-A was significantly increased in patients with T2DM while plasma levels were in the same range as for controls. Individual levels varied in a wide range. Serum levels were 4.9 times higher in controls and 7.3 times higher in T2DM as compared to plasma levels. T2DM was associated with significantly higher levels of hsCRP, ALAT, and albumin/creatinine ratio. When calculated for tertiles of HbA1c, we observed a highly significant increase from tertile one to the upper tertile for serum VEGF-A but not for plasma VEGF-A. Correlation analysis revealed a significant relationship between VEGF-A, HbA1c, inflammation, and diabetic nephropathy. Our results indicate that increased VEGF-A levels in T2DM significantly depend on quality of HbA1c control. Serum levels of VEGF-A, with a strong contribution of platelet derived VEGF, better reflect the glycemic burden than plasma levels of VEGF-A. Mechanistic studies are needed to explore links to inflammation and diabetic nephropathy.

Thiazolidinedione response in familial lipodystrophy patients with LMNA mutations: a case series.

Type 2 familial partial lipodystrophy (FPLD2) patients show impaired glucose and lipid metabolism resulting from lipodystrophic 'lipid pressure' and an intrinsic defect in skeletal muscle metabolism. Since mutated lamin A may interfere with peroxisome proliferator activator gamma (PPARγ) expression, we hypothesized that PPARγ stimulation improves fat distribution and metabolic abnormalities in these patients. 5 nondiabetic FPLD2 patients were treated with rosiglitazone over 12 months. We assessed body composition, body fat distribution, and skinfold thickness/subcutaneous tissue thickness. We also determined venous glucose, insulin, and free fatty acid (FFA) concentrations, and respiratory quotient (RQ) before and during oral glucose tolerance testing. Adipose tissue and muscle fasting and postprandial metabolism were studied by microdialysis. Within 12 months treatment, hip circumference increased from 93.6±2.78 cm to 96.2±2.3 cm (p<0.05). Rosiglitazone reduced fasting glucose levels and liver transaminases. Baseline and postprandial FFA concentrations were significantly lower after 12 months treatment. RQ and muscle interstitial pyruvate and lactate did not respond to treatment. We conclude that PPARγ stimulation with rosiglitazone modestly improves glucose metabolism in FPLD2 patients presumably through proximal adipose tissue expansion. The intrinsic muscular metabolic defect does not respond to rosiglitazone.

Knockdown of the gene encoding Drosophila tribbles homologue 3 (Trib3) improves insulin sensitivity through peroxisome proliferator-activated receptor-γ (PPAR-γ) activation in a rat model of insulin resistance.

AIMS/HYPOTHESIS: Insulin action is purportedly modulated by Drosophila tribbles homologue 3 (TRIB3), which in vitro prevents thymoma viral proto-oncogene (AKT) and peroxisome proliferator-activated receptor-γ (PPAR-γ) activation. However, the physiological impact of TRIB3 action in vivo remains controversial. METHODS: We investigated the role of TRIB3 in rats treated with either a control or Trib3 antisense oligonucleotide (ASO). Tissue-specific insulin sensitivity was assessed in vivo using a euglycaemic-hyperinsulinaemic clamp. A separate group was treated with the PPAR-γ antagonist bisphenol-A-diglycidyl ether (BADGE) to assess the role of PPAR-γ in mediating the response to Trib3 ASO. RESULTS: Trib3 ASO treatment specifically reduced Trib3 expression by 70% to 80% in liver and white adipose tissue. Fasting plasma glucose, insulin concentrations and basal rate of endogenous glucose production were unchanged. However, Trib3 ASO increased insulin-stimulated whole-body glucose uptake by ~50% during the euglycaemic-hyperinsulinaemic clamp. This was attributable to improved skeletal muscle glucose uptake. Despite the reduction of Trib3 expression, AKT2 activity was not increased. Trib3 ASO increased white adipose tissue mass by 70% and expression of Ppar-γ and its key target genes, raising the possibility that Trib3 ASO improves insulin sensitivity primarily in a PPAR-γ-dependent manner. Co-treatment with BADGE blunted the expansion of white adipose tissue and abrogated the insulin-sensitising effects of Trib3 ASO. Finally, Trib3 ASO also increased plasma HDL-cholesterol, a change that persisted with BADGE co-treatment. CONCLUSIONS/INTERPRETATION: These data suggest that TRIB3 inhibition improves insulin sensitivity in vivo primarily in a PPAR-γ-dependent manner and without any change in AKT2 activity.

Neurohumoral and metabolic response to exercise in water.

Atrial natriuretic peptide (ANP) stimulates lipid mobilization and lipid oxidation in humans. The mechanism appears to promote lipid mobilization during exercise. We tested the hypothesis that water immersion augments exercise-induced ANP release and that the change in ANP availability is associated with increased lipid mobilization and lipid oxidation. In an open randomized and cross-over fashion we studied 17 men (age 31+/-3.6 years; body mass index 24+/-1.7 kg/m(2); body fat 17+/-6.7%) on no medication. Subjects underwent two incremental exercise tests on a bicycle ergometer. One test was conducted on land and the other test during immersion in water up to the xiphoid process. In a subset (n=7), we obtained electromyography recordings in the left leg. We monitored gas exchange, blood pressure, and heart rate. In addition, we obtained blood samples towards the end of each exercise step to determine ANP, norepinephrine, epinephrine, lactate, free fatty acids, insulin, and glucose concentrations. Heart rate, systolic blood pressure, and oxygen consumption at the anaerobic threshold and during peak exercise were similar on land and with exercise in water. The respiratory quotient was mildly reduced when subjects exercised in water. Glucose and lactate measurements were decreased whereas free fatty acid concentrations were increased with exercise in water. Water immersion attenuated epinephrine and norepinephrine and augmented ANP release during exercise. Even though water immersion blunts exercise-induced sympathoadrenal activation, lipid mobilization and lipid oxidation rate are maintained or even improved. The response may be explained by augmented ANP release.

Intensive lifestyle modifications with or without liraglutide 3mg vs. sleeve gastrectomy: A three-arm non-randomised, controlled, pilot study.

BACKGROUND/OBJECTIVES: As only 1% of clinically eligible subjects choose to undergo surgical treatment for obesity, other options should be investigated. This study aimed to assess the effects of intensive lifestyle modification (ILM) with or without 3-mg liraglutide daily vs. sleeve gastrectomy (SG) on BMI after 1 year. SUBJECTS/METHODS: In this study performed at an Italian university hospital, non-diabetic patients eligible for bariatric surgery were recruited from a weight-loss clinic and had the option to choose from three possible weight-loss programmes up to an allocation of 25 subjects in each arm matched by BMI and age. ILM consisted in 813kcal of a very low-calorie diet (VLCD) for 1 month, followed by a diet of 12kcal/kg body weight of high protein and high fat for 11 months plus 30min of brisk walking daily and at least 3h of aerobic exercise weekly. SG patients followed a VLCD for 1 month and a free diet thereafter. Patients were evaluated at baseline and at 1, 3, 6, 9 and 12 months. RESULTS: A total of 75 patients were enrolled; retention was 100% in the SG and 85% in the two medical arms. SG reduced BMI by 32% (P<0.001 vs. medical arm), while ILM+liraglutide and ILM led to BMI reductions of 24% and 14%, respectively (P<0.001). More women allocated themselves to the ILM+liraglutide group. Weight loss was 43kg with SG, 26kg with ILM+liraglutide and 15kg with ILM alone. Lean body mass reductions were -11.6kg with SG, -6.3kg with ILM and -8.3kg with ILM+liraglutide. Prevalence of prediabetes was significantly lower with ILM+liraglutide, and insulin resistance was reduced by about 70% by both ILM+liraglutide and SG vs. 39% by ILM alone. Cardiometabolic risk factors were greatly reduced in all three groups. DISCUSSION: At least in the short-term, liraglutide 3.0mg once daily associated with drastic calorie-intake restriction and intensive physical activity promoted a 24% weight loss, which was almost two times greater than ILM alone and only about 25% less than with SG, while preserving lean body mass. Although this study was non-randomised, it was designed to explore the efficacy of medical treatments for obesity in everyday clinical practice.

Fetuin A is a Predictor of Liver Fat in Preoperative Patients with Nonalcoholic Fatty Liver Disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) are frequent comorbidities in perioperative patients. However, the predictive role of the hepatokine fetuin A was not evaluated in this collective. OBJECTIVE: To study fetuin A as predictor of NAFLD/NASH in preoperative patients. METHODS: 58 subjects were included. Fetuin A was studied in patients undergoing open abdominal surgery and in a subset with acute liver failure. Blood and liver specimens were sampled. NAFLD was histologically evaluated. Liver fat was additionally analyzed by an enzymatic approach, circulating fetuin A by enzyme linked-immunosorbent assay, fetuin A mRNA by reverse-transcription PCR. RESULTS: Univariate correlation studies linked fetuin A to liver steatosis (r = 0.40, p = .029) and hepatocellular ballooning degeneration (r = 0.34, p = .026). Compared to non-NAFLD subjects fetuin A was increased in NAFLD (p = .009) and in NASH (p = .029). However, when corrected for main confounders by linear modeling, fetuin A remained related to hepatic steatosis, but not to ballooning degeneration or other NAFLD features. In support of this, biochemically analyzed liver lipids correlated with fetuin A in plasma (r = 0.34, p = .033) and with hepatic fetuin A mRNA (r = 0.54, p < .001). In addition, plasma fetuin A was related to hepatic mRNA (r = 0.32, p = .036), while circulating levels were reduced by 64% with acute liver failure (p < .001), confirming the liver as main fetuin A source. CONCLUSION: Fetuin A is suggested as noninvasive biomarker of hepatic steatosis in preoperative settings.

Menopause-related oral alveolar bone resorption: a review of relatively unexplored consequences of estrogen deficiency.

OBJECTIVE: The alveolar processes of the maxilla and mandible provide the bony framework for tooth support. Osteoporotic changes of these bones may directly affect tooth stability and retention. This report reviews studies that have evaluated the relationship between systemic osteoporosis and oral alveolar bone mass as well as the effect of estrogen use on oral alveolar bone and tooth retention. DESIGN: Ten years (1989-1998) literature review. RESULTS: Studies reviewed demonstrate a positive correlation between systemic bone mass and systemic osteoporosis to oral bone resorption. Estrogen replacement therapy affects oral bone in a manner similar to the way it affects other sites. CONCLUSIONS: It is evident that postmenopausal estrogen users may retain more teeth after menopause. Sustained oral health and better tooth retention are potentially additional benefits for hormone replacement therapy users after menopause.

Effect of clomiphene on the functional morphology of oviductal and uterine mucosa.

The effect of clomiphene on the functional morphology of the uterine and oviductal mucosa was studied in rabbits by means of light and electron microscopy (SEM and TEM). Tissues were obtained from mature nulliparous animals receiving subcutaneous doses ranging from 0.01-10 mg/kg per day. In all cases the effects were evaluated 2 days after termination of treatment. With 2 and 10 mg, effects were studied up to 12 and 7 days, respectively. Normally appearing oviductal and endometrial tissues, corresponding to various stages of the cycle, were observed with doses up to 5 mg. However, a burst of cellular secretory activity becomes evident with the administration of higher doses. Apical protrusions or cytoplasmic portions seem to be extruded, and draw attention. These cytologic events are concentrated near gland openings in the endometrium and can be seen abundantly among cilia of oviductal cells. Other ultrastructural changes are evident as well. These histologic changes may reflect nonsynchronous cellular activities which in turn interfere with oviductal and endometrial functions before implantation.

Diurnal variation of fetal activity.

Fetal movements (FM) in utero are an expression of fetal well-being, and the importance of assessing these movements has been shown in cases of chronic fetal distress. The diurnal variations were studied in 2 groups of high-risk pregnant women who assessed FM by subjective perception. The patients in the first group assessed FM before and after meals. The majority (86%) reported no significant difference in fetal activity before and after meals; the remaining 14% noted a constant decrease after meals. Of the second group, which assessed FM 3 times daily 82% discerned no significant differences and 18% showed significant diurnal variations. It is concluded that assessment of FM is not necessarily dependent on a strict timetable.

Successful full-term pregnancy in homozygous beta-thalassemia major: case report and review of the literature.

Patients afflicted by homozygous beta-thalassemia suffer from severe anemia and hypersplenism and are dependent on blood transfusions. The consequent hypoxia and massive tissue iron deposition lead to concomitant cardiac, hepatic, and endocrine system failure. Hemodynamic changes related to gestation may aggravate the underlying multiorgan damage of the pregnant mother and lead to high fetal wastage. These entanglements may be prevented by performing thorough maternal and fetal surveillance and by maintaining the hemoglobin concentration above 10 g/dL. We describe a successful full-term pregnancy in a patient with transfusion-dependent homozygous beta-thalassemia major.

Intracytoplasmic sperm injection, fertilization, and embryo transfer after retrieval of spermatozoa by testicular biopsy from an azoospermic male with testicular tubular atrophy.

OBJECTIVE: To achieve fertilization and cleavage by spermatozoa retrieved by testicular biopsy from a male with testicular tubular atrophy. DESIGN: Clinical trial. SETTING: Private reproductive institute. PATIENT: Azoospermic male with demonstrated testicular tubular atrophy and almost complete spermatogenic arrest. INTERVENTION: Open biopsy retrieval of testicular tissue and sperm followed by intracytoplasmic sperm injection. MAIN OUTCOME MEASURES: Fertilization and cleavage. RESULTS: One four- to six-cell embryo was formed after intracytoplasmic sperm injection of five eggs with extruded polar bodies by retrieved sperm. CONCLUSION: Intracytoplasmic sperm injection after testicular sperm aspiration may be attempted in cases with severely decreased spermatogenesis and result in fertilization, cleavage, and embryo transfer.