Publications by authors named "Bruno Lapauw"

76 Publications

In patients with controlled acromegaly, indices of glucose homeostasis correlate with IGF-1 levels rather than with type of treatment.

Clin Endocrinol (Oxf) 2021 Mar 13. Epub 2021 Mar 13.

Department of Endocrinology, Ghent University Hospital, Ghent, Belgium.

Objective: Acromegaly is accompanied by abnormalities in glucose and lipid metabolism which improve upon treatment. Few studies have investigated whether these improvements differ between treatment modalities. This study aimed to compare glucose homeostasis, lipid profiles and postprandial gut hormone response in patients with controlled acromegaly according to actual treatment.

Design: Cross-sectional study at a tertiary care centre.

Patients: Twenty-one patients with acromegaly under stable control (ie insulin growth factor 1 [IGF1] levels below sex- and age-specific thresholds and a random growth hormone level <1.0 µg/L) after surgery (n = 5), during treatment with long-acting somatostatin analogues (n = 10) or long-acting somatostatin analogues + pegvisomant (n = 6) were included.

Measurements: Glucose, insulin, total cholesterol and high-density lipoprotein-cholesterol were measured in fasting serum samples. Glucose, insulin, triglycerides, glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 were measured during a mixed meal test. Insulin sensitivity was evaluated by a hyperinsulinaemic-euglycaemic clamp.

Results: There were no significant differences in glucose tolerance, insulin sensitivity or postprandial gut hormone responses between the three groups. Positive correlations between IGF1 levels and HbA1c, fasting glucose and insulin levels and postprandial area under the curve (AUC) of glucose and insulin and also an inverse association between IGF1 and glucose disposal rate were found in the whole cohort (all p < .05, lowest p = .001 for postprandial AUC glucose with r  = 0.660).

Conclusion: In this cross-sectional study in patients with controlled acromegaly, there were no differences in glucose homeostasis or postprandial substrate metabolism according to treatment modality. However, a lower IGF1 level seems associated with a better metabolic profile.
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http://dx.doi.org/10.1111/cen.14461DOI Listing
March 2021

Metabolism of testosterone during weight loss in men with obesity.

J Steroid Biochem Mol Biol 2021 May 18;209:105851. Epub 2021 Feb 18.

Department of Endocrinology, Ghent University Hospital, Ghent, Belgium.

Objective: Men with obesity often have low total and, with increasing adiposity, also low free testosterone (T) levels, which can partially restore during weight loss. Although this is partly explained by lower sex hormone binding globulin (SHBG) production and hypothalamic-pituitary downregulation, it is still not unravelled whether changes in androgen metabolism contribute to this phenomenon. Therefore, early changes in urinary excretion of T and its metabolites, during weight loss, in men with obesity are investigated.

Design: Longitudinal study.

Methods: Fourteen men with obesity (age 52(45-60)years, BMI 42.6(41.8-44.8)kg/m²) underwent gastric bypass surgery (GBS). Before surgery and 3 weeks, 6 weeks, 6 months and 1 year thereafter, 24 h urine and fasting serum samples were collected. Serum T and estradiol (E) levels were analyzed using LC-MS/MS and urinary metabolites of T with GC-MS/MS.

Results: Already three weeks after GBS, serum SHBG and total T levels increased and remained increased as compared to baseline (all,p < 0.0125). Gonadotropins and (free) E levels were unchanged, serum E/T ratio decreased (p < 0.0125). Total amount of urinary T increased non-significantly with mean increases of 53 % one year after GBS (p = 0.026). Urinary E/T, estrone/T, 3α-androstanediol/T and androsterone/T ratios decreased after GBS (p < 0.0125).

Conclusions: Restoration of circulating T levels during weight loss in this population is not only brought about by normalization of circulating SHBG levels, but increased production of and alterations in T metabolism also contribute. More specifically, relative decreases in aromatization and lower 5α-reductase activity might also be involved in restoring T levels in men with obesity.
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http://dx.doi.org/10.1016/j.jsbmb.2021.105851DOI Listing
May 2021

Late dumping syndrome or postprandial reactive hypoglycaemic syndrome after bariatric surgery.

Nat Rev Endocrinol 2021 May;17(5):317

Department of Endocrinology, Ghent University Hospital, Ghent, Belgium.

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http://dx.doi.org/10.1038/s41574-021-00473-6DOI Listing
May 2021

THE ADDED AND INTERPRETATIVE VALUE OF CGM-DERIVED PARAMETERS IN TYPE 1 DIABETES DEPENDS ON THE LEVEL OF GLYCEMIC CONTROL.

Endocr Pract 2021 Jan 18;27(1):44-50. Epub 2020 Nov 18.

Department of Endocrinology, Ghent University Hospital, Belgium.

Objective: In type 1 diabetes mellitus (T1DM) management, continuous glucose monitoring (CGM)-derived parameters can provide additional insights, with time in range (TIR) and other parameters reflecting glycemic control and variability being put forward. This study aimed to examine the added and interpretative value of the CGM-derived indices TIR and coefficient of variation (CV%) in T1DM patients stratified according to their level of glycemic control by means of HbA1C.

Methods: T1DM patients with a minimum disease duration of 10 years and without known macrovascular disease were enrolled. Patients were equipped with a blinded CGM device for 7 days. TIR and time spent in hypoglycemia and hyperglycemia were determined, and CV% was used as a parameter for glycemic variability. Pearson (r) and Spearman correlations (r) and a regression analysis were used to examine associations.

Results: Ninety-five patients (age: 45 ± 10 years; HbA1C level: 7.7% ± 0.8% [61 ± 7 mmol/mol]) were included (mean blood glucose [MBG]: 159 ± 31 mg/dL; TIR: 55.8% ± 14.9%; CV%: 43.5% ± 7.8%) and labeled as having good (HbA1C level ≤7% [≤53 mmol/mol]; n = 20), moderate (7%-8%; n = 44), or poor (>8% [>64 mmol/mol]; n = 31) glycemic control. HbA1C was significantly associated with MBG (r = 0.48, P < .001) and time spent in hyperglycemia (total: r = 0.52; level 2: r = 0.46; P < .001) but not with time spent in hypoglycemia and CV%, even after an analysis of the HbA1C subgroups. Similarly, TIR was negatively associated with HbA1C (r = -0.53; P < .001), MBG (r = -0.81; P < .001), and time spent in hyperglycemia (total: r = -0.90; level 2: r = -0.84; P < .001) but not with time in hypoglycemia. The subgroup analyses, however, showed that TIR was associated with shorter time spent in level-2 hypoglycemia in patients with good (r = -0.60; P = .007) and moderate (r = -0.25; P = .047) glycemic control. In contrast, CV% was strongly positively associated with time in hypoglycemia (total: r = 0.78; level 2: r = 0.76; P < .001) but not with TIR or time in hyperglycemia in the entire cohort, although the subgroup analyses showed that TIR was negatively associated with CV% in patients with good glycemic control (r = -0.81, P < .001) and positively associated in patients with poor glycemic control (r = +0.47; P < .01).

Conclusion: The CGM-derived metrics TIR and CV% are related to clinically important situations, TIR being strongly dependent on hyperglycemia and CV% being reflective of hypoglycemic risk. However, the interpretation and applicability of TIR and CV% and their relationship depends on the level of glycemic control of the individual patient, with CV% generally adding less clinically relevant information in those with poor control. This illustrates the need for further research and evaluation of composite measures of glycemic control in T1DM.
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http://dx.doi.org/10.4158/EP-2020-0293DOI Listing
January 2021

Early Decline of Androgen Levels in Healthy Adult Men: An Effect of Aging Per Se? A Prospective Cohort Study.

J Clin Endocrinol Metab 2021 Mar;106(4):1074-1083

Department of Endocrinology, Ghent University Hospital, Ghent, Belgium.

Context: Androgen levels have been shown to decline in aging men. However, there is no consensus on the effect of aging, (changes in) body mass index (BMI), lifestyle factors, and intercurrent disease.

Objective: Investigating longitudinal changes in serum androgen levels in healthy men in relation to body composition, lifestyle factors, and intercurrent disease.

Design, Setting, And Participants: Longitudinal, population-based sibling pair study at a university research center. 999 healthy men aged 24 to 46 years of whom 691 were reevaluated after a mean period of 12 years.

Main Outcome Measures: Serum SHBG, LH, and FSH levels measured using immuno-assays. Testosterone (T), estradiol (E2), dihydro-testosterone (DHT), and androstenedione (Adione) measured using liquid chromatography-tandem mass spectometry, free T calculated (cFT).

Results: Baseline age was 34 ± 6 years. Mean BMI increased by 1.19 kg/m2, T levels decreased by 14.2% (20.8 nmol/L vs. 17.8 nmol/L), cFT by 19.1% (392 pmol/L vs. 317 pmol/L), DHT by 15.6% (1.5 nmol/L vs.1.3 nmol/L), and Adione by 10.7% (3.7 nmol/L vs. 3.3 nmol/L; all P < 0.001). E2 did not change over time. SHBG increased by 3.0% (39.8 nmol/L vs. 41.0 nmol/L), LH by 5.8% (4.6 U/L vs. 4.9 U/L) and FSH by 14.7% (4.3 U/L vs. 5.1 U/L) (all P < 0.001). For T, cFT, DHT, Adione, and SHBG, these longitudinal changes persisted after adjustment for confounders (all P < 0.001).

Conclusion: Serum androgen levels start declining early during adult life and independently from changes in BMI and other lifestyle factors, suggesting that aging per se leads to an altered sex steroid status. Given the concurrent rise in gonadotropin levels, the decline in androgen status most likely arises from primary decrease in testicular function.
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http://dx.doi.org/10.1210/clinem/dgaa915DOI Listing
March 2021

MANAGEMENT OF ENDOCRINE DISEASE: Rationale and current evidence for testosterone therapy in the management of obesity and its complications.

Eur J Endocrinol 2020 Dec;183(6):R167-R183

Department of Endocrinology, Ghent University Hospital, Ghent, Belgium.

Overt hypogonadism in men adversely affects body composition and metabolic health, which generally improve upon testosterone (TS) therapy. As obese men often display lower serum TS levels, in particular when they present with the metabolic syndrome (MetS) or type 2 diabetes (T2DM), there have been claims that androgen therapy prevents or reverses obesity and improves metabolic health. This has contributed to the increase in TS prescriptions during the past two decades. In this narrative review, based on findings from larger observational studies and randomized controlled intervention trials, we evaluate whether low TS predicts or predisposes to obesity and its metabolic consequences, and whether obese men with low TS are truly hypogonadal. We further describe the mechanisms underlying the bi-directional relationships of TS levels with obesity and metabolic health, and finally assess the evidence for TS therapy in men with obesity, MetS and/or T2DM, considering efficacy, safety concerns and possible alternative approaches. It is concluded that low serum sex hormone-binding globulin and total TS levels are highly prevalent in obese men, but that only those with low free TS levels and signs or symptoms of hypogonadism should be considered androgen deficient. These alterations are reversible upon weight loss. Whether low TS is a biomarker rather than a true risk factor for metabolic disturbances remains unclear. Considering the limited number of sound TS therapy trials have shown beneficial effects, the modest amplitude of these effects, and unresolved safety issues, one cannot in the present state-of-the-art advocate TS therapy to prevent or reverse obesity-associated metabolic disturbances. Instead, the focus should remain on lifestyle measures and management of obesity-related consequences.
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http://dx.doi.org/10.1530/EJE-20-0394DOI Listing
December 2020

Expression of ACE2, the SARS-CoV-2 Receptor, in Lung Tissue of Patients With Type 2 Diabetes.

Diabetes 2020 12 6;69(12):2691-2699. Epub 2020 Oct 6.

Laboratory for Translational Research in Obstructive Pulmonary Diseases, Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.

Increased expression of pulmonary ACE2, the SARS-CoV-2 receptor, could contribute to increased infectivity of COVID-19 in patients with diabetes, but ACE2 expression has not been studied in lung tissue of subjects with diabetes. We therefore studied ACE2 mRNA and protein expression in lung tissue samples of subjects with and without diabetes that were collected between 2002 and 2020 from patients undergoing lobectomy for lung tumors. For RT-PCR analyses, samples from 15 subjects with diabetes were compared with 91 randomly chosen control samples. For immunohistochemical staining, samples from 26 subjects with diabetes were compared with 66 randomly chosen control samples. mRNA expression of ACE2 was measured by quantitative RT-PCR. Protein levels of ACE2 were visualized by immunohistochemistry on paraffin-embedded lung tissue samples and quantified in alveolar and bronchial epithelium. Pulmonary ACE2 mRNA expression was not different between subjects with or without diabetes. In contrast, protein levels of ACE2 were significantly increased in both alveolar tissue and bronchial epithelium of patients with diabetes compared with control subjects, independent of smoking, chronic obstructive pulmonary disease, BMI, renin-angiotensin-aldosterone system inhibitor use, and other potential confounders. To conclude, we show increased bronchial and alveolar ACE2 protein expression in patients with diabetes. Further research is needed to elucidate whether upregulation of ACE2 expression in airways and lungs has consequences on infectivity and clinical outcomes of COVID-19.
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http://dx.doi.org/10.2337/db20-0669DOI Listing
December 2020

Role of testosterone in cognition and mobility of aging men.

Andrology 2020 11 31;8(6):1567-1579. Epub 2020 Aug 31.

Department of Endocrinology, Ghent University Hospital, Ghent, Belgium.

Background: Cognitive decline and impairment of physical performance and mobility are age-related clinical problems with major negative impact on quality of life of elderly men. In how far the decline of testosterone production contributes to these problems in older men and whether testosterone therapy can contribute to slow down, prevent, or reverse their development remains subjects of debate.

Objectives: This narrative review presents the current knowledge on association of sex steroid status with cognitive decline and impairment of physical function and mobility in elderly men and on the effects of testosterone therapy on cognition and on physical performance and mobility in elderly men.

Materials And Method: The review is based on electronic database searches with primary focus on evidence from larger prospective observational studies and from controlled randomized trials, respectively.

Results: In most observational studies, testosterone levels do not predict cognitive decline or development of Alzheimer's disease. In randomized trials, testosterone therapy did not significantly affect cognition in men with low or low-to-normal serum testosterone, regardless of whether they have preexisting cognitive impairment. Overall, observational data indicate that the usually moderate decline of androgen exposure in older men cannot fully account for the parallel decline of physical performance and mobility. Trials of testosterone therapy in older men with low or low-normal serum testosterone, whether they were generally healthy or suffered from physical function impairments, either did not show any effect on mobility and physical performance or showed limited effects of uncertain clinical relevancy.

Discussion And Conclusions: The whole of the evidence tends to downplay the role of sex steroid status in the decline of cognitive function and impairment of physical function and mobility in older men. Based on the available evidence, prevention or treatment of cognitive decline or of impairment of mobility and physical function are not valid indications for testosterone treatment in older men with low or low-to-normal serum testosterone levels.
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http://dx.doi.org/10.1111/andr.12872DOI Listing
November 2020

The effectiveness and cost-effectiveness of an integrated osteoporosis care programme for postmenopausal women in Flanders: study protocol of a quasi-experimental controlled design.

Arch Osteoporos 2020 07 22;15(1):107. Epub 2020 Jul 22.

Department of Public Health and Primary Care, Ghent University, Ghent, Belgium.

Osteoporosis causes high individual and societal burden, due to limited attention to fracture prevention. Integrated care for chronic conditions has shown to facilitate management of these conditions, improving clinical outcomes alongside quality of life and cost-effectiveness. This manuscript describes an integrated osteoporosis care programme that will be implemented in primary care.

Objective: To provide a comprehensive description of a quasi-experimental study design in which a newly developed integrated osteoporosis care (IOC) programme for the management of postmenopausal osteoporosis (PO) in primary care (PC) is implemented and will be compared with care as usual (CAU).

Methods: A literature research was performed and expert meetings have been taking place, which has led to the development of a complex PC intervention based on framework for integrated people-centred health services (IPCHS).

Results: This manuscript describes the developmental process of the preclinical phase of a quasi-experimental real-world design and the interventions as a result of this process that will be implemented during the clinical phase, along with the evaluation that will take place alongside the clinical phase: An integrative approach for the management of PO in primary care was developed and will be implemented in greater region of Ghent (GRG), Belgium. The approach consists of a complex intervention targeting patients and PC stakeholders in osteoporosis care (e.g. general practitioners (GPs), physiotherapists, nurses, pharmacists). A comparison will be made with CAU using medication possession ratios (MPR) of included patients as primary outcome. These data will be obtained from the national health database. Secondary outcomes are physician outcomes, patient-reported outcome measures (PROMs), and patient-reported experience measures (PREMs). A cost-effectiveness evaluation will be performed if the programme appears to be effective in terms of MPR.

Trial Registration: ClinicalTrials.gov : NCT03970902.
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http://dx.doi.org/10.1007/s11657-020-00776-7DOI Listing
July 2020

The role of soluble receptor for advanced glycation end-products (sRAGE) in the general population and patients with diabetes mellitus with a focus on renal function and overall outcome.

Crit Rev Clin Lab Sci 2021 Mar 15;58(2):113-130. Epub 2020 Jul 15.

Department of Nephrology, Ghent University Hospital, Ghent, Belgium.

Isoforms of the receptor for advanced glycation end-product (RAGE) protein, which lack the transmembrane and the signaling (soluble RAGE or sRAGE) domains are hypothesized to counteract the detrimental action of the full-length receptor by acting as a decoy, and they provide a potential tool to treat RAGE-associated diseases. Multiple studies have explored the relationship between sRAGE and endogenous secretory RAGE and its polymorphism and obesity, metabolic syndrome, atherosclerosis, kidney function, and increased mortality in the general population. In addition, sRAGE may be a key player in the pathogenesis of diabetes mellitus and its microvascular (e.g. kidney disease) as well as macrovascular (e.g. cardiovascular disease) complications. In this review, we focus on the role of sRAGE as a biomarker in these specific areas. As there is a lack of an underlying unifying hypothesis about how sRAGE changes according to the disease condition or risk factor, there is a call to incorporate all three players of the AGE-RAGE axis into a new universal biomarker/risk marker: (AGE + RAGE)/sRAGE. However, the measurement of RAGE in humans is not practical as it is a cell-bound receptor for which tissue is required for analysis. A high AGE/sRAGE ratio may be a valuable alternative and practical universal biomarker/risk marker for diseases associated with the AGE-RAGE axis, irrespective of low or high serum sRAGE concentrations.
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http://dx.doi.org/10.1080/10408363.2020.1791045DOI Listing
March 2021

Physiological Disturbance in Fatty Liver Energy Metabolism Converges on IGFBP2 Abundance and Regulation in Mice and Men.

Int J Mol Sci 2020 Jun 10;21(11). Epub 2020 Jun 10.

Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at the Heinrich-Heine-University Düsseldorf, Auf'm Hennekamp 65, 40225 Düsseldorf, Germany.

Fatty liver occurs from simple steatosis with accumulated hepatic lipids and hepatic insulin resistance to severe steatohepatitis, with aggravated lipid accumulation and systemic insulin resistance, but this progression is still poorly understood. Analyses of hepatic gene expression patterns from alb-SREBP-1c mice with moderate, or aP2-SREBP-1c mice with aggravated, hepatic lipid accumulation revealed IGFBP2 as key nodal molecule differing between moderate and aggravated fatty liver. Reduced IGFBP2 expression in aggravated fatty liver was paralleled with promoter hypermethylation, reduced hepatic IGFBP2 secretion and IGFBP2 circulating in plasma. Physiologically, the decrease of IGFBP2 was accompanied with reduced fatty acid oxidation and increased de novo lipogenesis potentially mediated by IGF1 in primary hepatocytes. Furthermore, methyltransferase and sirtuin activities were enhanced. In humans, IGFBP2 serum concentration was lower in obese men with non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) compared to non-obese controls, and liver fat reduction by weight-loss intervention correlated with an increase of IGFBP2 serum levels. In conclusion, hepatic IGFBP2 abundance correlates to its circulating level and is related to hepatic energy metabolism and de novo lipogenesis. This designates IGFBP2 as non-invasive biomarker for fatty liver disease progression and might further provide an additional variable for risk prediction for pathogenesis of fatty liver in diabetes subtype clusters.
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http://dx.doi.org/10.3390/ijms21114144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312731PMC
June 2020

Rapid LA-REIMS and comprehensive UHPLC-HRMS for metabolic phenotyping of feces.

Talanta 2020 Sep 14;217:121043. Epub 2020 Apr 14.

Ghent University, Faculty of Veterinary Medicine, Department of Veterinary Public Health and Food Safety, Laboratory of Chemical Analysis, Salisburylaan 133, 9820, Merelbeke, Belgium; Queen's University Belfast, School of Biological Sciences, Lisburn Road 97, Belfast, United Kingdom. Electronic address:

Ambient ionization-based techniques hold great potential for rapid point-of-care applicable metabolic fingerprinting of tissue and fluids. Hereby, feces represents a unique biospecimen as it integrates the complex interactions between the diet, gut microbiome and host, and is therefore ideally suited to study the involvement of the diet-gut microbiome axis in metabolic diseases and their treatments at a molecular level. We present a new method for rapid (<10 s) metabolic fingerprinting of feces, i.e. laser-assisted rapid evaporative ionization mass spectrometry (LA-REIMS) with an Nd:YAG laser (2940 nm) and quadrupole Time-of-Flight mass spectrometer as main components. The LA-REIMS method was implemented on mimicked crude feces samples from individuals that were assigned a state of type 2 diabetes or euglycaemia. Based on the generated fingerprints, enclosing 4923 feature ions, significant segregation according to disease classification was achieved through orthogonal partial least squares discriminant analysis (Q(Y) of 0.734 and p-value of 1.93e) and endorsed by a general classification accuracy of 90.5%. A comparison between the discriminative performance of the novel LA-REIMS and our established ultra-high performance liquid-chromatography high-resolution MS (UHPLC-HRMS) metabolomics and lipidomics methodologies for fingerprinting of stool was performed. Based on the supervised modelling results upon UHPLC-HRMS (Q(Y) ≥ 0.655 and p-value ≤ 4.11 e), equivalent or better discriminative performance of LA-REIMS fingerprinting was concluded. Eventually, comprehensive UHPLC-HRMS was employed to assess metabolic alterations as observed for the defined classes, whereby metformin treatment of the type 2 diabetes patients was considered a relevant study factor to acquire new mechanistic insights. More specifically, ten metabolization products of metformin were identified, with (hydroxylated) triazepinone and metformin-cholesterol reported for the first time in vivo.In conclusion, LA-REIMS was established as an expedient strategy for rapid metabolic fingerprinting of feces, whereby potential implementations may relate, but are not limited to differential diagnosis and treatment efficacy evaluation of metabolic diseases. Yet, LC-HRMS remains essential for in-depth biological interpretation.
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http://dx.doi.org/10.1016/j.talanta.2020.121043DOI Listing
September 2020

Bladder Paraganglioma.

J Belg Soc Radiol 2020 May 12;104(1):25. Epub 2020 May 12.

UZ Ghent, BE.

A submucosal bladder wall lesion with high signal on T2-weighted MRI warrants blood and urine analysis to rule out a paraganglioma.
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http://dx.doi.org/10.5334/jbsr.2064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227393PMC
May 2020

Use of Culture to Reach Metabolically Adequate Beta-cell Dose by Combining Donor Islet Cell Isolates for Transplantation in Type 1 Diabetes Patients.

Transplantation 2020 10;104(10):e295-e302

Diabetes Research Center, University Hospital and Diabetes Research Center, Vrije Universiteit Brussel-VUB, Brussel, Belgium.

Background: Clinical islet transplantation is generally conducted within 72 hours after isolating sufficient beta-cell mass. A preparation that does not meet the sufficient dose can be cultured until this is reached after combination with subsequent ones. This retrospective study examines whether metabolic outcome is influenced by culture duration.

Methods: Forty type 1 diabetes recipients of intraportal islet cell grafts under antithymocyte globulin induction and mycophenolate mofetil-tacrolimus maintenance immunosuppression were analyzed. One subgroup (n = 10) was transplanted with preparations cultured for ≥96 hours; in the other subgroup (n = 30) grafts contained similar beta-cell numbers but included isolates that were cultured for a shorter duration. Both subgroups were compared by numbers with plasma C-peptide ≥0.5 ng/mL, low glycemic variability associated with C-peptide ≥1.0 ng/mL, and with insulin independence.

Results: The subgroup with all cells cultured ≥96 hours exhibited longer C-peptide ≥0.5 ng/mL (103 versus 48 mo; P = 0.006), and more patients with low glycemic variability and C-peptide ≥1.0 ng/mL, at month 12 (9/10 versus 12/30; P = 0.005) and 24 (7/10 versus 6/30; P = 0.007). In addition, 9/10 became insulin-independent versus 15/30 (P = 0.03). Grafts with all cells cultured ≥96 hours did not contain more beta cells but a higher endocrine purity (49% versus 36%; P = 0.03). In multivariate analysis, longer culture duration and older recipient age were independently associated with longer graft function.

Conclusions: Human islet isolates with insufficient beta-cell mass for implantation within 72 hours can be cultured for 96 hours and longer to combine multiple preparations in order to reach the desired beta-cell dose and therefore result in a better metabolic benefit.
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http://dx.doi.org/10.1097/TP.0000000000003321DOI Listing
October 2020

Urinary detection of rapid-acting insulin analogs in healthy humans.

Drug Test Anal 2020 Nov 3;12(11-12):1629-1635. Epub 2020 Jun 3.

Department of Diagnostic Sciences, Doping Control Laboratory, Ghent University, Zwijnaarde, Belgium.

Human insulin and its synthetic analogs are considered as life-saving drugs for people suffering from diabetes mellitus. Next to the therapeutic use, scientific and non-scientific literature (e.g. bodybuilding forums; antidoping intelligence and investigation reports) indicate that these prohibited substances are used as performance enhancing agents. In the present report, the development and validation of a sensitive analytical strategy is described for the urinary detection of three rapid-acting insulin analogs (Lispro, Aspart, Glulisine). The method is based on sample purification by the combination of ultrafiltration and immunoaffinity purification and subsequent analysis by nano-flow liquid chromatography coupled to high resolution mass spectrometry. Next to the results on different validation parameters (LOD: 10 pg/mL; recovery: 25-48%; matrix effect: -3-(-8) %), data on urinary elimination times, which were obtained in the frame of an administration study with the participation of healthy volunteers, are presented. The determined detection windows (~9 hours) are expected to help to evaluate current routine analytical methods and aim to aid doping authorities to set appropriate target windows for efficient testing.
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http://dx.doi.org/10.1002/dta.2817DOI Listing
November 2020

Does muscle strength change over time in patients with hypermobile Ehlers-Danlos syndrome/ Hypermobility Spectrum Disorder? An 8-year follow-up study.

Arthritis Care Res (Hoboken) 2020 Apr 15. Epub 2020 Apr 15.

Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.

Objective: Reduced maximal muscle strength and strength endurance has been found in patients with hypermobile Ehlers-Danlos syndrome/Hypermobility Spectrum Disorder (hEDS/HSD) and is recognized as a common associated feature of the disorder. However, it is currently not documented to which extent these parameters change over time. Therefore, an 8-year follow-up study was performed to investigate this evolution.

Methods: Thirty female patients (mean age: 41 years) with hEDS/HSD and 17 controls participated at baseline and eight years later. Maximal muscle strength and strength endurance tests of the knee flexors and extensors (Biodex), and two lower limb posture maintenance tests were performed to evaluate static strength endurance. In addition, muscle mass and density were evaluated by dual-energy X-ray absorptiometry and peripheral quantitative computed tomography.

Results: Maximal muscle strength and strength endurance were significantly lower at both baseline and follow-up in the hEDS/HSD group compared to the control group (p≤0.007). Maximal muscle strength of the knee flexors (decreased in the control group: pɳ : 0.139), strength endurance of the knee extensors (decreased in the hEDS/HSD group and increased in the control group: pɳ : 0.244) and muscle density (decreased in the hEDS/HSD group: pɳ : 0.263) showed a significantly different evolution over eight years. No other significant differences in evolution were found.

Conclusion: Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on effectiveness of different types of muscle training strategies in hEDS/HSD patients.
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http://dx.doi.org/10.1002/acr.24220DOI Listing
April 2020

The impact of sensory and/or sensorimotor neuropathy on lower limb muscle endurance, explosive and maximal muscle strength in patients with type 2 diabetes mellitus.

J Diabetes Complications 2020 06 24;34(6):107562. Epub 2020 Feb 24.

Department of Rehabilitation Sciences, Ghent University, Corneel Heymanslaan 10, 9000 Ghent, Belgium. Electronic address:

Aims: The purpose of this study was to investigate the impact of diabetic neuropathy (dNP) on lower limb endurance, explosive and maximal muscle strength in patients with Type 2 Diabetes Mellitus (T2DM).

Methods: Fifty-four participants, aged between 55 and 85, were enrolled in this observational comparative study. The patients with T2DM had an average HbA1c of 7.4% (±1.03) and diabetes duration of 13 years. Participants were classified by means of electroneuromyography as T2DM without dNP (dNP-; n = 8), T2DM with sensory dNP (dNPs; n = 13), T2DM with sensorimotor dNP (dNPsm; n = 14), and healthy controls without neuropathy (C; n = 19). Maximal muscle strength and muscle endurance of the dominant knee and ankle were measured by dynamometry, while explosive muscle strength was evaluated by mechanography.

Results: Muscle endurance "total work" in knee extension and ankle plantar flexion was higher in the healthy controls compared to dNP-, dNPs and dNPsm, in knee flexion compared to dNPs and dNPsm, and in ankle dorsiflexion compared to dNPsm only (p<0.05). Furthermore, relative explosive muscle strength "total power/body weight" and relative maximal muscle strength "peak torque/lean body mass of the dominant leg" considering knee flexion, ankle plantar flexion and dorsiflexion, were higher in healthy controls compared to the dNPsm group, and for maximal muscle strength ankle dorsiflexion even between dNP- and dNPsm (p < 0.05).

Conclusions: Muscle endurance is impaired in patients with T2DM, independent of the presence of dNP. Explosive and maximal muscle strength are more likely affected by the presence and severity of dNP.
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http://dx.doi.org/10.1016/j.jdiacomp.2020.107562DOI Listing
June 2020

The relationship between glycaemic variability and cardiovascular autonomic dysfunction in patients with type 1 diabetes: A systematic review.

Diabetes Metab Res Rev 2020 07 3;36(5):e3301. Epub 2020 Mar 3.

Department of Rehabilitation Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.

Rigorous glycaemic control-reflected by low HbA1c goals-is of the utmost importance in the prevention and management of complications in patients with type 1 diabetes mellitus (T1DM). However, previous studies suggested that short-term glycaemic variability (GV) is also important to consider as excessive glucose fluctuations may have an additional impact on the development of diabetic complications. The potential relationship between GV and the risk of cardiovascular autonomic neuropathy (CAN), a clinical expression of cardiovascular autonomic dysfunction, is of increasing interest. This systematic review aimed to summarize existing evidence concerning the relationship between GV and cardiovascular autonomic dysfunction in T1DM. An electronic database search of Medline (PubMed), Web of Science and Embase was performed up to October 2019. There were no limits concerning year of publication. Methodological quality was evaluated using the Newcastle Ottawa Scale for observational studies. Six studies (four cross-sectional and two prospective cohorts) were included. Methodological quality of the studies varied from level C to A2. Two studies examined the association between GV and heart rate variability (HRV), and both found significant negative correlations. Regarding cardiovascular autonomic reflex tests (CARTs), two studies did not, while two other studies did find significant associations between GV parameters and CART scores. However, associations were attenuated after adjusting for covariates such as HbA1c, age and disease duration. In conclusion, this systematic review found some preliminary evidence supporting an association between GV and cardiovascular autonomic dysfunction in T1DM. Hence, uncertainty remains whether high GV can independently contribute to the onset or progression of CAN. The heterogeneity in the methodological approach made it difficult to compare different studies. Future studies should therefore use uniformly evaluated continuous glucose monitoring-derived parameters of GV, while standardized assessment of HRV, CARTs and other potential cardiac autonomic function parameters is needed for an unambiguous definition of CAN.
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http://dx.doi.org/10.1002/dmrr.3301DOI Listing
July 2020

Bariatric Surgery for Treatment of Hypothalamic Obesity After Craniopharyngioma Therapy: a Matched Case-Control Study.

Obes Surg 2020 Jun;30(6):2439-2444

Department of Gastrointestinal Surgery, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.

Craniopharyngioma and its treatment lead to weight gain and pituitary hormone deficiencies. This study aimed to investigate the effectiveness of bariatric surgery for treatment of hypothalamic obesity after craniopharyngioma therapy. Five patients with hypothalamic obesity after craniopharyngioma treatment were included. Patients were treated with sleeve gastrectomy or Roux-en-Y gastric bypass and individually matched to 2 control patients treated for common obesity. At 2 years of follow-up, total and excess weight loss in cases were 14.7% (p = 0.002) and 38.0% (p = 0.001), respectively; differences between both groups were 13.6% (p = 0.02) and 31.6% (p = 0.03). Minor postoperative alterations in hormone substitution in all 5 cases were observed. Thus, bariatric surgery induced significant weight loss in patients with craniopharyngioma-related hypothalamic obesity, even though a superior weight loss in controls was observed.
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http://dx.doi.org/10.1007/s11695-020-04391-wDOI Listing
June 2020

The effects of age and obesity on postprandial dynamics of serum testosterone levels in men.

Clin Endocrinol (Oxf) 2020 03 23;92(3):214-221. Epub 2019 Dec 23.

Department of Endocrinology, Ghent University Hospital, Ghent, Belgium.

Objective: Guidelines recommend using fasting samples to evaluate testosterone (T) levels in men, as free and total T levels decrease postprandially. However, it is not clear whether these dynamics are affected by age or obesity. This could be relevant given the obesity epidemic, ageing population and the barrier for screening which fasting could impose.

Design/participants: A total of 43 men underwent a solid mixed meal tolerance test. Serum samples were taken fasting, and at 30, 60 and 120 minutes postprandially. A commercial immunoassay was used to determine sex hormone-binding globulin (SHBG) levels, liquid chromatography coupled to tandem mass spectroscopy for total T concentrations and free T levels were calculated.

Results: Postprandially, both total and free T were lower at all-time points compared with fasting (all, P < .005). At 60 minutes, maximum mean decreases of 15 ± 15% and 17 ± 16% were seen for total and free T levels, respectively. Younger men had greater decreases in both total and free T levels compared with men older than 40 years (all, P < .05). A greater decrease at 30 and 60 minutes postprandially was observed for both total and free T levels in nonobese vs obese men (all, P < .05).

Conclusions: After a mixed meal, total and free T serum levels decreased whereas SHBG levels did not change. Interestingly, postprandial decreases were less pronounced in men older than 40 years and/or with obesity. Although this study indicates less pronounced decreases in certain men, fasting samples remain a prerequisite for establishing correct diagnosis of male hypogonadism.
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http://dx.doi.org/10.1111/cen.14141DOI Listing
March 2020

Effects of Gender-Affirming Hormone Therapy on Insulin Sensitivity and Incretin Responses in Transgender People.

Diabetes Care 2020 02 18;43(2):411-417. Epub 2019 Nov 18.

Department of Endocrinology, Ghent University Hospital, Ghent, Belgium.

Objective: The long-term influences of sex hormone administration on insulin sensitivity and incretin hormones are controversial. We investigated these effects in 35 transgender men (TM) and 55 transgender women (TW) from the European Network for the Investigation of Gender Incongruence (ENIGI) study.

Research Design And Methods: Before and after 1 year of gender-affirming hormone therapy, body composition and oral glucose tolerance tests (OGTTs) were evaluated.

Results: In TM, body weight (2.8 ± 1.0 kg; < 0.01), fat-free mass (FFM) (3.1 ± 0.9 kg; < 0.01), and waist-to-hip ratio (-0.03 ± 0.01; < 0.01) increased. Fasting insulin (-1.4 ± 0.8 mU/L; = 0.08) and HOMA of insulin resistance (HOMA-IR) (2.2 ± 0.3 vs. 1.8 ± 0.2; = 0.06) tended to decrease, whereas fasting glucose (-1.6 ± 1.6 mg/dL), glucose-dependent insulinotropic polypeptide (GIP) (-1.8 ± 1.0 pmol/L), and glucagon-like peptide 1 (GLP-1) (-0.2 ± 1.1 pmol/L) were statistically unchanged. Post-OGTT areas under the curve (AUCs) for GIP (2,068 ± 1,134 vs. 2,645 ± 1,248 [pmol/L] × min; < 0.01) and GLP-1 (2,352 ± 796 vs. 2,712 ± 1,015 [pmol/L] × min; < 0.01) increased. In TW, body weight tended to increase (1.4 ± 0.8 kg; = 0.07) with decreasing FFM (-2.3 ± 0.4 kg; < 0.01) and waist-to-hip ratio (-0.03 ± 0.01; < 0.01). Insulin (3.4 ± 0.8 mU/L; < 0.01) and HOMA-IR (1.7 ± 0.1 vs. 2.4 ± 0.2; < 0.01) rose, fasting GIP (-1.4 ± 0.8 pmol/L; < 0.01) and AUC GIP dropped (2,524 ± 178 vs. 1,911 ± 162 [pmol/L] × min; < 0.01), but fasting glucose (-0.3 ± 1.4 mg/dL), GLP-1 (1.3 ± 0.8 pmol/L), and AUC GLP-1 (2,956 ± 180 vs. 2,864 ± 93 [pmol/L] × min) remained unchanged.

Conclusions: In this cohort of transgender persons, insulin sensitivity but also post-OGTT incretin responses tend to increase with masculinization and to decrease with feminization.
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http://dx.doi.org/10.2337/dc19-1061DOI Listing
February 2020

Impact of Exercise-Nutritional State Interactions in Patients with Type 2 Diabetes.

Med Sci Sports Exerc 2020 03;52(3):720-728

Department of Endocrinology, Ghent University Hospital, Ghent, BELGIUM.

Introduction: This study examines the role of nutritional status during exercise training in patients with type 2 diabetes mellitus by investigating the effect of endurance-type exercise training in the fasted versus the fed state on clinical outcome measures, glycemic control, and skeletal muscle characteristics in male type 2 diabetes patients.

Methods: Twenty-five male patients (glycated hemoglobin (HbA1c), 57 ± 3 mmol·mol (7.4% ± 0.3%)) participated in a randomized 12-wk supervised endurance-type exercise intervention, with exercise being performed in an overnight-fasted state (n = 13) or after consuming breakfast (n = 12). Patients were evaluated for glycemic control, blood lipid profiles, body composition and physical fitness, and skeletal muscle gene expression.

Results: Exercise training was well tolerated without any incident of hypoglycemia. Exercise training significantly decreased whole-body fat mass (-1.6 kg) and increased high-density lipoprotein concentrations (+2 mg·dL), physical fitness (+1.7 mL·min·kg), and fat oxidation during exercise in both groups (PTIME < 0.05), with no between-group differences (PTIME × GROUP > 0.05). HbA1c concentrations significantly decreased after exercise training (PTIME < 0.001), with a significant greater reduction after consuming breakfast (-0.30% ± 0.06%) compared with fasted state (-0.08% ± 0.06%; mean difference, 0.21%; PTIME × GROUP = 0.016). No interaction effects were observed for skeletal muscle genes related to lipid metabolism or oxidative capacity.

Conclusions: Endurance-type exercise training in the fasted or fed state do not differ in their efficacy to reduce fat mass, increase fat oxidation capacity, and increase cardiorespiratory fitness and high-density lipoprotein concentrations or their risk of hypoglycemia in male patients with type 2 diabetes. HbA1c seems to be improved more with exercise performed in the postprandial compared with the postabsorptive state.
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http://dx.doi.org/10.1249/MSS.0000000000002165DOI Listing
March 2020

Insulin resistance associates with hepatic lobular inflammation in subjects with obesity.

Endocr Connect 2019 Sep;8(9):1294-1301

Department of Endocrinology, Ghent University Hospital, Ghent, Belgium.

Purpose: Obese subjects with nonalcoholic fatty liver disease (NAFLD) are more prone to develop additional metabolic disturbances such as systemic insulin resistance (IR) and type 2 diabetes. NAFLD is defined by hepatic steatosis, lobular inflammation, ballooning and stage of fibrosis, but it is unclear if and which components could contribute to IR.

Objective: To assess which histological components of NAFLD associate with IR in subjects with obesity, and if so, to what extent.

Methods: This cross-sectional study included 78 obese subjects (mean age 46 ± 11 years; BMI 42.2 ± 4.7 kg/m2). Glucose levels were analysed by hexokinase method and insulin levels with electrochemiluminescence. Homeostasis model assessment-estimated insulin resistance (HOMA-IR) was calculated. Liver biopsies were evaluated for histological components of NAFLD.

Results: A positive association between overall NAFLD Activity Score and HOMA-IR was found (r s = 0.259, P = 0.022). As per individual components, lobular inflammation and fibrosis stage were positively associated with HOMA-IR, glucose and insulin levels (P < 0.05), and HOMA-IR was higher in patients with more inflammatory foci or higher stage of fibrosis. These findings were independent of age, BMI, triglyceride levels, diabetes status and sex (all P < 0.043). In a combined model, lobular inflammation, but not fibrosis, remained associated with HOMA-IR.

Conclusion: In this group of obese subjects, a major contributing histological component of NAFLD to the relation between NAFLD severity and IR seems to be the grade of hepatic lobular inflammation. Although no causal relationship was assessed, preventing or mitigating this inflammatory response in obesity might be of importance in controlling obesity-related metabolic disturbances.
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http://dx.doi.org/10.1530/EC-19-0366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6765320PMC
September 2019

The adipokine sFRP4 induces insulin resistance and lipogenesis in the liver.

Biochim Biophys Acta Mol Basis Dis 2019 10 20;1865(10):2671-2684. Epub 2019 Jul 20.

Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center at the Heinrich-Heine-University Duesseldorf, Leibniz Center for Diabetes Research, Auf'm Hennekamp 65, 40225 Duesseldorf, Germany; German Center of Diabetes Research Partner, Duesseldorf, Germany. Electronic address:

Secreted frizzled-related protein (sFRP) 4 is an adipokine with increased expression in white adipose tissue from obese subjects with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). Yet, it is unknown whether sFRP4 action contributes to the development of these pathologies. Here, we determined whether sFRP4 expression in visceral fat associates with NAFLD and whether it directly interferes with insulin action and lipid and glucose metabolism in primary hepatocytes and myotubes. The association of sFRP4 with clinical measures was investigated in obese men with or without type 2 diabetes and with or without biopsy-proven NAFLD. To determine the impact of sFRP4 on metabolic parameters, primary human myotubes (hSkMC), or primary hepatocytes from metabolic healthy C57Bl6 and from systemic insulin-resistant mice, i.e. aP2-SREBP-1c, were used. Gene expression of sFRP4 in visceral fat from obese men associated with insulin sensitivity, triglycerides and NAFLD. In C57Bl6 hepatocytes, sFRP4 disturbed insulin action. Specifically, sFRP4 decreased the abundance of IRS1 and FoxO1 together with impaired insulin-mediated activation of Akt-signalling and glycogen synthesis and a reduced suppression of gluconeogenesis by insulin. Moreover, sFRP4 enhanced insulin-stimulated hepatic de novo lipogenesis (DNL). In hSkMC, sFRP4 induced glycolysis rather than inhibiting insulin signalling. Finally, in hepatocytes from aP2-SREBP-1c mice, sFRP4 potentiates existing insulin resistance. Collectively, we show that sFRP4 interferes with hepatocyte insulin action. Physiologically, sFRP4 promotes DNL in hepatocytes and glycolysis in myotubes. These sFRP4-mediated responses may result in a vicious cycle, in which enhanced rates of DNL and glycolysis aggravate hepatic lipid accumulation and insulin resistance.
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http://dx.doi.org/10.1016/j.bbadis.2019.07.008DOI Listing
October 2019

Histologically proven hepatic steatosis associates with lower testosterone levels in men with obesity.

Asian J Androl 2020 May-Jun;22(3):252-257

Department of Endocrinology, Ghent University Hospital, 9000 Ghent, Belgium.

Men with obesity often present with low testosterone (T) and sex hormone-binding globulin (SHBG) levels. Several mechanisms for this have been proposed, but as SHBG is secreted by hepatocytes and sex steroids undergo hepatic metabolization, this study investigates whether severity and histological components of nonalcoholic fatty liver disease (NAFLD) are associated with sex steroid levels in obese men. This cross-sectional study included 80 obese men (age: 46 ± 11 years; body mass index: 42.2 ± 5.5 kg m). Serum levels of total T and estradiol (E) were measured using liquid chromatography coupled with tandem mass spectroscopy (LC/MS-MS) and SHBG and gonadotropins by immunoassay. Liver biopsies were evaluated using Steatosis, Activity, and Fibrosis scoring. Participants with steatohepatitis had similar median (1quartile-3 quartile) total T levels (7.6 [5.0-11.0] nmol l vs 8.2 [7.2-10.9] nmol l; P = 0.147), lower calculated free T (cFT) levels (148.9 [122.9-188.8] pmol l vs 199.5 [157.3-237.6] pmol l; P = 0.006), and higher free E/T ratios (10.0 [6.4-13.9] x10 vs 7.1 [5.7-10.7] x10.
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http://dx.doi.org/10.4103/aja.aja_68_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275796PMC
July 2019

Aging and the Male Reproductive System.

Endocr Rev 2019 08;40(4):906-972

Department of Surgery and Cancer, Institute of Reproductive and Developmental Biology, Imperial College London, London, United Kingdom.

This narrative review presents an overview of current knowledge on fertility and reproductive hormone changes in aging men, the factors driving and modulating these changes, their clinical consequences, and the benefits and risks of testosterone (T) therapy. Aging is accompanied by moderate decline of gamete quality and fertility. Population mean levels show a mild total T decline, an SHBG increase, a steeper free T decline, and a moderate LH increase with important contribution of comorbidities (e.g., obesity) to these changes. Sexual symptoms and lower hematocrit are associated with low T and are partly responsive to T therapy. The relationship of serum T with body composition and metabolic health is bidirectional; limited beneficial effects of T therapy on body composition have only marginal effects on metabolic health and physical function. Skeletal changes are associated primarily with estradiol and SHBG. Cognitive decline is not consistently linked to low T and is not improved by T therapy. Although limited evidence links moderate androgen decline with depressive symptoms, T therapy has small beneficial effects on mood, depressive symptoms, and vitality in elderly patients with low T. Suboptimal T (and/or DHT) has been associated with increased risk of stroke, but not of ischemic heart disease, whereas an association with mortality probably reflects that low T is a marker of poor health. Globally, neither severity of clinical consequences attributable to low T nor the nature and magnitude of beneficial treatment effects justify the concept of some broadly applied "T replacement therapy" in older men with low T. Moreover, long-term safety of T therapy is not established.
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http://dx.doi.org/10.1210/er.2018-00178DOI Listing
August 2019

A practical approach towards the evaluation of aberrant thyroid function tests.

Acta Clin Belg 2020 Apr 26;75(2):155-162. Epub 2019 Feb 26.

Department of Clinical Pathology, Ghent University Hospital, Ghent, Belgium.

: To provide insight in patterns and causes of aberrant thyroid function tests (TFT) and to propose a practical approach for clinicians.: Starting from an illustrative case report, an extensive literature search was performed, resulting in a narrative literature review.: TFT that cannot be explained by the negative feedback principle of the hypothalamo-pituitary-thyroid axis are a challenge for every clinician. Various alternative explanations for these TFT should be considered before drawing the conclusion of thyroid disorder, since incorrect diagnosis and treatment can have severe consequences for the patient.For example, the combination of elevated or normal TSH with elevated free T4 or T3 levels may result from the use of certain drugs or lab interference, while low or normal TSH with low T3 or T4 can often be explained by non-thyroidal illness or central hypothyroidism due to pituitary failure. Correct identification of these clinical situations requires understanding thyroid hormone metabolism and action, knowledge of some laboratory techniques, and a multistep evaluation process.: To avoid incorrect diagnosis and thus treatment, clinicians should be aware of the existence of aberrant TFT and know how to decipher them.
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http://dx.doi.org/10.1080/17843286.2019.1577531DOI Listing
April 2020

Secondary Adrenal Insufficiency after Treatment with Budesonide for Autoimmune Hepatitis.

Case Rep Gastroenterol 2018 Sep-Dec;12(3):597-601. Epub 2018 Oct 2.

Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium.

Autoimmune hepatitis (AIH) is a rare cause of chronic liver disease. The backbone of treatment is immunosuppressive medication, typically prednisolone as induction therapy and azathioprine as a maintenance therapy. Side effects of the long-term use of systemic corticosteroids are well known and have led to the use of alternative induction regimens. An attractive alternative is budesonide, a nonhalogenated glucocorticosteroid characterized by a high first-pass effect in the liver (90%), resulting in a high topical anti-inflammatory activity and a low systemic activity. It should be stressed that budesonide is contraindicated in patients with established cirrhosis with portal hypertension and portocaval shunting. In this case report, we present the first case of adrenal insufficiency following treatment with budesonide for AIH.
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http://dx.doi.org/10.1159/000492204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6206950PMC
October 2018

Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation.

Nat Commun 2018 10 26;9(1):4455. Epub 2018 Oct 26.

Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, USA.

Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves' disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.
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http://dx.doi.org/10.1038/s41467-018-06356-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6203810PMC
October 2018

Angiopoietin-2 Promotes Pathological Angiogenesis and Is a Therapeutic Target in Murine Nonalcoholic Fatty Liver Disease.

Hepatology 2019 03 12;69(3):1087-1104. Epub 2019 Feb 12.

Department of Gastroenterology and Hepatology, Hepatology Research Unit, Ghent University, Ghent, Belgium.

Angiogenesis contributes to the development of nonalcoholic steatohepatitis (NASH) and promotes inflammation, fibrosis, and progression to hepatocellular carcinoma (HCC). Angiopoietin-2 (Ang-2) is a key regulator of angiogenesis. We aimed to investigate the role of Ang-2 and its potential as a therapeutic target in NASH using human samples, in vivo mouse models, and in vitro assays. Serum Ang-2 levels were determined in 104 obese patients undergoing bariatric surgery and concomitant liver biopsy. The effect of the Ang-2/Tie2 receptor inhibiting peptibody L1-10 was evaluated in the methionine-choline deficient (MCD) and streptozotocin-western diet nonalcoholic fatty liver disease mouse models, and in vitro on endothelial cells and bone marrow-derived macrophages. The hepatic vasculature was visualized with µCT scans and scanning electron microscopy of vascular casts. Serum Ang-2 levels were increased in patients with histological NASH compared with patients with simple steatosis and correlated with hepatic CD34 immunoreactivity as a marker of hepatic angiogenesis. Serum and hepatic Ang-2 levels were similarly increased in mice with steatohepatitis. Both preventive and therapeutic L1-10 treatment reduced hepatocyte ballooning and fibrosis in MCD diet-fed mice and was associated with reduced hepatic angiogenesis and normalization of the vascular micro-architecture. Liver-isolated endothelial cells and monocytes from MCD-fed L1-10-treated mice showed reduced expression of leukocyte adhesion and inflammatory markers, respectively, compared with cells from untreated MCD diet-fed mice. In the streptozotocin-western diet model, therapeutic Ang-2 inhibition was able to reverse NASH and attenuate HCC progression. In vitro, L1-10 treatment mitigated increased cytokine production in lipopolysaccharide-stimulated endothelial cells but not in macrophages. Conclusion: Our findings provide evidence for Ang-2 inhibition as a therapeutic strategy to target pathological angiogenesis in NASH.
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http://dx.doi.org/10.1002/hep.30294DOI Listing
March 2019