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Subacute thyroiditis (SAT) is a self-limited inflammatory disease and a rare cause of thyrotoxicosis. Although the exact etiology of SAT is not sufficiently understood, it is generally associated to viral infections. Current evidence highlights that SAT may be a potentially uncommon manifestation of ongoing Coronavirus disease 2019 (COVID-19) infection or a post-viral complication of the disease. Despite that SAT is a rare manifestation associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease both in ongoing and resolved COVID-19 infection, the ever-increasing numbers of COVID-19 patients strengthens the possibility that this particular disease entity will be of more immediate concern in the future. The current work aims to summarize the approach of SARS-CoV-2-associated SAT, present its pathophysiology, outline current research evidence found in the literature, and discuss potential differential diagnoses and diagnostic dilemmas through an illustrative case.

Diurnal carbohydrate and fat distribution modulates glycaemic control in rodents. In humans, the optimal timing of both macronutrients and its effects on glycaemic control after prolonged consumption are not studied in detail. In this cross-over trial, 29 non-obese men were randomized to two four-week diets: (1) carbohydrate-rich meals until 13.30 and fat-rich meals between 16.30 and 22.00 (HC/HF) versus (2) inverse sequence of meals (HF/HC). After each trial period two meal tolerance tests were performed, at 09.00 and 15.40, respectively, according to the previous intervention. On the HF/HC diet, whole-day glucose level was increased by 7.9% (p = 0.026) in subjects with impaired fasting glucose and/or impaired glucose tolerance (IFG/IGT, n = 11), and GLP-1 by 10.2% (p = 0.041) in normal glucose-tolerant subjects (NGT, n = 18). Diet effects on fasting GLP-1 (p = 0.009) and PYY (p = 0.034) levels were observed in IFG/IGT, but not in NGT. Afternoon decline of glucose tolerance was more pronounced in IFG/IGT and associated with a stronger decrease of postprandial GLP-1 and PYY levels, but not with changes of cortisol rhythm. In conclusion, the HF/HC diet shows an unfavourable effect on glycaemic control in IFG/IGT, but not in NGT subjects. Consequently, large, carbohydrate-rich dinners should be avoided, primarily by subjects with impaired glucose metabolism.

Liver fibrosis is a critical complication of obesity-induced fatty liver disease. Wnt1 inducible signaling pathway protein 1 (WISP1/CCN4), a novel adipokine associated with visceral obesity and insulin resistance, also contributes to lung and kidney fibrosis. The aim of the present study was to investigate the role of CCN4 in liver fibrosis in severe obesity. For this, human liver biopsies were collected from 35 severely obese humans (BMI 42.5 ± 0.7 kg/m2, age 46.7 ± 1.8 y, 25.7% males) during bariatric surgery and examined for the expression of CCN4, fibrosis, and inflammation markers. Hepatic stellate LX-2 cells were treated with human recombinant CCN4 alone or in combination with LPS or transforming growth factor beta (TGF-β) and examined for fibrosis and inflammation markers. CCN4 mRNA expression in the liver positively correlated with BMI and expression of fibrosis markers COL1A1, COL3A1, COL6A1, αSMA, TGFB1, extracellular matrix turnover enzymes TIMP1 and MMP9, and the inflammatory marker ITGAX/CD11c. In LX-2 cells, the exposure to recombinant CCN4 caused dose-dependent induction of MMP9 and MCP1. CCN4 potentiated the TGF-β-mediated induction of COL3A1, TIMP1, and MCP1 but showed no interaction with LPS treatment. Our results suggest a potential contribution of CCN4 to the early pathogenesis of obesity-associated liver fibrosis.

Reduced Hepatic Insulin Extraction in Response to Gastric Inhibitory Polypeptide Compensates for Reduced Insulin Secretion in Normal-Weight and Normal Glucose Tolerant First-Degree Relatives of Type 2 Diabetic Patients Natalia N. Rudovich , Helmut J. Rochlitz and Andreas F.H. Pfeiffer From the Department of Clinical Nutrition, German Institute of Human Nutrition Potsdam-Rehbrücke, and the Department of Endocrinology, Diabetes and Nutrition, Campus B. Franklin, Charite University Medicine, Berlin, Germany Address correspondence and reprint requests to Andreas F.H. Pfeiffer, German Institute of Human Nutrition Potsdam-Rehbrücke, Department of Clinical Nutrition, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany. E-mail: afhp{at}mail.dife.de Abstract Our objective was to study whether young first-degree relatives of patients with type 2 diabetes (FDRs) have altered insulin secretion and insulin clearance in response to gastric inhibitory polypeptide (GIP) in combination with glucose and arginine. A hyperglycemic clamp (11.1 mmol/l for 115 min), followed by addition of GIP (2 pmol · kg −1 · min −1 , 60–115 min) and an arginine bolus and infusion (10 mg · kg −1 · min −1 , 90–115 min), was conducted on 14 healthy volunteers and 13 FDRs. Both groups had normal glucose tolerance. FDRs were more insulin resistant (HOMA IR ) under basal conditions ( P = 0.003). FDRs demonstrated significant global impairment in insulin secretion capacity, which was not specific for one of the secretagogues. Insulin clearance was significantly reduced in the group of FDRs under basal conditions and in response to GIP, but there was no general defect in insulin clearance in response to glucose and arginine. The HOMA IR correlated negatively ( P < 0.01) with insulin clearance under basal conditions ( r = −0.96) and under GIP infusion ( r = −0.56). We propose that impairment in insulin secretion capacity and decreased insulin sensitivity is compensated for several mechanisms, one of which includes a GIP-dependent reduction of the insulin clearance that will increase peripheral insulin levels to maintain normoglycemia. AUC, area under the curve FDRs, first-degree relative of patient with type 2 diabetes GIP, gastric inhibitory polypeptide GLP, glucagon-like peptide HOMA, homeostasis model assessment IR, insulin resistance ISR, insulin secretion rate MCR, metabolic clearance rate Footnotes Accepted June 2, 2004. Received September 30, 2003. DIABETES

Background Diets high in cereal-fiber (HCF) have been shown to improve whole-body insulin sensitivity. In search for potential mechanisms we hypothesized that a supplemented HCF-diet influences the composition of the human gut microbiota and/or biomarkers of colonic carbohydrate fermentation. Methods We performed a randomized controlled 18-week intervention in group-matched overweight participants. Fecal samples of 69 participants receiving isoenergetic HCF (cereal-fiber 43 g/day), or control (cereal-fiber 14 g/day), or high-protein (HP, 28% of energy-intake, cereal-fiber 14 g/day), or moderately high cereal fiber/protein diets (MIX; protein 23% of energy-intake, cereal-fiber 26 g/day) with comparable fat contents were investigated for diet-induced changes of dominant groups of the gut microbiota, and of fecal short-chain fatty-acids (SCFA) including several of their proposed targets, after 0, 6, and 18-weeks of dietary intervention. In vitro fermentation of the cereal fiber extracts as used in the HCF and MIX diets was analyzed using gas chromatography. Diet-induced effects on whole-body insulin-sensitivity were measured using euglycaemic-hyperinsulinemic clamps and re-calculated in the here investigated subset of n = 69 participants that provided sufficient fecal samples on all study days. Results Gut microbiota groups and biomarkers of colonic fermentation were comparable between groups at baseline (week 0). No diet-induced differences were detected between groups during this isoenergetic intervention, neither in the full model nor in uncorrected subgroup-analyses. The cereal-fiber extract as used for preparation of the supplements in the HCF and MIX groups did not support in vitro fermentation. Fecal acetate, propionate, and butyrate concentrations remained unchanged, as well as potential targets of increased SCFA, whereas valerate increased after 6-weeks in the HP-group only (p = 0.037). Insulin-sensitivity significantly increased in the HCF-group from week-6 (baseline M-value 3.8 ± 0.4 vs 4.3 ± 0.4 mg·kg -1 ·min -1 , p = 0.015; full model 0-18-weeks, treatment-x-time interaction, p = 0.046). Conclusions Changes in the composition of the gut microbiota and/or markers of colonic carbohydrate fermentation did not contribute explaining the observed early onset and significant improvement of whole-body insulin sensitivity with the here investigated HCF-diet. Trial registration This trial was registered at http://www.clinicaltrials.gov as NCT00579657

Aims/hypothesis Obesity is associated with elevated monocyte chemoattractant protein-1 (MCP-1), a proinflammatory chemokine related to diabetes and cardiovascular disease. Since obesity is triggered by energy dense diets, we hypothesised that nutrient induced intestinal hormones such as glucose-dependent insulinotropic peptide (GIP) may directly stimulate the release of chemokines from adipose tissue and induce low-grade inflammation. Methods GIP effects on gene expression and secretion of inflammatory markers were studied by microarray analysis and PCR from human subcutaneous fat biopsies of slightly obese but healthy volunteers in the metabolic ward of German Institute of Human Nutrition, Department of Clinical Nutrition, Potsdam-Rehbrücke. To allocate the participants to the study arms they were numbered in order of their recruitment and then assigned to the groups by a random number generator. In a randomised, single-blind (participants) crossover design, the participants received GIP infusions in postprandial concentrations (2 pmol kg −1  min −1 ) or saline (154 mmol/l NaCl) infusions for 240 min either alone, in combination with hyperinsulinaemic–euglycaemic (EU) or hyperinsulinaemic–hyperglycaemic (HC) clamps. Possible mechanisms of GIP effects were investigated in single and co-cultures of macrophage and adipocyte cell lines and in primary human monocytes, macrophages and adipocytes. Results A total of 17 participants were randomised to the following groups: EU with GIP infusion ( n  = 9); EU with NaCl infusion ( n  = 9); HC with GIP infusion ( n  = 8); HC with NaCl infusion ( n  = 8); sole GIP infusion ( n  = 11) and sole placebo infusion ( n  = 11). All 17 individuals were analysed. The study is completed. In human subcutaneous adipose tissue (hSCAT), infusions of GIP significantly increased inflammatory chemokine and cytokine gene networks in transcriptomic microarray analyses. Particularly MCP-1 (180 ± 26%), MCP-2 (246 ± 58%) and IL-6 (234 ± 40%) mRNA levels in adipose tissue as well as circulating plasma concentrations of MCP-1 (165 ± 12 vs 135 ± 13 pg/ml; GIP vs saline after 240 min; p  < 0.05 for all variables) in humans increased independently of circulating insulin or glucose plasma concentrations. GIP stimulation increased Mcp-1 mRNA-expression in co-cultures of differentiated 3T3L1-adipocytes and RAW 264.7 macrophages but not in the isolated cell lines. Similarly, GIP increased MCP-1 transcripts in co-cultures of primary human macrophages with human adipocytes. GIP receptor ( GIPR ) transcripts were present in primary monocytes and the different cell lines and induced activation of extracellular related kinase (ERK) as well as increases in cAMP, indicating functional receptors. Conclusions/interpretation Our findings suggest that the nutrient induced gut hormone GIP may initiate adipose tissue inflammation by triggering a crosstalk of adipocytes and macrophages involving MCP-1. Trial registration: ClinicalTrials.gov NCT00774488 Funding: This work was supported by the German Research Foundation (DFG): grant No. Pf164/021002

Abstract Context Meal timing affects metabolic homeostasis and body weight, but how composition and timing of meals affect plasma lipidomics in humans is not well studied. Objective We used high throughput shotgun plasma lipidomics to investigate effects of timing of carbohydrate and fat intake on lipid metabolism and its relation to glycemic control. Design 29 nondiabetic men consumed (1) a high-carb test meal (MTT-HC) at 09.00 and a high-fat meal (MTT-HF) at 15.40; or (2) MTT-HF at 09.00 and MTT-HC at 15.40. Blood was sampled before and 180 minutes after completion of each MTT. Subcutaneous adipose tissue (SAT) was collected after overnight fast and both MTTs. Prior to each investigation day, participants consumed a 4-week isocaloric diet of the same composition: (1) high-carb meals until 13.30 and high-fat meals between 16.30 and 22:00 or (2) the inverse order. Results 12 hour daily lipid patterns showed a complex regulation by both the time of day (67.8%) and meal composition (55.4%). A third of lipids showed a diurnal variation in postprandial responses to the same meal with mostly higher responses in the morning than in the afternoon. Triacylglycerols containing shorter and more saturated fatty acids were enriched in the morning. SAT transcripts involved in fatty acid synthesis and desaturation showed no diurnal variation. Diurnal changes of 7 lipid classes were negatively associated with insulin sensitivity, but not with glucose and insulin response or insulin secretion. Conclusions This study identified postprandial plasma lipid profiles as being strongly affected by meal timing and associated with insulin sensitivity.

Aims/hypothesisWingless-type (Wnt) inducible signalling pathway protein-1 (WISP1) has been recently identified as a proinflammatory adipokine. We examined whether WISP1 expression and circulating levels are altered in type 2 diabetes and whether WISP1 affects insulin signalling in muscle cells and hepatocytes.MethodsSerum and visceral adipose tissue (VAT) biopsies, for analysis of circulating WISP1 levels by ELISA and WISP1 mRNA expression by real-time quantitative RT-PCR, were collected from normal-weight men (control group, n = 33) and obese men with (n = 46) and without type 2 diabetes (n = 56) undergoing surgery. Following incubation of primary human skeletal muscle cells (hSkMCs) and murine AML12 hepatocytes with WISP1 and insulin, insulin signalling was analysed by western blotting. The effect of WISP1 on insulin-stimulated glycogen synthesis and gluconeogenesis was investigated in hSkMCs and murine hepatocytes, respectively.ResultsCirculating WISP1 levels were higher in obese men (independent of diabetes status) than in normal-weight men (mean [95% CI]: 70.8 [55.2, 86.4] ng/l vs 42.6 [28.5, 56.6] ng/l, respectively; p < 0.05). VAT WISP1 expression was 1.9-fold higher in obese men vs normal-weight men (p < 0.05). Circulating WISP1 levels were positively associated with blood glucose in the OGTT and circulating haem oxygenase-1 and negatively associated with adiponectin levels. In hSkMCs and AML12 hepatocytes, recombinant WISP1 impaired insulin action by inhibiting phosphorylation of insulin receptor, Akt and its substrates glycogen synthase kinase 3β, FOXO1 and p70S6 kinase, and inhibiting insulin-stimulated glycogen synthesis and suppression of gluconeogenic genes.Conclusions/interpretationCirculating WISP1 levels and WISP1 expression in VAT are increased in obesity independent of glycaemic status. Furthermore, WISP1 impaired insulin signalling in muscle and liver cells.

Meal timing affects metabolic regulation in humans. Most studies use blood samples for their investigations. Saliva, although easily available and non-invasive, seems to be rarely used for chrononutritional studies. In this pilot study, we tested if saliva samples could be used to study the effect of timing of carbohydrate and fat intake on metabolic rhythms. In this cross-over trial, 29 nonobese men were randomized to two isocaloric 4-week diets: (1) carbohydrate-rich meals until 13:30 and high-fat meals between 16:30 and 22:00 or (2) the inverse order of meals. Stimulated saliva samples were collected every 4 h for 24 h at the end of each intervention, and levels of hormones and inflammatory biomarkers were assessed in saliva and blood. Cortisol, melatonin, resistin, adiponectin, interleukin-6 and MCP-1 demonstrated distinct diurnal variations, mirroring daytime reports in blood and showing significant correlations with blood levels. The rhythm patterns were similar for both diets, indicating that timing of carbohydrate and fat intake has a minimal effect on metabolic and inflammatory biomarkers in saliva. Our study revealed that saliva is a promising tool for the non-invasive assessment of metabolic rhythms in chrononutritional studies, but standardisation of sample collection is needed in out-of-lab studies.