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Department of Gastroenterology, Turku University Hospital, Turku, Finland
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Department of Endocrinology, Turku University Hospital, Turku, Finland
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Aims/hypothesis
The mechanisms for improved glycemic control after bariatric surgery in subjects with type 2 diabetes (T2D) are not fully known. We hypothesized that dynamic hepatic blood responses to a mixed-meal are changed after bariatric surgery in parallel with an improvement in glucose tolerance.
Methods
A total of ten morbidly obese subjects with T2D were recruited to receive a mixed-meal and a glucose-dependent insulinotropic polypeptide (GIP) infusion before and early after (within a median of less than three months) bariatric surgery, and hepatic blood flow and volume (HBV) were measured repeatedly with combined positron emission tomography/MRI. Ten lean non-diabetic individuals served as controls.
Results
Bariatric surgery leads to a significant decrease in weight, accompanied with an improved β-cell function and glucagon-like peptide 1 (GLP-1) secretion, and a reduction in liver volume. Blood flow in portal vein (PV) was increased by 1.65-fold (P = 0.026) in response to a mixed-meal in subjects after surgery, while HBV decreased in all groups (P < 0.001). When the effect of GIP infusion was tested separately, no change in hepatic arterial and PV flow was observed, but HBV decreased as seen during the mixed-meal test.
Conclusions/interpretation
Early after bariatric surgery, PV flow response to a mixed-meal is augmented, improving digestion and nutrient absorption. GIP influences the post-prandial reduction in HBV thereby diverting blood to the extrahepatic sites.
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Medical Microbiology Department, College of Basic Medicine, Qingdao University, Qingdao, China
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Physiology Department, College of Basic Medicine, Qingdao University, Qingdao, China
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Ghrelin plays a pivotal role in the regulation of food intake, body weight and energy metabolism. However, these effects of ghrelin in the lateral parabrachial nucleus (LPBN) are unexplored. C57BL/6J mice and GHSR−/− mice were implanted with cannula above the right LPBN and ghrelin was microinjected via the cannula to investigate effect of ghrelin in the LPBN. In vivo electrophysiological technique was used to record LPBN glucose-sensitive neurons to explore potential udnderlying mechanisms. Microinjection of ghrelin in LPBN significantly increased food intake in the first 3 h, while such effect was blocked by [D-Lys3]-GHRP-6 and abolished in GHSR−/− mice. LPBN ghrelin microinjection also significantly increased the firing rate of glucose-excited (GE) neurons and decreased the firing rate of glucose-inhibited (GI) neurons. Additionally, LPBN ghrelin microinjection also significantly increased c-fos expression. Chronic ghrelin administration in the LPBN resulted in significantly increased body weight gain. Meanwhile, no significant changes were observed in both mRNA and protein expression levels of UCP-1 in BAT. These results demonstrated that microinjection of ghrelin in LPBN could increase food intake through the interaction with growth hormone secretagogue receptor (GHSR) in C57BL/6J mice, and its chronic administration could also increase body weight gain. These effects might be associated with altered firing rate in the GE and GI neurons.
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Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, Hunan, China
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Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, Hunan, China
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Objective
Ghrelin regulates body weight, food intake, and blood glucose. It also regulates insulin secretion from pancreatic islet cells. LEAP2 is a newly discovered endogenous ligand of the growth hormone secretagogue’s receptor (GHSR). It not only antagonizes the stimulation of GHSR by ghrelin but also inhibits the constitutive activation of GHSR as an inverse agonist. Type 2 diabetes (T2D) patients have endocrine disorders with metabolic imbalance. Plasma levels of ghrelin and LEAP2 may be changed in obese and T2D patients. However, there is no report yet on circulating LEAP2 levels or ghrelin/LEAP2 ratio in T2D patients. In this study, fasting serum ghrelin and LEAP2 levels in healthy adults and T2D patients were assessed to clarify the association of two hormones with different clinical anthropometric and metabolic parameters.
Design
A total of 16 females and 40 males, ages 23–68 years old normal (n = 27), and T2D patients (n = 29) were enrolled as a cross-sectional cohort.
Results
Serum levels of ghrelin were lower but serum levels of LEAP2 were higher in T2D patients. Ghrelin levels were positively correlated with fasting serum insulin levels and HOMA-IR in healthy adults. LEAP2 levels were positively correlated with age and hemoglobin A1c (HbA1c) in all tested samples. Ghrelin/LEAP2 ratio was negatively correlated with age, fasting blood glucose, and HbA1c.
Conclusions
This study demonstrated a decrease in serum ghrelin levels and an increase in serum LEAP2 levels in T2D patients. LEAP2 levels were positively correlated with HbA1c, suggesting that LEAP2 was associated with T2D development. The ghrelin/LEAP2 ratio was closely associated with glycemic control in T2D patients showing a negative correlation with glucose and HbA1c.
INSERM, University of Rouen, Department of Endocrinology, Departments of Endocrinology, Pathology, Department of Pathology, Department of Endocrinology, INSERM, U982, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Institute for Research and Innovation in Biomedicine, Mont‐Saint‐Aignan, France
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INSERM, University of Rouen, Department of Endocrinology, Departments of Endocrinology, Pathology, Department of Pathology, Department of Endocrinology, INSERM, U982, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Institute for Research and Innovation in Biomedicine, Mont‐Saint‐Aignan, France
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INSERM, University of Rouen, Department of Endocrinology, Departments of Endocrinology, Pathology, Department of Pathology, Department of Endocrinology, INSERM, U982, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Institute for Research and Innovation in Biomedicine, Mont‐Saint‐Aignan, France
INSERM, University of Rouen, Department of Endocrinology, Departments of Endocrinology, Pathology, Department of Pathology, Department of Endocrinology, INSERM, U982, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Institute for Research and Innovation in Biomedicine, Mont‐Saint‐Aignan, France
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INSERM, University of Rouen, Department of Endocrinology, Departments of Endocrinology, Pathology, Department of Pathology, Department of Endocrinology, INSERM, U982, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Institute for Research and Innovation in Biomedicine, Mont‐Saint‐Aignan, France
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INSERM, University of Rouen, Department of Endocrinology, Departments of Endocrinology, Pathology, Department of Pathology, Department of Endocrinology, INSERM, U982, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Institute for Research and Innovation in Biomedicine, Mont‐Saint‐Aignan, France
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Hirsutism induced by hyperandrogenism can be associated with polycystic ovary syndrome, 21-hydroxylase (OH) deficiency or androgen-secreting tumors, including ovarian and adrenal tumors. Adrenal androgen-secreting tumors are frequently malignant. Adrenal oncocytomas represent rare causes of hyperandrogenism. The aim of the study was to investigate steroidogenic enzyme expression and steroid secretion in an androgen-secreting adrenal oncocytoma in a young woman presenting with hirsutism. Hyperandrogenism was diagnosed on the basis of elevated plasma Δ4-androstenedione and testosterone levels. Pelvic ultrasound was normal, CT scanning revealed a right adrenal mass. Androgens were assessed in adrenal and ovarian vein samples and proved a right adrenal origin. Adrenalectomy normalized androgen levels and the adrenal tumor was diagnosed as an oncocytoma. Real time-PCR, immunohistochemistry and cell culture studies were performed on tumor explants to investigate the steroid secretion profile. Among enzymes required for cortisol synthesis, 17α-OH and 3β-hydroxysteroid dehydrogenase 2 (3β-HSD2) were highly expressed whereas 21-OH and 11β-OH were weakly produced at the mRNA and/or protein levels. Enzymes involved in testosterone production, 17β-HSD5 and 17β-HSD3, were also detected. ACTH receptor was present in the tissue. Cortisol, Δ4-androstenedione and testosterone secretions by cultured cells were increased by ACTH. These results provide the first demonstration, to our knowledge, of abnormal expression profile of steroidogenic enzymes in an adrenocortical oncocytoma. Our results also indicate that Δ4-androstenedione hypersecretion resulted from high 17α-OH and 3β-HSD2 expression in combination with low expression of 21-OH and 11β-OH. Testosterone production was ascribed to occurrence of 17β-HSD5 and 17β-HSD3. Finally, our results indicate that androgen secretion was stimulated by ACTH.
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Diabetes Centre, Departments of Internal Medicine, General Practice, Langerhans Medical Research Group, Department of Internal Medicine, Division of Cell Biology, Faculty of Health Sciences, Isala Clinics, PO Box 10400, 8000 G.K. Zwolle, The Netherlands
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Diabetes Centre, Departments of Internal Medicine, General Practice, Langerhans Medical Research Group, Department of Internal Medicine, Division of Cell Biology, Faculty of Health Sciences, Isala Clinics, PO Box 10400, 8000 G.K. Zwolle, The Netherlands
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Diabetes Centre, Departments of Internal Medicine, General Practice, Langerhans Medical Research Group, Department of Internal Medicine, Division of Cell Biology, Faculty of Health Sciences, Isala Clinics, PO Box 10400, 8000 G.K. Zwolle, The Netherlands
Diabetes Centre, Departments of Internal Medicine, General Practice, Langerhans Medical Research Group, Department of Internal Medicine, Division of Cell Biology, Faculty of Health Sciences, Isala Clinics, PO Box 10400, 8000 G.K. Zwolle, The Netherlands
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Diabetes Centre, Departments of Internal Medicine, General Practice, Langerhans Medical Research Group, Department of Internal Medicine, Division of Cell Biology, Faculty of Health Sciences, Isala Clinics, PO Box 10400, 8000 G.K. Zwolle, The Netherlands
Diabetes Centre, Departments of Internal Medicine, General Practice, Langerhans Medical Research Group, Department of Internal Medicine, Division of Cell Biology, Faculty of Health Sciences, Isala Clinics, PO Box 10400, 8000 G.K. Zwolle, The Netherlands
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Diabetes Centre, Departments of Internal Medicine, General Practice, Langerhans Medical Research Group, Department of Internal Medicine, Division of Cell Biology, Faculty of Health Sciences, Isala Clinics, PO Box 10400, 8000 G.K. Zwolle, The Netherlands
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In type 1 diabetes mellitus (T1DM), low concentrations of IGF1 and high concentrations of IGF-binding protein 1 (IGFBP1) have been reported. It has been suggested that these abnormalities in the GH–IGF1 axis are due to low insulin concentrations in the portal vein. We hypothesized that the i.p. route of insulin administration increases IGF1 concentrations when compared with the s.c. route of insulin administration. IGF1 and IGFBP1 concentrations in samples derived from an open-label, randomized cross-over trial comparing the effects of s.c. and i.p. insulin delivery on glycaemia were determined. T1DM patients were randomized to receive either 6 months of continuous i.p. insulin infusion (CIPII) through an implantable pump (MIP 2007C, Medtronic) followed by 6 months of s.c. insulin infusion or vice versa with a washout phase in between. Data from 16 patients who had complete measurements during both treatment phases were analysed. The change in IGF1 concentrations during CIPII treatment was 10.4 μg/l (95% CI −0.94, 21.7 μg/l; P=0.06) and during s.c. insulin treatment was −2.2 μg/l (95% CI −13.5, 9.2 μg/l; P=0.69). When taking the effect of treatment order into account, the estimated change in IGF1 concentrations was found to be 12.6 μg/l (95% CI −3.1, 28.5 μg/l; P=0.11) with CIPII treatment compared with that with s.c. insulin treatment. IGFBP1 concentrations decreased to −100.7 μg/l (95% CI −143.0, −58.3 μg/l; P<0.01) with CIPII treatment. During CIPII treatment, parts of the GH–IGF1 axis changed compared with that observed during s.c. insulin treatment. This supports the hypothesis that the i.p. route of insulin administration is of importance in the IGF1 system.
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Purpose
To evaluate the clinical characteristics and prognostic factors in patients with adrenocortical carcinoma (ACC) in South Korea.
Methods
A nationwide, registry-based survey was conducted to identify pathologically proven ACC at 25 tertiary care centers in South Korea between 2000 and 2014. Cox proportional hazard model and log-rank test were adopted for survival analysis.
Results
Two hundred four patients with ACC were identified, with a median follow-up duration of 20 months (IQR 5–52 months). The median age at diagnosis was 51.5 years (IQR 40–65.8 years), and ACC was prevalent in women (n = 110, 53.9%). Abdominal pain was the most common clinical symptom (n = 70, 40.2%), and ENSAT stage 2 was most common (n = 62, 30.4%) at the time of diagnosis. One hundred sixty-nine patients underwent operation, while 17 were treated with other modalities. The remission rate was 48%, and median recurrence-free survival time was 46 months. Estimated 5-year recurrence-free rate was 44.7%. There were more women, large tumor, atypical mitosis, venous invasion, and higher mitotic count in cancer recurrence group. Estimated 5-year overall survival and disease-specific survival rates were 64.5 and 70.6%, respectively. Higher ENSAT stage and advanced pathologic characteristics were risk factors for all-cause mortality of ACC. Large tumor size and cortisol-secreting tumor were additional risk factors for ACC-specific death.
Conclusions
We report the first epidemiologic study regarding ACC in an Asian population. ENSAT stage 4; lymph node involvement; non-operative group; and invasion of vein, sinusoid, or capsule were associated with an increased risk for all-cause mortality.
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Purpose
Chromogranin A (CgA) and neuron-specific enolase (NSE) are important markers for neuroendocrine tumors; however, the clinical value of combining these markers has not been well studied. In this study, we investigated the utility of each marker individually and in combination for patients with nonfunctional pancreatic neuroendocrine tumors (NF-pNETs).
Patients and Methods
In this study, NF-pNET patients and controls were recruited from December 2011 to March 2016; 784 serum samples from peripheral vein were collected. The clinical characteristics and biomarker values of all the individuals were recorded and analyzed. Tumor burdens were calculated by CT/MRI scan. Receiver-operating characteristic curves were constructed to assess the diagnostic predictive values; sensitivity and specificity were calculated to determine the cut-off value. Therapeutic responses reflected on the changes of the biomarkers’ concentration were assessed by the RECIST criterion. Clinical relations between the prognosis and the biomarker values were also analyzed. Statistical significance was defined as P value less than 0.05.
Results
Among the 167 NF-pNETs patients, 82 were males (49.1%) and the mean age was 50.0 (17.4). The mean CgA values of G1, G2 and G3 NF-pNENs were 75, 121 and 134 μg/L (P < 0.05), respectively. In NF-pNETs, CgA correlated with the WHO tumor grade (WHO G1 vs G2, P < 0.05); the linear regression relationships were found between the tumor burdens (both in pancreas and liver) and CgA concentration (P < 0.001); changes in CgA and NSE concentrations also reflect treatment response (P < 0.001).
Conclusion
CgA and NSE are important diagnostic and follow-up markers in patients with NF-pNETs. The combined monitoring of CgA and NSE possesses more accuracy than individual values of CgA and NSE at predicting prognosis and disease progression.
Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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Department of Clinical Biochemistry, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
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Department of Clinical Biochemistry, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
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Department of Pediatrics, Copenhagen University Hospital - Herlev & Gentofte, Copenhagen, Denmark
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Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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Repeated blood sampling is required in certain clinical and research settings, which is currently performed by drawing blood from venous catheters requiring manual handling of each sample at the time of collection. A novel body-worn device for repeated serial samples, Fluispotter®, with automated extraction, collection, and storage of up to 20 venous dried blood spot samples over the course of 20 h may overcome problems with current methods for serial sampling. The purpose of this study was to assess the performance and safety of Fluispotter for the first time in healthy subjects. Fluispotter consists of a cartridge with tubing, a reservoir for flushing solution, pumps and filterpaper, and a multi-lumen catheter placed in the brachial vein. We recruited healthy subjects for testing in an in-hospital setting. Fluispotter was attached by an anesthesiologist to 22 healthy subjects of which 9/22 (40.9%) participants had all 20 samples taken, which was lower than the goal of complete sampling in 80% of the subjects (P = 0.02). The main reason for sample failure was clogging of blood flow which was observed in 11/22 (50%) of the participants. No serious adverse events occurred, and the participants rated the pain from the insertion and the removal of catheter as very low. A cortisol profile showed nadir values at midnight and highest values at 05:00 h. Although full sampling was not successful in all participants, the Fluispotter technology proved safe and highly acceptable to the participants producing the expected cortisol profile without the requirement of staff during sample collection.
Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
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University Rehabilitation Institute, Ljubljana, Slovenia
FAMNIT, University of Primorska, Koper, Slovenia
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Clinical Institute of Radiology, University Medical Centre Ljubljana, Ljubljana, Slovenia
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Clinical Institute of Radiology, University Medical Centre Ljubljana, Ljubljana, Slovenia
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The 20-point clinical prediction SPACE score, the aldosterone-to-lowest potassium ratio (APR), aldosterone concentration (AC) and the AC relative reduction rate after saline infusion test (SIT) have recently been proposed for primary aldosteronism (PA) subtyping prior to adrenal vein sampling (AVS). To validate those claims, we performed a retrospective cross-sectional study that included all patients at our center who had positive SIT to confirm PA and were diagnosed with either bilateral disease (BPA) according to AVS or with lateralized disease (LPA) if biochemically cured after adrenalectomy from November 2004 to the end of 2019. Final diagnoses were used to evaluate the diagnostic performance of proposed clinical prediction tools. Our cohort included 144 patients (40 females), aged 32–72 years (mean 54 years); 59 with LPA and 85 with BPA. The originally suggested SPACE score ≤8 and SPACE score >16 rules yielded about 80% positive predictive value (PPV) for BPA and LPA, respectively. Multivariate analyses with the predictors constituting the SPACE score highlighted post-SIT AC as the most important predictor of PA subtype for our cohort. APR-based tool of <5 for BPA and >15 for LPA yielded about 75% PPV for LPA and BPA. The proposed post-SIT AC <8.79 ng/dL criterion yielded 41% sensitivity and 90% specificity, while the relative post-SIT AC reduction rate of >33.8% criterion yielded 80% sensitivity and 51% specificity for BPA prediction. The application of any of the validated clinical prediction tools to our cohort did not predict the PA subtype with the high diagnostic performance originally reported.
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Objective
This study aimed to reveal associations between metabolic hormones in cerebral spinal fluid (CSF) and cigarette smoking-induced weight gain and to explore the underlying mechanism.
Methods
A total of 156 adult men were included, comprising active smokers and nonsmokers. In addition to demographic information and body mass index (BMI), plasma levels of ApoA1 and ApoB, high-density lipoprotein, low-density lipoprotein, cholesterol, triglyceride, alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase in the participants were measured. Moreover, the metabolic hormones adiponectin, fibroblast growth factor 21 (FGF21), ghrelin, leptin, and orexin A, as well as the trace elements iron and zinc in CSF, were assessed.
Results
Compared to nonsmokers, active smokers showed higher BMI, and elevated CSF levels of FGF21, Zn, and Fe, but decreased levels of metabolic hormones adiponectin, ghrelin, leptin, and orexin A. Negative correlations existed between CSF FGF21 and ghrelin, between CSF Zn and ghrelin, as well as between CSF Fe and orexin A in active smokers. Furthermore, elevated CSF FGF21 and Zn predicted ghrelin level decrease in the smokers.
Conclusion
These data relate smoking-induced weight gain to its neurotoxic effect on the neurons that synthesize metabolic hormones such as adiponectin, ghrelin, leptin, or orexin A in the brain, by disrupting mitochondrial function and causing oxidative stress in the neurons.
