Purpose: Fibroblast growth factor (FGF) 21 is a circulating hormone with metabolic regulatory importance. In mice, FGF21 increases in response to a ketogenic diet and fasting. In humans, a similar increase is only observed after prolonged starvation. We aim to study the acute effects of ketone bodies on circulating FGF21 levels in humans.
Methods: Participants from three randomized, placebo-controlled crossover studies, with increased endogenous or exogenous ketone bodies, were included. Study 1: patients with type 1 diabetes (T1D) (n = 9) were investigated after a) insulin deprivation and lipopolysaccharide (LPS) injection and b) insulin-controlled euglycemia. Study 2: patients with T1D (n = 9) were investigated after a) total insulin deprivation for 9 hours and b) insulin-controlled euglycemia. Study 3: Healthy adults (n = 9) were examined during a) 3-hydroxybutyrate (OHB) infusion and b) saline infusion. Plasma FGF21 was measured with immunoassay in serial samples.
Results: Circulating OHB levels were significantly increased to 1.3, 1.5, and 5.5 mmol/l in the three studies, but no correlations with FGF21 levels were found. Also, no correlations between FGF21, insulin, or glucagon were found. Insulin deprivation and LPS injection resulted in increased plasma FGF21 levels at t = 120 min (p = .005) which normalized at t = 240 min.
Conclusion: We found no correlation between circulating FGF21 levels and levels of ketone bodies. This suggests that it is not ketosis per se which controls FGF21 production, but instead a rather more complex regulatory mechanism.
Trial registration: clinicaltrials.gov ID number: Study 1: NCT02157155 (5/6-2014), study 2: NCT02077348 (4/3-2014), and study 3: NCT02357550 (6/2-2015).
Introduction: To determine age and sex-specific thyrotropin (TSH) and free thyroxine (FT4) reference ranges according to body mass index (BMI) categories. Methods: With regards to the National Academy of Clinical Biochemistry (NACB) criteria, a total of 2818 individuals from the Tehran Thyroid Study population was selected and categorized in three BMI groups. Results: TSH levels did not differ significantly between BMI groups (p = .054). Females had statistically higher TSH levels than males in all BMI categories (p < .001). According to age-specific analyses, the youngest category (20-29 years) had the highest median values of serum TSH in all BMI groups. With increasing BMI, the 2.5th percentile of TSH remained approximately unchanged and the 97.5th percentile showed an increasing pattern. FT4 level was significantly higher in the normal weight group compared to obese individuals (p < .001); females had significantly lower FT4 levels than males in normal weight and obese groups (p < .001). According to age categories, the youngest group (20-29 years) had higher levels of FT4 than the elderly group in all BMI categories. A decreasing pattern in both 2.5th and 97.5th percentiles of FT4 was observed along with increasing BMI. Conclusions: Compared to the normal weight population, obese individuals have slightly lower FT4 concentrations accompanied by similar TSH levels. With increasing BMI, upper limits of TSH and FT4 show increasing and decreasing patterns, respectively.
Background: The novel coronavirus (SARS CoV-2) has caused significant morbidity and mortality in patients with diabetes. However, the effects of diabetes control including insulin use remain uncertain in terms of clinical outcomes of patients with COVID-19.Methods: In this single-center, retrospective observational study, all adult patients admitted to Einstein Medical Center, Philadelphia, from March 1 through April 24, 2020 with a diagnosis of COVID-19 and diabetes were included. Demographic, clinical and laboratory data, insulin dose at home and at the hospital, other anti-hyperglycemic agents use, and outcomes were obtained. Multivariate logistic regression was used to evaluate the factors associated with diabetes control and mortality.Results: Patients who used insulin at home had higher mortality compared to those who did not (35% vs 18% p = .015), this was true even after adjustment for demographics, comorbidities and a1c OR 2.65 95% CI (1.23-5.71) p = .013. However, the mean a1c and the median home requirements of insulin did not significantly differ among patients who died compared to the ones that survived. Patients who died had significantly higher inpatient insulin requirements (highest day insulin requirement recorded in units during hospitalization) 36 (11-86) vs 21 (8-52) p = .043 despite similar baseline a1c and steroid doses received. After adjusting for demographics, comorbidities and a1c, peak insulin requirements remained significantly associated with inpatient mortality OR 1.022 95% CI (1.00-1.04) p = .044.Conclusion: Among diabetic patients infected with COVID-19, insulin therapy at home was significantly independently associated with increased mortality. Peak daily inpatient insulin requirements was also independently associated with increased inpatient mortality.
Context: Populations severely affected by COVID-19 are also at risk for vitamin D deficiency. Common risk factors include older age, chronic illness, obesity, and non-Caucasian race. Vitamin D deficiency has been associated with risk for respiratory infections and failure, susceptibility and response to therapy for enveloped virus infection, and immune-mediated inflammatory reaction.Objective: To test the hypothesis that 25-hydroxyvitamin D[25(OH)D] deficiency is a risk factor for severity of COVID-19 respiratory and inflammatory complications.Design: We examined the relationship between prehospitalization 25(OH)D levels (obtained 1-365 days prior to admission) and COVID-19 clinical outcomes in 700 COVID-19 positive hospitalized patients.Primary Outcomes: Discharge status, mortality, length of stay, intubation status, renal replacement.Secondary Outcomes: Inflammatory markers.Results: 25(OH)D levels were available in 93 patients [25(OH)D:25(IQR:17-33)ng/mL]. Compared to those without 25(OH)D levels, those with measurements did not differ in age, BMI or distribution of sex and race, but were more likely to have comorbidities. Those with 25(OH)D < 20 ng/mL (n = 35) did not differ from those with 25(OH)D ≥ 20 ng/mL in terms of age, sex, race, BMI, or comorbidities. Low 25(OH)D tended to be associated with younger age and lower frequency of preexisting pulmonary disease. There were no significant between-group differences in any outcome. Results were similar in those ≥50 years, in male/female-only cohorts, and when differing 25(OH)D thresholds were used (<15 ng/mL and <30 ng/mL). There was no relationship between 25(OH)D as a continuous variable and any outcome, even after controlling for age and pulmonary disease.Conclusions: These preliminary data do not support a relationship between prehospitalization vitamin D status and COVID-19 clinical outcomes.
The vagus nerve and the celiaco-mesenteric ganglia (CMG) are required for reduction of meal size (MS) and prolongation of the intermeal interval (IMI) by intraperitoneal (ip) sulfated cholecystokinin-8 (CCK-8). However, recently we have shown that the gut regulates these responses. Therefore, reevaluating the role of the vagus and the CMG in the feeding responses evoked by CCK is necessary because the gut contains the highest concentration of enteric, vagal and splanchnic afferents and CCK-A receptors, which are required for reduction of food intake by this peptide, compared to other abdominal organs. To address this necessity, we injected sulfated CCK-8 (0, 0.1, 0.5, 1 and 3 nmol/kg) in the aorta, near the gastrointestinal sites of action of the peptide, in three groups of free-feeding rats (n = 10 rats per group), subdiaphragmatic vagotomy (VGX), celiaco-mesenteric ganglionectomy (CMGX) and sham-operated, and recorded seven feeding responses. In the sham group, CCK-8 reduced MS (normal chow), prolonged the intermeal interval (IMI, time between first and second meals), increased satiety ratio (SR, IMI/MS), shortened duration of first meal, reduced total (24 hrs) food intake and reduced number of meals relative to saline vehicle. Vagotomy attenuated all of the previous responses except IMI length and SR, and CMGX attenuated all of those responses. In conclusion, the feeding responses evoked by sulfated CCK-8 require, independently, the vagus nerve and the CMG.
Aims: To test the hypothesis that in non-diabetic patients with early-stage chronic kidney disease (CKD), the renal excretion of urate and glucose transportation are coupled and interconnected. Methods: A cross-sectional study of 255 non-diabetic participants with stage 1-2 CKD recruited from our department was conducted. Spearman's correlation and multiple linear regression analyses were used to study the correlation between urinary glucose and renal uric acid excretion. ANOVA was used to compare urinary uric acid excretion among three tertiles of urinary glucose (UG; UG1: UG<0.24 mmol/24 h/1.73 m2, UG2: 0.24 mmol/24 h/1.73 m2≤ UG≤0.55 mmol/24 h/1.73 m2, and UG3: UG>0.55 mmol/24 h/1.73 m2), the fractional excretion of glucose (FEG; FEG1: FEG<0.04%, FEG2: 0.04%≤FEG≤0.09%, and FEG3: FEG>0.09%) and the excretion of glucose per volume of glomerular filtration (EgGF; EgGF1: EgGF<1.95 μmol/L, EgGF2: 1.95 μmol/L≤ EgGF≤3.99 μmol/L, and EgGF3: EgGF>3.99 μmol/L). Results: According to the multiple linear regression analysis, FEG and EgGF were positively correlated with the excretion of uric acid per volume of glomerular filtration (EurGF) after adjusting for confounding factors. The EurGF levels in the highest tertiles of UG, FEG and EgGF were higher than those in the lowest tertiles of UG, FEG and EgGF. Conclusion: Urinary glucose excretion is closely related to renal excretion of uric acid in non-diabetic patients with stage 1-2 CKD.
Purpose: The purpose of the present study was to analyze the impact of the neutrophil-lymphocyte ratio (NLR) on the long-term outcomes of patients with adrenocortical carcinoma (ACC).
Methods: This retrospective, single-institution study included 48 patients with the diagnosis of ACC. The primary outcomes of the study were differences in overall survival (OS) and disease-specific survival (DSS) with respect to the NLR level.
Results: Patients with ENSAT stage IV had higher levels of NLR compared to those with ENSAT stage I-III (5.7 (1.6-12.5) vs 3.3 (1.3-11); p = .01). A higher NLR was also observed among patients with cortisol-secreting tumors (4.6 (1.7-12.5) vs 2.8 (1.3-10.3); p = .003) and those with Ki-67 index >10% (4.3 (1.3-12.5) vs 2.6 (1.6-11.0); p = .005). With respect to survival, the univariate analysis revealed worse ACC-related survival (p = .02) and OS (p = .004) in patients with NLR >3.9 than in those with NLR ≤3.9. In addition, patients with NLR >3.9 had a higher Weiss score (p = .046), a higher Ki-67 index (p = .006) and a higher disease stage (p = .01) compared to patients with NLR ≤3.9. No differences between the groups were observed regarding excess glucocorticoid secretion.
Conclusion: The study demonstrated that a higher NLR level in ACC patients was associated with unfavorable outcomes in terms of DSS and OS. These results indicate that NLR might be used as an additional marker in ACC risk stratification and identification of patients with the most adverse prognosis.
Background: Chronic kidney disease and hypoglycemia are common complications in individuals with diabetes. Currently, the association of renal function with hypoglycemic complications in type 2 diabetes mellitus (T2DM) is inconclusive. This study aims to assess the associations between estimated glomerular filtration rate (eGFR) and cumulative incidence of hypoglycemia, hypoglycemia-related hospitalizations, and incidence of outpatient hypoglycemia among T2DM patients in Thailand using a nationwide patient sample.
Methods: We conducted a nationwide retrospective cohort study based on the DM/HT study of the Medical Research Network of the Consortium of Thai Medical Schools. This study assessed adult T2DM patients from 831 public hospitals in Thailand in the year 2012-2013. eGFR was categorized into ≥90, 60-89, 30-59, 15-29, and <15 mL/min/1.73 m2. The associations between eGFR and hypoglycemia, hypoglycemia-related hospitalizations, and incidence of outpatient hypoglycemia were assessed using multivariate logistic regression and Poisson regression.
Results: A total of 25,056 T2DM patients with available eGFR were included in the analysis. The mean age was 60.9 ± 10.5 years. The cumulative incidence of hypoglycemia and hypoglycemia-related hospitalizations was 3.6% and 1.7%, respectively. Incidence of outpatient hypoglycemia, mild hypoglycemia, and severe hypoglycemia was 2.99 (2.59-3.43), 2.47 (2.11-2.88), and 0.52 (0.36-0.72) per 100 patient-years, respectively. Patients with eGFR of 30-59, 15-29, and <15 mL/min/1.73 m2 were significantly associated with an increased risk of hypoglycemia, hypoglycemia-related hospitalizations, and incidence of outpatient hypoglycemia when compared to patients with eGFR of ≥90 mL/min/1.73 m2.
Conclusion: Reduced eGFR was independently associated with increased hypoglycemia, hypoglycemia-related hospitalizations, and risk of outpatient hypoglycemia. Increasing awareness of the heightened risk of hypoglycemia with declining renal function may prompt changes to diabetic management for at-risk individuals.
Background: Various factors can affect incidence of thyroid disorders and disease profiles may show abrupt changes in endemic goitrous areas. In this study, it was aimed to analyze the American College of Radiology (ACR) Thyroid Imaging Reporting and Data System (TI-RADS) and the Bethesda System for Reporting Thyroid Cytopathology (BSRTC) in terms of risk of malignancy and general recommendations in an endemic goiter region (EGR).
Methods: In this retrospective study, a total of 500 patients who had thyroidectomy following thyroid fine needle aspiration biopsy were enrolled. For the assessment of thyroid cytology, BSRTC was used and for the evaluation of ultrasound features of thyroid nodules, ACR TIRADS lexicon was adopted. For the assessment of thyroid cytology, Bethesda classification was used and for the evaluation of ultrasound features of thyroid nodules, ACR TIRADS lexicon was adopted.
Results: In the EGR setting, benign category of BSRTC had a cancer risk of 6.2% which was two times more than the 2017 BSRTC revision reported. Nodules 10-14.9 mm in diameter had nearly 4 times higher malignancy risk than nodules >15 mm. In this group of patients, the risk of malignancy for TIRADS level 1, 2, 3, 4 and 5 was 1.16%, 2.94%, 7%, 45.64% and 94.44%, respectively. The malignancy rates for Bethesda system category I, II, III, IV, V and VI were as follows: 14.43%, 6.2%, 19.05%, 36.73%, 75.68% and 100%.
Conclusions: There are slight differences between the common set of standards and this study results regarding risk of malignancy. This brings up the question whether there is need for revision for the use of categories and the appropriate management in endemic goiter regions.
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