Early-phase insulin secretion during mixed-meal tolerance testing predicts ß-cell function and secretory capacity in cystic fibrosis.

Insulin secretion within 30 minutes of nutrient ingestion is reduced in people with cystic fibrosis (PwCF) and pancreatic insufficiency and declines with worsening glucose tolerance. The glucose potentiated arginine (GPA) test is validated for quantifying ß-cell secretory capacity as an estimate of functional ß-cell mass but requires technical expertise and is burdensome. This study sought to compare insulin secretion during mixed-meal tolerance testing (MMTT) to GPA-derived parameters in PwCF. Methods: Secondary data analysis of CF-focused prospective studies was performed in PwCF categorized as 1) pancreatic insufficient [PI-CF] or 2) pancreatic sufficient [PS-CF] and in 3) non-CF controls. MMTT: insulin secretory rates (ISR) were derived by parametric deconvolution using 2-compartment model of C-peptide kinetics, and incremental area under the curve (AUC) was calculated for 30, 60 and 180-minutes. GPA: acute insulin (AIR) and C-peptide responses (ACR) were calculated as average post-arginine insulin or C-peptide response minus pre-arginine insulin or C-peptide under fasting (AIRarg and ACRarg), ~230 mg/dL (AIRpot and ACRpot), and ~340 mg/dL (AIRmax and ACRmax) hyperglycemic clamp conditions. Relationships of MMTT to GPA parameters were derived using Pearson's correlation coefficient. Predicted values were generated for MMTT ISR and compared to GPA parameters using Bland Altman analysis to assess degree of concordance. Results: 85 PwCF (45 female; 75 PI-CF and 10 PS-CF) median (range) age 23 (6-56) years with BMI 23 (13-34) kg/m2, HbA1c 5.5 (3.8-10.2)%, and FEV1%-predicted 88 (26-125) and 4 non-CF controls of similar age and BMI were included. ISR AUC30min positively correlated with AIRarg (r=0.55), AIRpot (r=0.62), and AIRmax (r=0.46) and with ACRarg (r=0.59), ACRpot (r=0.60), and ACRmax (r=0.51) (all P<0.001). ISR AUC30min strongly predicted AIRarg (concordance=0.86), AIRpot (concordance=0.89), and AIRmax (concordance=0.76) at lower mean GPA values, but underestimated AIRarg, AIRpot, and AIRmax at higher GPA-defined ß-cell secretory capacity. Between test agreement was unaltered by adjustment for study group, OGTT glucose category, and BMI. Conclusion: Early-phase insulin secretion during MMTT can accurately predict GPA-derived measures of ß-cell function and secretory capacity when functional ß-cell mass is reduced. These data can inform future multicenter studies requiring reliable, standardized, and technically feasible testing mechanisms to quantify ß-cell function and secretory capacity.

Preservation of ß-cell Function in Pancreatic Insufficient Cystic Fibrosis With Highly Effective CFTR Modulator Therapy.

CONTEXT: Elexacaftor/tezacaftor/ivacaftor (ETI; Trikafta) enhances aberrant cystic fibrosis transmembrane conductance regulator function and may improve the insulin secretory defects associated with a deterioration in clinical outcomes in pancreatic insufficient cystic fibrosis (PI-CF). OBJECTIVE: This longitudinal case-control study assessed changes in ß-cell function and secretory capacity measures over 2 visits in individuals with PI-CF who were initiated on ETI after the baseline visit (2012-2018) and (1) restudied between 2019 and 2021 (ETI group) vs (2) those restudied between 2015 and 2018 and not yet treated with cystic fibrosis transmembrane conductance regulator modulator therapy (controls). METHODS: Nine ETI participants (mean ± SD age, 25 ± 5 years) and 8 matched controls were followed up after a median (interquartile range) 5 (4-7) and 3 (2-3) years, respectively (P < .01), with ETI initiation a median of 1 year before follow-up. Clinical outcomes, glucose-potentiated arginine, and mixed-meal tolerance test measures were assessed with comparisons of within- and between-group change by nonparametric testing. RESULTS: Glucose-potentiated insulin and C-peptide responses to glucose-potentiated arginine deteriorated in controls but not in the ETI group, with C-peptide changes different between groups (P < .05). Deterioration in basal proinsulin secretory ratio was observed in controls but improved, as did the maximal arginine-induced proinsulin secretory ratio, in the ETI group (P < .05 for all comparisons). During mixed-meal tolerance testing, early insulin secretion improved as evidenced by more rapid insulin secretory rate kinetics. CONCLUSION: ETI preserves ß-cell function in CF through effects on glucose-dependent insulin secretion, proinsulin processing, and meal-related insulin secretion. Further work should determine whether early intervention with ETI can prevent deterioration of glucose tolerance in PI-CF.

Bone metabolism and incretin hormones following glucose ingestion in young adults with pancreatic insufficient cystic fibrosis.

Background: Gut-derived incretin hormones, including glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 (GLP-1), regulate post-prandial glucose metabolism by promoting insulin production. GIP, GLP-1, and insulin contribute to the acute bone anti-resorptive effect of macronutrient ingestion by modifying bone turnover. Cystic fibrosis (CF) is associated with exocrine pancreatic insufficiency (PI), which perturbs the incretin response. Cross-talk between the gut and bone ("gut-bone axis") has not yet been studied in PI-CF. The objectives of this study were to assess changes in biomarkers of bone metabolism during oral glucose tolerance testing (OGTT) and to test associations between incretins and biomarkers of bone metabolism in individuals with PI-CF. Methods: We performed a secondary analysis of previously acquired blood specimens from multi-sample OGTT from individuals with PI-CF ages 14-30 years (n = 23). Changes in insulin, incretins, and biomarkers of bone resorption (C-terminal telopeptide of type 1 collagen [CTX]) and formation (procollagen type I N-terminal propeptide [P1NP]) during OGTT were computed. Results: CTX decreased by 32% by min 120 of OGTT (P < 0.001), but P1NP was unchanged. Increases in GIP from 0 to 30 mins (rho = -0.48, P = 0.03) and decreases in GIP from 30 to 120 mins (rho = 0.62, P = 0.002) correlated with decreases in CTX from mins 0-120. Changes in GLP-1 and insulin were not correlated with changes in CTX, and changes in incretins and insulin were not correlated with changes in P1NP. Conclusions: Intact GIP response was correlated with the bone anti-resorptive effect of glucose ingestion, represented by a decrease in CTX. Since incretin hormones might contribute to development of diabetes and bone disease in CF, the "gut-bone axis" warrants further attention in CF during the years surrounding peak bone mass attainment.

Effects of GLP-1 and GIP on Islet Function in Glucose-Intolerant, Pancreatic-Insufficient Cystic Fibrosis.

Impaired insulin and incretin secretion underlie abnormal glucose tolerance (AGT) in pancreatic insufficient cystic fibrosis (PI-CF). Whether the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) can enhance pancreatic islet function in cystic fibrosis (CF) is not known. We studied 32 adults with PI-CF and AGT randomized to receive either GLP-1 (n = 16) or GIP (n = 16) during glucose-potentiated arginine (GPA) testing of islet function on two occasions, with either incretin or placebo infused, in a randomized, double-blind, cross-over fashion. Another four adults with PI-CF and normal glucose tolerance (NGT) and four matched control participants without CF underwent similar assessment with GIP. In PI-CF with AGT, GLP-1 substantially augmented second-phase insulin secretion but without effect on the acute insulin response to GPA or the proinsulin secretory ratio (PISR), while GIP infusion did not enhance second-phase or GPA-induced insulin secretion but increased the PISR. GIP also did not enhance second-phase insulin in PI-CF with NGT but did so markedly in control participants without CF controls. These data indicate that GLP-1, but not GIP, augments glucose-dependent insulin secretion in PI-CF, supporting the likelihood that GLP-1 agonists could have therapeutic benefit in this population. Understanding loss of GIP's insulinotropic action in PI-CF may lead to novel insights into diabetes pathogenesis.

Utilization of the Healthy Eating Index in Cystic Fibrosis.

(1) Background: Malnutrition has been a hallmark of cystic fibrosis (CF) for some time, and improved nutritional status is associated with improved outcomes. While individuals with CF historically required higher caloric intake than the general population, new CF therapies and improved health in this population suggest decreased metabolic demand and prevalence of overweight and obesity have increased. This study aimed to (a) examine diet quality in a population of young adults with CF using the Healthy Eating Index, a measure of diet quality in accordance with the U.S. Dietary Guidelines for Americans and (b) evaluate and describe how subcomponents of the HEI might apply to individuals with CF (2) Methods: 3-day dietary recalls from healthy adolescents and young adults with CF were obtained and scored based on the Healthy Eating Index (3) Results: Dietary recalls from 26 (14M/12F) adolescents and young adults with CF (ages 16-23), were obtained. Individuals with CF had significantly lower HEI scores than the general population and lower individual component scores for total vegetables, greens and beans, total fruits, whole fruits, total protein, seafood and plant protein and sodium (p values < 0.01 for all). (4) Conclusion: Dietary quality was poor in these healthy adolescents and young adults with CF. Given the increased prevalence of overweight and obesity in CF, updated dietary guidance is urgently needed for this population. The Healthy Eating Index may be a valuable tool for evaluating dietary quality in CF.

An Outline of Contributing Vaccine Technologies for SARS CoV2 Advancing in Clinical and Preclinical Phase-Trials.

BACKGROUND: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS CoV2) is an RNA virus involving 4 structural and 16 non-structural proteins, and exhibiting high transmission potential and fatality. The emergence of this newly encountered beta coronavirus-SARS CoV2 has brought over 2 million people to death, and more than 10 billion people got infected across the globe as yet. Consequently, the global scientific community has contributed to the synthesis and design of effective immunization technologies to combat this virus. OBJECTIVES: This literature review was intended to gather an update on published reports of the vaccines advancing in the clinical trial phases or preclinical trials, to summarize the foundations and implications of contributing vaccine candidates inferring their impact in the pandemic repression. In addition, this literature review distinctly facilitates an outline of the overall vaccine effectiveness at current doses. METHODS: The reported data in this review was extracted from research articles, review articles and patents published from January 2020 to July 2021, available on Google Scholar, Pubmed, Pubmed Central, Research Gate, Science direct, and Free Patent Online Database by using combination of keywords. Moreover, some information is retrieved from native web pages of vaccine manufacturing companies' due to progressing research and unavailability of published research papers. CONCLUSION: Contributing vaccine technologies include: RNA (Ribonucleic acid) vaccines, DNA (Deoxyribonucleic acid) vaccines, viral vector vaccines, protein-based vaccines, inactivated vaccines, viruses-like particles, protein superglue, and live-attenuated vaccines. Some vaccines are prepared by establishing bacterial and yeast cell lines and as self-assembling adenovirus- derived multimeric protein-based self-assembling nanoparticle (ADDOmer). On May 19, WHO has issued an emergency use sanction of Moderna, Pfizer, Sinopharm, AstraZeneca, and Covishield vaccine candidates on account of clinical credibility from experimental data.

Infant Body Mass Index or Weight-for-Length and Risk of Undernutrition in Childhood Among Children with Cystic Fibrosis.

OBJECTIVES: To compare performance of weight-for-length and body mass index as estimators of undernutrition in children with cystic fibrosis (CF). STUDY DESIGN: We analyzed pediatric anthropometric data from the Cystic Fibrosis Foundation Patient Registry. Undernutrition was defined by weight-for-length z score (WFLZ) or body mass index z score (BMIZ) ≤-1 (15th-percentile). Group 1, reference group, consisted of subjects with both BMIZ and WFLZ >-1; group 2: BMIZ ≤-1 and WFLZ >-1; group 3: BMIZ >-1 and WFLZ ≤-1; and group 4: BMIZ and WFLZ ≤-1. Group differences in length-for-age-Z across ages 2-24 months were tested using generalized estimating equations. The association of group at age 2 months with BMIZ <-1 at age 6 years was tested using logistic regression adjusted for demographic and disease characteristics. RESULTS: Overall, 163 482 anthropometric measurements were available from 12 640 individuals, of whom 16.8% were discordant for undernutrition status at age 2 months. Discordance (1.5%-10%) was less common with increasing age. Length-for-age-Z was lower in group 2 than group 1 and group 3 between birth and 24 months (P < .05). Odds of WFLZ-defined undernourished at 2 months were lower for shorter individuals (OR 1.5, CI 1.4-1.6, P < .001). Undernutrition risk at age 6 years was greater for group 2 vs group 3 (OR 1.9 vs 1.0, P < .001). CONCLUSIONS: Infants with cystic fibrosis classified as undernourished by BMIZ, but not WFLZ, had greater risk of undernourished status later in childhood. Infants with low BMIZ but normal WFLZ tended to be shorter, suggesting BMIZ may better capture undernourished status than WFLZ in shorter infants.

Effect of Sitagliptin on Islet Function in Pancreatic Insufficient Cystic Fibrosis With Abnormal Glucose Tolerance.

PURPOSE: Impaired incretin secretion may contribute to the defective insulin secretion and abnormal glucose tolerance (AGT) that associate with worse clinical outcomes in pancreatic insufficient cystic fibrosis (PI-CF). The study objective was to test the hypothesis that dipeptidyl peptidase-4 (DPP-4) inhibitor-induced increases in intact incretin hormone [glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)] concentrations augment insulin secretion and glucagon suppression and lower postprandial glycemia in PI-CF with AGT. METHODS: 26 adults from Children's Hospital of Philadelphia and University of Pennsylvania CF Center with PI-CF and AGT [defined by oral glucose tolerance test glucose (mg/dL): early glucose intolerance (1-h ≥ 155 and 2-h < 140), impaired glucose tolerance (2-h ≥ 140 and < 200 mg/dL), or diabetes (2-h ≥ 200)] were randomized to a 6-month double-blind trial of DPP-4 inhibitor sitagliptin 100 mg daily or matched placebo; 24 completed the trial (n = 12 sitagliptin; n = 12 placebo). Main outcome measures were mixed-meal tolerance test (MMTT) responses for intact GLP-1 and GIP, insulin secretory rates (ISRs), glucagon suppression, and glycemia and glucose-potentiated arginine (GPA) test-derived measures of ß- and α-cell function. RESULTS: Following 6-months of sitagliptin vs placebo, MMTT intact GLP-1 and GIP responses increased (P < 0.001), ISR dynamics improved (P < 0.05), and glucagon suppression was modestly enhanced (P < 0.05) while GPA test responses for glucagon were lower. No improvements in glucose tolerance or ß-cell sensitivity to glucose, including for second-phase insulin response, were found. CONCLUSIONS: In glucose intolerant PI-CF, sitagliptin intervention augmented meal-related incretin responses with improved early insulin secretion and glucagon suppression without affecting postprandial glycemia.

An Overview of Immune Evasion Strategies of DNA and RNA Viruses.

A successful viral infection is due to the effective evasion of viruses of the immune system. The entry of viruses is usually detected by different cellular receptors including PRRs. Recognition of the viral genome leads to the production of interferons through a signaling stream. This review article provides brief information regarding escape mechanisms of DNA and RNA viruses from the host immune system. These strategies include viral endonuclease activity, cap snatching of host mRNA, the formation of replication organelles, stress granule formation, membrane modifications, action of proteases, and evasion from ISGs. Moreover, the strategies of DNA viruses to inhibit immune responses include subversion of mRNA, transcriptional factors, adaptor proteins, PRRs, evasion from T lymphocytes, genomic diversity, theft or seizure of host defense proteins, imitation of host factors like affecting cytokines and chemokines of the host, suppression or inhibition of apoptosis, and proteasomal degradation of host antiviral proteins by DNA viruses. The knowledge of these mechanisms is pivotal to understanding different methodologies that viruses have created to escape antiviral cellular reactions of the host as well as virus-host interactions and the origin of viral pathogenesis. Also, this knowledge is significant for the design of gene targeting vectors, antiviral vaccines, and the development of effective treatments directed against DNA and RNA viruses.

Genetic potential and height velocity during childhood and adolescence do not fully account for shorter stature in cystic fibrosis.

BACKGROUND: Despite improved health, shorter stature is common in cystic fibrosis (CF). We aimed to describe height velocity (HV) and contribution of height-related genetic variants to height (HT) in CF. METHODS: HV cohort: standard deviation scores (-Z) for HT, mid-parental height-adjusted HT (MPAH), and HV were generated using our Pediatric Center's CF Foundation registry data. HV-Z was compared with population means at each age (5-17 y), the relationship of HV-Z with HT-Z assessed, and HT-Z compared with MPAH-Z. GRS cohort: HT genetic risk-Z (HT-GRS-Z) were determined for pancreatic exocrine sufficient (PS) and insufficient (PI) youth and adults from our CF center and their relationships with HT-Z assessed. RESULTS: HV cohort: average HV-Z was normal across ages in our cohort but was 1.5× lower (p < 0.01) for each SD decrease in HT-Z. MPAH-Z was lower than HT-Z (p < 0.001). GRS cohort: HT-GRS-Z more strongly correlated with HT-Z and better explained height variance in PS (rho = 0.42; R2= 0.25) vs. PI (rho = 0.27; R2 = 0.11). CONCLUSIONS: Despite shorter stature compared with peers and mid-parental height, youth with CF generally have normal linear growth in mid- and late childhood. PI tempered the heritability of height. These results suggest that, in CF, final height is determined early in life in CF and genetic potential is attenuated by other factors. IMPACT: Children with CF remain shorter than their healthy peers despite advances in care. Our study demonstrates that children with CF have persistent shorter stature from an early age and fail to reach their genetic potential despite height velocities comparable to those of average maturing healthy peers and similar enrichment in known height increasing single-nucleotide polymorphisms (SNPs). Genetic risk scores better explained variability in pancreatic sufficient than in pancreatic insufficient individuals, suggesting that other modifying factors are in play for pancreatic insufficient individuals with CF. Given the CF Foundation's recommendation to target not only normal body mass index, but normal height percentiles as well, this study adds valuable insight to this discussion.

Hypoglycemia and Islet Dysfunction Following Oral Glucose Tolerance Testing in Pancreatic-Insufficient Cystic Fibrosis.

CONTEXT: Oral glucose tolerance test (OGTT)-related hypoglycemia is common in pancreatic-insufficient cystic fibrosis (PI-CF), but its mechanistic underpinnings are yet to be established. OBJECTIVE: To delineate the mechanism(s) underlying OGTT-related hypoglycemia. DESIGN AND SETTING: We performed 180-minute OGTTs with frequent blood sampling in adolescents and young adults with PI-CF and compared results with those from a historical healthy control group. Hypoglycemia (Hypo[+]) was defined as plasma glucose <65 mg/dL. We hypothesized that CF-Hypo[+] would demonstrate impaired early phase insulin secretion and persistent late insulin effect compared with control-Hypo[+], and explored the contextual counterregulatory response. MAIN OUTCOME MEASURE: OGTT 1-hour and nadir glucose, insulin, C-peptide, and insulin secretory rate (ISR) incremental areas under the curve (AUC) between 0 and 30 minutes (early) and between 120 and 180 minutes (late), and Δglucagon120-180min and Δfree fatty acids (FFAs)120-180min were compared between individuals with CF and control participants with Hypo[+]. RESULTS: Hypoglycemia occurred in 15/23 (65%) patients with CF (43% female, aged 24.8 [14.6-30.6] years) and 8/15 (55%) control participants (33% female, aged 26 [21-38] years). The CF-Hypo[+] group versus the control-Hypo[+] group had higher 1-hour glucose (197 ± 49 vs 139 ± 53 mg/dL; P = 0.05) and lower nadir glucose levels (48 ± 7 vs 59 ± 4 mg/dL; P < 0.01), while insulin, C-peptide, and ISR-AUC0-30 min results were lower and insulin and C-peptide, and AUC120-180min results were higher (P < 0.05). Individuals with CF-Hypo[+] had lower Δglucagon120-180min and ΔFFA120-180min compared with the control-Hypo[+] group (P < 0.01). CONCLUSIONS: OGTT-related hypoglycemia in PI-CF is associated with elevated 1-hour glucose, impaired early phase insulin secretion, higher late insulin exposure, and less increase in glucagon and FFAs. These data suggest that hypoglycemia in CF is a manifestation of islet dysfunction including an impaired counterregulatory response.

Abnormal glucose tolerance and the 50-gram glucose challenge test in Cystic fibrosis.

Diabetes has emerged as a major co-morbidity in cystic fibrosis (CF). The 75 g oral glucose tolerance test (OGTT) is used to screen for CF-related diabetes (CFRD) but is inconvenient, and adherence to screening is poor. The 50 g glucose challenge test (GCT) is shorter, performed non-fasting, and may serve to pre-screen the subset of individuals requiring confirmatory OGTT. We performed a pilot study in twenty-seven CF individuals across the glucose tolerance spectrum to test whether the GCT could identify subjects with abnormal glucose tolerance defined as 2-h OGTT glucose ≥7.8 mmol/L (2 h-AGT) or 1-h defined as 1-hr OGTT glucose ≥11.1 mmol/L (1 h-AGT). A GCT threshold of 8.1 mmol/L was 73% sensitive and 63% specific for 2hr-AGT and 80% sensitive and 65% specific for 1hr-AGT. Therefore, a screening GCT may reduce need for confirmatory OGTT for identifying AGT but a larger study is warranted to identify a robust cutoff for CFRD.

Dysregulated insulin in pancreatic insufficient cystic fibrosis with post-prandial hypoglycemia.

BACKGROUND: Post-prandial and oral glucose tolerance test-related hypoglycemia is common in cystic fibrosis (CF); however, the underlying mechanisms are unclear. METHODS: To understand the relationship of hypoglycemia with meal-related glucose excursion and insulin secretion, we analyzed plasma glucose, insulin, C-peptide, glucagon and incretins obtained during standardized mixed-meal tolerance tests (MMTT) in non-diabetic adolescents and young adults with pancreatic insufficient CF (PI-CF). RESULTS: Hypoglycemia, defined as glucose <70 mg/dL, occurred in 9/34 subjects at 150 (range:120-210) minutes following initial meal ingestion. Hypoglycemia[+] and hypoglycemia[-] groups did not differ in gender, age, lung function, HbA1c, or BMI. While 11/14 hypoglycemia[-] individuals displayed normal glucose tolerance (NGT), only 2/9 hypoglycemia[+] had NGT. Peak glucose was higher in hypoglycemia[+] vs hypoglycemia[-]. Compared to hypoglycemia[-] NGT, hypoglycemia[+] exhibited lower early-phase insulin secretion (ISR-AUC0-30min). ISR-AUC120-180min was not different in hypoglycemia[+] vs hypoglycemia[-] with abnormal glucose tolerance (AGT); however, glucose-AUC120-180min was lower in hypoglycemia[+] vs hypoglycemia[-] AGT. After adjusting for glucose-AUC, hypoglycemia[+] subjects tended to have higher ISR-AUC120-180min than hypoglycemia[-] AGT. Glucagon concentration did not differ between groups. Lower GLP-1-AUC30min and AUC180min and higher GIP-AUC30min were present in hypoglycemia[+] individuals. CONCLUSION: Hypoglycemia is common in PI-CF following MMTT and is associated with early glucose dysregulation (higher peak glucose), more impaired early-phase insulin secretion (lower ISR-AUC30min), and possibly late compensatory hyperinsulinemia. Further study is required to understand whether absence of glucagon difference in the hypoglycemia[+] individuals signals counterregulatory impairment, to delineate the role of incretins in hypoglycemia, and to determine the relationship of hypoglycemia to emergence of CFRD.

Advanced glycation end products (AGEs), protein aggregation and their cross talk: new insight in tumorigenesis.

Protein glycation and protein aggregation are two distinct phenomena being observed in cancer cells as factors promoting cancer cell viability. Protein aggregation is an abnormal interaction between proteins caused as a result of structural changes in them after any mutation or environmental assault. Protein aggregation is usually associated with neurodegenerative diseases like Alzheimer's and Parkinson's, but of late, research findings have shown its association with the development of different cancers like lung, breast and ovarian cancer. On the contrary, protein glycation is a cascade of irreversible nonenzymatic reaction of reducing sugar with the amino group of the protein resulting in the modification of protein structure and formation of advanced glycation end products (AGEs). These AGEs are reported to obstruct the normal function of proteins. Lately, it has been reported that protein aggregation occurs as a result of AGEs. This aggregation of protein promotes the transformation of healthy cells to neoplasia leading to tumorigenesis. In this review, we underline the current knowledge of protein aggregation and glycation along with the cross talk between the two, which may eventually lead to the development of cancer.

Higher Physician Body Mass Index is Associated with Increased Weight Bias in an Arab Country with High Prevalence of Obesity.

BACKGROUND: Obesity is a worldwide problem. The Arab world, and particularly the Middle East, has witnessed a recent dramatic rise in obesity and obesity-related diseases. Yet, little is known about physician attitudes toward or management of obesity in this region of the world. The purpose of this study is to explore physician perceptions and attitudes toward obesity in the United Arab Emirates (UAE). METHODS: A cross-sectional, self-administered anonymous survey of primary care physicians was performed between December 2015 and January 2017 at academic medical centers in the UAE. RESULTS: A total of 573 of 698 physicians (82% response rate) completed the survey. Thirty-seven percent of respondents met body mass index (BMI) criteria for overweight and 12% for obesity. Physicians had sufficient knowledge but lacked training in obesity management. Physician subspecialty impacted knowledge with internal medicine physicians showing better obesity knowledge (Chi-square 392, df 210, P = 0.00). There was no significant relationship between knowledge and attitudes with physician age, gender, or nationality. Attitudinal responses toward obesity management were generally positive. However, there was an inverse correlation between physician BMI and positive attitudes toward obesity management (Chi-square 1551, df 323, P = 0.00). CONCLUSIONS: Although our study did not find significant weight bias, negative attitudes were directly correlated with physician BMI, a significant concern as half of physicians surveyed reported BMIs consistent with overweight and obesity.

Islet Hormone and Incretin Secretion in Cystic Fibrosis after Four Months of Ivacaftor Therapy.

RATIONALE: Diabetes is associated with worse cystic fibrosis (CF) outcomes. The CFTR potentiator ivacaftor is suggested to improve glucose homeostasis in individuals with CF. OBJECTIVES: To test the hypothesis that clinically indicated ivacaftor would be associated with improvements in glucose tolerance and insulin and incretin secretion. METHODS: Oral glucose tolerance tests, mixed-meal tolerance tests, and glucose-potentiated arginine tests were compared preivacaftor initiation and 16 weeks postivacaftor initiation in CF participants with at least one CFTR gating or conductance mutation. Meal-related 30-minute (early phase) and 180-minute incremental area under the curves were calculated as responses for glucose, insulin, C-peptide, and incretin hormones; glucagon-like peptide-1; and glucose-dependent insulinotropic polypeptide. First-phase insulin secretion, glucose potentiation of arginine-induced insulin secretion, and disposition index were characterized by glucose-potentiated arginine stimulation tests. MEASUREMENTS AND MAIN RESULTS: Twelve subjects completed the study: six male/six female; seven normal/five abnormal glucose tolerance (oral glucose tolerance test 1-h glucose ≥155 and 2-h glucose <200 mg/dl); of median (minimum-maximum) age (13.8 yr [6.0-42.0]), body mass index-Z of 0.66 (-2.4 to 1.9), and FEV1% predicted of 102 (39-122). Glucose tolerance normalized in one abnormal glucose tolerance subject. Ivacaftor treatment did not alter meal responses except for an increase in early phase C-peptide (P = 0.04). First-phase (P = 0.001) and glucose potentiation of arginine-induced (P = 0.027) insulin secretion assessed by acute C-peptide responses improved after ivacaftor treatment. Consistent with an effect on ß-cell function, the disposition index relating the amount of insulin secreted for insulin sensitivity also improved (P = 0.04). CONCLUSIONS: Insulin secretion improved following 4 months of clinically indicated ivacaftor therapy in this relatively young group of patients with CF with normal to mildly impaired glucose tolerance, whereas incretin secretion remained unchanged.

Hydroxyl Group Difference between Anthraquinone Derivatives Regulate Different Cell Death Pathways via Nucleo-Cytoplasmic Shuttling of p53.

BACKGROUND: Despite a number of measures having been taken for cancer management, it is still the second leading cause of death worldwide. p53 is the protein principally being targeted for cancer treatment. Targeting p53 localization may be an effective strategy in chemotherapy as it controls major cell death pathways based on its cellular localization. Anthraquinones are bioactive compounds widely being considered as potential anticancer agents but their mechanism of action is yet to be explored. It has been shown that the number and position of hydroxyl groups within the different anthraquinones like Emodin and Chrysophanol reflects the number of intermolecular hydrogen bonds which affect its activity. Emodin contains an additional OH group at C-3, in comparison to Chrysophanol and may differentially regulate different cell death pathways in cancer cell. OBJECTIVE: The present study was aimed to investigate the effect of two anthraquinones Emodin and Chrysophanol on induction of different cell death pathways in human lung cancer cells (A549 cell line) and whether single OH group difference between these compounds differentially regulate cell death pathways. METHODS: The cytotoxic effect of Emodin and Chrysophanol was determined by the MTT assay. The expression of autophagy and apoptosis marker genes at mRNA and protein level after treatment was checked by the RT-PCR and Western Blot, respectively. For cellular localization of p53 after treatment, we performed immunofluorescence microscopy. RESULTS: We observed that both compounds depicted a dose-dependent cytotoxic response in A549 cells which was in concurrence with the markers associated with oxidative stress such as an increase in ROS generation, decrease in MMP and DNA damage. We also observed that both compounds up-regulated the p53 expression where Emodin causes nuclear p53 localization, which leads to down-regulation in mTOR expression and induces autophagy while Chrysophanol inhibits p53 translocation into nucleus, up-regulates mTOR expression and inhibits autophagy. CONCLUSION: From this study, it may be concluded that the structural difference of single hydroxyl group may switch the mechanism from one pathway to another which could be useful in the future to improve anticancer treatment and help in the development of new selective therapies.

Is Educating Girls the Best Investment for South Asia? Association Between Female Education and Fertility Choices in South Asia: A Systematic Review of the Literature.

Background: Universal education is a key strategy to enhance the well-being of individuals and improve the economic and social development of societies. A large proportion of school-aged girls in developing countries are not attending schools. Approximately one-third of South Asian girls do not attend school and in some regions only one in four girls attend primary school. Eliminating gender disparities in school attendance may lead to improvements in female education and reproductive health. Objectives: To conduct a systematic review of the available data from international organizations and regional registries to explore the association between female education and fertility choices in South Asia. Methods: Systematic review and synthesis of secondary data. Data sources: MEDLINE, Embase, Google Scholar, World Health Organization, World Bank, United Nations Population Fund, Millennium Development Goals, Institute of Health Management, World Fact book, United States Centers for Disease Control and Prevention and regional registries were searched for papers published between 1970 and October 2016 and the included papers contained data from 1960. Study eligibility criteria and data abstraction process: Studies were included if they contained data on (i) female education and/or literacy levels in South Asia; and (ii) fertility behavior in South Asian females. Quality of the included studies and extracted data were assessed by two independent reviewers. Results: According to the World Bank report in 2016, the female literacy rate in South Asia has increased from 45.5% in 2000 to 57.0% in 2010 while a decreased trend of total fertility rate (i.e., number of children born per woman) was observed from 6.0 in 1960 to 2.6 in 2014. Limitations: Only studies in English were included. Conclusion: A negative relationship seems to exist between levels of literacy and total fertility rates in South Asian females which if further improved may contribute to longer-term improvements in maternal and child health.