Association of Adiponutrin/Patatin Like Phospholipase 3 (PNPLA3) I148M Gene Variant with Chronic Hepatitis C in Egyptian Children

Background: Chronic hepatitis C (CHC) represents a leading cause of liver-related mortality worldwide. The patatin-like phospholipase domain-containing 3 gene (PNPLA3/adiponutrin) rs738409 (I148M) single-nucleotide polymorphism (SNP) has been reported to be linked with the severity and progression of liver fat content and liver fibrosis in CHC among different racial groups. Such reports are lacking in CHC Egyptian children. Aim of Study: To evaluate the possible association of PNPLA3-I148M gene variant with the severity of liver fat content and liver fibrosis in Egyptian children with CHC. Patients and Methods: Fifty normal-weighted children (mean age 10.62±2.59 years) with CHC were subjected to genotyping of PNPLA3-I148M gene variant using the real time PCR TaqMan assay. FibroScan examination for assessment of both liver fibrosis by Fibroscan liver stiffness (LMS) and liver steatosis by the controlled attenuation parameter (CAP) scores and histological examination of liver biopsies for assessment of liver steatosis, and METAVIER scoring for necroinflammatory activity grades and liver fibrosis stages were done for all patients as well as appropriate laboratory investigations. APRI and FIB-4 indices as well as insulin resistance using HOMA-IR were also calculated. Results: 34 cases (68%) had CC genotype (wild CC genotype) ,9 cases (18%) had CG genotype (heterozygous for the risk G allele) and 7 cases (14%) had GG genotype (homozygous for the risk G allele). Significant higher values of LSM and CAP steatosis scores were found in patients with CG and GG genotypes compared to those with CC genotype. CG gene variant and GG gene variant were significant positive predictive factors for histopathological liver steatosis and fibrosis stages and inflammatory activity grades among the studied patients. Significant higher values of many laboratory variables (AST, fasting blood glucose, fasting serum insulin, and HOMA-IR) but lower platelets count was found in patients with G allele (CG+ GG) compared to patients without G allele (CC). In addition, significant positive correlations between PNPLA3-I148M gene variant and indicators of hepatic steatosis and fibrosis and many laboratory parameters (AST, APRI, FIB4, FBS, fasting serum insulin, and HOMA-IR) but a significant negative correlation between PNPLA3-I148M gene variant and platelet cell count were found among the studied patients. Conclusion: Data of this study suggested that polymorphisms in the PNPLA3 I148M gene variant could contribute to the severity of hepatic steatosis and fibrosis of the studied Egyptian children with CHC.

Adopting a Mediterranean-style eating pattern with low, but not moderate, unprocessed, lean red meat intake reduces fasting serum trimethylamine N-oxide (TMAO) in adults who are overweight or obese

A Mediterranean-style eating pattern (MED-EP) may include moderate red meat intake. However, it is unknown if the pro-atherogenic metabolite trimethylamine N-oxide (TMAO) is affected by the amount of red meat consumed with a MED-EP. The results presented are from a secondary, retrospective objective of an investigator-blinded, randomized, crossover, controlled feeding trial (two 5-wk interventions separated by a 4-wk washout) to determine if a MED-EP with 200g unprocessed lean red meat/wk (MED-CONTROL) reduces circulating TMAO concentrations compared to a MED-EP with 500g unprocessed lean red meat/wk (MED-RED). Participants were 27 women and 12 men (n=39 total) who were either overweight or obese (BMI: 30.5 ± 0.3 kg/m2 mean ± SEM). Serum samples were obtained following an overnight fast both before (pre) and after (post) each intervention. Fasting serum TMAO, choline, carnitine, and betaine concentrations were measured using a targeted Liquid chromatography-mass spectrometry. Data were analyzed to assess if (a) TMAO and related metabolites differed by intervention, and (b) if changes in TMAO were associated with changes in Framingham 10-year risk score. Serum TMAO was lower post-intervention following MED-CONTROL compared to MED-RED intervention (post-MED-CONTROL 3.1 ± 0.2 µM vs. post-MED-RED 5.0 ± 0.5 µM, p<0.001), and decreased following MED-CONTROL (pre- vs post-MED-CONTROL, p = 0.025). Exploratory analysis using mixed model analysis of covariance identified a positive association between changes in TMAO and changes in HOMA-IR (p = 0.036). These results suggest that lower amounts of red meat intake leads to lower TMAO concentrations in the context of a MED-EP.

Gas Chromatography–Mass Spectroscopy-Based Metabolomics Analysis Reveals Potential Biochemical Markers for Diagnosis of Gestational Diabetes Mellitus

Due to many adverse effects of gestational diabetes mellitus (GDM) on the mother and fetus, its diagnosis is crucial. The presence of GDM can be confirmed by an abnormal fasting plasma glucose level (aFPG) and/or oral glucose tolerance test (OGTT) performed mostly between 24 and 28 gestational week. Both aFPG and abnormal glucose tolerance (aGT) are used to diagnose GDM. In comparison to measurement of FPG, OGTT is time-consuming, usually inconvenient for the patient, and very often needs to be repeated. Therefore, it is necessary to seek tests that will be helpful and convenient to diagnose GDM. For this reason, we investigated the differences in fasting serum metabolites between GDM women with abnGM and normal FPG (aGT-GDM group), with aFPG and normal glucose metabolism (aFPG-GDM group) as well as pregnant women with normal glucose tolerance (NGT) being a control group. Serum metabolites were measured by an untargeted approach using gas chromatography–mass spectrometry (GC–MS). In the discovery phase, fasting serum samples collected from 79 pregnant women (aFPG-GDM, n = 24; aGT-GDM, n = 26; NGT, n = 29) between 24 and 28 weeks of gestation (gwk) were fingerprinted. A set of metabolites (α–hydroxybutyric acid (α–HB), β–hydroxybutyric acid (β–HB), and several fatty acids) significant in aGT-GDM vs NGT but not significant in aFPG-GDM vs NGT comparison in the discovery phase was selected for validation. These metabolites were quantified by a targeted GC–MS method in a validation cohort consisted of 163 pregnant women (aFPG-GDM, n = 51; aGT-GDM, n = 44; and NGT, n = 68). Targeted analyses were also performed on the serum collected from 92 healthy women in the first trimester (8–14 gwk) who were NGT at this time, but in the second trimester (24–28 gwk) they were diagnosed with GDM. It was found that α–HB, β–HB, and several fatty acids were associated with aGT-GDM. A combination of α–HB, β–HB, and myristic acid was found highly specific and sensitive for the diagnosis of GDM manifested by aGT-GDM (AUC = 0.828) or to select women at a risk of aGT-GDM in the first trimester (AUC = 0.791). Our findings provide new potential markers of GDM and may have implications for its early diagnosis.

Effects of Proton Pump Inhibitor Therapy, H. pylori Infection and Gastric Preneoplastic Pathology on Fasting Serum Gastrin Concentrations

BackgroundHypergastrinaemia occasionally indicates the presence of a gastrinoma. However it is much more commonly associated with various benign causes including proton pump inhibitor (PPI) use, Helicobacter pylori infection and/or atrophic gastritis. The extent to which these factors interact to influence fasting serum gastrin concentrations remains incompletely understood.Materials and MethodsFasting serum gastrin concentrations were measured by radioimmunoassay in 1,400 patients attending for diagnostic oesophagogastro-duodenoscopy. After exclusions, 982 patients were divided into four groups and their results analysed. We compared gastrin concentrations in normal patients (no H. pylori infection, no PPI use and no histological evidence of gastric preneoplasia (n=233)), with those in patients who were taking regular PPIs (H. pylori negative with no gastric preneoplasia (n=301)), patients who had active H. pylori infection but no gastric preneoplasia (n=164) and patients with histologically confirmed gastric preneoplasia (n=284).ResultsMedian fasting gastrin concentration in the normal group was 20pM and was significantly increased in PPI users (46pM, p&lt;0.0001), patients with active H. pylori infection (27pM, p&lt;0.0001), and patients with antral (25pM, p&lt;0.01) or corpus (48pM, p&lt;0.0001) gastric preneoplasia. PPI use resulted in further significant increases in fasting serum gastrin concentrations in patients who were infected with H. pylori (50pM, n=56) or who had antral gastric preneoplasia (53pM, n=87), but did not significantly alter serum gastrin concentrations in patients with corpus preneoplasia (90pM, n=66).ConclusionsPPI use, H. pylori infection and atrophic gastritis all caused significant elevations of median fasting gastrin concentrations. However, several patients who had potential risk factors for hypergastrinaemia still demonstrated fasting serum gastrin concentrations within the normal range.

Sustained efficacy and safety of burosumab, a monoclonal antibody to FGF23, in children with X-linked hypophosphatemia

Purpose In X-linked hypophosphatemia (XLH), excess FGF23 causes hypophosphatemia and low calcitriol, leading to musculoskeletal disease with clinical consequences. XLH treatment options include conventional oral phosphate with active vitamin D, or monotherapy with burosumab, a monoclonal antibody approved to treat children and adults with XLH. We have previously reported outcomes up to 64 weeks, and here, we report safety and efficacy follow-up results up to 160 weeks from an open-label, multicenter, randomized, dose-finding trial of burosumab for 5 to 12 year-old children with XLH. Methods After one week of conventional therapy washout, patients were randomized 1:1 to burosumab every 2 weeks (Q2W) or every 4 weeks (Q4W) for 64 weeks, with dosing titrated based on fasting serum phosphorus levels between baseline and Week 16. From Week 66 to Week 160, all patients received Q2W burosumab. Results Twenty-six children were randomized initially into each Q2W and Q4W group and all completed treatment to Week 160. In 41 children with open distal femoral and proximal tibial growth plates (from both treatment groups), total Rickets Severity Score significantly decreased by 0.9±0.1 (least squares mean±SE; p&lt;0.0001) from baseline to Week 160. Fasting serum phosphorus increases were sustained by burosumab therapy throughout the study, with an overall population mean (SD) of 3.35 (0.39) mg/dL, within the pediatric normal range (3.2 to 6.1 mg/dL) at Week 160 (mean change from baseline p&lt;0.0001). Most adverse events were mild to moderate in severity. Main conclusions In children with XLH, burosumab administration for 160 weeks improved phosphate homeostasis and rickets and was welltolerated. Long-term safety was consistent with the reported safety profile of burosumab.

PSVI-9 Effects of dietary boron supplementation on growth performance, fasting and postprandial serum insulin, and glucose concentration of pigs

A 49-d experiment evaluated the effects of supplemental boron (B) on growth, and serum insulin and glucose concentration of pigs. Crossbred pigs [n = 48; initial body weight (BW) 19.18 ± 0.29 kg] were randomly allotted to 1 of 4 diets based on BW and sex. Diets were corn-SBM-based, formulated to meet NRC (2012) nutrient requirement estimates, and were supplemented with 0, 25, 50, or 100 mg B/kg diet as sodium tetraborate decahydrate. On d 20 and 41, blood samples were collected. Fasting samples were collected following an overnight fast; then a postprandial sample was taken approximately 50 minutes after the pigs had 10 minutes of ad libitum access to feed. Samples were processed and serum analyzed for insulin and glucose concentration. Increasing B levels resulted in a linear decrease for overall ADG (0.87, 0.86, 0.85, and 0.82 kg, P = 0.02). On d 20, supplemental B resulted in a quadratic response on fasting serum glucose concentration (5.25, 4.80, 4.65, and 5.01, P = 0.03) and a linear decrease in postprandial serum insulin concentration (29.1, 25.5, 18.2, and 18.1 µU/mL, P = 0.02). Furthermore, there was a tendency for a linear decrease in fasting insulin:glucose ratio (0.85, 0.84, 0.42, and 0.59, P = 0.08), which became more noticeable during the postprandial state (3.96, 3.63, 2.63, and 2.73, P = 0.02). Again on d 41, there was a quadratic response on fasting serum glucose concentration (4.32, 4.07, 3.91, and 4.68, P = 0.01) with supplemental B. Results suggest that supplemental boron may impact serum insulin and glucose concentrations by reducing the amount of insulin needed to maintain glucose concentrations. However, higher levels of supplemental boron did result in suppressed growth performance. Thus, additional research is warranted to determine the optimum level of supplemental B.

Efficacy and Safety of Tirzepatide in Patients with Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomized Phase II/III Trials

Tirzepatide is a novel once-a-week dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, currently under trial to assess glycemic efficacy and safety in people with type 2 diabetes. A systematic review and meta-analysis were conducted to investigate the efficacy of tirzepatide on glycated hemoglobin (HbA1c, %), fasting serum glucose (mg/dL), and body weight (kg) in patients with uncontrolled type 2 diabetes (HbA1c > 7.0%). Mean changes for efficacy and proportions (safety) with corresponding 95% confidence intervals (CIs) were used to provide pooled estimates. A total of four randomized controlled trials, comprising 2783 patients of whom 69.4% (n = 1934) were treated with 5 mg (n = 646), 10 mg (n = 641), or 15 mg (n = 647) of tirzepatide, were compared to the placebo (n = 192) or the selective GLP-1 receptor agonist (n = 523). The pooled analysis showed that tirzepatide treatment resulted in a greater lowering of the HbA1c (−1.94%, 95% CI: −2.02 to −1.87), fasting serum glucose (−54.72 mg/dL, 95% CI: −62.05 to −47.39), and body weight (−8.47, 95% CI: −9.66 to −7.27). We also found that improvement in the HbA1c levels was still maintained at weeks 26 and 40 from the long-term trials. As for safety, only 3% experienced hypoglycemia, and 4% (95% CI: 2 to 6) experienced serious adverse events, while the discontinuation of therapy percentage was 7% (95% CI: 5 to 8). Tirzepatide significantly improved glycemic control and body weight and had an acceptable safety profile, indicating that it is an effective therapeutic option for glucose-lowering in patients with type 2 diabetes mellitus.

Vitamin D supplementation improves fasting insulin levels and HDL cholesterol in infertile men

Context Vitamin D has been linked with glucose and lipid metabolism. Men with impaired gonadal function have a higher risk of metabolic syndrome and mortality, and vitamin D status may be a reversible modulator. Objective Determine the effect of daily vitamin D and calcium supplementation for 150 days on glucose and lipid homeostasis in infertile men. Design A single-center, double-blinded, randomized clinical trial (NCT01304927), 307 infertile men were randomized (1:1) to a single dose of 300,000 IU cholecalciferol followed by 1,400 IU cholecalciferol + 500 mg of calcium daily (n=151) or placebo (n=156) for 150 days. Reported metabolic parameters including fasting plasma glucose, HbA1c, fasting serum insulin, homeostatic model assessment of insulin resistance (HOMA-IR), fasting plasma cholesterols and triglyceride were secondary endpoints. The primary endpoint semen quality has previously been reported. Results Men receiving vitamin D supplementation improved their vitamin D status, while vitamin D status was aggravated in the placebo group characterized by higher serum parathyroid hormone (PTH). At end of trial, men receiving vitamin D supplementation had 13% lower fasting serum insulin concentrations compared with the placebo-treated group (65 vs. 74 pmol/L, P = 0.018) and 19% lower HOMA-IR (2.2 vs. 2.7, P = 0.025). Moreover, men in the vitamin D group had higher high-density lipoprotein (HDL) cholesterol levels (1.38 vs. 1.32 mmol/L, P = 0.008) compared with the placebo group. Conclusion High-dose vitamin D supplementation had beneficial effects on glucose homeostasis and HDL cholesterol levels in infertile men.

Residual C-peptide secretion and hypoglycemia awareness in people with type 1 diabetes

IntroductionThis study aimed to assess the association between fasting serum C-peptide levels and the presence of impaired awareness of hypoglycemia (IAH) in people with type 1 diabetes.Research design and methodsWe performed a cross-sectional study among 509 individuals with type 1 diabetes (diabetes duration 5–65 years). Extensive clinical data and fasting serum C-peptide concentrations were collected and related to the presence or absence of IAH, which was evaluated using the validated Dutch version of the Clarke questionnaire. A multivariable logistic regression model was constructed to investigate the association of C-peptide and other clinical variables with IAH.ResultsIn 129 (25%) individuals, residual C-peptide secretion was detected, while 75 (15%) individuals reported IAH. The median (IQR) C-peptide concentration among all participants was 0.0 (0.0–3.9) pmol/L. The prevalence of severe hypoglycemia was lower in people with demonstrable C-peptide versus those with absent C-peptide (30% vs 41%, p=0.025). Individuals with IAH were older, had longer diabetes duration, more frequently had macrovascular and microvascular complications, and more often used antihypertensive drugs, antiplatelet agents and cholesterol-lowering medication. There was a strong association between IAH and having a severe hypoglycemia in the preceding year. In multivariable regression analysis, residual C-peptide, either continuously or dichotomous, was associated with lower prevalence of IAH (p=0.040–0.042), while age at diabetes onset (p=0.001), presence of microvascular complications (p=0.003) and body mass index (BMI) (p=0.003) were also independently associated with the presence of IAH.ConclusionsHigher BMI, the presence of microvascular complications and higher age at diabetes onset were independent risk factors for IAH in people with type 1 diabetes, while residual C-peptide secretion was associated with lower risk of this complication.