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Sonal Singh, Caitrin W McDonough, Yan Gong, Wael A Alghamdi, Meghan J Arwood, Salma A Bargal, Leanne Dumeny, Wen-Yi Li, Mai Mehanna, Bradley Stockard, Guang Yang, Felipe A de Oliveira, Natalie C Fredette, Mohamed H Shahin, Kent R Bailey, Amber L Beitelshees, Eric Boerwinkle, Arlene B Chapman, John G Gums, Stephen T Turner, Rhonda M Cooper-DeHoff, Julie A Johnson
BACKGROUND: Thiazide and thiazide-like diuretics are first-line medications for treating uncomplicated hypertension. However, their use has been associated with adverse metabolic events, including hyperglycemia and incident diabetes mellitus, with incompletely understood mechanisms. Our goal was to identify genomic variants associated with thiazide-like diuretic/chlorthalidone-induced glucose change. METHODS AND RESULTS: Genome-wide analysis of glucose change after treatment with chlorthalidone was performed by race among the white (n=175) and black (n=135) participants from the PEAR-2 (Pharmacogenomic Evaluation of Antihypertensive Responses-2)...
March 9, 2018: Journal of the American Heart Association
Larry A Cogburn, Danielle N Smarsh, Xiaofei Wang, Nares Trakooljul, Wilfrid Carré, Harold B White
BACKGROUND: A strain of Leghorn chickens (rd/rd), unable to produce a functional riboflavin-binding protein, lays riboflavin-deficient eggs, in which all embryos suddenly die at mid-incubation (days 13-15). This malady, caused by riboflavin deficiency, leads to excessive lipid accumulation in liver, impaired β-oxidation of lipid, and severe hypoglycemia prior to death. We have used high-density chicken microarrays for time-course transcriptional scans of liver in chicken embryos between days 9-15 during this riboflavin-deficiency-induced metabolic catastrophe...
March 5, 2018: BMC Genomics
Cherubino Di Lorenzo, Gianluca Coppola, Davide Di Lenola, Maurizio Evangelista, Giulio Sirianni, Paolo Rossi, Giorgio Di Lorenzo, Mariano Serrao, Francesco Pierelli
Introduction: Drug-resistant cluster headache (CH) is still an open clinical challenge. Recently, our group observed the clinical efficacy of a ketogenic diet (KD), usually adopted to treat drug-resistant epilepsies, on migraine. Aim: Here, we aim to detect the effect of KD in a group of drug-resistant chronic CH (CCH) patients. Materials and methods: Eighteen drug-resistant CCH patients underwent a 12-week KD (Modified Atkins Diet, MAD), and the clinical response was evaluated in terms of response (≥50% attack reduction)...
2018: Frontiers in Neurology
Yasuyo Urasaki, Chi Zhang, Ji-Xin Cheng, Thuc T Le
Current assessment of non-alcoholic fatty liver disease (NAFLD) with histology is time-consuming, insensitive to early-stage detection, qualitative, and lacks information on etiology. This study explored alternative methods for fast and quantitative assessment of NAFLD with hyperspectral stimulated Raman scattering (SRS) microscopy and nanofluidic proteomics. Hyperspectral SRS microscopy quantitatively measured liver composition of protein, DNA, and lipid without labeling and sensitively detected early-stage steatosis in a few minutes...
February 26, 2018: Scientific Reports
Yang Qiu, Rachel J Perry, João-Paulo G Camporez, Xian-Man Zhang, Mario Kahn, Gary W Cline, Gerald I Shulman, Daniel F Vatner
Exposure to the toxins methylene cyclopropyl acetic acid (MCPA) and methylene cyclopropyl glycine (MCPG) of unripe ackee and litchi fruit can lead to hypoglycemia and death; however, the molecular mechanisms by which MCPA and MCPG cause hypoglycemia have not been established in vivo To determine the in vivo mechanisms of action of these toxins we infused them into conscious rodents and assessed rates of hepatic gluconeogenesis and ketogenesis, hepatic acyl-CoA and hepatic acetyl-CoA content, and hepatocellular energy charge...
February 26, 2018: Biochemical Journal
Meiyuan Zhang, Weilan Sun, Jin Qian, Yan Tang
Liver coordinates a series of metabolic adaptations to maintain systemic energy balance and provide adequate nutrients for critical organs, tissues and cells during starvation. However, the mediator(s) implicated in orchestrating these fasting-induced adaptive responses and the underlying molecular mechanisms are still obscure. Here we show that hepatic growth differentiation factor 15 (GDF15) is regulated by IRE1α-XBP1s branch and promotes hepatic fatty acids β-oxidation and ketogenesis upon fasting. GDF15 expression was exacerbated in liver of mice subjected to long-term fasted or ketogenic diet feeding...
February 1, 2018: Redox Biology
Brendan Egan
The ketone bodies acetoacetate, β-hydroxybutyrate (βHB) and acetone are small, lipid-derived molecules that are generated during ketogenesis, a process that is amplified during fasting, starvation, ketogenic diets, and prolonged glycogen-depleting exercise. This article is protected by copyright. All rights reserved.
February 22, 2018: Journal of Physiology
Joydeep Sarkar, Gaurav Dwivedi, Qian Chen, Iris E Sheu, Mark Paich, Colleen M Chelini, Paul M D'Alessandro, Samuel P Burns
A computational model of the physiological mechanisms driving an individual's health towards onset of type 2 diabetes (T2D) is described, calibrated and validated using data from the Diabetes Prevention Program (DPP). The objective of this model is to quantify the factors that can be used for prevention of T2D. The model is energy and mass balanced and continuously simulates trajectories of variables including body weight components, fasting plasma glucose, insulin, and glycosylated hemoglobin among others on the time-scale of years...
2018: PloS One
David Polidori, Hiroaki Iijima, Maki Goda, Nobuko Maruyama, Nobuya Inagaki, Peter A Crawford
SGLT2 inhibitors have been associated with increased serum ketone bodies in patients with type 2 diabetes mellitus (T2DM). This analysis evaluated serum ketone body levels and variability in 1,278 Japanese patients with T2DM treated with canagliflozin 100 or 200 mg. Similar mean increases in ketone body concentrations of ~2-fold were seen with both canagliflozin doses. Median (interquartile range) percent change from baseline was 62% (0;180) for acetoacetate and 78% (2;236) for β-hydroxybutyrate. Approximately 2/3 of the variability in each ketone measure was attributed to intra-subject variability...
January 17, 2018: Diabetes, Obesity & Metabolism
Zilong Zhao, Daqian Xu, Zheng Wang, Lin Wang, Ruomei Han, Zhenzhen Wang, Lujian Liao, Yan Chen
Peroxisome proliferator-activated receptor α (PPARα) is a key transcriptional factor that regulates hepatic lipid catabolism by stimulating fatty acid oxidation and ketogenesis in an adaptive response to nutrient starvation. However, how PPARα is regulated by post-translational modification is poorly understood. Here, we identified that PAQR3 promotes PPARα ubiquitination through the E3 ubiquitin ligase HUWE1, thereby negatively modulating PPARα functions both in vitro and in vivo. Adenovirus-mediated Paqr3 knockdown and liver-specific deletion of the Paqr3 gene reduced hepatic triglyceride levels while increasing fatty acid oxidation and ketogenesis upon fasting...
January 13, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Hüseyin Demirbilek, Khalid Hussain
Pancreatic β-cells are finely tuned to secrete insulin so that plasma glucose levels are maintained within a narrow physiological range (3.5-5.5 mmol/L). Hyperinsulinaemic hypoglycaemia (HH) is the inappropriate seretion of insulin in the presence of low plasma glucose levels and leads to severe and persistent hypoglycaemia in neonates and children. Mutations in 12 different key genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, UCP2, HNF4A, HNF1A, HK1, PGM1 and PMM2) that are involved in the regulation of insulin secretion from pancreatic β-cells have been described to be responsible for the underlying molecular mechanisms leading to congenital HH...
December 27, 2017: Journal of Clinical Research in Pediatric Endocrinology
K Zhao, Y H Chen, G B Penner, M Oba, L L Guan
BACKGROUND: The transition from a high forage to a highly fermentable diet can induce digestive disorders in the rumen. To date, the host mechanisms that regulate the adaption to such dietary transition are largely unknown. To understand the molecular mechanisms involved in such phenomena, RNA-sequencing was performed to identify the changes in the transcriptome of ruminal epithelia during gradual transition from a diet containing 0% to 89% grain. RESULTS: In total, the expression of 11,044, 11,322 and 11,282 genes were detected in ruminal epithelia of beef heifers (n = 15) fed 0%, 72% and 89% barley grain diet, respectively...
December 19, 2017: BMC Genomics
Keiichiro Matoba, Yuan Lu, Rongli Zhang, Eric R Chen, Panjamaporn Sangwung, Benlian Wang, Domenick A Prosdocimo, Mukesh K Jain
Adipose tissue stores energy in the form of triglycerides. The ability to regulate triglyceride synthesis and breakdown based on nutrient status (e.g., fed versus fasted) is critical for physiological homeostasis and dysregulation of this process can contribute to metabolic disease. Whereas much is known about hormonal control of this cycle, transcriptional regulation is not well understood. Here, we show that the transcription factor Kruppel-like factor 15 (KLF15) is critical for the control of adipocyte lipid turnover...
December 12, 2017: Cell Reports
S Mann, F A Leal Yepes, J J Wakshlag, E Behling-Kelly, J A A McArt
Despite the widespread use of treatments for postpartum hyperketonemia in dairy cows, there is currently a lack of evidence comparing their effects on both the resolution of hyperketonemia and the potential effects on the liver of affected animals. The objective of our work was to investigate the effect of commonly used hyperketonemia treatments on hepatic triglyceride and glycogen content as well as on the mRNA and protein abundance of key enzymes involved in gluconeogenesis, ketogenesis, and lipid metabolism...
February 2018: Journal of Dairy Science
Kanako Esaki, Masanori Tsukamoto, Eiji Sakamoto, Takeshi Yokoyama
BACKGROUND AND OBJECTIVES: Preoperative oral carbohydrate therapy has been suggested to attenuate postoperative insulin resistance. The purpose of this study was to investigate the effect of a carbohydrate-rich beverage given preoperatively on intraoperative glucose metabolism. METHODS AND STUDY DESIGN: This study was a randomised, open-label, placebo-controlled trial. Patients undergoing oral-maxillofacial surgery were divided into two groups. In the glucose group, patients took glucose (50 g/278 mL, p...
2018: Asia Pacific Journal of Clinical Nutrition
Shantel Olivares, Anne S Henkel
OBJECTIVE: Fibroblast growth factor 21 (FGF21), a key regulator of the metabolic response to fasting, is highly induced by endoplasmic reticulum (ER) stress. The X-box binding protein 1 (Xbp1) is one of several ER stress proteins that has been shown to directly activate the FGF21 promoter. We aimed to determine whether hepatic Xbp1 is required for induction of hepatic FGF21 in vivo. METHODS: Mice bearing a hepatocyte-specific deletion of Xbp1 (Xbp1LKO ) were subjected to fasting, pharmacologic ER stress, or a ketogenic diet, all potent stimuli of Fgf21 expression...
December 2017: Molecular Metabolism
C Binsch, T Jelenik, A Pfitzer, M Dille, S Müller-Lühlhoff, S Hartwig, S Karpinski, S Lehr, D G Kabra, A Chadt, M Roden, H Al-Hasani, T R Castañeda
OBJECTIVE: Ribosomal protein S6 Kinase-1 (S6K1) has been linked to resistance exercise-mediated improvements in glycemia. We hypothesized that S6K1 may also play a role in regulating glycemic control in response to endurance exercise training. METHODS: S6k1-knockout (S6K1KO) and WT mice on a 60 cal% high-fat diet were trained for 4 weeks on treadmills, metabolically phenotyped, and compared to sedentary controls. RESULTS: WT mice showed improved glucose tolerance after training...
November 2017: Molecular Metabolism
Chamara Dalugama, Indika Bandara Gawarammana
BACKGROUND: The increasing global prevalence of both dengue and diabetes may warrant closer observation for glycemic control and adapted fluid management to diminish the risk for a severe clinical presentation of dengue. Dengue illness is rarely known to precipitate diabetic ketoacidosis among diabetic patients. Both type 1 and type 2 diabetes increase the release of pro-inflammatory cytokines by various mechanisms and increase the risk of plasma leak in dengue fever. Acute pancreatitis is an atypical and rare presentation of dengue fever...
October 28, 2017: Journal of Medical Case Reports
Neha S Patel, Michelle A Van Name, Eda Cengiz, Lori R Carria, Stuart A Weinzimer, William V Tamborlane, Jennifer L Sherr
BACKGROUND: Enthusiasm for the benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i) as an adjunctive treatment in type 1 diabetes (T1D) has been offset by the possible increased risk of diabetic ketoacidosis (DKA). Since pump-treated T1D patients are susceptible to DKA due to infusion site problems, this study was undertaken to assess how treatment with SGLT2i affects patterns of early metabolic decompensation following suspension of basal insulin. METHODS: Ten T1D participants (age 19-35 years, duration 10 ± 8 years, A1c 7...
November 2017: Diabetes Technology & Therapeutics
Elke Rudloff
Practical relevance: Diabetic ketoacidosis (DKA) is a not uncommon emergency in both newly diagnosed and poorly regulated diabetic cats. When there is a heightened metabolic rate and energy requirement due to concurrent illness, an increase in the release of glucose counter-regulatory hormones causes insulin receptor resistance, lipolysis, free fatty acid release and ketogenesis. This necessitates not only treatment to eliminate the ketosis and control blood glucose, but also investigation of concurrent illnesses...
November 2017: Journal of Feline Medicine and Surgery
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