Browsing by Subject "GLUCOSE"

Sort by: Order: Results:

Now showing items 21-40 of 48
  • Luukkonen, Panu K.; Zhou, You; Sädevirta, Sanja; Leivonen, Marja; Arola, Johanna; Oresic, Matej; Hyotylainen, Tuulia; Yki-Jarvinen, Hannele (2016)
    Background & Aims: Recent data in mice have identified de novo ceramide synthesis as the key mediator of hepatic insulin resistance (IR) that in humans characterizes increases in liver fat due to IR ('Metabolic NAFLD' but not that due to the I148M gene variant in PNPLA3 ('PNPLA3 NAFLD'). We determined which bioactive lipids co-segregate with IR in the human liver. Methods: Liver lipidome was profiled in liver biopsies from 125 subjects that were divided into equally sized groups based on median HOMA-IR ('High and Low HOMA-IR', n = 62 and n = 63) or PNPLA3 genotype (PNPIA3(148MM/MI), n = 61 vs. PNPLA3(148II), n = 64). The subjects were also divided into 4 groups who had either IR, the I148M gene variant, both of the risk factors or neither. Results: Steatosis and NASH prevalence were similarly increased in 'High HOMA-IR' and PNPLA3(148MM/MI) groups compared to their respective control groups. The 'High HOMA-IR' but not the PNPLA3(148MM/MI) group had features of IR. The liver in 'High HOMA-IR' vs. low HOMA-IR' was markedly enriched in saturated and monounsaturated triacylglycerols and free fatty acids, dihydroceramides (markers of de novo ceramide synthesis) and ceramides. Markers of other ceramide synthetic pathways were unchanged. In PNPLA3(148MM/MI) vs. PNPLA3(148II), the increase in liver fat was due to polyunsaturated triacylglycerols while other lipids were unchanged. Similar changes were observed when data were analyzed using the 4 subgroups. Conclusions: Similar increases in liver fat and NASH are associated with a metabolically harmful saturated, ceramide-enriched liver lipidome in 'Metabolic NAFLD' but not in 'PNPLA3 NAFLD'. This difference may explain why metabolic but not PNPLA3 NAFLD increases the risk of type 2 diabetes and cardiovascular disease. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
  • Laitakari, Anna; Tapio, Joona; Mäkelä, Kari A.; Herzig, Karl-Heinz; Dengler, Franziska; Gylling, Helena; Walkinshaw, Gail; Myllyharju, Johanna; Dimova, Elitsa Y.; Serpi, Raisa; Koivunen, Peppi (2020)
    Non-alcoholic fatty liver disease (NAFLD) parallels the global obesity epidemic with unmet therapeutic needs. We investigated whether inhibition of hypoxia-inducible factor prolyl 4-hydroxylase-2 (HIF-P4H-2), a key cellular oxygen sensor whose inhibition stabilizes HIF, would protect from NAFLD by subjecting HIF-P4H-2-deficient (Hif-p4h-2(gt/gt)) mice to a high-fat, high-fructose (HFHF) or high-fat, methionine-choline-deficient (HF-MCD) diet. On both diets, the Hif-p4h-2(gt/gt) mice gained less weight and had less white adipose tissue (WAT) and its inflammation, lower serum cholesterol levels, and lighter livers with less steatosis and lower serum ALT levels than the wild type (WT). The intake of fructose in majority of the Hif-p4h-2(gt/gt) tissues, including the liver, was 15-35% less than in the WT. We found upregulation of the key fructose transporter and metabolizing enzyme mRNAs, Slc2a2, Khka, and Khkc, and higher ketohexokinase activity in the Hif-p4h-2(gt/gt) small intestine relative to the WT, suggesting enhanced metabolism of fructose in the former. On the HF-MCD diet, the Hif-p4h-2(gt/gt) mice showed more browning of the WAT and increased thermogenesis. A pharmacological pan-HIF-P4H inhibitor protected WT mice on both diets against obesity, metabolic dysfunction, and liver damage. These data suggest that HIF-P4H-2 inhibition could be studied as a novel, comprehensive treatment strategy for NAFLD. Key messages center dot HIF-P4H-2 inhibition enhances intestinal fructose metabolism protecting the liver. center dot HIF-P4H-2 inhibition downregulates hepatic lipogenesis. center dot Induced browning of WAT and increased thermogenesis can also mediate protection. center dot HIF-P4H-2 inhibition offers a novel, comprehensive treatment strategy for NAFLD.
  • Shen, Yun; Li, Weiqin; Leng, Junhong; Zhang, Shuang; Liu, Huikun; Li, Wei; Wang, Leishen; Tian, Huiguang; Chen, Jinbo; Qi, Lu; Yang, Xilin; Yu, Zhijie; Tuomilehto, Jaakko; Hu, Gang (2019)
    Aims: To investigate the risk of postpartum metabolic syndrome in women with GDM compared with those without GDM in a Chinese population. Methods: Tianjin GDM observational study included 1263 women with a history of GDM and 705 women without GDM. Multivariate logistic regression was used to assess risks of postpartum metabolic syndrome between women with and without GDM. Postpartum metabolic syndrome was diagnosed by two commonly used criteria. Results: During a mean 3.53 years of follow up, 256 cases of metabolic syndrome were identified by using the NCEPATPIII criteria and 244 cases by using the IDF criteria. Multivariable-adjusted odds ratios of metabolic syndrome in women with GDM compared with those without GDM were 3.66 (95% confidence interval [CI] 2.02-6.63) for NCEP ATPIII criteria and 3.90 (95% CI 2.13-7.14) for IDF criteria. Women with GDM had higher multivariable-adjusted odds ratios of central obesity, hypertriglyceridemia, and high blood pressure than women without GDM. The multivariable-adjusted odds ratios of low HDL cholesterol and hyperglycemia were not significant between women with and without GDM, however, the multivariable-adjusted odds ratio of hyperglycemia became significant when we used the modified criteria. Conclusions: The present study indicated that women with prior GDM had significantly higher risks for postpartum metabolic syndrome, as well as its individual components. (C) 2019 Elsevier B.V. All rights reserved.
  • Luukkonen, Panu K.; Tukiainen, Taru; Juuti, Anne; Sammalkorpi, Henna; Haridas, P. A. Nidhina; Niemelä, Onni; Arola, Johanna; Orho-Melander, Marju; Hakkarainen, Antti; Kovanen, Petri T.; Dwivedi, Om; Groop, Leif; Hodson, Leanne; Gastaldelli, Amalia; Hyötyläinen, Tuulia; Oresic, Matej; Yki-Järvinen, Hannele (2020)
    Carriers of the hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) gene variant (rs72613567:TA) have a reduced risk of NASH and cirrhosis but not steatosis. We determined its effect on liver histology, lipidome, and transcriptome using ultra performance liquid chromatography-mass spectrometry and RNA-seq. In carriers and noncarriers of the gene variant, we also measured pathways of hepatic fatty acids (de novo lipogenesis [ONLI and adipose tissue lipolysis [ATL] using (H2O)-H-2 and H-2-glycerol) and insulin sensitivity using H-3-glucose and euglycemic-hyperinsulinemic clamp) and plasma cytokines. Carriers and noncarriers had similar age, sex and BMI. Fibrosis was significantly less frequent while phospholipids, but not other lipids, were enriched in the liver in carriers compared with noncarriers. Expression of 274 genes was altered in carriers compared with noncarriers, consisting predominantly of downregulated inflammation-related gene sets. Plasma IL-6 concentrations were lower, but DNL, ATL and hepatic insulin sensitivity were similar between the groups. In conclusion, carriers of the HSD17B13 variant have decreased fibrosis and expression of inflammation-related genes but increased phospholipids in the liver. These changes are not secondary to steatosis, ONL, ATL, or hepatic insulin sensitivity. The increase in phospholipids and decrease in fibrosis are opposite to features of choline-deficient models of liver disease and suggest HSD17B13 as an attractive therapeutic target.
  • Huang, Yisong; Ollikainen, Miina; Muniandy, Maheswary; Zhang, Tao; van Dongen, Jenny; Hao, Guang; van Der Most, Peter J.; Pan, Yue; Pervjakova, Natalia; Sun, Yan; Hui, Qin; Lahti, Jari; Fraszczyk, Eliza; Lu, Xueling; Sun, Dianjianyi; Richard, Melissa A.; Willemsen, Gonneke; Heikkila, Kauko; Leach, Irene Mateo; Mononen, Nina; Kähönen, Mika; Hurme, Mikko A.; Raitakari, Olli T.; Drake, Amanda J.; Perola, Markus; Nuotio, Marja-Liisa; Huang, Yunfeng; Khulan, Batbayar; Räikkönen, Katri; Wolffenbuttel, Bruce H. R.; Zhernakova, Alexandra; Fu, Jingyuan; Zhu, Haidong; Dong, Yanbin; van Vliet-Ostaptchouk, Jana V.; Franke, Lude; Eriksson, Johan G.; Fornage, Myriam; Milani, Lili; Lehtimäki, Terho; Vaccarino, Viola; Boomsma, Dorret; van Der Harst, Pim; de Geus, Eco J. C.; Salomaa, Veikko; Li, Shengxu; Chen, Wei; Su, Shaoyong; Wilson, James; Snieder, Harold; Kaprio, Jaakko; Wang, Xiaoling (2020)
    We conducted an epigenome-wide association study meta-analysis on blood pressure (BP) in 4820 individuals of European and African ancestry aged 14 to 69. Genome-wide DNA methylation data from peripheral leukocytes were obtained using the Infinium Human Methylation 450k BeadChip. The epigenome-wide association study meta-analysis identified 39 BP-related CpG sites withP
  • Kristensen, Peter L.; Pedersen-Bjergaard, Ulrik; Due-Andersen, Rikke; Hoi-Hansen, Thomas; Grimmeshave, Lise; Lyssenko, Valeriya; Groop, Leif; Holst, Jens J.; Vaag, Allan A.; Thorsteinsson, Birger (2016)
    Introduction: In healthy carriers of the T allele of the transcription factor 7-like 2 (TCF7L2), fasting plasma glucagon concentrations are lower compared with those with the C allele. We hypothesised that presence of the T allele is associated with a diminished glucagon response during hypoglycaemia and a higher frequency of severe hypoglycaemia (SH) in type 1 diabetes (T1DM). Material and methods: This is a post hoc study of an earlier prospective observational study of SH and four mechanistic studies of physiological responses to hypoglycaemia. 269 patients with T1DM were followed in a one-year observational study. A log-linear negative binomial model was applied with events of SH as dependent variable and TCF7L2 alleles as explanatory variable. In four experimental studies including 65 people, TCF7L2 genotyping was done and plasma glucagon concentration during experimental hypoglycaemia was determined. Results: Incidences of SH were TT 0.54, TC 0.98 and CC 1.01 episodes per patient-year with no significant difference between groups. During experimental hypoglycaemia, the TCF7L2 polymorphism did not influence glucagon secretion. Discussion: Patients with T1DM carrying the T allele of the TCF7L2 polymorphism do not exhibit diminished glucagon response during hypoglycaemia and are not at increased risk of severe hypoglycaemia compared with carriers of the C allele.
  • Gordin, Daniel; Saraheimo, Markku; Tuomikangas, Jaana; Soro-Paavonen, Aino; Forsblom, Carol; Paavonen, Karri Jorma Antero; Steckel-Hamann, Birgit; Vandenhende, Francois; Nicolaou, Loizos; Pavo, Imre; Koivisto, Veikko; Groop, Per-Henrik (2016)
    Context: Patients with type 2 diabetes (T2D) are at an increased risk of cardiovascular disease. Objective: The objective of the study was to determine whether postprandial hyperglycemia affects arterial function in T2D. Design: Asingle-center, open-label study of three groups of men were studied: 1) T2D patients with albuminuria (n = 22), 2) T2D patients without albuminuria (n = 24), and 3) nondiabetic controls (n = 25). Patients were randomized to a two-period crossover study schedule, ingesting breakfast, with or without insulin lispro (to induce low or high postprandial glycemia). Main Outcome Measures: Arterial stiffness was assessed by calculating pulse wave velocity (PWV) and augmentation index using applanation tonometry, and endothelial dysfunction was assessed using peripheral arterial tonometry, 30 minutes before breakfast and up to 240 minutes after breakfast. Results: At baseline, arterial stiffness was increased in patients. When adjusted for age and body mass index, in a combined group of patients with and without albuminuria, brachial PWV was higher during low (P = .032) and high (P = .038) postprandial glycemia vs controls. These differences were driven by the albuminuria group vs controls during low (P = .014) and high (P = .018) postprandial glycemia. No differences were observed in aortic PWV, augmentation index, or peripheral arterial tonometry ratio between patients and controls. Endothelin-1 and IL-6 were higher, and superoxide dismutase was lower, during postprandial hyperglycemia in T2D patients vs controls. Conclusions: In patients with T2D and albuminuria, brachial PWV was higher under postprandial hyperglycemic conditions, relative to controls. These data suggest that hyperglycemia induces an increase in stiffness of intermediate-sized arteries. We found no changes in other parts of the arterial bed.
  • Jain, Ruchi; Ozgumus, Turkuler; Jensen, Troels Mygind; du Plessis, Elsa; Keindl, Magdalena; Moller, Cathrine Laustrup; Falhammar, Henrik; Nystrom, Thomas; Catrina, Sergiu-Bogdan; Jorneskog, Gun; Jessen, Leon Eyrich; Forsblom, Carol; Haukka, Jani K.; Groop, Per-Henrik; Rossing, Peter; Groop, Leif; Eliasson, Mats; Eliasson, Bjorn; Brismar, Kerstin; Al-Majdoub, Mahmoud; Nilsson, Peter M.; Taskinen, Marja-Riitta; Ferrannini, Ele; Spegel, Peter; Berg, Tore Julsrud; Lyssenko, Valeriya (2020)
    Identification of biomarkers associated with protection from developing diabetic complications is a prerequisite for an effective prevention and treatment. The aim of the present study was to identify clinical and plasma metabolite markers associated with freedom from vascular complications in people with very long duration of type 1 diabetes (T1D). Individuals with T1D, who despite having longer than 30 years of diabetes duration never developed major macro- or microvascular complications (non-progressors; NP) were compared with those who developed vascular complications within 25 years from diabetes onset (rapid progressors; RP) in the Scandinavian PROLONG (n = 385) and DIALONG (n = 71) cohorts. The DIALONG study also included 75 healthy controls. Plasma metabolites were measured using gas and/or liquid chromatography coupled to mass spectrometry. Lower hepatic fatty liver indices were significant common feature characterized NPs in both studies. Higher insulin sensitivity and residual beta-cell function (C-peptide) were also associated with NPs in PROLONG. Protection from diabetic complications was associated with lower levels of the glycolytic metabolite pyruvate and APOCIII in PROLONG, and with lower levels of thiamine monophosphate and erythritol, a cofactor and intermediate product in the pentose phosphate pathway as well as higher phenylalanine, glycine and serine in DIALONG. Furthermore, T1D individuals showed elevated levels of picolinic acid as compared to the healthy individuals. The present findings suggest a potential beneficial shunting of glycolytic substrates towards the pentose phosphate and one carbon metabolism pathways to promote nucleotide biosynthesis in the liver. These processes might be linked to higher insulin sensitivity and lower liver fat content, and might represent a mechanism for protection from vascular complications in individuals with long-term T1D.
  • Tanaka, Yuki; Shimanaka, Yuta; Caddeo, Andrea; Kubo, Takuya; Mao, Yanli; Kubota, Tetsuya; Kubota, Naoto; Yamauchi, Toshimasa; Mancina, Rosellina Margherita; Baselli, Guido; Luukkonen, Panu; Pihlajamäki, Jussi; Yki-Järvinen, Hannele; Valenti, Luca; Arai, Hiroyuki; Romeo, Stefano; Kono, Nozomu (2021)
    Objective Non-alcoholic fatty liver disease (NAFLD) is a common prelude to cirrhosis and hepatocellular carcinoma. The genetic rs641738 C>T variant in the lysophosphatidylinositol acyltransferase 1 (LPIAT1)/membrane bound O-acyltransferase domain-containing 7, which incorporates arachidonic acid into phosphatidylinositol (PI), is associated with the entire spectrum of NAFLD. In this study, we investigated the mechanism underlying this association in mice and cultured human hepatocytes. Design We generated the hepatocyte-specific Lpiat1 knockout mice to investigate the function of Lpiat1 in vivo. We also depleted LPIAT1 in cultured human hepatic cells using CRISPR-Cas9 systems or siRNA. The effect of LPIAT1-depletion on liver fibrosis was examined in mice fed high fat diet and in liver spheroids. Lipid species were measured using liquid chromatography-electrospray ionisation mass spectrometry. Lipid metabolism was analysed using radiolabeled glycerol or fatty acids. Results The hepatocyte-specific Lpiat1 knockout mice developed hepatic steatosis spontaneously, and hepatic fibrosis on high fat diet feeding. Depletion of LPIAT1 in cultured hepatic cells and in spheroids caused triglyceride accumulation and collagen deposition. The increase in hepatocyte fat content was due to a higher triglyceride synthesis fueled by a non-canonical pathway. Indeed, reduction in the PI acyl chain remodelling caused a high PI turnover, by stimulating at the same time PI synthesis and breakdown. The degradation of PI was mediated by a phospholipase C, which produces diacylglycerol, a precursor of triglyceride. Conclusion We found a novel pathway fueling triglyceride synthesis in hepatocytes, by a direct metabolic flow of PI into triglycerides. Our findings provide an insight into the pathogenesis and therapeutics of NAFLD.
  • Helle, Emmi; Priest, James R. (2020)
    Congenital heart disease (CHD) is the most common anatomical malformation occurring live-born infants and an increasing cause of morbidity and mortality across the lifespan and throughout the world. Population-based observations have long described associations between maternal cardiometabolic disorders and the risk of CHD in the offspring. Here we review the epidemiological evidence and clinical observations relating maternal obesity and diabetes mellitus to the risk of CHD offspring with particular attention to mechanistic models of maternal-fetal risk transmission and first trimester disturbances of fetal cardiac development. A deeper understanding of maternal risk factors holds the potential to improve both prenatal detection of CHD by identifying at-risk pregnancies, along with primary prevention of disease by improving preconception and prenatal treatment of at-risk mothers.
  • van Leeuwen, Elisabeth M.; Sabo, Aniko; Bis, Joshua C.; Huffman, Jennifer E.; Manichaikul, Ani; Smith, Albert V.; Feitosa, Mary F.; Demissie, Serkalem; Joshi, Peter K.; Duan, Qing; Marten, Jonathan; van Klinken, Jan B.; Surakka, Ida; Nolte, Ilja M.; Zhang, Weihua; Mbarek, Hamdi; Li-Gao, Ruifang; Trompet, Stella; Verweij, Niek; Evangelou, Evangelos; Lyytikainen, Leo-Pekka; Tayo, Bamidele O.; Deelen, Joris; van der Most, Peter J.; van der Laan, Sander W.; Arking, Dan E.; Morrison, Alanna; Dehghan, Abbas; Franco, Oscar H.; Hofman, Albert; Rivadeneira, Fernando; Sijbrands, Eric J.; Uitterlinden, Andre G.; Mychaleckyj, Josyf C.; Campbell, Archie; Hocking, Lynne J.; Padmanabhan, Sandosh; Brody, Jennifer A.; Rice, Kenneth M.; White, Charles C.; Harris, Tamara; Isaacs, Aaron; Campbell, Harry; Lange, Leslie A.; Rudan, Igor; Kolcic, Ivana; Navarro, Pau; Zemunik, Tatijana; Salomaa, Veikko; Ripatti, Samuli; CHARGE Lipids Working Grp (2016)
    Background So far, more than 170 loci have been associated with circulating lipid levels through genome-wide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels. Methods We used the 1000 Genomes Project as a reference panel for the imputations of GWAS data from similar to 60 000 individuals in the discovery stage and similar to 90 000 samples in the replication stage. Results Our study resulted in the identification of five new associations with circulating lipid levels at four loci. All four loci are within genes that can be linked biologically to lipid metabolism. One of the variants, rs116843064, is a damaging missense variant within the ANGPTL4 gene. Conclusions This study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels.
  • Jutila, Eveliina; Koivunen, Risto; Kiiski, Iiro; Bollström, Roger; Sikanen, Tiina; Gane, Patrick (2018)
    Cytochrome P450 (CYP) is a superfamily of enzymes in charge of elimination of the majority of clinically used drugs and other xenobiotics. This study focuses on the development of a rapid microfluidic lateral flow assay to study human phase I metabolism reactions mediated by CYP2A6 isoenzyme, the major detoxification route for many known carcinogens and drugs, with coumarin 7-hydroxylation, as the prototype model reaction. Assay fabrication utilizes custom-designed porous functionalized calcium carbonate (FCC) coatings and inkjet-printed fluid barriers. All materials used are novel and carefully chosen to preserve biocompatibility. The design comprises separate zones for reaction, separation and detection, and an absorbent pad to keep the assay wet for extended periods (up to 10 min) even when heated to physiological temperature. The concept enables CYP assays to be made at lower cost than conventional well-plate assays, while providing increased selectivity at equally high speed, owing to the possibility for simultaneous chromatographic separation of the reaction products from the reactants on the FCC coating. The developed concept provides a viable rapid prediction of the interaction risks related to metabolic clearance of drugs and other xenobiotics, and exemplifies a novel coating technology illustrating the opportunity to broaden application functionality.
  • Wrigstedt, P.; Keskiväli, J.; Repo, T. (2016)
    We describe herein an efficient microwave-assisted aqueous biphasic dehydration of carbohydrates to 5-hydroxymethylfurfural (HMF). The effects of several alkali metal salts in aqueous phase, organic solvents as an extractive phase and Lewis acids are evaluated on the reaction. Specifically, starting from fructose, the use of bromide salts in aqueous phase and the common organic solvent MeCN or lignocellulose-derived gamma-valerolactone (GVL) as organic extractors are highly beneficial, leading to excellent HMF yields of up to 91% with HCl as a Bronsted acid catalyst. In conjunction with an isomerization catalyst, the method was applicable to glucose as well as various disaccharides and cellulose, affording HMF in notably good yields, particularly with GVL as an extractor and reusable Amberlyst-38(wet) as an acid catalyst. The exceptionally high HMF yields obtained in aqueous solutions is attributed to the combined effect of the biphasic reaction system and the application of microwaves, which ensures short reaction times and minimized by-product formation thereof.
  • Bayoumi, Ali; Elsayed, Asmaa; Han, Shuanglin; Petta, Salvatore; Adams, Leon A.; Aller, Rocio; Khan, Anis; Garcia-Monzon, Carmelo; Arias-Loste, Maria Teresa; Miele, Luca; Latchoumanin, Olivier; Alenizi, Shafi; Gallego-Duran, Rocio; Fischer, Janett; Berg, Thomas; Craxi, Antonio; Metwally, Mayada; Qiao, Liang; Liddle, Christopher; Yki-Järvinen, Hannele; Bugianesi, Elisabetta; Romero-Gomez, Manuel; George, Jacob; Eslam, Mohammed (2021)
    Fibroblast growth factor 21 (FGF21) is a liver-derived hormone with pleiotropic beneficial effects on metabolism. Paradoxically, FGF21 levels are elevated in metabolic diseases. Interventions that restore metabolic homeostasis reduce FGF21. Whether abnormalities in FGF21 secretion or resistance in peripheral tissues is the initiating factor in altering FGF21 levels and function in humans is unknown. A genetic approach is used to help resolve this paradox. The authors demonstrate that the primary event in dysmetabolic phenotypes is the elevation of FGF21 secretion. The latter is regulated by translational reprogramming in a genotype- and context-dependent manner. To relate the findings to tissues outcomes, the minor (A) allele of rs838133 is shown to be associated with increased hepatic inflammation in patients with metabolic associated fatty liver disease. The results here highlight a dominant role for translation of the FGF21 protein to explain variations in blood levels that is at least partially inherited. These results provide a framework for translational reprogramming of FGF21 to treat metabolic diseases.
  • Lallukka-Brück, Susanna; Isokuortti, Elina; Luukkonen, Panu K.; Hakkarainen, Antti; Lundbom, Nina; Sutinen, Jussi; Yki-Järvinen, Hannele (2020)
    Background: Abnormal glucose metabolism and nonalcoholic fatty liver disease (NAFLD) are common in patients with human immunodeficiency virus (HIV+ patients), but longitudinal data are lacking. We determined the natural course of NAFLD (liver fat [LFAT]) and type 2 diabetes mellitus (T2DM) in HIV+ patients with and without lipodystrophy (LD+ and LD-, respectively) during a 16-year longitudinal study. Methods: LFAT (by proton magnetic resonance spectroscopy) and clinical characteristics were measured in 41 HIV+ patients at baseline and after 16 years. Liver fibrosis was estimated by measuring liver stiffness using transient elastography (TE) and magnetic resonance elastography (MRE) at 16 years. We also longitudinally studied 28 healthy subjects. Results: During follow-up, the HIV+ patients gained more body fat (8.6% 0.7%) than the control patients (4.5% 0.6%, P <.001). Features of insulin resistance increased significantly in the HIV+ patients but not the control patients. A significant proportion (20%, P <.01 vs 0% at baseline) of the HIV+ but none of the control patients developed T2DM. LFAT was significantly higher at baseline in the LD+ (4.3 [1.9-11.8]) than the LD- (1.0 [0.5-1.5]; P <.001) HIV+ patients. LFAT remained stable during follow-up in all groups. At follow-up, liver stiffness measured with TE was similar among all HIV, LD+, LD-, and control patients and between the LD+ and LD- patients measured with MRE. Advanced fibrosis by MRE was observed in 3 of LD+ and none of LD- patients. Conclusions: During 16 years of follow-up, progression of NAFLD is rare compared to development of T2DM in HIV+ patients.
  • Lallukka, Susanna; Sadevirta, Sanja; Kallio, Markus T.; Luukkonen, Panu K.; Zhou, You; Hakkarainen, Antti; Lundbom, Nina; Orho-Melanders, Marju; Yki-Jarvinen, Hannele (2017)
    Liver fat can be non-invasively measured by proton magnetic resonance spectroscopy (H-1-MRS) and fibrosis estimated as stiffness using transient elastography (FibroScan). There are no longitudinal data on changes in liver fat in Europids or on predictors of liver stiffness using these methods. We determined liver fat (1H-MRS) and clinical characteristics including features of insulin resistance at baseline and after a median follow-up period of 11.3 (range 7.3-13.4) years in 97 Finnish subjects. Liver stiffness was measured at 11.3 years. Liver fat content decreased by 5% (p <0.05) over time. Values at baseline and 11.3 years were closely interrelated (r = 0.81, p <0.001). Baseline liver fat (OR 1.32; 95% CI: 1.15-1.50) and change in BMI (OR 1.67; 95% CI: 1.24-2.25) were independent predictors of liver fat at 11.3 years (AUROC 0.90; 95% CI: 0.83-0.96). Baseline liver fat (AUROC 0.84; 95% CI: 0.76-0.92) predicted liver fat at 11.3 years more accurately than routinely available parameters (AUROC 0.76; 95% CI: 0.65-0.86, p = 0.02). At 11.3 years, 29% of the subjects had increased liver stiffness. Baseline liver fat (OR 2.17; 95% CI: 1.05-4.46) was an independent predictor of increased liver stiffness. These data show that liver fat is more important than the associated metabolic abnormalities as the predictor of future liver fat and fibrosis.
  • Paliwal, Vasundhara; Raju, Sajan C.; Modak, Arnab; Phale, Prashant S.; Purohit, Hemant J. (2014)
  • Service, Susan K.; Teslovich, Tanya M.; Fuchsberger, Christian; Ramensky, Vasily; Yajnik, Pranav; Koboldt, Daniel C.; Larson, David E.; Zhang, Qunyuan; Lin, Ling; Welch, Ryan; Ding, Li; McLellan, Michael D.; O'Laughlin, Michele; Fronick, Catrina; Fulton, Lucinda L.; Magrini, Vincent; Swift, Amy; Elliott, Paul; Jarvelin, Marjo-Riitta; Kaakinen, Marika; McCarthy, Mark I.; Peltonen, Leena; Pouta, Anneli; Bonnycastle, Lori L.; Collins, Francis S.; Narisu, Narisu; Stringham, Heather M.; Tuomilehto, Jaakko; Ripatti, Samuli; Fulton, Robert S.; Sabatti, Chiara; Wilson, Richard K.; Boehnke, Michael; Freimer, Nelson B. (2014)
  • Haridas, P. A. Nidhina; Soronen, Jarkko; Sädevirta, Sanja; Mysore, Raghavendra; Quagliarini, Fabiana; Pasternack, Arja; Metso, Jari; Perttila, Julia; Leivonen, Marja; Smas, Cynthia M.; Fischer-Posovszky, Pamela; Wabitsch, Martin; Ehnholm, Christian; Ritvos, Olli; Jauhiainen, Matti; Olkkonen, Vesa M.; Yki-Jarvinen, Hannele (2015)
    Objective: Circulating ANGPTL8 has recently been used as a marker of insulin action. We studied expression and insulin regulation of ANGPTL8 and ANGPTL3 in vivo and in vitro. Design and Methods: Expression of ANGPTL8 and ANGPTL3 was studied in 34 paired samples of human liver and adipose tissue. Effects of insulin on 1) plasma concentrations and adipose tissue expression of ANGPTL8 and ANGPTL3 (in vivo 6-h euglycemic hyperinsulinemia; n = 18), and 2) ANGPTL8 and ANGPTL3 gene and protein expression in immortalized human hepatocytes (IHH) and adipocytes were measured. Effect of ANGPTL3 on secretion of ANGPTL8 in cells stably over-expressing ANGPTL3, -8, or both was determined. Results: ANGPTL3 was only expressed in the liver, whereas ANGPTL8 was expressed in both tissues. In vivo hyperinsulinemia significantly decreased both plasma ANGPTL8 and ANGPTL3 at 3 and 6 hours. Insulin increased ANGPTL8 expression in human adipose tissue 14- and 18-fold at 3 and 6 hours and ANGPTL8 was the most insulin-responsive transcript on microarray. Insulin also increased ANPGTL8 in cultured adipocytes and IHH but the protein mainly remained intracellular. In vitro in IHH, insulin decreased ANGPTL3 gene expression and secretion of ANGPTL3 into growth medium. Overexpression of ANGPTL8 in CHO cells did not result in its release into culture medium while abundant secretion occurred in cells co-expressing ANGPTL3 and -8. Conclusions: Insulin decreases plasma ANGPTL3 by decreasing ANGPTL3 expression in the liver. Insulin markedly increases ANGPTL8 in adipose tissue and the liver but not in plasma. These data show that measurement of plasma ANGPTL3 but not -8 reflects insulin action in target tissues.
  • EFSA Panel Dietetic Prod Nutr Al (2018)
    Following a request from the European Commission, the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) was asked to deliver an opinion on D-ribose as a novel food (NF) pursuant to Regulation (EU) 2015/2283. The applicant intends to market the NF as ingredient in a variety of foods, food supplements and in certain foods for specific groups. The NF is produced by fermentation using a transketolase-deficient strain of Bacillus subtilis and marketed as Bioenergy Ribose (TM). The information provided on the batch-to-batch variability, specifications, stability, production process and history of the organism used as a source of the NF is sufficient and does not raise safety concerns. The Panel considers that the effects observed in a subchronic toxicity study in rats could be the consequence of nutritional imbalances, but toxicological effects could not be ruled out; from this study, the Panel derived a No observed adverse effect level (NOAEL) of 3.6 g/kg body weight (bw) per day. From the human studies indicating a potential decrease in glucose levels and/or the occurrence of transient symptomatic hypoglycaemia at intakes of 10 g of D-ribose, the Panel defined 70 mg/kg bw per day as the NOAEL with respect to hypoglycaemia that can be considered applicable for adults. For children, the Panel acknowledges the lack of human data directly relevant for this population group. Based on the NOAEL derived from the subchronic toxicity study in rats, an acceptable level of intake of 36 mg/kg bw per day was defined that would also take into account the potentially increased sensitivity of certain population groups to hypoglycaemia. The Panel concludes that the NF is safe for the general population at intake levels up to 36 mg/kg bw per day and considers that the safety of the NF at the intended uses and use levels as proposed by the applicant has not been established. (C) 2018 European Food Safety Authority. EFSA Journal published by John Wiley and Sons Ltd on behalf of European Food Safety Authority.