Effects of Meal Fructose/Glucose Composition on Postprandial Glucose Appearance and Hepatic Glycogen Synthesis in Healthy Subjects
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Journal of Clinical Medicine Article Effects of Meal Fructose/Glucose Composition on Postprandial Glucose Appearance and Hepatic Glycogen Synthesis in Healthy Subjects Cristina Barosa 1, Rogério T. Ribeiro 2, Rita Andrade 2, João F. Raposo 2 and John G. Jones 1,2,* 1 Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal; [email protected] 2 Education and Research Center, Associação Protetora dos Diabéticos de Portugal (APDP), 1250-189 Lisbon, Portugal; [email protected] (R.T.R.); [email protected] (R.A.); [email protected] (J.F.R.) * Correspondence: john.griffi[email protected] Abstract: Dietary fructose overshadows glucose in promoting metabolic complications. Intestinal fructose metabolism (IFM) protects against these effects in rodents, by favoring gluconeogenesis, but the extent of IFM in humans is not known. We therefore aimed to infer the extent of IFM by comparing the contribution of dietary fructose to systemic glucose and hepatic glycogen appearance postprandially. Twelve fasting healthy subjects ingested two protein meals in random order, one supplemented with 50 g 5/95 fructose/glucose (LF) and the other with 50 g 55/45 fructose/glucose (HF). Sources of postprandial plasma glucose appearance and hepatic glycogen synthesis were determined with deuterated water. Plasma glucose excursions, as well as pre- and post-meal insulin, c-peptide, and triglyceride levels were nearly identical for both meals. The total gluconeogenic contribution to plasma glucose appearance was significantly higher for HF versus LF (65 ± 2% vs. Citation: Barosa, C.; Ribeiro, R.T.; 34 ± 3%, p < 0.001). For HF, Krebs cycle anaplerosis accounted for two-thirds of total gluconeogenesis Andrade, R.; Raposo, J.F.; Jones, J.G. (43 ± 2%) with one-third from Triose-P sources (22 ± 1%). With LF, three-quarters of the total Effects of Meal Fructose/Glucose gluconeogenic contribution originated via Krebs cycle anaplerosis (26 ± 2%) with one-quarter from Composition on Postprandial Triose-P sources (9 ± 2%). HF and LF gave similar direct and indirect pathway contributions to Glucose Appearance and Hepatic Glycogen Synthesis in Healthy hepatic glycogen synthesis. Increasing the fructose/glucose ratio had significant effects on glucose Subjects. J. Clin. Med. 2021, 10, 596. appearance sources but no effects on hepatic glycogen synthesis sources, consistent with extensive https://doi.org/10.3390/jcm10040596 IFM. The majority of fructose carbons were converted to glucose via the Krebs cycle. Academic Editors: Tomoaki Morioka Keywords: fructose; deuterated water; glycemic profile; indirect pathway; intestinal gluconeogenesis and Radica Alicic Received: 21 October 2020 Accepted: 29 January 2021 Published: 5 February 2021 1. Introduction Over the past few decades, consumption of refined sugar, which includes sucrose Publisher’s Note: MDPI stays neutral and high-fructose corn syrup, has sharply increased worldwide and is implicated in the with regard to jurisdictional claims in increased prevalence of obesity and its metabolic complications such as nonalcoholic fatty published maps and institutional affil- liver disease (NAFLD) and type 2 diabetes [1,2]. While the glucose and fructose components iations. of refined sugar are isocaloric, the pathophysiology of NAFLD and related complications seems to be accelerated more by fructose than glucose [2]. Thus, there is high interest in understanding how this is linked to the differential metabolism of these sugars by the body. The liver has long been assumed to be the main site for fructose metabolism [3,4]. Copyright: © 2021 by the authors. However, recent studies in mice have shown a capacity for intestinal fructose metabolism Licensee MDPI, Basel, Switzerland. coupled to intestinal gluconeogenesis [4,5]. By this mechanism, fructose is immediately This article is an open access article metabolized by intestinal tissues, with glucose and other metabolic products such as lactate distributed under the terms and and alanine appearing in the portal vein blood [4]. This has two important implications conditions of the Creative Commons for the metabolism of refined sugar. First, metabolism of fructose by the liver is limited Attribution (CC BY) license (https:// to conditions where the intestinal capacity is exceeded, for example following high sugar creativecommons.org/licenses/by/ 4.0/). intake. Second, to the extent that fructose is converted to glucose by the intestine, intake of a J. Clin. Med. 2021, 10, 596. https://doi.org/10.3390/jcm10040596 https://www.mdpi.com/journal/jcm J. Clin. Med. 2021, 10, 596 2 of 12 J. Clin. Med. 2021, 10, x FOR PEER REVIEW 2 of 12 tatefructose and alanine load thatappearing is within in the the portal intestinal vein blood metabolic [4]. This capacityhas two important will result implica- in a portal vein glucose tionsexcursion for the metabolism resembling of thatrefined from sugar. a glucose First, metabolism load of theof fructose same size.by the Thus, liver is from lim- the perspective of itedthe to portal conditions glucose where sensor, the intestinalβ-cell capacity insulin is response, exceeded, andfor example systemic following glycemic high excursion, fructose sugar intake. Second, to the extent that fructose is converted to glucose by the intestine, intakeand glucose of a fructose loads load of thisthat is size within are indistinguishable.the intestinal metabolic The capacity activity will of result intestinal in a gluconeogenesis portalappears vein to glucose be highly excursion species resembling dependent that from [5], a and glucose for load humans, of the thesame capacity size. Thus, of intestinal fructose frommetabolism the perspective in relation of the portal to the glucose amount sensor, of refined β-cell insulin sugar response, intake isand not systemic well characterized. glycemic excursion, fructose and glucose loads of this size are indistinguishable.2 The ac- Thus, our aim was to apply deuterated water ( H2O) to determine the sources of tivity of intestinal gluconeogenesis appears to be highly species dependent [5], and for humans,systemic the glucose capacity of appearance intestinal fructose and hepaticmetabolism glycogen in relation synthesis to the amount following of refined meal tolerance tests sugarwith intake low andis not high well characterized. fructose levels, respectively. Thus,As summarizedour aim was to apply in Figure deuterated1, the water contribution (2H2O) to determine of the the meal sources fructose of sys- and glucose com- temicponents glucose to appearance the appearance and hepatic of circulating glycogen synthesis glucose following and hepatic meal tolerance glycogen tests can be estimated withby measuringlow and high fructose their positional levels, respectively.2H-enrichments from 2H O[6–8]. In humans, the 2H- As summarized in Figure 1, the contribution of the meal fructose and2 glucose com- ponentsenrichment to the appearance distribution of circulating of the glucosyl glucose and components hepatic glycogen of newly-synthesized can be estimated liver glycogen bycan measuring be noninvasively their positional measured 2H-enrichments via from “chemical 2H2O [6–8] biopsy”. In humans, of uridinethe 2H-enrich- diphosphate glucose men(UDP-glucose)t distribution of by the Paracetamol glucosyl components and analysis of newly- ofsynthesized the urinary liver glycogen Paracetamol can be glucuronide prod- noninvasivelyuct [9,10]. From measured this via information, “chemical biopsy” the fractional of uridine diphosphate contributions glucose of direct(UDP-glu- and indirect pathway cose) by Paracetamol and analysis of the urinary Paracetamol glucuronide product [9,10]. Fromfluxes this to information, newly-synthesized the fractional glycogen contributions can of bedirect estimated. and indirect Fructose pathway isfluxes metabolized to glyco- togen newly exclusively-synthesized via glycogen the indirect can be estimated. pathway Fructose [8], while is metabolized dietary glucose to glycogen is converted ex- to glycogen clusivelyvia both via direct the indirect and indirect pathway pathways[8], while dietary [11–13 glucose]. Thus, is converted the relative to glycogen contributions via of direct and bothindirect direct pathwaysand indirect topathways hepatic [11 glycogen–13]. Thus,synthesis the relative arecontributions influenced of direct in part and by the availability indirectof fructose pathways relative to hepatic to glucose glycogen at synthesis the hepatocyte are influenced level. in part by the availability of fructose relative to glucose at the hepatocyte level. 2 2 [5- H],[6S- H]Glycogen [5-2H]Glycogen Glycogen 2 2 [5- H],[6S- H]UDPG 2 2 [5- H]Glucuronide [5- H]UDPG Glucuronide UDPG 2 2 [5- H],[6S- H]Glucose Glucose-6-P [5-2H]Glucose Glucose Fructose-6-P Lactate, Alanine Fructose-1,6-P2 2 2 H2O H2O Pyruvate G-3-P DHAP Fructose + Glucose 2 Figure 1. Metabolic scheme relating H-enrichment2 in positions 5 and 6 of circulating glucose, UDPFigure-glucose 1. Metabolic (UDPG), glucuronide scheme relatingand hepaticH-enrichment glycogen with the in utilization positions of 5fructose and 6 and of circulatingglu- glucose, UDP- coseglucose from the (UDPG), test meal. glucuronide On conversion and of fructose hepatic to glycogendihydroxyacetone withthe phosphate utilization (DHAP) of and fructose and glucose from glyceraldehydethe test meal.-3- Onphosphate conversion (G-3-P), of hydrogen fructose exchange to dihydroxyacetone mediated by triose phosphate phosphate isomerase (DHAP) and glyceraldehyde-