The region of enteral nutrient exposure may be an important determinant of postprandial incretin hormone secretion and blood glucose homoeostasis. We compared responses of plasma glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), insulin and glucagon, and blood glucose to a standardised glucose infusion into the proximal jejunum and duodenum in healthy humans. Ten healthy males were evaluated during a standardised glucose infusion (2 kcal min−1 over 120 min) into the proximal jejunum (50 cm post pylorus) and were compared with another 10 healthy males matched for ethnicity, age and body mass index who received an identical glucose infusion into the duodenum (12 cm post pylorus). Blood was sampled frequently for measurements of blood glucose and plasma hormones. Plasma GLP-1, GIP and insulin responses, as well as the insulin:glucose ratio and the insulinogenic index 1 (IGI1) were greater (P<0.05 for each) after intrajejunal (i.j.) than intraduodenal glucose infusion, without a significant difference in blood glucose or plasma glucagon. Pooled analyses revealed direct relationships between IGI1 and the responses of GLP-1 and GIP (r=0.48 and 0.56, respectively, P<0.05 each), and between glucagon and GLP-1 (r=0.70, P<0.001). In conclusion, i.j. glucose elicits greater incretin hormone and insulin secretion than intraduodenal glucose in healthy humans, suggesting regional specificity of the gut–incretin axis.T Wu, S S Thazhath, C S Marathe, M J Bound, K L Jones, M Horowitz and C K Rayne

Bound, M.

Horowitz, M.

Jones, K.

Marathe, C.

Rayner, C.

Thazhath, S.

Wu, T.

Nutrition and Diabetes

Adelaide Research &amp; Scholarship

PUBLISHED VERSION  http://hdl.handle.net/2440/98876   T Wu, S S Thazhath, C S Marathe, M J Bound, K L Jones, M Horowitz and C K Rayner Comparative effect of intraduodenal and intrajejunal glucose infusion on the gut-incretin axis response in healthy males Nutrition and Diabetes, 2015; 5(5):e156-1-e156-4 This work is licensed under a Creative Commons Attribution 4.0 International License. Originally published at: http://doi.org/10.1038/nutd.2015.6                   PERMISSIONS   http://creativecommons.org/licenses/by/4.0/      OPENSHORT COMMUNICATIONComparative effect of intraduodenal and intrajejunal glucoseinfusion on the gut–incretin axis response in healthy malesT Wu1,2, SS Thazhath1,2, CS Marathe1,2, MJ Bound1,2, KL Jones1,2, M Horowitz1,2 and CK Rayner1,2The region of enteral nutrient exposure may be an important determinant of postprandial incretin hormone secretion and bloodglucose homoeostasis. We compared responses of plasma glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropicpolypeptide (GIP), insulin and glucagon, and blood glucose to a standardised glucose infusion into the proximal jejunum andduodenum in healthy humans. Ten healthy males were evaluated during a standardised glucose infusion (2 kcal min− 1 over120min) into the proximal jejunum (50 cm post pylorus) and were compared with another 10 healthy males matched for ethnicity,age and body mass index who received an identical glucose infusion into the duodenum (12 cm post pylorus). Blood was sampledfrequently for measurements of blood glucose and plasma hormones. Plasma GLP-1, GIP and insulin responses, as well as theinsulin:glucose ratio and the insulinogenic index 1 (IGI1) were greater (Po0.05 for each) after intrajejunal (i.j.) than intraduodenalglucose infusion, without a signiﬁcant difference in blood glucose or plasma glucagon. Pooled analyses revealed directrelationships between IGI1 and the responses of GLP-1 and GIP (r= 0.48 and 0.56, respectively, Po0.05 each), and betweenglucagon and GLP-1 (r= 0.70, Po0.001). In conclusion, i.j. glucose elicits greater incretin hormone and insulin secretion thanintraduodenal glucose in healthy humans, suggesting regional speciﬁcity of the gut–incretin axis.Nutrition & Diabetes (2015) 5, e156; doi:10.1038/nutd.2015.6; published online 18 May 2015INTRODUCTIONRoux-en-Y gastric bypass leads to remarkable improvements inglycaemic control in type 2 diabetes, associated with an enhancedincretin effect (the phenomenon of an ampliﬁed insulin responseto enteral vs intravenous (i.v.) glucose, mediated by glucagon-likepeptide-1 (GLP-1) and glucose-dependent insulinotropic polypep-tide (GIP)).1,2 This may relate to diversion of nutrients more distallyin the small intestine, as similar beneﬁts are observed with theendoluminal sleeve device.3 We hypothesised that bypassing theduodenum would elicit a greater response of the gut–incretin axisto small intestinal glucose infusion, and compared plasma GLP-1,GIP, insulin and glucagon, and blood glucose responses toa standardised glucose infusion into the proximal jejunum andduodenum in healthy humans.SUBJECTS AND METHODSTen healthy males received an intrajejunal (i.j.) glucose infusion;data regarding blood glucose, and plasma insulin, glucagon andGLP-1 have been reported previously.4 These, together withplasma GIP, were compared with 10 healthy males who receivedan intraduodenal (i.d.) glucose infusion (Table 1). All subjectsprovided written, informed consent. Protocols were approved bythe Royal Adelaide Hospital Human Research Ethics Committee.On the evening before each study (~1900 hours), each subjectconsumed a standardised beef lasagne meal (McCain, Wendouree,VIC, Australia), and then fasted from solids and refrained fromliquids after 2200 hours. Subjects attended the laboratory at~ 0800 hours the following day, when a multilumen siliconecatheter (Dentsleeve International, Ontario, Canada) was posi-tioned transnasally in either the duodenum or proximal jejunum(infusion port: 12 vs 50 cm beyond the pylorus) by peristalsis, withmonitoring of antral and duodenal transmucosal potentialdifference.4 In the i.j. study, a balloon was inﬂated 30 cm beyondthe pylorus to exclude the duodenum.4 Enteral glucose was theninfused at 2 kcal min− 1 for 120min (t= 0–120min). An i.v. cannulawas inserted into a forearm vein for blood sampling. Bloodsamples were collected at frequent intervals into ice-chilled EDTAtubes and immediately centrifuged at 3200 r.p.m., for 15min at 4 °C.Plasma was separated and stored at − 70 °C until analysed.Blood glucose was measured by glucometer (MedisensePrecision QID, Bedford, MA, USA). Plasma total GLP-1 wasmeasured by radioimmunoassay (GLP1T-36HK; Linco Research,St Charles, MO, USA) with a sensitivity of 3 pmol l− 1, and intra- andinter-assay coefﬁcients of variation (CVs) of 6.8% and 8.5%,respectively. Plasma total GIP was measured by radioimmunoas-say modiﬁed from a previously published method,5 witha sensitivity of 2 pmol l− 1, and intra- and inter-assay CVs of 5.1%and 8.8%, respectively. Plasma insulin was measured by enzyme-linked immunosorbent assay (10-1113; Mercodia, Uppsala,Sweden) with a sensitivity of 1 mU l− 1 and intra- and inter-assayCVs of 2.7% and 7.8%, respectively. Plasma glucagon wasmeasured by radioimmunoassay (GL-32 K; Millipore, Billerica, MA,USA) with a sensitivity of 20 pgml− 1, and intra- and inter-assayCVs of 15% and 10.5%, respectively.Student’s unpaired t-test was used to compare subjectdemographics, fasting biochemical measures and insulinogenicindex 1 (IGI1), which was calculated from insulin (I) and glucose (G)1Discipline of Medicine, The University of Adelaide, Royal Adelaide Hospital, Adelaide, South Australia, Australia and 2Centre of Research Excellence in Translating NutritionalScience to Good Health, The University of Adelaide, Adelaide, South Australia, Australia. Correspondence: Professor CK Rayner, Discipline of Medicine, The University of Adelaide,Royal Adelaide Hospital, Level 6, Eleanor Harald Building, North Terrace, Adelaide 5000, South Australia, Australia.E-mail: chris.rayner@adelaide.edu.auReceived 20 January 2015; revised 22 March 2015; accepted 5 April 2015Citation: Nutrition & Diabetes (2015) 5, e156; doi:10.1038/nutd.2015.6www.nature.com/nutdconcentrations, as (I30-I0)/(G30-G0), to evaluate β-cell responsiveness.6Two-way analysis of variance, with treatment and time as factors,was used to compare responses between the two studies.Pearson’s correlation was used to assess relationships betweenintegrated area under the curve (ΔAUC), calculated using thetrapezoidal rule, for incretin hormones and both IGI1 and ΔAUCfor glucagon. Analyses were performed using Prism 6.0 software(GraphPad, La Jolla, CA, USA). Data are represented as mean± s.e.;Po0.05 (two sided) was considered statistically signiﬁcant.RESULTSDemographics and fasting values did not differ between the twostudies (Table 1). During enteral glucose infusion, plasma GLP-1increased substantially with i.j. administration (time effect:Po0.001), but minimally with i.d. delivery (time effect:P= 0.003), and was greater for i.j. than i.d. glucose (treatmenteffect: P= 0.037). Plasma GIP increased promptly on both days(time effect: Po0.001), and concentrations were also greater withi.j. glucose (treatment effect: P= 0.017). Blood glucose concentra-tions increased to ~ 8mmol l− 1 on both days, and werenumerically, but not signiﬁcantly, lower with i.j. glucose. However,plasma insulin, the insulin:glucose ratio and IGI1 (12.0 ± 1.4 vs5.6 ± 1.3 mUmmol− 1) were all greater with i.j. glucose (treatmenteffect: Po0.05 for all). Plasma glucagon did not change with i.j.glucose, but fell slightly with i.d. glucose (time effect: Po0.001),without signiﬁcant difference between the two (Figure 1).On pooling data from all 20 subjects, IGI1 was related directly toΔAUC for total GLP-1 and GIP (r= 0.48, P= 0.036 and r= 0.56,P= 0.012, respectively). ΔAUC for glucagon was related directly toΔAUC for GLP-1 (r= 0.70, Po0.001), but not GIP.CONCLUSIONWe showed that i.j. glucose elicited greater incretin and insulinrelease than i.d. glucose in healthy males, supporting the conceptthat directing nutrients more distally in the small intestine couldameliorate type 2 diabetes. Blood glucose did not differsigniﬁcantly, probably because of the modest glycaemic excursionin these healthy individuals. However, we cannot rule out a type 2error due to the small size of each group.Enteral glucose was delivered at 2 kcal min− 1 on both days,which is within the physiological range of gastric emptying.7 Theinfusion site was 38 cm more distal in the i.j. study; given that thesmall intestine can absorb glucose at 2 kcal min− 1 per 30 cm inhealth,8,9 this would have allowed substantially greater interactionof glucose with more distal gut regions where GLP-1-releasingL-cells are more abundant. This is consistent with observations ofenhanced GLP-1 secretion after implantation of a duodenal-jejunalsleeve.3 Alternatively, exclusion of the duodenum may have a rolein ameliorating diabetes (the ‘foregut hypothesis’).10 The relativecontribution of more distal gut exposure vs duodenal exclusionshould be evaluated in subsequent studies. The greater GIPresponse to i.j. glucose may also reﬂect a higher density of GIPsecreting K-cells in the proximal jejunum than duodenum inhumans, as seen in pigs.11 Moreover, the expression of sodiumglucose co-transporter-1 may be of relevance12—this wasreported to be greater in the jejunum than duodenum inrodents.13Plasma glucagon decreased during i.d. glucose infusion, butremained unchanged during i.j. glucose infusion. This may bepartly accounted for by the interplay between GLP-1 and GIP onpancreatic α-cells; the glucagonostatic effect of GLP-1 is blunted,14and the glucagonotropic effect of GIP is potentiated,15 in thecontext of relatively low blood glucose concentrations. Surpris-ingly, a direct relationship between glucagon and GLP-1 wasobserved, which might imply a contribution of GLP-2, a hormoneco-secreted with GLP-1 and potent at stimulating glucagon.16Differences in glucagon between the i.d. and i.j. studies may havecontributed to the lack of difference in blood glucoseconcentrations.We inﬂated a balloon in the i.j. study to exclude the duodenum;this per se would be unlikely to enhance incretin secretion.17Exclusion of bile in the i.j. study would not affect GIP secretion,18and if anything would favour a reduced GLP-1 response.4 In thei.d. study, it is possible that some of the infused glucose couldhave reﬂuxed into the stomach, but this should have beenminimised by the increased pyloric tone associated with i.d.glucose infusion.19Our study has limitations, which should be recognised. First,our observations were made in a parallel study design, witha relatively small number of subjects in each group; however, thesubjects were well matched and the differences in plasma incretinhormones and insulin were consistent between the two studies.Therefore, increasing the sample size in a crossover study isunlikely to alter the study conclusions. Furthermore, smallintestinal glucose was delivered into two sites at a single rate. Itwould be of interest to employ different rates of glucose infusioninto various sites in order better to characterise the regionalspeciﬁcity of the gut–incretin axis. Finally, the balance of evidenceseems to suggest alterations in secretion and/or action of incretinhormones in obesity and type 2 diabetes.20 For example, thesecretion of GLP-1 is reportedly impaired in obesity, while GIPsecretion may be enhanced.20 In the case of type 2 diabetes, theinsulinotropic effect of GIP is largely diminished, although that ofGLP-1 is better preserved. These pathophysiological featureswarrant further evaluation of the gut–incretin physiology in thepresence of obesity and/or type 2 diabetes.In summary, our observations indicate that i.j. glucose elicitsgreater incretin hormone and insulin secretion than i.d. glucose inhealthy humans, suggesting regional speciﬁcity of the gut–incretin axis.Table 1. Demographics and fasting biochemical measures of subjects in the intrajejunal (i.j.) vs intraduodenal (i.d.) studyai.j. study i.d. studySubjects 10 healthy males (8 Caucasians and 2 Asians) 10 healthy males (8 Caucasians and 2 Asians)Age (years) 33.4± 6.0 33.4± 5.3BMI (kgm− 2) 24.5± 1.1 25.0± 1.0Fasting glucose (mmol l− 1) 5.0± 0.1 5.4± 0.1Fasting insulin (mU l− 1) 3.1± 0.4 2.5± 0.5Fasting insulin:glucose ratio (mUmmol − 1) 0.6± 0.1 0.5± 0.1Fasting GLP-1 (pmol l− 1) 19.2± 2.0 24.1± 2.4Fasting GIP (pmol l− 1) 14.0± 1.6 15.3± 2.7Fasting glucagon (pgml− 1) 54.9± 7.9 52.5± 2.6Abbreviations: BMI, body mass index; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1. aData are represented as mean± s.e.;Student's unpaired t-test was used to determine the statistical signiﬁcance. Po0.05 was considered statistically signiﬁcant.Regional speciﬁcity of incretin releaseT Wu et al2Nutrition & Diabetes (2015) 1 – 4CONFLICT OF INTERESTThe study was supported by the National Health and Medical Research Council(NHMRC) project grant (No. APP1066815). TW has received research funding fromAstraZeneca. CKR has received research funding from Merck, Eli Lilly and Novartis.MH has participated in the advisory boards and/or symposia for Novo Nordisk, Sanoﬁ,Novartis, Eli Lilly, Merck Sharp & Dohme, Boehringer Ingelheim and AstraZeneca, andhas received honoraria for his activity. KLJ’s salary is provided by an NHMRC SeniorCareer Development Award (627011). The remaining authors declare no conﬂict ofinterest.ACKNOWLEDGEMENTSWe wish to thank Ms Kylie Lange (Centre of Research Excellence in TranslatingNutritional Science to Good Health, University of Adelaide) for her expert statisticaladvice.AUTHOR CONTRIBUTIONSTW was involved in the conception of the study, the study design andcoordination, subject recruitment, data collection and interpretation, statisticalanalysis and drafting of the manuscript; SST and CSM were involved indata collection and interpretation, and drafting of the manuscript; MJB assisteddata collection; MH and KLJ were involved in conception of the study and datainterpretation; CKR was involved in conception and design of the study, datainterpretation. All authors critically reviewed the manuscript, and haveapproved the publication of the ﬁnal version of the manuscript.REFERENCES1 Laferrere B, Teixeira J, McGinty J, Tran H, Egger JR, Colarusso A et al. Effect ofweight loss by gastric bypass surgery versus hypocaloric diet on glucose andincretin levels in patients with type 2 diabetes. J Clin Endocrinol Metab 2008; 93:2479–2485.2 Laferrere B, Heshka S, Wang K, Khan Y, McGinty J, Teixeira J et al. Incretin levels andeffect are markedly enhanced 1 month after Roux-en-Y gastric bypass surgery inobese patients with type 2 diabetes. Diabetes Care 2007; 30: 1709–1716.3 de Jonge C, Rensen SS, Verdam FJ, Vincent RP, Bloom SR, Buurman WA et al.Endoscopic duodenal-jejunal bypass liner rapidly improves type 2 diabetes. ObesSurg 2013; 23: 1354–1360.4 Wu T, Bound MJ, Standﬁeld SD, Jones KL, Horowitz M, Rayner CK. Effects oftaurocholic acid on glycemic, glucagon-like peptide-1, and insulin responses tosmall intestinal glucose infusion in healthy humans. J Clin Endocrinol Metab 2013;98: E718–E722.5 Wishart J, Morris HA, Horowitz M. Radioimmunoassay of gastric inhibitorypolypeptide in plasma. Clin Chem 1992; 38: 2156–2157.6 Herzberg-Schafer SA, Staiger H, Heni M, Ketterer C, Guthoff M, Kantartzis K et al.Evaluation of fasting state-/oral glucose tolerance test-derived measures of insulinFigure 1. Comparative responses of plasma total GLP-1 (a), total GIP (b), blood glucose (c), plasma insulin (d), the insulin:glucose ratio (e) andplasma glucagon (f) during an intrajejunal (i.j.) and intraduodenal (i.d.) glucose infusion at the rate of 2 kcal min− 1 (t= 0–120min) in healthymales (n= 10 each). P-values are for (A): differences by experiment, (B) differences over time and (AB): differences due to the interaction ofexperiment and time. Data are represented as mean± s.e.; Po0.05 was considered statistically signiﬁcant.Regional speciﬁcity of incretin releaseT Wu et al3Nutrition & Diabetes (2015) 1 – 4release for the detection of genetically impaired beta-cell function. PLoS One2010; 5: e14194.7 Brener W, Hendrix TR, McHugh PR. Regulation of the gastric emptying of glucose.Gastroenterology 1983; 85: 76–82.8 Duchman SM, Ryan AJ, Schedl HP, Summers RW, Bleiler TL, Gisolﬁ CV. Upper limitfor intestinal absorption of a dilute glucose solution in men at rest. Med Sci SportsExerc 1997; 29: 482–488.9 Modigliani R, Bernier JJ. Absorption of glucose, sodium, and water by the humanjejunum studied by intestinal perfusion with a proximal occluding balloon and atvariable ﬂow rates. Gut 1971; 12: 184–193.10 Rubino F, Marescaux J. Effect of duodenal-jejunal exclusion in a non-obese animalmodel of type 2 diabetes: a new perspective for an old disease. Ann Surg 2004;239: 1–11.11 Mortensen K, Christensen LL, Holst JJ, Orskov C. GLP-1 and GIP are colocalized in asubset of endocrine cells in the small intestine. Regul Pept 2003; 114: 189–196.12 Wu T, Zhao BR, Bound MJ, Checklin HL, Bellon M, Little TJ et al. Effects of differentsweet preloads on incretin hormone secretion, gastric emptying, and post-prandial glycemia in healthy humans. Am J Clin Nutr 2012; 95: 78–83.13 Woyengo TA, Rodriguez-Lecompte JC, Adeola O, Nyachoti CM. Histomorphologyand small intestinal sodium-dependent glucose transporter 1 gene expression inpiglets fed phytic acid and phytase-supplemented diets. J Anim Sci 2011; 89:2485–2490.14 Nauck MA, Heimesaat MM, Behle K, Holst JJ, Nauck MS, Ritzel R et al. Effects ofglucagon-like peptide 1 on counterregulatory hormone responses, cognitive func-tions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clampexperiments in healthy volunteers. J Clin Endocrinol Metab 2002; 87: 1239–1246.15 Meier JJ, Gallwitz B, Siepmann N, Holst JJ, Deacon CF, Schmidt WE et al. Gastricinhibitory polypeptide (GIP) dose-dependently stimulates glucagon secretion inhealthy human subjects at euglycaemia. Diabetologia 2003; 46: 798–801.16 Meier JJ, Nauck MA, Pott A, Heinze K, Goetze O, Bulut K et al. Glucagon-likepeptide 2 stimulates glucagon secretion, enhances lipid absorption, and inhibitsgastric acid secretion in humans. Gastroenterology 2006; 130: 44–54.17 Little TJ, Doran S, Meyer JH, Smout AJ, O'Donovan DG, Wu KL et al. The release ofGLP-1 and ghrelin, but not GIP and CCK, by glucose is dependent upon the lengthof small intestine exposed. Am J Physiol Endocrinol Metab 2006; 291: E647–E655.18 Bjornsson OG, Fletcher DR, Christoﬁdes ND, Bloom SR, Chadwick VS. Duodenalperfusion with sodium taurocholate inhibits biliary but not pancreatic secretion inman. Clin Sci (Lond) 1982; 62: 651–659.19 Rayner CK, Schwartz MP, van Dam PS, Renooij W, de Smet M, Horowitz M et al.Upper gastrointestinal responses to intraduodenal nutrient in type 1 diabetesmellitus. Eur J Gastroenterol Hepatol 2004; 16: 183–189.20 Deacon CF, Ahren B. Physiology of incretins in health and disease. Rev Diabet Stud2011; 8: 293–306.This work is licensed under a Creative Commons Attribution 4.0International License. The images or other third party material in thisarticle are included in the article’s Creative Commons license, unless indicatedotherwise in the credit line; if the material is not included under the Creative Commonslicense, users will need to obtain permission from the license holder to reproduce thematerial. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/Regional speciﬁcity of incretin releaseT Wu et al4Nutrition & Diabetes (2015) 1 – 4

Comparative effect of intraduodenal and intrajejunal glucose infusion on the gut-incretin axis response in healthy males

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Comparative effect of intraduodenal and intrajejunal glucose infusion on the gut-incretin axis response in healthy males

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Adelaide Research & Scholarship

Comparative effect of intraduodenal and intrajejunal glucose infusion on the gut-incretin axis response in healthy males

Abstract

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Adelaide Research &amp; Scholarship

Adelaide Research & Scholarship