Background/Aims: In contrast to streptozotocin (STZ)-induced rodent models of diabetes, there are no thorough characterizations of the intestinal phenotype and the underlying changes in the global gene-expression of genetic models of diabetes, such as the Zucker diabetic fatty (ZDF) rat. The aim of the present study was to characterize the intestine in the ZDF rat. Methods: The intestine of ZDF rats and lean controls was examined macroscopically and histologically, and ribonucleic acid sequencing (RNAseq) was performed in samples of jejunal mucosa. Results: We observed an increased mass and length of the small and large intestines in ZDF rats. RNAseq showed an increased expression of Pdk2 and Pdk4, which are involved in the regulation of glucose and fatty acid metabolism, and increased expression of genes involved in gluconeogenesis and peroxisomal beta-oxidation in jejunal mucosa. Conclusion: Intestinal enlargement in ZDF rats is likely driven by increased food intake, since (i) it also occurs in obese and normoglycemic Zucker fatty rats, and (ii) insulin treatment of STZ-induced diabetic rats reduced the food intake and mass of the small intestine. Results from RNAseq indicate that small intestinal epithelial cells in ZDF rats have developed insulin resistance, and support that a normal physiological effect of insulin in the enterocytes is the regulation of glucose metabolism.

Journal Section:
Original Paper
Keywords:
Insulin resistance, Lipid metabolism, Zucker diabetic fatty rats, Intestine, Food intake
1.
Andreelli F, Amouyal C, Magnan C, Mithieux G: What can bariatric surgery teach us about the pathophysiology of type 2 diabetes? Diabetes Metab 2009;35(6 pt 2):499-507.
2.
Pories WJ, Albrecht RJ: Etiology of type II diabetes mellitus: role of the foregut. World J Surg 2001;25:527-531.
3.
Rubino F, Forgione A, Cummings DE, Vix M, Gnuli D, Mingrone G, Castagneto M, Marescaux J: The mechanism of diabetes control after gastrointestinal bypass surgery reveals a role of the proximal small intestine in the pathophysiology of type 2 diabetes. Ann Surg 2006;244:741-749.
4.
Saeidi N, Meoli L, Nestoridi E, Gupta NK, Kvas S, Kucharczyk J, Bonab AA, Fischman AJ, Yarmush ML, Stylopoulos N: Reprogramming of intestinal glucose metabolism and glycemic control in rats after gastric bypass. Science 2013;341:406-410.
5.
Adachi T, Mori C, Sakurai K, Shihara N, Tsuda K, Yasuda K: Morphological changes and increased sucrase and isomaltase activity in small intestines of insulin-deficient and type 2 diabetic rats. Endocr J 2003;50:271-279.
6.
Croset M, Rajas F, Zitoun C, Hurot JM, Montano S, Mithieux G: Rat small intestine is an insulin-sensitive gluconeogenic organ. Diabetes 2001;50:740-746.
7.
Feingold KR: Importance of small intestine in diabetic hypercholesterolemia. Diabetes 1989;38:141-145.
8.
Feingold KR, Moser A, Adi S, Soued M, Grunfeld C: Small intestinal fatty acid synthesis is increased in diabetic rats. Endocrinology 1990;127:2247-2252.
9.
Fischer KD, Dhanvantari S, Drucker DJ, Brubaker PL: Intestinal growth is associated with elevated levels of glucagon-like peptide 2 in diabetic rats. Am J Physiol 1997;273(4 pt 1):E815-E820.
10.
Liu L, Yu YL, Liu C, Wang XT, Liu XD, Xie L: Insulin deficiency induces abnormal increase in intestinal disaccharidase activities and expression under diabetic states, evidences from in vivo and in vitro study. Biochem Pharmacol 2011;82:1963-1970.
11.
Rajas F, Croset M, Zitoun C, Montano S, Mithieux G: Induction of PEPCK gene expression in insulinopenia in rat small intestine. Diabetes 2000;49:1165-1168.
12.
Zoubi SA, Mayhew TM, Sparrow RA: The small intestine in experimental diabetes: cellular adaptation in crypts and villi at different longitudinal sites. Virchows Arch 1995;426:501-507.
13.
Brubaker PL, So DC, Drucker DJ: Tissue-specific differences in the levels of proglucagon-derived peptides in streptozotocin-induced diabetes. Endocrinology 1989;124:3003-3009.
14.
Kreymann B, Yiangou Y, Kanse S, Williams G, Ghatei MA, Bloom SR: Isolation and characterisation of GLP-1 7-36 amide from rat intestine. Elevated levels in diabetic rats. FEBS Lett 1988;242:167-170.
15.
Jervis EL, Levin RJ: Anatomic adaptation of the alimentary tract of the rat to the hyperphagia of chronic alloxan-diabetes. Nature 1966;210:391-393.
16.
Sukhotnik I, Shamir R, Bashenko Y, Mogilner JG, Chemodanov E, Shaoul R, Coran AG, Shehadeh N: Effect of oral insulin on diabetes-induced intestinal mucosal growth in rats. Dig Dis Sci 2011;56:2566-2574.
17.
Ait-Omar A, Monteiro-Sepulveda M, Poitou C, Le Gall M, Cotillard A, Gilet J, Garbin K, Houllier A, Chateau D, Lacombe A, Veyrie N, Hugol D, Tordjman J, Magnan C, Serradas P, Clement K, Leturque A, Brot-Laroche E: GLUT2 accumulation in enterocyte apical and intracellular membranes: a study in morbidly obese human subjects and ob/ob and high fat-fed mice. Diabetes 2011;60:2598-2607.
18.
Dyer J, Wood IS, Palejwala A, Ellis A, Shirazi-Beechey SP: Expression of monosaccharide transporters in intestine of diabetic humans. Am J Physiol Gastrointest Liver Physiol 2002;282:G241-G248.
19.
Verdam FJ, Greve JW, Roosta S, van Eijk H, Bouvy N, Buurman WA, Rensen SS: Small intestinal alterations in severely obese hyperglycemic subjects. J Clin Endocrinol Metab 2011;96:E379-E383.
20.
Caspary WF, Winckler K, Creutzfeldt W: Intestinal brush border enzyme activity in juvenile and maturity onset diabetes mellitus. Diabetologia 1974;10:353-355.
21.
Clark JB, Palmer CJ, Shaw WN: The diabetic Zucker fatty rat. Proc Soc Exp Biol Med 1983;173:68-75.
22.
Chua SC Jr, Chung WK, Wu-Peng XS, Zhang Y, Liu SM, Tartaglia L, Leibel RL: Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor. Science 1996;271:994-996.
23.
Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM: Positional cloning of the mouse obese gene and its human homologue. Nature 1994;372:425-432.
24.
Leonard BL, Watson RN, Loomes KM, Phillips AR, Cooper GJ: Insulin resistance in the Zucker diabetic fatty rat: a metabolic characterisation of obese and lean phenotypes. Acta Diabetol 2005;42:162-170.
25.
Peterson RG, Shaw WN: Zucker diabetic fatty rat as a model for non-insulin-dependent diabetes mellitus. ILAR J 1990;32:16-19.
26.
Tokuyama Y, Sturis J, DePaoli AM, Takeda J, Stoffel M, Tang J, Sun X, Polonsky KS, Bell GI: Evolution of beta-cell dysfunction in the male Zucker diabetic fatty rat. Diabetes 1995;44:1447-1457.
27.
Corpe C, Sreenan S, Burant C: Effects of type-2 diabetes and troglitazone on the expression patterns of small intestinal sugar transporters and PPAR-gamma in the Zucker diabetic fatty rat. Digestion 2001;63:116-123.
28.
Hansen CF, Vrang N, Sangild PT, Jelsing J: Novel insight into the distribution of L-cells in the rat intestinal tract. Am J Transl Res 2013;5:347-358.
29.
Hvid H, Blouin MJ, Birman E, Damgaard J, Poulsen F, Fels JJ, Fledelius C, Hansen BF, Pollak M: Treatment with insulin analog X10 and IGF-1 increases growth of colon cancer allografts. PLoS One 2013;8:e79710.
30.
Popesko V, Rajtová V, Horák J: A Colour Atlas of the Anatomy of Small Laboratory Animals. London, Wolfe Publishing Ltd., 1992.
31.
Moolenbeek C, Ruitenberg EJ: The ‘Swiss roll': a simple technique for histological studies of the rodent intestine. Lab Anim 1981;15:57-59.
32.
Dahlqvist A: Assay of intestinal disaccharidases. Anal Biochem 1968;22:99-107.
33.
Stern JS, Johnson PR: Spontaneous activity and adipose cellularity in the genetically obese Zucker rat (fafa). Metabolism 1977;26:371-380.
34.
Wren AM, Small CJ, Ward HL, Murphy KG, Dakin CL, Taheri S, Kennedy AR, Roberts GH, Morgan DG, Ghatei MA, Bloom SR: The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion. Endocrinology 2000;141:4325-4328.
35.
Rao JN, Wang JY: Integrated Systems Physiology: From Molecule to Function to Disease; Regulation of Gastrointestinal Mucosal Growth. San Rafael, Morgan & Claypool Life Sciences, Copyright (c) 2011 by Morgan & Claypool Life Sciences, 2010.
36.
Hartmann B, Thulesen J, Hare KJ, Kissow H, Orskov C, Poulsen SS, Holst JJ: Immunoneutralization of endogenous glucagon-like peptide-2 reduces adaptive intestinal growth in diabetic rats. Regul Pept 2002;105:173-179.
37.
Roberge JN, Brubaker PL: Secretion of proglucagon-derived peptides in response to intestinal luminal nutrients. Endocrinology 1991;128:3169-3174.
38.
Hammond KA, Konarzewski M, Torres RM, Diamond J: Metabolic ceilings under a combination of peak energy demands. Physiol Zool 1994;67:1479-1506.
39.
Granneman JG, Stricker EM: Food intake and gastric emptying in rats with streptozotocin-induced diabetes. Am J Physiol 1984;247(6 pt 2):R1054-R1061.
40.
de Luca C, Kowalski TJ, Zhang Y, Elmquist JK, Lee C, Kilimann MW, Ludwig T, Liu SM, Chua SC Jr: Complete rescue of obesity, diabetes, and infertility in db/db mice by neuron-specific LEPR-B transgenes. J Clin Invest 2005;115:3484-3493.
41.
Dryden S, Pickavance L, Frankish HM, Williams G: Increased neuropeptide Y secretion in the hypothalamic paraventricular nucleus of obese (fa/fa) Zucker rats. Brain Res 1995;690:185-188.
42.
Ganguly PK: Neuropeptide Y level in paraventricular nucleus of experimental diabetic rats: correlation with sympathetic activity and body weight. Int J Gen Med 2010;3:321-325.
43.
Deacon CF: What do we know about the secretion and degradation of incretin hormones? Regul Pept 2005;128:117-124.
44.
Federico LM, Naples M, Taylor D, Adeli K: Intestinal insulin resistance and aberrant production of apolipoprotein B48 lipoproteins in an animal model of insulin resistance and metabolic dyslipidemia: evidence for activation of protein tyrosine phosphatase-1B, extracellular signal-related kinase, and sterol regulatory element-binding protein-1c in the fructose-fed hamster intestine. Diabetes 2006;55:1316-1326.
45.
Honka H, Makinen J, Hannukainen JC, Tarkia M, Oikonen V, Teras M, Fagerholm V, Ishizu T, Saraste A, Stark C, Vahasilta T, Salminen P, Kirjavainen A, Soinio M, Gastaldelli A, Knuuti J, Iozzo P, Nuutila P: Validation of [18F]fluorodeoxyglucose and positron emission tomography (PET) for the measurement of intestinal metabolism in pigs, and evidence of intestinal insulin resistance in patients with morbid obesity. Diabetologia 2013;56:893-900.
46.
Makinen J, Hannukainen JC, Karmi A, Immonen HM, Soinio M, Nelimarkka L, Savisto N, Helmio M, Ovaska J, Salminen P, Iozzo P, Nuutila P: Obesity-associated intestinal insulin resistance is ameliorated after bariatric surgery. Diabetologia 2015;58:1055-1062.
47.
Helliwell PA, Richardson M, Affleck J, Kellett GL: Stimulation of fructose transport across the intestinal brush-border membrane by PMA is mediated by GLUT2 and dynamically regulated by protein kinase C. Biochem J 2000;350(pt 1):149-154.
48.
Kellett GL, Helliwell PA: The diffusive component of intestinal glucose absorption is mediated by the glucose-induced recruitment of GLUT2 to the brush-border membrane. Biochem J 2000;350(pt 1):155-162.
49.
Tobin V, Le Gall M, Fioramonti X, Stolarczyk E, Blazquez AG, Klein C, Prigent M, Serradas P, Cuif MH, Magnan C, Leturque A, Brot-Laroche E: Insulin internalizes GLUT2 in the enterocytes of healthy but not insulin-resistant mice. Diabetes 2008;57:555-562.
50.
Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI: An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 2006;444:1027-1031.
51.
Burant CF, Flink S, DePaoli AM, Chen J, Lee WS, Hediger MA, Buse JB, Chang EB: Small intestine hexose transport in experimental diabetes. Increased transporter mRNA and protein expression in enterocytes. J Clin Invest 1994;93:578-585.
52.
Corpe CP, Basaleh MM, Affleck J, Gould G, Jess TJ, Kellett GL: The regulation of GLUT5 and GLUT2 activity in the adaptation of intestinal brush-border fructose transport in diabetes. Pflugers Arch 1996;432:192-201.
53.
Bowker-Kinley MM, Davis WI, Wu P, Harris RA, Popov KM: Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex. Biochem J 1998;329(pt 1):191-196.
54.
Randle PJ: Fuel selection in animals. Biochem Soc Trans 1986;14:799-806.
55.
Wu P, Sato J, Zhao Y, Jaskiewicz J, Popov KM, Harris RA: Starvation and diabetes increase the amount of pyruvate dehydrogenase kinase isoenzyme 4 in rat heart. Biochem J 1998;329(pt 1):197-201.
56.
Wu P, Inskeep K, Bowker-Kinley MM, Popov KM, Harris RA: Mechanism responsible for inactivation of skeletal muscle pyruvate dehydrogenase complex in starvation and diabetes. Diabetes 1999;48:1593-1599.
57.
Wu P, Blair PV, Sato J, Jaskiewicz J, Popov KM, Harris RA: Starvation increases the amount of pyruvate dehydrogenase kinase in several mammalian tissues. Arch Biochem Biophys 2000;381:1-7.
58.
Randle PJ: Regulatory interactions between lipids and carbohydrates: the glucose fatty acid cycle after 35 years. Diabetes Metab Rev 1998;14:263-283.
59.
Kwon HS, Harris RA: Mechanisms responsible for regulation of pyruvate dehydrogenase kinase 4 gene expression. Adv Enzyme Regul 2004;44:109-121.
60.
Majer M, Popov KM, Harris RA, Bogardus C, Prochazka M: Insulin downregulates pyruvate dehydrogenase kinase (PDK) mRNA: potential mechanism contributing to increased lipid oxidation in insulin-resistant subjects. Mol Genet Metab 1998;65:181-186.
61.
Reddy JK: Nonalcoholic steatosis and steatohepatitis. III. Peroxisomal beta-oxidation, PPAR alpha, and steatohepatitis. Am J Physiol Gastrointest Liver Physiol 2001;281:G1333-G1339.
62.
Hashimoto T: Peroxisomal beta-oxidation enzymes. Cell Biochem Biophys 2000;32(spring):63-72.
63.
Ussar SK, Kahn CR: Intestinal Epithelial Insulin Signaling Plays an Important Role in the Regulation of Whole Body Glucose and Lipid Homeostasis. Chicago, American Diabetes Association 73rd Scientific Sessions, 2013.
64.
Karimian Azari E, Leitner C, Jaggi T, Langhans W, Mansouri A: Possible role of intestinal fatty acid oxidation in the eating-inhibitory effect of the PPAR-α agonist Wy-14643 in high-fat diet fed rats. PLoS One 2013;8:e74869.
65.
Uchida A, Slipchenko MN, Cheng JX, Buhman KK: Fenofibrate, a peroxisome proliferator-activated receptor α agonist, alters triglyceride metabolism in enterocytes of mice. Biochim Biophys Acta 2011;1811:170-176.
66.
Goldstein JL, Brown MS: The LDL receptor. Arterioscler Thromb Vasc Biol 2009;29:431-438.
67.
Li T, Chen W, Chiang JY: PXR induces CYP27A1 and regulates cholesterol metabolism in the intestine. J Lipid Res 2007;48:373-384.
68.
Rajas F, Bruni N, Montano S, Zitoun C, Mithieux G: The glucose-6 phosphatase gene is expressed in human and rat small intestine: regulation of expression in fasted and diabetic rats. Gastroenterology 1999;117:132-139.
69.
Watford M: Is the small intestine a gluconeogenic organ. Nutr Rev 2005;63:356-360.
70.
Hansen GH, Niels-Christiansen LL, Danielsen EM: Leptin and the obesity receptor (OB-R) in the small intestine and colon: a colocalization study. J Histochem Cytochem 2008;56:677-685.
71.
Lostao MP, Urdaneta E, Martinez-Anso E, Barber A, Martinez JA: Presence of leptin receptors in rat small intestine and leptin effect on sugar absorption. FEBS Lett 1998;423:302-306.
72.
Doi T, Liu M, Seeley RJ, Woods SC, Tso P: Effect of leptin on intestinal apolipoprotein AIV in response to lipid feeding. Am J Physiol Regul Integr Comp Physiol 2001;281:R753-R759.
73.
Morton NM, Emilsson V, Liu YL, Cawthorne MA: Leptin action in intestinal cells. J Biol Chem 1998;273:26194-26201.
74.
Brun P, Castagliuolo I, Di Leo V, Buda A, Pinzani M, Palu G, Martines D: Increased intestinal permeability in obese mice: new evidence in the pathogenesis of nonalcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol 2007;292:G518-G525.
© 2016 S. Karger AG, Basel
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
2016
You do not currently have access to this content.