Modulation of gut microbiota contributes to effects of intensive insulin therapy on intestinal morphological alteration in high-fat-diet-treated mice

  • Hongdong Wang
  • Wenjuan Tang
  • Pengzi Zhang
  • Zhou Zhang
  • Jielei He
  • Dalong Zhu
  • Yan BiEmail author
Original Article
Part of the following topical collections:
  1. Gut Microbiome and Metabolic Disorders



Disturbance of intestinal homeostasis promotes the development of type 2 diabetes. Although intensive insulin therapy has been shown to promote extended glycemic remission in newly diagnosed type 2 diabetic patients through multiple mechanisms, its effect on intestinal homeostasis remains unknown.


This study evaluated the effects of intensive insulin therapy on intestinal morphometric parameters in a hyperglycemic mice model induced by high-fat diet (HFD). 16S rRNA V4 region sequencing and multivariate analysis were utilized to evaluate the structural changes of gut microbiota.


HFD-induced increases in the lengths of villus, microvillus and crypt depth were significantly reversed after intensive insulin therapy. Moreover, intestinal proliferation was notably decreased after intensive insulin therapy, whereas intestinal apoptosis was further increased. Importantly, intensive insulin therapy significantly shifted the overall structure of the HFD-disrupted gut microbiota toward that of mice fed a normal diet and changed the gut microbial composition. The abundances of 54 operational taxonomic units (OTUs) were changed by intensive insulin therapy. Thirty altered OTUs correlated with two or more intestinal morphometric parameters and were designated ‘functionally relevant phylotypes.’


For the first time, our data indicate that intensive insulin therapy recovers diabetes-associated gut structural abnormalities and restores the microbiome landscape. Moreover, specific altered ‘functionally relevant phylotypes’ correlates with improvement in diabetes-associated gut structural alterations.


Gut microbiota Type 2 diabetes Intestinal morphology Intensive insulin therapy 



This work was supported by the National Natural Science Foundation of China Grant Awards (81770819, 81570737, 81370947, 81570736, 81500612, 81400832, 81600637, 81600632 and 81703294), the National Key Research and Development Program of China (2016YFC1304804 and 2017YFC1309605), the Jiangsu Provincial Key Medical Discipline (ZDXKB2016012), the Key Project of Nanjing Clinical Medical Science, Jiangsu Province Key Research and Development Program (BE2016606), the Jiangsu Provincial Medical Talent (ZDRCA2016062), the Natural Science Foundation of Jiangsu Province of China (BK20170125), the Jiangsu Provincial Medical Youth Talent (QNRC2016020, QNRC2016019 and QNRC2016018), the Medical Scientific Research Foundation of Jiangsu Province of China (Z201610 and Q2017006), the Science and Technology Project of Administration of Traditional Chinese Medicine of Jiangsu Province of China (YB2015072), the Six Talent Peaks Project of Jiangsu Province of China (WSN-165 and SWYY-091), the Fundamental Research Funds for the Central Universities (021414380444, 021414380092, 021414380208, 021414380160, 021414380142, 021414380279, 021414380296 and 021414380317), the Nanjing Science and Technology Development Project (ZKX16036, YKK16105 and 201605019) and the Nanjing Health Youth Talent (QRX17123).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All animal studies were conducted according to guidelines established by the Research Animal Care Committee of Drum Tower Hospital Affiliated to Nanjing University Medical School.

Informed consent

For this type of study informed consent is not required.

Supplementary material

592_2019_1436_MOESM1_ESM.docx (901 kb)
Supplementary material 1 (DOCX 901 kb)


  1. 1.
    Zheng Y, Ley SH, Hu FB (2018) Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol 14(2):88–98. CrossRefPubMedGoogle Scholar
  2. 2.
    Weng J, Li Y, Xu W et al (2008) Effect of intensive insulin therapy on beta-cell function and glycaemic control in patients with newly diagnosed type 2 diabetes: a multicentre randomised parallel-group trial. Lancet 371(9626):1753–1760. CrossRefPubMedGoogle Scholar
  3. 3.
    Hu Y, Li L, Xu Y et al (2011) Short-term intensive therapy in newly diagnosed type 2 diabetes partially restores both insulin sensitivity and beta-cell function in subjects with long-term remission. Diabetes Care 34(8):1848–1853. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Nathan DM, Buse JB, Davidson MB et al (2006) Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 29(8):1963–1972. CrossRefPubMedGoogle Scholar
  5. 5.
    Bravi MC, Armiento A, Laurenti O et al (2006) Insulin decreases intracellular oxidative stress in patients with type 2 diabetes mellitus. Metab Clin Exp 55(5):691–695. CrossRefPubMedGoogle Scholar
  6. 6.
    Kaneto H, Nakatani Y, Kawamori D et al (2005) Role of oxidative stress, endoplasmic reticulum stress, and c-Jun N-terminal kinase in pancreatic beta-cell dysfunction and insulin resistance. Int J Biochem Cell Biol 37(8):1595–1608. CrossRefPubMedGoogle Scholar
  7. 7.
    Juurinen L, Tiikkainen M, Hakkinen AM, Hakkarainen A, Yki-Jarvinen H (2007) Effects of insulin therapy on liver fat content and hepatic insulin sensitivity in patients with type 2 diabetes. Am J Physiol Endocrinol Metab 292(3):E829–E835. CrossRefPubMedGoogle Scholar
  8. 8.
    LeRoith D, Fonseca V, Vinik A (2005) Metabolic memory in diabetes–focus on insulin. Diabetes Metab Res Rev 21(2):85–90. CrossRefPubMedGoogle Scholar
  9. 9.
    Bi Y, Sun WP, Chen X et al (2008) Effect of early insulin therapy on nuclear factor kappaB and cytokine gene expressions in the liver and skeletal muscle of high-fat diet, streptozotocin-treated diabetic rats. Acta Diabetol 45(3):167–178. CrossRefPubMedGoogle Scholar
  10. 10.
    Petit V, Arnould L, Martin P et al (2007) Chronic high-fat diet affects intestinal fat absorption and postprandial triglyceride levels in the mouse. J Lipid Res 48(2):278–287. CrossRefPubMedGoogle Scholar
  11. 11.
    Scoaris CR, Rizo GV, Roldi LP et al (2010) Effects of cafeteria diet on the jejunum in sedentary and physically trained rats. Nutrition 26(3):312–320. CrossRefPubMedGoogle Scholar
  12. 12.
    Adachi T, Mori C, Sakurai K, Shihara N, Tsuda K, Yasuda K (2003) Morphological changes and increased sucrase and isomaltase activity in small intestines of insulin-deficient and type 2 diabetic rats. Endocr J 50(3):271–279CrossRefGoogle Scholar
  13. 13.
    Troy S, Soty M, Ribeiro L et al (2008) Intestinal gluconeogenesis is a key factor for early metabolic changes after gastric bypass but not after gastric lap-band in mice. Cell Metab 8(3):201–211. CrossRefPubMedGoogle Scholar
  14. 14.
    Mao J, Hu X, Xiao Y et al (2013) Overnutrition stimulates intestinal epithelium proliferation through beta-catenin signaling in obese mice. Diabetes 62(11):3736–3746. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Dyer J, Wood IS, Palejwala A, Ellis A, Shirazi-Beechey SP (2002) Expression of monosaccharide transporters in intestine of diabetic humans. Am J Physiol Gastrointest Liver Physiol 282(2):G241–G248. CrossRefPubMedGoogle Scholar
  16. 16.
    Mithieux G, Bady I, Gautier A, Croset M, Rajas F, Zitoun C (2004) Induction of control genes in intestinal gluconeogenesis is sequential during fasting and maximal in diabetes. Am J Physiol Endocrinol Metab 286(3):E370–E375. CrossRefPubMedGoogle Scholar
  17. 17.
    Verdam FJ, Greve JW, Roosta S et al (2011) Small intestinal alterations in severely obese hyperglycemic subjects. J Clin Endocrinol Metab 96(2):E379–E383. CrossRefPubMedGoogle Scholar
  18. 18.
    Peck BC, Mah AT, Pitman WA, Ding S, Lund PK, Sethupathy P (2017) Functional transcriptomics in diverse intestinal epithelial cell types reveals robust microRNA sensitivity in intestinal stem cells to microbial status. J Biol Chem 292(7):2586–2600. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Velasquez-Manoff M (2015) Gut microbiome: the peacekeepers. Nature 518(7540):S3–S11. CrossRefPubMedGoogle Scholar
  20. 20.
    Chevalier C, Stojanovic O, Colin DJ et al (2015) Gut microbiota orchestrates energy homeostasis during cold. Cell 163(6):1360–1374. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Dossa AY, Escobar O, Golden J, Frey MR, Ford HR, Gayer CP (2016) Bile acids regulate intestinal cell proliferation by modulating EGFR and FXR signaling. Am J Physiol Gastrointest Liver Physiol 310(2):G81–G92. CrossRefPubMedGoogle Scholar
  22. 22.
    Krishna-Subramanian S, Hanski ML, Loddenkemper C et al (2012) UDCA slows down intestinal cell proliferation by inducing high and sustained ERK phosphorylation. Int J Cancer 130(12):2771–2782. CrossRefPubMedGoogle Scholar
  23. 23.
    Zeng H, Claycombe KJ, Reindl KM (2015) Butyrate and deoxycholic acid play common and distinct roles in HCT116 human colon cell proliferation. J Nutr Biochem 26(10):1022–1028. CrossRefPubMedGoogle Scholar
  24. 24.
    Wang H, Wang X, Zhu Y, Chen F, Sun Y, Han X (2015) Increased androgen levels in rats impair glucose-stimulated insulin secretion through disruption of pancreatic beta cell mitochondrial function. J Steroid Biochem Mol Biol 154:254–266. CrossRefPubMedGoogle Scholar
  25. 25.
    Feng W, Wang H, Zhang P et al (1861) Modulation of gut microbiota contributes to curcumin-mediated attenuation of hepatic steatosis in rats. Biochem Biophys Acta 7:1801–1812. CrossRefGoogle Scholar
  26. 26.
    Stickle D, Turk J (1997) A kinetic mass balance model for 1,5-anhydroglucitol: applications to monitoring of glycemic control. Am J Physiol 273(4 Pt 1):E821–E830PubMedGoogle Scholar
  27. 27.
    Mah AT, Van Landeghem L, Gavin HE, Magness ST, Lund PK (2014) Impact of diet-induced obesity on intestinal stem cells: hyperproliferation but impaired intrinsic function that requires insulin/IGF1. Endocrinology 155(9):3302–3314. CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Creamer B, Shorter RG, Bamforth J (1961) The turnover and shedding of epithelial cells. I. The turnover in the gastro-intestinal tract. Gut 2:110–118CrossRefGoogle Scholar
  29. 29.
    Andres SF, Santoro MA, Mah AT et al (2015) Deletion of intestinal epithelial insulin receptor attenuates high-fat diet-induced elevations in cholesterol and stem, enteroendocrine, and Paneth cell mRNAs. Am J Physiol Gastrointest Liver Physiol 308(2):G100–G111. CrossRefPubMedGoogle Scholar
  30. 30.
    Salzman NH, Bevins CL (2013) Dysbiosis—a consequence of Paneth cell dysfunction. Semin Immunol 25(5):334–341. CrossRefPubMedGoogle Scholar
  31. 31.
    Ussar S, Haering MF, Fujisaka S et al (2017) Regulation of glucose uptake and enteroendocrine function by the intestinal epithelial insulin receptor. Diabetes 66(4):886–896. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Berr F, Kullak-Ublick GA, Paumgartner G, Munzing W, Hylemon PB (1996) 7 alpha-dehydroxylating bacteria enhance deoxycholic acid input and cholesterol saturation of bile in patients with gallstones. Gastroenterology 111(6):1611–1620CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia S.r.l., part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of EndocrinologyDrum Tower Hospital Affiliated to Nanjing University Medical SchoolNanjingChina

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