Skeletal Response to Insulin in the Naturally Occurring Type 1 Diabetes Mellitus Mouse Model

Overview

Journal JBMR Plus

Publisher Oxford University Press

Date 2021 May 12

PMID 33977201

Citations 8

Authors

Manisha Dixit

Zhongbo Liu

Sher Bahadur Poudel

Gozde Yildirim

Yanjiao Zhang Zhang

Shilpa Mehta

Omer Murik

Geona Altarescu

Yoshifumi Kobayashi

Emi Shimizu

Mitchell B Schaffler

Shoshana Yakar

Affiliations

Soon will be listed here.

Abstract

Patients with type 1 diabetes mellitus (T1DM) exhibit reduced BMD and significant increases in fracture risk. Changes in BMD are attributed to blunted osteoblast activity and inhibited bone remodeling, but these cannot fully explain the impaired bone integrity in T1DM. The goal of this study was to determine the cellular mechanisms that contribute to impaired bone morphology and composition in T1DM. Nonobese diabetic (NOD) mice were used, along with μCT, histomorphometry, histology, Raman spectroscopy, and RNAseq analyses of several skeletal sites in response to naturally occurring hyperglycemia and insulin treatment. The bone volume in the axial skeleton was found to be severely reduced in diabetic NOD mice and was not completely resolved with insulin treatment. Decreased bone volume in diabetic mice was associated with increased sclerostin expression in osteocytes and attenuation of bone formation indices without changes in bone resorption. In the face of blunted bone remodeling, decreases in the mineral:matrix ratio were found in cortical bones of diabetic mice by Raman microspectroscopy, suggesting that T1DM did not affect the bone mineralization process per se, but rather resulted in microenvironmental alterations that favored mineral loss. Bone transcriptome analysis indicated metabolic shifts in response to T1DM. Dysregulation of genes involved in fatty acid oxidation, transport, and synthesis was found in diabetic NOD mice. Specifically, pyruvate dehydrogenase kinase isoenzyme 4 and glucose transporter 1 levels were increased, whereas phosphorylated-AKT levels were significantly reduced in diabetic NOD mice. In conclusion, in addition to the blunted bone formation, osteoblasts and osteocytes undergo metabolic shifts in response to T1DM that may alter the microenvironment and contribute to mineral loss from the bone matrix. © 2021 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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References

Wang Y, Liu W, Masuyama R, Fukuyama R, Ito M, Zhang Q . Pyruvate dehydrogenase kinase 4 induces bone loss at unloading by promoting osteoclastogenesis. Bone. 2011; 50(1):409-19. DOI: 10.1016/j.bone.2011.07.012. View

Niemeier A, Niedzielska D, Secer R, Schilling A, Merkel M, Enrich C . Uptake of postprandial lipoproteins into bone in vivo: impact on osteoblast function. Bone. 2008; 43(2):230-237. DOI: 10.1016/j.bone.2008.03.022. View

Verrotti A, Basciani F, Morgese G, Chiarelli F . Leptin levels in non-obese and obese children and young adults with type 1 diabetes mellitus. Eur J Endocrinol. 1998; 139(1):49-53. DOI: 10.1530/eje.0.1390049. View

Parfitt A, Drezner M, Glorieux F, Kanis J, MALLUCHE H, Meunier P . Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res. 1987; 2(6):595-610. DOI: 10.1002/jbmr.5650020617. View

Wysolmerski J . Osteocytes remove and replace perilacunar mineral during reproductive cycles. Bone. 2013; 54(2):230-6. PMC: 3624069. DOI: 10.1016/j.bone.2013.01.025. View

Scholin A, Siegbahn A, Lind L, Berne C, Sundkvist G, Bjork E . CRP and IL-6 concentrations are associated with poor glycemic control despite preserved beta-cell function during the first year after diagnosis of type 1 diabetes. Diabetes Metab Res Rev. 2004; 20(3):205-10. DOI: 10.1002/dmrr.427. View

Li Z, Frey J, Wong G, Faugere M, Wolfgang M, Kim J . Glucose Transporter-4 Facilitates Insulin-Stimulated Glucose Uptake in Osteoblasts. Endocrinology. 2016; 157(11):4094-4103. PMC: 5086531. DOI: 10.1210/en.2016-1583. View

Driver J, Serreze D, Chen Y . Mouse models for the study of autoimmune type 1 diabetes: a NOD to similarities and differences to human disease. Semin Immunopathol. 2010; 33(1):67-87. DOI: 10.1007/s00281-010-0204-1. View

Huang B, Wu P, Harris R . Regulation of pyruvate dehydrogenase kinase expression by peroxisome proliferator-activated receptor-alpha ligands, glucocorticoids, and insulin. Diabetes. 2002; 51(2):276-83. DOI: 10.2337/diabetes.51.2.276. View

10.

Tsentidis C, Gourgiotis D, Kossiva L, Doulgeraki A, Marmarinos A, Galli-Tsinopoulou A . Higher levels of s-RANKL and osteoprotegerin in children and adolescents with type 1 diabetes mellitus may indicate increased osteoclast signaling and predisposition to lower bone mass: a multivariate cross-sectional analysis. Osteoporos Int. 2015; 27(4):1631-1643. DOI: 10.1007/s00198-015-3422-5. View

11.

Janghorbani M, van Dam R, Willett W, Hu F . Systematic review of type 1 and type 2 diabetes mellitus and risk of fracture. Am J Epidemiol. 2007; 166(5):495-505. DOI: 10.1093/aje/kwm106. View

12.

Bar L, Feger M, Fajol A, Klotz L, Zeng S, Lang F . Insulin suppresses the production of fibroblast growth factor 23 (FGF23). Proc Natl Acad Sci U S A. 2018; 115(22):5804-5809. PMC: 5984514. DOI: 10.1073/pnas.1800160115. View

13.

Neumann T, Hofbauer L, Rauner M, Lodes S, Kastner B, Franke S . Clinical and endocrine correlates of circulating sclerostin levels in patients with type 1 diabetes mellitus. Clin Endocrinol (Oxf). 2013; 80(5):649-55. DOI: 10.1111/cen.12364. View

14.

Danne T, Gruters A, Wladimirova A, Weber B, Horn R, Mayr B . Gender-specific differences of serum leptin in obese and normal-weight adolescents: studies in type-I diabetes and Turner syndrome. Horm Res. 1997; 48(3):103-7. DOI: 10.1159/000185498. View

15.

Holness M, Bulmer K, Gibbons G, Sugden M . Up-regulation of pyruvate dehydrogenase kinase isoform 4 (PDK4) protein expression in oxidative skeletal muscle does not require the obligatory participation of peroxisome-proliferator-activated receptor alpha (PPARalpha). Biochem J. 2002; 366(Pt 3):839-46. PMC: 1222844. DOI: 10.1042/BJ20020754. View

16.

Snell-Bergeon J, West N, Mayer-Davis E, Liese A, Marcovina S, DAgostino Jr R . Inflammatory markers are increased in youth with type 1 diabetes: the SEARCH Case-Control study. J Clin Endocrinol Metab. 2010; 95(6):2868-76. PMC: 2902077. DOI: 10.1210/jc.2009-1993. View

17.

Hamed E, Abu Faddan N, Elhafeez H, Sayed D . Parathormone--25(OH)-vitamin D axis and bone status in children and adolescents with type 1 diabetes mellitus. Pediatr Diabetes. 2011; 12(6):536-46. DOI: 10.1111/j.1399-5448.2010.00739.x. View

18.

Serreze D, Gaedeke J, Leiter E . Hematopoietic stem-cell defects underlying abnormal macrophage development and maturation in NOD/Lt mice: defective regulation of cytokine receptors and protein kinase C. Proc Natl Acad Sci U S A. 1993; 90(20):9625-9. PMC: 47622. DOI: 10.1073/pnas.90.20.9625. View

19.

Danielson K, Elliott M, LeCaire T, Binkley N, Palta M . Poor glycemic control is associated with low BMD detected in premenopausal women with type 1 diabetes. Osteoporos Int. 2008; 20(6):923-33. PMC: 2748939. DOI: 10.1007/s00198-008-0763-3. View

20.

Boskey A, DiCarlo E, Paschalis E, West P, Mendelsohn R . Comparison of mineral quality and quantity in iliac crest biopsies from high- and low-turnover osteoporosis: an FT-IR microspectroscopic investigation. Osteoporos Int. 2005; 16(12):2031-8. PMC: 1457020. DOI: 10.1007/s00198-005-1992-3. View