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01.09.2009 | Article | Ausgabe 9/2009

Diabetologia 9/2009

Skeletal myoblast transplantation for attenuation of hyperglycaemia, hyperinsulinaemia and glucose intolerance in a mouse model of type 2 diabetes mellitus

Zeitschrift:
Diabetologia > Ausgabe 9/2009
Autoren:
L. Ye, K. O. Lee, L. P. Su, W. C. Toh, H. K. Haider, P. K. Law, W. Zhang, S. P. Chan, E. K. W. Sim
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1007/​s00125-009-1421-9) contains supplementary material, which is available to authorised users.

Abstract

Aims/hypothesis

We aimed to demonstrate the feasibility and efficacy of intra-muscular transplantation of human skeletal myoblasts (hSkMs) for attenuation of hyperglycaemia and improvement of insulin sensitivity using a mouse model of type 2 diabetes mellitus.

Methods

KK Cg-Ay/J mice, aged 12 to 14 weeks, underwent an initial intraperitoneal glucose tolerance test (GTT) and were divided into the following groups: KK control group, basal medium (M199) only; KK myoblast group, with hSkM transplantation; KK fibroblast group, with human fibroblast transplantation. Non-diabetic C57BL mice were used as an additional normal control and also had hSkM transplantation. Cells were transplanted intra-muscularly into the skeletal muscles of the mice. All animals were treated with ciclosporin for 6 weeks only. HbA1c and fasting GTT, as well as serum adiponectin, cholesterol, insulin and triacylglycerol were studied.

Results

Immunohistochemistry studies showed extensive survival of the transplanted hSkMs in the skeletal muscles at 12 weeks, with nuclei of the hSkMs integrated into the host muscle fibres. Repeat GTT showed a significant decrease in glucose concentrations in the KK myoblast group compared with the KK control and KK fibroblast groups. The KK myoblast group also had reduced mean HbA1c, cholesterol, insulin and triacylglycerol, and increased adiponectin compared with the KK control and KK fibroblast groups. C57BL mice showed no change in glucose homeostasis after hSkM transplant.

Conclusions/interpretation

Human skeletal myoblast transplantation attenuated hyperglycaemia and hyperinsulinaemia and improved glucose tolerance in the KK mouse. This novel approach of improving muscle insulin resistance may be a potential alternative treatment for type 2 diabetes mellitus.

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Zusatzmaterial
ESM Fig. 1 a Human skeletal myoblasts were labelled with DAPI with 100% labelling efficiency. The nuclei (blue fluorescence) are hSkMs labelled with DAPI. b Cells were double-labelled with BrdU with 50 to 60% labelling efficiency. The nuclei (brown) are hSkMs labelled with BrdU. The cells were counterstained with haematoxylin (nuclear localised bluish-purple colour) to show all cell nuclei. c DAPI+ hSkM nuclei in KK mouse skeletal muscle at 12 weeks after treatment and (d) the same tissue section counterstained with haematoxylin and eosin to show the structure of the tissue. e Mouse skeletal muscle section was immunostained for BrdU expression and inset magnified (f). Fluorescent in situ hybridisation analyses for detection of hSkM nuclei DNA in mouse skeletal muscle section were conducted, with (g, h) human pan centromeric probe-labelled nuclei (green fluorescence) that were stained with DAPI (blue) and (i, j) mouse pan centromeric probe-labelled nuclei (red fluorescence) stained with DAPI. Magnification (a–e) 100×, (f) 200× and (g–j) 400× (PDF 361 kb)
125_2009_1421_MOESM1_ESM.pdf
ESM Fig. 2 a DAPI+ mouse skeletal muscle tissue section was immunostained for skeletal myosin (green fluorescence) and the same tissue section counterstained with (b) iodine to show all the nuclei (orange fluorescence). c DAPI+ (blue fluorescence) mouse skeletal muscle tissue section was immunostained for dystrophin (green fluorescence) to delineate the boundary of skeletal myofibres. The same tissue section was counterstained (d) with iodine to show all the nuclei (orange fluorescence). Magnification (a, b) 400×, (c, d) 200× (PDF 215 kb)
125_2009_1421_MOESM2_ESM.pdf
ESM Fig. 3 Western blot analyses of mouse skeletal muscle tissue for insulin receptor (IR), IRS-1, PI3K, AKT and GLUT4 at baseline and 0.5 h after i.p. glucose injection. Quantification of blots (%) is provided below. *p < 0.05 vs KK control group and KK myoblast group 1; †p < 0.05 vs KK control group (PDF 156 kb)
125_2009_1421_MOESM3_ESM.pdf
ESM Fig. 4 Mouse skeletal muscle AKT activity (a, b) in fluorescence intensity (FI) and (c, d) PI3K activity. Graphs show (a, c) baseline condition and (b, d) condition at 0.5 h after i.p. glucose injection. FI, fluorescence intensity. White bar, basal condition; grey bar, 0.5 h after i.p. glucose injection (PDF 13 kb)
125_2009_1421_MOESM4_ESM.pdf
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