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. 2022 Aug 22;4(8):1071–1083. doi: 10.1038/s42255-022-00617-6

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© The Author(s) 2022

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Extended Data Fig. 2 — Change in body weight (a) and food intake (b) of 47-wk old male DIO C57BL6/J mice treated daily s.c. with Vhcl (n = 8 mice) or 50 nmol/kg of either GLP-1RA (n = 7 mice), Tesaglitazar (n = 8 mice), GLP-1RA/Tesaglitazar (n = 8 mice) or GLP-1RA + Tesaglitazar (n = 8 mice). Cumulative food intake was assessed per cage in n = 4/4/4/4 cages containing n = 8/7/8/8 mice (b). Glucose-stimulated insulin secretion in islets isolated from n = 10 male 18-wk old C57BL6/J mice (Run 1) and n = 10 female 12-wk old C57BL/6 J mice (Run 2), and which were treated with either control, GLP-1RA, GLP-1/Tesaglitazar or GLP-1RA + Tesaglitazar (n = 6/6/6/5 biologically independent replicates) under dynamic drug concentrations up to 3 nM under glucose concentrations of 10 mM (c,d). Data in (c,d) represent combined results from the two independent runs. Islets were pooled and separated randomly between the treatment groups. After 4 min of low glucose (2.7 mM), levels of glucose were increased to 10 mM at t = 5 min. The peak at t = 10 min represents 1^st phase insulin secretion, the peak at t = 80 min represents treatment with 2.7 mM glucose + 30 mM KCL (c,d). Glucose-stimulated insulin secretion in pooled islets isolated from 10–15-wk old male (n = 9) and female (n = 6) C57BL6/J mice treated with either control, GLP-1RA or GLP-1RA + Tesaglitazar (n = 9/6/6 biologically independent biological replicates) (e) or with control or GLP-1RA/Tesaglitazar (n = 9/6 independent biological replicates) (f) under dynamic glucose concentrations ranging from 2.7–16 mM at drug concentrations of 3 nM. Urinary albumin over creatinine ratio in 49-wk old male DIO C57BL6/J mice after 14 days of daily s.c. treatment with Vhcl or 50 nmol/kg of either GLP-1RA/Tesaglitazar, GLP-1RA, Tesaglitazar, GLP-1RA + Tesaglitazar (n = 8/5/6/7/8 mice) (g). Urinary samples of a mouse model for diabetic nephropathy (GIPRdn)³² (n = 3 mice) serves as positive control (g). Representative images of histopathological analysis of liver, iWAT, kidney and heart in 49-wk old male DIO C57BL6/J mice after 14 days of daily s.c. treatment with 50 nmol/kg (scale bar liver/iWAT: 100 µm, kidney/heart: 50 µm) (h). Representative confocal images of pancreatic sections obtained in 49-wk old male DIO C57BL6/J mice after 14 days of daily s.c. treatment with 50 nmol/kg and stained for different pancreatic hormones (scale bar 50 μm) (i). Pancreatic islet size (j) and hormone content between different groups (k-m) of 49-wk old male DIO C57BL6/J mice after 14 days of daily s.c. treatment with Vhcl or 50 nmol/kg of either GLP-1RA, Tesaglitazar, GLP-1RA + Tesglitazar or GLP-1RA/Tesaglitazar. Sample sizes are n = 4/3/4/4/4 mice (j) and n = 3/3/3/3 mice (k-m). Data in panel a and b have been analyzed by 2-way ANOVA using the Bonferroni’s multiple comparison test for individual time points. Data in panel d, g, and j-m have been analyzed by 1-way ANOVA with Bonferroni multiple comparison test. Data represent means ± SEM; asterisks indicate * p < 0.05, ** p < 0.01, *** p < 0.001. Blue asterisks in panel a and b indicate significance of GLP-1RA/Tesaglitazar over the fixed dose combination of the GLP-1RA + Tesaglitazar. Exact p-values for treatment effects are (a) p = 0.0105, (d) p = 0.0089 (Cntrl. vs. GLP-1RA), p = 0.0021 (Cntrl. vs. GLP-1RA/Tesaglitazar), p = 0.0011 (Cntrl. vs. GLP-1RA + Tesaglitazar). For exact p-values at individual time points (a,b) see data source file.

Source data