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. 2022 Feb 3;77(2):215-220.
doi: 10.1093/gerona/glab254.

Canagliflozin Increases Intestinal Adenoma Burden in Female ApcMin/+ Mice

Justin Korfhage  1 , Mary E Skinner  1 , Jookta Basu  1 , Joel K Greenson  1 , Richard A Miller  1   2 , David B Lombard  1   2   3
Affiliations

Canagliflozin Increases Intestinal Adenoma Burden in Female ApcMin/+ Mice

Justin Korfhage et al. J Gerontol A Biol Sci Med Sci. .

Abstract

The diabetes drug canagliflozin extends life span in male mice. Since malignant neoplasms are the major cause of death in most mouse strains, this observation suggests that canagliflozin might exert anti-neoplastic effects in male mice. Here, we treated a mouse neoplasia model, the adenoma-prone ApcMin/+ strain, with canagliflozin, to test the effects of this drug on intestinal tumor burden. Surprisingly, canagliflozin increased the total area of intestine involved by adenomas, an effect most marked in the distal intestine and in female mice. Immunohistochemical analysis suggested that canagliflozin may not influence adenoma growth via direct SGLT1/2 inhibition in neoplastic cells. Our results are most consistent with a model where canagliflozin aggravates adenoma development by altering the anatomic distribution of intestinal glucose absorption, as evidenced by increases in postprandial GLP-1 levels driven by delayed glucose absorption. We hypothesize that canagliflozin exacerbates adenomatosis in the ApcMin/+ model via complex, cell-non-autonomous mechanisms, and that sex differences in GLP-1 responses may in part underlie sexually dimorphic effects of this drug on life span.

Keywords: GLP-1; Polyposis; SGLT1; SGLT2.

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Figures

Figure 1.
Figure 1.
Canagliflozin increases adenoma burden in ApcMin/+ mice. (A) Timeline of canagliflozin treatment and feeding procedures of ApcMin/+ mice. Mice were fed a diet of canagliflozin (cana) or control chow for 70–72 days then fasted for 18 hours prior to sacrifice. (B) Average cross-sectional area of adenomas from control and canagliflozin treated mice was measured using ImageJ oval tool. Each point represents the mean adenoma size from a single mouse. Adenomas in canagliflozin treated mice (mean: 2.631 mm2) were significantly larger than adenomas in control mice (mean: 2.114 mm2); drug effect, p < .05, 2-way ANOVA; sex effect and interaction were n.s. (C) The total area of the SI involved by adenomas in each mouse was summed and plotted. Each point represents an individual mouse. The area of the SI involved by adenomas in canagliflozin mice (mean: 200 mm2) was significantly greater than control mice (mean: 134 mm2); drug effect, p < .01, 2-way ANOVA; sex effect and interaction were n.s. (D) The number of adenomas in each mouse was counted and plotted. Each point represents one mouse. Canagliflozin-treated mice (mean: 76) did not exhibit significantly more adenomas than control mice (mean: 63.67); drug effect, p = .22, 2-way ANOVA; sex effect and interaction were n.s. (B–D) Significant differences within sex and region were determined by 2-tailed Student’s t test and are displayed on each graph. *p < .05, **p < .01. (E) Representative images of adenomas in the duodenum, jejunum, and ileum. Adenomas are identified with black arrows. Scalebar = 10 mm.
Figure 2.
Figure 2.
Increased adenoma burden in canagliflozin-treated mice is concentrated in the distal SI. (A) Variance in the size of individual adenomas accounted for by canagliflozin (cana), sex, and region was analyzed by 3-way ANOVA using a linear mixed effects model, treating each mouse ID as a random effect and region as a repeated measure. Mean adenoma size was plotted for each mouse. (B) Total cross-sectional area involved by adenomas was plotted for each mouse. 3-way ANOVA was performed using a linear mixed effects model with region as a repeated measurement. (C) Adenoma number in each region of the SI was analyzed for each mouse and compared by 3-way ANOVA using a linear mixed effects model with region as a repeated measurement. (A–C) Each point represents one mouse. ANOVA tables are displayed to the right of each figure. Significant differences within sex and region were determined by 2-tailed Student’s t test and are displayed on each graph. *p < .05, **p < .01, ***p < .001, ****p < .0001.
Figure 3.
Figure 3.
Canagliflozin treatment elevates postprandial serum GLP-1 levels. (A) Timeline of canagliflozin treatment prior to obtaining serum. (B) Total GLP-1 levels were measured by colorimetric ELISA assay. Each point represents the mean of 2 technical replicates from the serum of one mouse. (C) Active GLP-1 levels were measured by a luminescent ELISA assay. Each point represents the mean of 2 technical replicates from the serum of one mouse. (B–C) The effects of canagliflozin and sex were analyzed by 2-way ANOVA. ANOVA tables are presented below graphs. Significant differences within each sex were determined by 2-tailed Student’s t test and are displayed on each plot. *p < .05, **p < .01.
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