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Comparative Study
. 2017 May 3;7(1):1461.
doi: 10.1038/s41598-017-01432-w.

Development of a Novel Zebrafish Model for Type 2 Diabetes Mellitus

Liqing Zang  1 , Yasuhito Shimada  2   3 , Norihiro Nishimura  4
Affiliations
Comparative Study

Development of a Novel Zebrafish Model for Type 2 Diabetes Mellitus

Liqing Zang et al. Sci Rep. .

Abstract

Obesity is a major cause of type 2 diabetes mellitus (T2DM) in mammals. We have previously established a zebrafish model of diet-induced obesity (DIO zebrafish) by overfeeding Artemia. Here we created DIO zebrafish using a different method to induce T2DM. Zebrafish were overfed a commercially available fish food using an automated feeding system. We monitored the fasting blood glucose levels in the normal-fed group (one feed/day) and overfed group (six feeds/day) over an 8-week period. The fasting blood glucose level was significantly increased in DIO zebrafish compared with that of normal-fed zebrafish. Intraperitoneal and oral glucose tolerance tests showed impaired glucose tolerance by overfeeding. Insulin production, which was determined indirectly by measuring the EGFP signal strength in overfed Tg(-1.0ins:EGFP) sc1 zebrafish, was increased in DIO zebrafish. The anti-diabetic drugs metformin and glimepiride ameliorated hyperglycaemia in the overfed group, suggesting that this zebrafish can be used as a model of human T2DM. Finally, we conducted RNA deep sequencing and found that the gene expression profiling of liver-pancreas revealed pathways common to human T2DM. In summary, we developed a zebrafish model of T2DM that shows promise as a platform for mechanistic and therapeutic studies of diet-induced glucose intolerance and insulin resistance.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
Body weights (g), fasting blood glucose of overfed (DIO) and normal-fed (non-DIO) zebrafish, and effect of calorie restriction on DIO zebrafish. (a) DIO zebrafish gain weight progressively over an 8-week period. Representative images of DIO (upper) and non-DIO (lower) zebrafish are shown in the panel. Non-DIO group: n = 14; DIO group: n = 29. (b) Changes in the fasting blood glucose concentrations of the non-DIO and DIO groups. Non-DIO group: n = 14; DIO group: n = 29. (c) Changes in fasting blood glucose concentrations after calorie restriction for 2 and 4 weeks. n = 5–8. Values are means ± SE. *P < 0.05, **P < 0.01 vs. the non-DIO group.
Figure 2
Figure 2
Impaired glucose tolerance in DIO zebrafish. (a) Intraperitoneal glucose tolerance test (IPGTT) in non-DIO and DIO zebrafish with blood glucose levels determined after fasting (0 min) and 30, 90, and 180 min after intraperitoneal injection of 0.5 mg glucose/g body weight; n = 5 fish/time point. (b) Oral glucose tolerance test (OGTT) in non-DIO and DIO zebrafish with blood glucose levels determined after fasting (0 min) and 30, 60, and 120 min after oral administration of 1.25 mg glucose/g body weight; n = 5 fish/time point. Values are means ± SE. *P < 0.05, **P < 0.01 vs. the non-DIO group.
Figure 3
Figure 3
Increased insulin production in DIO zebrafish. (a) Fasting blood glucose concentrations of ins-EGFP zebrafish after 3 months of normal feeding or overfeeding. n = 10. (b) Insulin-EGFP signals in exocrine pancreas were monitored in non-DIO and DIO ins-EGFP zebrafish by fluorescence stereoscopic microscopy. Scale bar = 0.5 mm. (c) Graph of the percentage of EGFP positive signal area in entire image. n = 3. (d) Graph of relative EGFP intensities from panel b. n = 3. (e) Western blot analysis for GFP signals in liver-pancreas tissue of non-DIO and DIO ins-EGFP. Full-length blots are presented in Supplementary Fig. S3. Values are means ± SE. *P < 0.05, **P < 0.01 vs. the non-DIO group.
Figure 4
Figure 4
The effects of anti-diabetic drugs on DIO zebrafish. (a) Effect of metformin (20 μM) on blood glucose levels of DIO zebrafish after 7 days’ treatment. (b) Effect of glimepiride (100 μM) on blood glucose levels of DIO zebrafish after 24 h treatment. n = 5–10. Values are means ± SE. *P < 0.05, **P < 0.01 vs. the non-DIO group.
Figure 5
Figure 5
Pathways of insulin secretion in pancreas and insulin resistance in liver of DIO zebrafish and T2DM patients. Insulin secretion pathways in (a) DIO zebrafish and (b) pancreatic beta cells of T2DM human patients (GSE20966). Pathways of insulin resistance in (c) DIO zebrafish and (d) human hyperglycaemic liver (GSE23343). Red and blue denote genes with increased and decreased expression, respectively. Grey denotes genes that were not detected in the RNA-seq assay or DNA microarray.
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