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Kill two birds with one stone: making multi-transgenic pre-diabetes mouse models through insulin resistance and
Siyuan Kong1,2, Jinxue Ruan1, Kaiyi Zhang1
1State Key Laboratory of Animal Nutrition & Key Laboratory of Farm Animal Genetic Resource and Germplasm Innovation of Ministry of Agriculture, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, Beijing, China.
Background:
Type 2 diabetes is characterized by insulin resistance accompanied by defective insulin secretion. Transgenic mouse models play an important role in medical research. However, single transgenic mouse models may not mimic the complex phenotypes of most cases of type 2 diabetes.
Methods:
Focusing on genes related to pancreatic islet damage, peripheral insulin resistance and related environmental inducing factors, we generated single-transgenic (C/EBP homology protein, CHOP) mice (CHOP mice), dual-transgenic (human islet amyloid polypeptide, hIAPP; CHOP) mice (hIAPP-CHOP mice) and triple-transgenic (11β-hydroxysteroid dehydrogenase type 1, 11β-HSD1; hIAPP; CHOP) mice (11β-HSD1-hIAPP- CHOP mice). The latter two types of transgenic (Tg) animals were induced with high-fat high-sucrose diets (HFHSD). We analyzed the diabetes-related symptoms and histology features of the transgenic animals.
Results:
Comparing symptoms on the spot-checked points, we determined that the triple-transgene mice were more suitable for systematic study. The results of intraperitoneal glucose tolerance tests (IPGTT) of triple-transgene animals began to change 60 days after induction (p < 0.001). After 190 days of induction, the body weights (p < 0.01) and plasma glucose of the animals in Tg were higher than those of the animals in Negative Control (Nc). After sacrificed, large amounts of lipid were found deposited in adipose (p < 0.01) and ectopically deposited in the non-adipose tissues (p < 0.05 or 0.01) of the animals in the Tg HFHSD group. The weights of kidneys and hearts of Tg animals were significantly increased (p < 0.01). Serum C peptide (C-P) was decreased due to Tg effects, and insulin levels were increased due to the effects of the HFHSD in the Tg HFHSD group, indicating that damaged insulin secretion and insulin resistance hyperinsulinemia existed simultaneously in these animals. The serum corticosterone of Tg was slightly higher than those of Nc due to the effects of the 11βHSD-1 transgene and obesity. In Tg HFHSD, hepatic adipose deposition was more severe and the pancreatic islet area was enlarged under compensation, accompanying apoptosis. In the transgenic control diet (Tg ControlD) group, hepatic adipose deposition was also severe, pancreatic islets were damaged, and their areas were decreased (p < 0.05), and apoptosis of pancreatic cells occurred. Taken together, these data show the transgenes led to early-stage pathological changes characteristic of type 2 diabetes in the triple-transgene HFHSD group. The disease of triple-transgenic mice was more severe than that of dual or single-transgenic mice.
Conclusion:
The use of multi-transgenes involved in insulin resistance and pancreatic apoptosis is a better way to generate polygene-related early-stage diabetes models.
Insights
Generating multi-gene transgenic mouse models with high-fat, high-sucrose diets effectively mimics early-stage type 2 diabetes. These models exhibit insulin resistance and pancreatic dysfunction, crucial for studying complex diabetes phenotypes.
Area of Science:
- Molecular Biology
- Genetics
- Endocrinology
- Pathology
Background:
- Type 2 diabetes (T2D) is characterized by insulin resistance and impaired insulin secretion.
- Single transgenic mouse models often fail to replicate the complex T2D phenotype.
- Developing more comprehensive models is essential for understanding T2D pathogenesis.
Purpose of the Study:
- To create and evaluate multi-gene transgenic mouse models for T2D research.
- To investigate the combined effects of specific transgenes and diet on diabetes development.
- To establish a more accurate preclinical model for studying early-stage T2D.
Main Methods:
- Generated single (CHOP), dual (hIAPP-CHOP), and triple (11β-HSD1-hIAPP-CHOP) transgenic mice.
- Administered high-fat, high-sucrose diets (HFHSD) to induce diabetes-related phenotypes.
- Assessed diabetes symptoms, glucose tolerance (IPGTT), body weight, plasma glucose, lipid deposition, organ weights, serum markers (C-peptide, insulin, corticosterone), and pancreatic islet histology.
Main Results:
- Triple-transgenic mice on HFHSD exhibited significant changes in glucose tolerance, body weight, and plasma glucose compared to controls.
- Increased lipid deposition in adipose and non-adipose tissues, enlarged kidneys and hearts were observed in triple-transgenic HFHSD mice.
- Simultaneous insulin resistance and defective insulin secretion (low C-peptide, high insulin) were evident, alongside hepatic steatosis and pancreatic islet apoptosis, indicating early-stage T2D pathology.
Conclusions:
- Multi-gene transgenic models incorporating insulin resistance and apoptosis pathways are superior for creating polygenic early-stage diabetes models.
- The triple-transgene model (11β-HSD1-hIAPP-CHOP) with HFHSD induction provides a robust platform for T2D research.
- This approach better recapitulates the complex pathophysiology of T2D compared to single-gene models.
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