Abstract
BackgroundType 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.MethodsFocusing 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.ResultsComparing 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.ConclusionThe use of multi-transgenes involved in insulin resistance and pancreatic apoptosis is a better way to generate polygene-related early-stage diabetes models.
Highlights
In the Tg High-fat high-sucrose diet (HFHSD) group, hepatic adipose deposition was more severe and the pancreatic islet area was enlarged under compensation, accompanying apoptosis
In the Tg ControlD group, hepatic adipose deposition was severe, pancreatic islets were damaged, and their areas were decreased (p
Dual and triple transgenic C57BL/6 mice with a porcine apolipoprotein E promoter fragment linked to the 11β-HSD1 gene and/or a porcine insulin promoter fragment linked to the C/EBP homology protein (CHOP) gene and the hIAPP gene were generated. pGL3-PIPCHOP is a single transgene vector in which the CHOP gene is driven by pancreas-specific PIP
Summary
Type 2 diabetes mellitus (T2DM), which is characterized by peripheral insulin resistance and impaired insulin secretion, is a chronic metabolic disease that has shown an increased incidence in obese and aged individuals in recent years(Association 2009; Lee & Cox 2011).T2DM is a multifactorial disease that is associated with genetic factors such as susceptibility genes and environmental factors such as intake of high-fat and high-sucrose diets(Nath et al.2016; Qiu et al 2016). β-cell failure and peripheral insulin resistance are pathogenic features ofT2DM(Kahn 2003; Lee & Cox 2011). The transgenic mouse models that have been used in diabetes research are involved with single transgenes, focusing on the insulin gene or its mutants. They mainly provide information related to Type 1 diabetes
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