Phenotypic characterization of polygenic type 2 diabetes in TALLYHO/JngJ mice

Abstract

The TALLYHO/JngJ (TH) strain is a newly established, polygenic mouse model for type 2 diabetes (T2D) and obesity, and we have previously reported some key physiological features of this model after the overt onset of diabetes. In the present work, we conducted a comprehensive phenotypic characterization of TH in order to completely characterize this new and relevant model for human T2D and obesity. We monitored the development of obesity and diabetes starting at 4 weeks of age by measuring body weight, glucose tolerance, and plasma levels of insulin, glucose, and triglyceride. Additionally, histological alterations in the pancreas and glucose uptake and glucose transporter 4 (GLUT4) content in soleus muscle were also examined. Compared with age-and sex-matched C57BL/6J (B6) mice, both male and female TH mice were significantly heavier, hyperleptinemic, and hyperinsulinemic at 4 weeks of age, without glucose intolerance or hyperglycemia. TH mice maintained higher body weights throughout the study period of 16 weeks. The hyperinsulinemia in TH mice worsened with age, but to a lesser degree in females than in males. Both the male and the female TH mice had enlarged pancreatic islets. Male TH mice showed impaired glucose tolerance at 8 weeks that became more prominent at 16 weeks. Plasma glucose levels continuously increased with age in male TH mice resulting in frank diabetes, while female TH mice remained normoglycemic throughout the study. Impaired glucose tolerance and hyperglycemia in male TH mice were accompanied by impaired 2-deoxyglucose uptake in the soleus muscle at basal and insulin-stimulated states, but without any reduction in GLUT4 content. Interestingly, male TH mice exhibited a drastic elevation in plasma triglyceride levels in the pre-diabetic stage that was maintained throughout the study. These findings suggest that obesity and insulin resistance are an inherent part of the TH phenotype and glucose intolerance is evident preceding progression to overt diabetes in male TH mice.

Incorporation of therapeutically modified bacteria into gut microbiota inhibits obesity

“…Consistent with pNAPEEcN preserving sensitivity to insulin action during high-fat feeding, mice treated with pNAPE-EcN had higher levels of p-S473-AKT in their liver per unit of circulating insulin (p-AKT-INS) than did control mice ( Figure 12A). When stimulated with a bolus of 0.75 IU/kg obesity more typical of human disease has led to the development of mice with polygenic obesity such as TallyHo/Jng (TallyHo) mice (42)(43)(44)(45). Female TallyHo mice have been reported to rapidly gain excess weight and body fat (relative to C57BL6J mice) in the first 12 weeks of life, even while consuming a standard chow diet and without displaying the hyperglycemia seen in male TallyHo mice (45).…”

Type 1 diabetic bone loss is prevented by novel osteogenic factors

“…Body weight continues to increase with age, but obesity in these mice is less severe than some other diabetic models [49]. Increased plasma triglycerides, cholesterol, and fatty acid levels are noticeable from 4 to 8 weeks of age [49]. Diabetes is present only in male mice [47].…”

“…TallyHo mice are fatter and weigh more than controls by 4 weeks of age [47,48]. Body weight continues to increase with age, but obesity in these mice is less severe than some other diabetic models [49]. Increased plasma triglycerides, cholesterol, and fatty acid levels are noticeable from 4 to 8 weeks of age [49].…”

“…Diabetes is present only in male mice [47]. Other characteristics of the TallyHo mouse include enlarged pancreatic islets, hyperleptinemia, and poor wound healing [48,49]. Investigations of the skeletal phenotype in TallyHo mice have utilized two different control strains [47,50].…”

Development of Improved Animal Models for the Study of Diabetes

“…The treatment with leptin results in decreased glucose-stimulated insulin secretion, which demonstrate that letin plays an important role in initiation of glucose intolerance in TH mice [113]. Both males and females develop early moderate hyperplasia and hypertrophy of pancreatic islets, but only the males continue these lesions with β-cell degranulation, discrete vacuolization, different degrees of islet atrophy and fibrosis [114]. Vascular dysfunction occurs in TH mice, expressed mainly in aorta, carotid arteries and cerebral arterioles as a consequence of PGH2/TxA2 receptor activation and cytochrome p450 products and oxidative stress and elevated activity of Rho kinase, respectively [115,116].…”