Basic Science Newsbrief November 2011

 

TALLYHO, a Polygenic Mouse Model of Type 2 Diabetes With Obesity

 
By: Jung Han Kim and Joan C. Edwards

 

Type 2 diabetes (T2D) is the most common form of human diabetes, accounting for over 90% of cases and often coexists with obesity.  The etiology of T2D involves genetic predisposition and nongenetic risk factors such as age, diet and life style.  Supporting evidence for heritability includes the pronounced ethnic differences in T2D prevalence and strong familial aggregation of the disease.  Most common forms of T2D in humans follow polygenic inheritances: i.e., multiple genes are involved in the development of the disease.  The pathophysiological mechanism of T2D is characterized by a combination of peripheral insulin resistance and b-cell dysfunction.  

The TALLYHO/Jng (TH) mouse is a relatively new genetic model of T2D with obesity.  This inbred strain was developed by Dr. Naggert’s research group at The Jackson Laboratory and first published in 2001.  Since 2004, TH mice are commercially available from Jax.  TH mice spontaneously develop T2D as in humans.  The development of T2D in these mice follows a complex mode of inheritance, which accurately reflects the common T2D in humans.  TH mice manifest many phenotypic traits that are consistent with those in T2D patients.  In the literature, there are some discrepancies in metabolic phenotypes across the locations where the TH mice are housed.  To demonstrate that TH mice are an appropriate model for human T2D, this brief report summarizes the up-to-date information on metabolic and genetic characteristics of TH mice.
 
T2D is a progressive disease, preceded by a period of insulin resistance and impaired glucose tolerance.  At pre-diabetic stage, male TH mice develop impaired tolerance to glucose loading, which is accompanied by hypersecretion of insulin during the glucose tolerance test.  With age the glucose intolerance increases, and insulin secretion during the test becomes less profound.  The glucose intolerance progresses to hyperglycemia (>300 mg/dL, non fasting) in male TH mice at around 14 weeks of age. The Langerhans islets are hypertrophied in TH mice at 4 weeks through adult ages, suggesting the presence of sustained stimuli for insulin secretion presumably due to peripheral insulin resistance.  Degranulation of b-cell and abnormal architecture in islets are also evident in male TH mice at later stage of the disease.  Glucose uptake stimulated by insulin is impaired in soleus muscle and adipocytes isolated from TH mice.  Male TH mice exhibit overnight fasting hyperglycemia.  However, thus far, hepatic insulin resistance has not been well characterized in TH mice. 

Obesity in TH mice is characterized by increased body weight as well as fat pad weight including subcutaneous and visceral fat. At 4 wks of age, TH mice exhibit about 3-fold higher plasma leptin levels than age- and sex-matched C57BL/6 mice.  At 12 wks of age, the mean body weight of TH mice becomes 32 g (female) and 35 g (male).  
 
Many T2D patients display dyslipidemia characterized by increased triglycerides, increased small dense LDL cholesterol, and decreased HDL cholesterol.  Notably, hypertriglyceridemia occurs years before diabetes in T2D patients and is known to be a strong predictor of diabetes.  Hypertriglyceridemia in TH mice is detectable at pre-diabetic stage of 4 weeks of age and maintained through adult ages.  TH mice also exhibit increased levels of plasma cholesterol and free fatty acids.  Diabetes-associated complications are not yet well characterized in TH mice, but certain degrees of endothelial dysfunction and considerably decreased bone density are known.

In conclusion, T2D in humans is a complex polygenic disease.  Animal models with a similar genetic basis, such as TH mice, are appropriate resources for understanding the genetic architecture of the common complex disease of T2D.  Further, TH mice have a profile of physiological anomalies very similar to those that are present in the majority of T2D patients.  Therefore, information obtained from TH mice will provide important insights regarding diabetes genes and pathology that can be tested in humans.

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