Animal Models of Type 2 Diabetes: The GK Rat


     
The Microbiome and Visceral Pain Studying the long-term complications of diabetic pathology is more relevant than ever, driving increased interest in animal models of type 2 diabetes. According to the World Health Organization (WHO) the number of people with diabetes (includes both type 1 and type 2) has risen from 108 million in 1980 to 422 million in 2014.

"[Diabetes] is a major cause of blindness, kidney failure, heart attacks, stroke, and lower limb amputation. Over time, diabetes can damage the heart, blood vessels, eyes, kidneys, and nerves. Adults with diabetes have a 2-3-fold increased risk of heart attacks and strokes. Combined with reduced blood flow, neuropathy in the feet increases the chance of foot ulcers, infection and eventual need for limb amputation. Diabetic retinopathy is an important cause of blindness and occurs as a result of long-term accumulated damage to the small blood vessels in the retina. 2.6% of global blindness can be attributed to diabetes. Diabetes is among the leading causes of kidney failure." (WHO Media Center, 2016).

Common Animal Models of Type 2 Diabetes

There are a variety of mouse and rat models which can be used to study aspects of type 2 diabetes:

Varying aspects and severity of complications

Model Model Type Obesity Retinopathy Nephropathy Neuropathy Hepatic Impairment Cardiomyopathy
Goto-Kakizaki (GK) Rat Polygenic No Yes Yes Yes Yes Yes
Zucker Diabetic Fatty (ZDF) Rat# Monogenic Yes Yes Yes Yes Yes Yes
STZ Induced Mouse or Rat Induced No Yes Yes Yes Yes Yes
Diabetic (db/db) Mouse Monogenic Yes Yes No Yes Yes Yes
DIO C57BL/6 Mouse# Induced+ Yes No No Yes Yes Yes
KK-Ay Mouse Polygenic Yes Yes Yes No Yes Yes
NON Mouse# Polygenic Yes No Yes No Yes No
Obese (ob/ob) Mouse Monogenic Yes No Only on BTBR background Yes Yes Yes
Key:
# Specific diet required
+ More robust diet induced obesity in C57BL/6NTac (Gareski T, 2009)

Studying Long-term Pathology in Animal Models of Type 2 Diabetes

The ob/ob and db/db mice, as well as the Zucker Diabetic Fatty rat, are all well-characterized and frequently-used diabetic models which exhibit a mutation in the leptin (ob/ob) or leptin receptor gene (ZDF, db/db). They are useful for studying particular disease characteristics, but do not necessarily represent the human disease state as mutations in these genes are not frequently the cause of type 2 diabetes in humans.

Diet-induced obese (DIO) C57BL/6 mice can be used to effectively model pre-diabetic symptoms and study the progression of metabolic syndrome. DIO mice allow researchers to look at factors that can be controlled at earlier disease stages and study behaviors and compounds that can slow progression of the disease or reverse disease development.

The Goto-Kakizaki (GK) rat is a well-characterized model of type 2 diabetes which exhibits certain diabetic complications such as nephropathy and retinopathy, making them ideal for studying long-term complications of the disease.

Goto-Kakizaki Publications Read the Related Publications:

Diabetes Model Highlight: GK Rat

The Goto-Kakizaki (GK) rat is a polygenic non-obese Wistar substrain that develops adult onset type 2 diabetes early in life. This model was developed in the 1970s by Goto and associates at Tohoku University in Sendai, Japan, by selecting breeder pairs with the highest glucose levels from a colony of Wistar rats. Repeated selection of breeders based on blood glucose levels resulted in glucose intolerance after five generations.

  • "The GK rat is an appropriate animal model with which to study the etiology of T2D and is very useful for evaluating potential antidiabetic drug effects." (Wang X, 2014)
  • The GK is characterized by a moderate fasting hyperglycemia, hypoinsulinemia, normolipidemia, impaired glucose tolerance, and an early onset of diabetic complications. (Poretsky, 2010)
  • "The presence of chronic inflammation is suggested...despite the absence of obesity in these animals. The results support the hypothesis that chronic inflammation contributes to diabetes in the GK rat in the absence of obesity." (Nie J, 2011)

Husbandry

The model is a relatively poor breeder, with an average litter size of six pups. Taconic Biosciences has found that each female will generally only produce one to two litters, as breeding performance declines significantly after two litters.

Females should be set up for breeding in pairs at nine-to-ten weeks of age with ten-to-twelve week old males. Harem mating with isolation of pregnant females provides better outcomes compared to pair mating. Rats should be weaned at approximately twenty-eight days of age versus the standard twenty-one days for other rat models.

Experimental Applications

GK rats are an ideal model for studying comorbidities of type 2 diabetes as they exhibit characteristics such as retinopathy, nephropathy, neuropathy, and cardiovascular complications similar to those seen in human disease.

Numerous studies have demonstrated that the GK rat is a valuable tool for studying these impairments.

The GK rat:

  • exhibits changes in renal structure and function (Schrivers BF, 2004) (Janssan U, 2004)
  • develops hypertension and cardiac hypertrophy (Grönholm T, 2005) (Fuentes-Antrás J, 2015)
  • exhibits aspects of diabetic retinopathy (Gong C, 2016) (Miyamoto K, 1996)
  • neuropathy (Murakawa Y, 2002)
  • hepatic impairment (Jorgensen, 2012)
Additionally, the GK rat is better suited than otherwise comparable mice for certain study types, as surgical interventions and imaging are easier in models with a larger body size.

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References:
1. Fuentes-Antrás J, et. al. (2015). Updating Experimental Models of Diabetic Cardiomyopathy. J Diabetes Research, Article ID 656795, 15 pages.
2. Gareski T, et. al. (2009). The Severity of Insulin Resistance in C57BL/6 MiceDependson Genetic Background and Dietary Fat Source. Abstract# 1713-P. American Diabetes Association.
3. Gong C, et. al. (2016). The Development of Diabetic Retinopathyin the Goto-Kakizaki Rat and the Expression of Angiogenesis-Related Signals. Clin J Physiol, 100-108.
4. Grönholm T, et. al. (2005). Vasopeptidase inhibition has beneficial cardiac effects in spontaneously diabetic Goto-Kakizaki rats. Eur J Pharmacol, 267-76.
5. Janssan U, et. al. (2004). The Quest for a model of type II diabetes with nephropathy: the Goto Kakizaki rat. J Nephrol, 769-73.
6. Jorgensen W, et. al. (2012). Progression of type 2 diabetes in GK rats affects muscle andlivermitochondria differently: pronounced reduction of complex II fluxis observed in liver only. Am J Physiol Endocrinol Metab, E515-23.
7. Miyamoto K, et. al. (1996). Evaluation of retinal microcirculatory alterations in the Goto-Kakizaki rat. Aspontaneous model of non-insulin-dependent diabetes. Invest Optahlmol Vis Sci, 989-905.
8. Murakawa Y, et. al. (2002). Impairedglucose tolerance and insulinopenia in the GK-rat causes peripheral neuropathy. Diabetes Metab. Res. Rev., 473-83.
9. Nie J, et. al. (2011). Differential muscle gene expression as a function of diseaseprogressionin Goto-Kakizaki diabetic rats. Mol Cell Endocrinol, 1-2.
10. Poretsky, L. (2010). Principles of Diabetes Mellitus. Springer US.
11. Schrivers BF, et. al. (2004). Long-term renal changes in the Goto-Kakizaki rat, a model o flean type 2 diabetes. Nephrol Dial Tranplant, 1092-97.
12. Wang X, et. a. (2014). Diabetes disease progression in Goto-Kakizaki rats: effects of salsalate treatment. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy, 381-89.
13. WHO Media Center. (2016, November). WHO - Diabetes. Retrieved from World Health Organization.
14. Wong, S, et. al. (2016). Animal models of metabolic syndrome: a review. Nutrition & Metabolism.