The objective of the present study was to develop a rat model that replicates the natural history and metabolic characteristics of human
type 2 diabetes and is also suitable for pharmacological screening. Male Sprague-Dawley rats (160-180 g) were divided into two groups and fed with commercially available normal pellet diet (
NPD) (12% calories as fat) or in-house prepared high-fat diet (HFD) (58% calories as fat), respectively, for a period of 2 weeks. The HFD-fed rats exhibited significant increase in
body weight, basal plasma
glucose (PGL),
insulin (PI),
triglycerides (PTG) and total
cholesterol (PTC) levels as compared to
NPD-fed control rats. Besides, the HFD rats showed significant reduction in
glucose disappearance rate (K-value) on intravenous
insulin glucose tolerance test (IVIGTT).
Hyperinsulinemia together with reduced
glucose disappearance rate (K-value) suggested that the feeding of HFD-induced
insulin resistance in rats. After 2 weeks of dietary manipulation, a subset of the rats from both groups was injected intraperitoneally with low dose of
streptozotocin (STZ) (35 mg kg(-1)).
Insulin-resistant HFD-fed rats developed frank
hyperglycemia upon STZ injection that, however, caused only mild elevation in PGL in
NPD-fed rats. Though there was significant reduction in PI level after STZ injection in HFD rats, the reduction observed was only to a level that was comparable with
NPD-fed control rats. In addition, the levels of PTG and PTC were further accentuated after STZ treatment in HFD-fed rats. In contrast, STZ (35 mg kg(-1), i.p.) failed to significantly alter PI, PTG and PTC levels in
NPD-fed rats. Thus, these fat-fed/STZ-treated rats simulate natural
disease progression and metabolic characteristics typical of individuals at increased risk of developing
type 2 diabetes because of
insulin resistance and
obesity. Further, the fat-fed/STZ-treated rats were found to be sensitive for
glucose lowering effects of
insulin sensitizing (
pioglitazone) as well as insulinotropic (
glipizide) agents. Besides, the effect of
pioglitazone and
glipizide on the plasma
lipid parameters (PTG and PTC) was shown in these diabetic rats. The present study represents that the combination of HFD-fed and low-dose STZ-treated rat serves as an alternative animal model for
type 2 diabetes simulating the human syndrome that is also suitable for testing anti-diabetic agents for the treatment of
type 2 diabetes.