The increasing production of genetically-modified mouse models has necessitated studies to determine the inherent physiological characteristics of commonly used mouse strains. In this study we examined insulin secretory function in response to an intravenous bolus of glucose or glucose plus arginine in anesthetized C57BL/6, DBA/2 and 129T2 mice fed either a control or high fat diet for 6 weeks. The results show that 129T2 mice had higher fasting plasma glucose levels and lower fasting plasma insulin levels compared with C57BL/6 and DBA/2 mice regardless of diet. Furthermore, 129T2 mice were glucose intolerant and secreted significantly less insulin in response to glucose and glucose plus arginine irrespective of diet compared with the other two strains of mice. DBA/2 mice hypersecreted insulin in response to glucose and glucose plus arginine compared with C57BL/6 and 129T2 mice. Moreover while first phase insulin secretion was appropriately increased in response to the high fat diet in C57BL/6 and 129T2 mice, this was not the case for DBA/2 mice. Mean islet area was decreased in response to a high fat diet in DBA/2 mice, while there was no dietary effect on the other two strains. This study highlights the inherent genetic differences that exist among seemingly normal strains of mice that are commonly used to make transgenic and knockout mice. Understanding these differences will provide researchers with the information to choose the appropriate genetic background on which to express their particular genetic alteration.

Although it is now becoming more evident that the strain of mouse used to generate genetically modified models for the study of endocrine disorders contributes to the ensuing phenotype, metabolic characterization of these common strains used to produce genetically altered mice has been limited. The aim of this study therefore was to measure various metabolic parameters in C57BL/6, DBA/2, and 129T2 mice fed a control or a high-fat diet. Mice were fed either a control (7 g/100 g) or a high-fat (60 g/100 g) diet for 6 wk. During wk 6, spontaneous and voluntary physical activity and resting energy expenditure were determined. DBA/2 mice that consumed the control diet gained more weight and had larger regional fat pad depots than either C57BL/6 or 129T2 mice (P < 0.05). Spontaneous and voluntary activity was lower in 129T2 mice compared with DBA/2 or C57BL/6 mice (P < 0.05). Resting energy expenditure (corrected for body weight) was greater in C57BL/6 mice than in DBA/2 or 129T2 mice (P < 0.05), whereas glucose and fat oxidation did not differ among the 3 strains of mice. Plasma glucose concentrations in food-deprived mice were higher and insulin concentrations lower in 129T2 compared with C57BL/6 mice (P < 0.05), but were not affected by the high-fat diet in any of the 3 strains tested. This study shows that these 3 commonly used inbred strains of mice have different inherent metabolic characteristics. It further highlights that the background strain used to produce genetically modified mice is critical to the resultant phenotype.

Aims/hypothesis. To study the secondary consequences of impaired suppression of endogenous glucose production (EGP) we have created a transgenic rat overexpressing the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) in the kidney. The aim of this study was to determine whether peripheral insulin resistance develops in these transgenic rats. Methods. Whole body rate of glucose disappearance (R d ) and endogenous glucose production were measured basally and during a euglycaemic/hyperinsulinaemic clamp in phosphoenolpyruvate carboxykinase transgenic and control rats using [6-3 H]-glucose. Glucose uptake into individual tissues was measured in vivo using 2-[1-14 C]-deoxyglucose. Results. Phosphoenolpyruvate carboxykinase transgenic rats were heavier and had increased gonadal and infrarenal fat pad weights. Under basal conditions, endogenous glucose production was similar in phosphoenolpyruvate carboxykinase transgenic and control rats (37.4±1.1 vs 34.6±2.6 µmol/kg/min). Moderate hyperinsulinaemia (810 pmol/l) completely suppressed EGP in control rats (−0.6±5.5 µmol/kg/min, p<0.05) while there was no suppression in phosphoenolpyruvate carboxykinase rats (45.2±7.9 µmol/kg/min). Basal R d was comparable between PEPCK transgenic and control rats (37.4±1.1 vs 34.6±2.6 µmol/kg/min) but under insulin-stimulated conditions the increase in R d was greater in control compared to phosphoenolpyruvate carboxykinase transgenic rats indicative of insulin resistance (73.4±11.2 vs 112.0±8.0 µmol/kg/min, p<0.05). Basal glucose uptake was reduced in white and brown adipose tissue, heart and soleus while insulin-stimulated transport was reduced in white and brown adipose tissue, white quadriceps, white gastrocnemius and soleus in phosphoenolpyruvate carboxykinase transgenic compared to control rats. The impairment in both white and brown adipose tissue glucose uptake in phosphoenolpyruvate carboxykinase transgenic rats was associated with a decrease in GLUT4 protein content. In contrast, muscle GLUT4 protein, triglyceride and long-chain acylCoA levels were comparable between PEPCK transgenic and control rats. Conclusions/interpretation. A primary defect in suppression of EGP caused adipose tissue and muscle insulin resistance. [Diabetologia (2003[Diabetologia ( ) 46:1338[Diabetologia ( -1347