Differential effect of inbred mouse strain (C57BL/6, DBA/2, 129T2) on insulin secretory function in response to a high fat diet

Abstract

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.

Mouse strain-dependent variation in obesity and glucose homeostasis in response to high-fat feeding

“…Although they showed the largest increase in body weight and also gained substantial amounts of fat mass, they became only marginally glucose intolerant on the HFD, as reported previously [1]. They exhibited similar differences in lipid accumulation, mitochondrial metabolism, inflammation and oxidative stress to other strains.…”

“…They exhibited similar differences in lipid accumulation, mitochondrial metabolism, inflammation and oxidative stress to other strains. However, they did exhibit a large increase in fasting insulin, suggesting that compensatory hyperinsulinaemia reduces HFD-induced glucose intolerance in this strain [1,4].…”

“…Some problems with these and other previous strain comparisons are the use of diverse HFDs varying in lipid and carbohydrate content and the investigation of limited variables that may underpin the development of metabolic disease and importantly some contradictory findings. For example, FVB/N mice have been characterised as both obesity-prone [6] and obesity-resistant [3], with similar contradictory observations reported for DBA/2 mice [1,7]. The C57BL/6 mouse strain is generally suggested to be the best strain for studying metabolic disease.…”

“…However, when creating genetically manipulated mice, consideration must be given to the genetic background on which the mouse is created and differences in metabolic phenotype that might be associated with gene manipulation on mixed genetic backgrounds. Several previous studies have shown that mouse strains can differ substantially in their metabolic phenotype under normal low-fat diet (LFD) conditions and in response to a high-fat diet (HFD) [1][2][3][4][5]. Some problems with these and other previous strain comparisons are the use of diverse HFDs varying in lipid and carbohydrate content and the investigation of limited variables that may underpin the development of metabolic disease and importantly some contradictory findings.…”

Too much of a good thing: why it is bad to stimulate the beta cell to secrete insulin

“…We found that in contrast to C57BL/6 mice, which have a genetic disruption in Nnt, and the 129T2 mice, which show low levels of expression, the diabetes-susceptible DBA/2 mice show a fivefold overexpression of this gene, which encodes the mitochondrial proton pump known as nicotinamide nucleotide transhydrogenase. Insulin secretion was elevated in DBA/2 mice relative to that in C57BL/6 and 129T2 mice [18][19][20] Interestingly, we found that other strains of mice (BALB/c, FVB/N) that have previously been shown to be susceptible to diabetes when subjected to genetically induced obesity and insulin resistance also displayed increased NNT activity. We suggest that reduced NNT levels in the C57BL/6 and 129T2 strains result in lowered insulin secretion and mild glucose intolerance [21], and that protection against the development of diabetes in response to genetically induced obesity and insulin resistance may paradoxically be due to a reduced ability of the beta cell to secrete insulin.…”