Genetic Analysis of Glucose Tolerance in Inbred Mouse Strains: Evidence for Polygenic Control

Abstract

To determine genetic factors involved in diabetes susceptibility in inbred strains of mice, we initially evaluated differences in fed plasma glucose and insulin concentrations among six strains (AKR/J, C3H/HeJ, C57BL/6J, C57L/J, DBA/2J, and SWR/J). There was considerable variation in fed plasma glucose concentration, with C3H/HeJ mice the most glucose tolerant (174 +/- 7 mg/dl) and C57BL/6J mice the least glucose tolerant (252 +/- 7 mg/dl, P less than .0001 vs. C3H/HeJ mice). Glycosylated hemoglobin of C57BL/6J mice (4.0 +/- 0.06%) was also higher than that of C3H/HeJ mice (3.52 +/- 0.06%, P less than .0001). The fed plasma insulin concentration did not differ between these two strains. Glucose tolerance was further evaluated in overnight-fasted C3H/HeJ and C57BL/6J mice by an intraperitoneal glucose tolerance test (IPGTT). Although fasting plasma glucose did not differ, the most remarkable difference in plasma glucose during IPGTT between C57BL/6J and C3H/HeJ mice was noted at 30 min (489 +/- 29 vs. 227 +/- 20 mg/dl, P less than .001). To determine the number of genes involved in the phenotypic difference in glucose tolerance, C57BL/6J males were crossed with C3H/HeJ females (F1, C3H/HeJ X C57BL/6J), and the F1 hybrid females were backcrossed with C57BL/6J males (backcrossed, F1 X C57BL/6J). Plasma glucose after 30 min on IPGTT was 219 +/- 8 (n = 21), 456 +/- 18 (n = 23), and 292 +/- 13 (n = 23) mg/dl for C3H/HeJ, C57BL/6J, and F1 mice, respectively (P less than .001 for all comparisons).(ABSTRACT TRUNCATED AT 250 WORDS)

The Sweet Pee Model for Sglt2 Mutation

“…This level is comparable to that reported in the literature for C3H/ HeJ inbred mouse strain. 15 However, no significant proteinuria was detected. The protein-to-creatinine ratios ϮSEM at 21 weeks were 4.79 Ϯ 1.4, 4.02 Ϯ 1.08, and 4.18 Ϯ 1.0 mg/mg for WT, heterozygotes, and MT, respectively (P ϭ NS).…”

A genetic and physiological study of impaired glucose homeostasis control in C57BL/6J mice

“…Second-phase insulin release is also impaired in comparison with AKR/J [14] and DBA/2 [6] mice, but is not significantly different to C3H mice (at least at 8 weeks of age) [5]. A defect in first-phase insulin secretion also appears to be present in C57BL/6J mice fed a high-fat diet [17], and is accompanied by an unchanged insulin response and delayed glucose clearance over the first 4 weeks of a high-fat diet [18].…”

“…5 Fura-2 imaging Islet cells were cultured on 35-mm Fluorodishes (World Precision Instruments, Stevenage, UK) and incubated with 3 μmol/l Fura-2-AM (Molecular Probes, Paisley, UK) for 40 min at 37°C. They were imaged at room temperature (20-24°C) using a fluorescence system (IonOptix, Boston, MA, USA), with 340 and 380 nm dual excitation.…”

“…On normal diets, C57BL/6J mice appear to have normal free-fed plasma insulin levels, but postprandial first-phase insulin release is impaired when compared to glucose-tolerant control strains, including C3H [5,16]. Second-phase insulin release is also impaired in comparison with AKR/J [14] and DBA/2 [6] mice, but is not significantly different to C3H mice (at least at 8 weeks of age) [5].…”

“…The C57BL/6J mouse exhibits defects in glucose tolerance that are independent of obesity [5,6]. Feeding C57BL/6J mice with high-fat diets results in insulin resistance, increased fasting plasma glucose levels and diabetes [7][8][9][10].…”