Hyperglycemia in apolipoprotein E-deficient mouse strains with different atherosclerosis susceptibility

Background: Type 2 diabetes mellitus (T2DM) is associated with an increased risk of atherosclerotic vascular disease, but it is unknown whether the other way around is true too. C57BL/6 (B6) and BALB/cJ (BALB) are two mouse strains that differ markedly in their susceptibility to atherosclerosis. In this study we investigated the development of diet-induced T2DM in these two strains. Methods and Results: When deficient in apolipoprotein E (apoE(-/-)) and fed a Western diet for 12 weeks, atherosclerosis-susceptible B6 mice developed significant hyperglycemia. In contrast, atherosclerosis-resistant BALB apoE(-/-) mice had much lower plasma glucose levels than B6.apoE(-/-) mice on either chow or Western diet and during an intraperitoneal glucose tolerance test. In response to glucose BALB.apoE(-/-) mice displayed both the first and second phases of insulin secretion but the second phase of insulin secretion was absent in B6.apoE(-/-) mice. In response to insulin B6.apoE(-/-) mice showed a deeper and longer-lasting fall in blood glucose levels while BALB.apoE(-/-) mice showed little reduction in glucose levels. Pancreatic islet area of BALB. apoE(-/-) mice on light microscopy nearly doubled the area of B6.apoE(-/-) mice. Most circulating proinflammatory cytokines were lower in BALB.apoE(-/-) than in B6.apoE(-/-) mice on the Western diet, as determined by protein arrays. Increased macrophage infiltration in islets was observed in B6.apoE(-/-) mice by immunostaining for Mac2 and also by flow cytometry. Conclusion: This study demonstrates that defects in insulin secretion rather than defects in insulin resistance explain the marketed difference in susceptibility to T2DM in the B6.apoE(-/-) and BALB.apoE(-/-) mouse model. A smaller islet mass and more prominent islet inflammation may explain the vulnerability of B6.apoE(-/-) mice to diet-induced diabetes.