Lepr^db/db mouse models of Type 2 diabetes exhibit rapid defects in RPE electrophysiology that correlate with systemic hyperglycemia.

Abstract

Purpose: To determine the effects of Type 2 diabetes on function of the outer retina as measured by electroretinography.

Methods: Lepr^db/db mice were bred on BKS and B6.BKS background strains to establish two models of Type 2 diabetes. Lepr^db/db mice and control littermates (Lepr^+/db ;Lepr^+/+) underwent standard strobe flash electroretinography and DC-ERG testing beginning at 4 weeks of age. Blood glucose and plasma insulin levels were measured. Histological analysis and in vivo imaging was performed to assess structure of the outer retina.

Results: In comparison to control littermates, Lepr^db/db mice on the BKS background displayed elevated blood glucose levels at 4 weeks, and became overtly hyperglycemic at 8 weeks of age, which was sustained. DC-ERG testing of these mice demonstrated reductions in the c-wave, revealing disrupted RPE function as early as 4 weeks of age. While b-wave amplitude was reduced at 8 weeks of age, a-wave amplitude was normal at both time points. Lepr^db/db mice on the B6.BKS background were severely hyperglycemic by 4 weeks of age; however, blood glucose levels fell to normoglycemic levels by 12 weeks and were only slightly elevated compared to control littermates until 24 weeks, when hyperglycemia returned. These mice displayed hyperinsulinemia and obesity for the duration of their lives. Reductions in c-wave amplitude for the B6.BKS mice were also identified as early as 4 weeks; reductions in other measures of RPE function were observed at both 8 and 12 weeks. B-wave amplitude was also reduced at 8 weeks in the B6.BKS Lepr^db/db mice, which remained low through 16 weeks of age. At 12 weeks, a-wave amplitudes were also reduced. At 24 weeks, when mice were morbidly obese and hyperglycemic, measures of RPE function, both a- and b- wave amplitudes, as well as the light adapted response was reduced in B6.BKS mice compared to littermate controls. No structural damage was observed by in vivo imaging or histological analysis in either strain of Lepr^db/db mice at any age.

Conclusions: The Lepr^db/db mouse model of Type 2 diabetes displays altered outer retina function at times which correlate with hyperglycemia and precede the development of vascular damage, oxidative stress, or anatomical abnormality. These findings demonstrate that outer retina function is markedly affected by elevated glucose levels.

Keywords: 510 electroretinography: non-clinical • 498 diabetes • 701 retinal pigment epithelium