Serum biomarkers correlate with retinal function changes in a high fat diet (HFD)+STZ model of Type II diabetes

Abstract

Purpose : The gold standard model for Type I diabetes is the high dose streptozotocin (STZ, 100 mg/kg) rodent model, with over 9,000 publications. For Type II diabetes, many potential models aim to accurately and reliably mimic clinical complications and disease progression. Here, we investigated retinal and metabolic changes in a high fat diet (HFD) plus low dose STZ (30 mg/kg) model of Type II diabetes with the goal of characterizing biomarkers.

Methods : Long Evans rats were allocated to a naïve control group (n=12), HFD group (n=14), or HFD+STZ group (n=17). HFD+STZ rats were classified as Type I (n=8) or Type II (n=9) based on metabolic assessments: glucose tolerance, fed blood glucose, weights, and blood insulin levels using ELISA. Visual function using the optomotor response (OMR) was assessed every 2 wks. Retinal function using electroretinogram (ERG) was measured at 4 and 8 wks. Rats were euthanized after 8 wks, and retinas and serum were assessed for 12 metabolic markers using a U-PLEX Rat Metabolic Combo 1 multiplex kit.

Results : Type I rats exhibited severe impairments in glucose tolerance, >250 mg/dL fed blood glucose (391.70 mg/dL), reduced body weight (28.1%), and very low insulin (0.43 ng/mL). Type II rats exhibited moderate changes in glucose tolerance and fed blood glucose (163.37 mg/dL) with weight (619.5g) and insulin (3.76 ng/mL) values similar to naïve controls (580.75g, 4.68 ng/mL). Deficits in OMR were observed in Type I and Type II rats in spatial frequency (Type I: 15.0%; Type II: 11.6%) and contrast sensitivity (Type I: 30.5%; Type II: 26.1%) at 8 wks post-STZ (p<0.0001). ERG delays in dim oscillatory potential implicit times were also observed in Type II rats at 8 wks (p<0.05). Type I rats had reduced serum levels of BDNF, C-Peptide, and leptin (p<0.05 to 0.001), and serum levels of BDNF, C-Peptide, leptin, PYY, and glucagon correlated with visual and retinal function measurements (R²=0.1023 to 0.2624; p<0.05 to 0.001).

Conclusions : Type II diabetic rats exhibited early retinal and visual deficits while modeling a more moderate diabetic state. Other researchers have shown that the HFD+STZ rat replicates clinical changes in VEGF and inflammation, further underscoring its utility as a Type II model for diabetic retinopathy (DR). Serum levels of metabolism-relevant markers correlated with visual and retinal function, highlighting their potential as biomarkers for DR.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.