Retinopathy in a novel model of metabolic syndrome and type 2 diabetes: new insight on the inflammatory paradigm

FASEB J. 2014 May;28(5):2038-46. doi: 10.1096/fj.12-215715. Epub 2014 Feb 26.

Abstract

The pathogenesis of diabetic retinopathy (DR) in metabolic syndrome (MetS) and type 2 diabetes (T2D) is not well studied, partly because an appropriate model has not been developed. Recently, we introduced a novel model of spontaneous T2D and MetS that replicates the relevant features of the human disease. In the current study, we investigated the retinal vascular changes in these animals. Experimental DR in streptozotocin (STZ)-injected rodents is described as an inflammatory disease, in which intercellular adhesion molecule 1 (ICAM-1) plays a key role. In comparison, advanced diabetes (HbA1c>10%) in the Nile grass rat (NGR) was associated with lower ICAM-1 protein expression when compared with that in normal or moderately diabetic animals. Vascular cell adhesion molecule 1 (VCAM-1) expression, however, was unaffected by the disease state. As opposed to the STZ-induced model of DR, in diabetic NGRs, most leukocytes accumulated in the retinal arteries. Consistent with the ICAM-1 reduction, leukocyte accumulation was significantly reduced in advanced disease. Similarly, leukocyte adhesions were significantly lower, with elevated plasma triglycerides (>200 mg/dl), and cholesterol (>240 mg/dl). However, these adhesions were significantly higher in animals with higher plasma insulin (>5 μIU/ml) and leptin (>20 ng/ml), suggesting a role for these hormones in diabetic retinal leukostasis. Diabetic NGRs showed substantial retinal endothelial injury, primarily in the microvessels, including vascular tortuosity, obliterated acellular capillaries, and pericyte ghosts. The NGR provides a convenient and realistic model for investigation of retinal changes in MetS/T2D with convincing advantages over the commonly used STZ-induced T1D.

Keywords: Nile grass rat; adhesion molecules; adipokines.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adiponectin / metabolism
  • Animals
  • Blood-Retinal Barrier / metabolism
  • Cell Adhesion
  • Diabetes Complications / pathology*
  • Diabetes Mellitus, Type 2 / pathology*
  • Diabetic Retinopathy / pathology*
  • Disease Models, Animal
  • Female
  • Glycated Hemoglobin A / metabolism
  • Inflammation / pathology*
  • Insulin / blood
  • Intercellular Adhesion Molecule-1 / metabolism
  • Leptin / blood
  • Leukocytes / cytology
  • Lipids / blood
  • Male
  • Metabolic Syndrome / complications*
  • Rats
  • Retina / metabolism
  • Retinal Vessels / metabolism
  • Streptozocin
  • Triglycerides / metabolism
  • Vascular Cell Adhesion Molecule-1 / metabolism

Substances

  • Adiponectin
  • Glycated Hemoglobin A
  • Insulin
  • Leptin
  • Lipids
  • Triglycerides
  • Vascular Cell Adhesion Molecule-1
  • Intercellular Adhesion Molecule-1
  • Streptozocin