Altered chronic glycemic control in a clinically relevant model of rat thoracic spinal contusion

Abstract

The lifetime risk for Type-2 diabetes mellitus remains higher in people with spinal cord injuries than in the able-bodied population. However, the mechanisms driving this disparity remain poorly understood. The goal of the current study was to evaluate the impact of a palatable high-fat diet (HFD) on glycemic regulation using a rodent model of moderate thoracic contusion. Animals were placed on either Chow or HFD and tolerance to glucose, insulin, and ENSURE mixed meal were investigated. Important targets in the gut-brain axis were investigated. HFD consumption equally induced weight gain in SCI and naïve rats over CH rats. Elevated blood glucose was observed during intraperitoneal GTT in HFD-fed rats over CH-fed rats. ITT was unremarkable amongst the three groups. Gavage of ENSURE resulted in high GLP-1 release from SCI rats over naïve controls. An elevation in terminal total GLP-1 was measured, with a marked reduction in circulating dipeptidyl peptidase 4 (DPP4), the GLP-1 cleaving enzyme, in SCI rats, compared to naïve. Increased glucagon mRNA in the pancreas and reduced immunoreactive glucagon-positive staining in the pancreas in SCI rats compared to controls suggested increased glucagon turnover. Finally, GLP-1 receptor gene expression in the ileum, the primary source of GLP-1 production and release, in SCI rats suggests the responsivity of the gut to altered circulating GLP-1 in the body. In conclusion, the actions of GLP-1 and its preprohormone, glucagon, are markedly uncoupled from their actions on glucose control in the SCI rat. More work is required to understand GLP-1 in the human.