| dc.description.abstract | Diabetes and metabolic syndrome has risen to epidemic proportions in both humans and veterinary species. Diabetes is characterized by a lack of insulin production (type 1) or action (type 2), with subsequent alterations in glucose transport and utilization in insulin-sensitive tissue. Importantly, diabetes is well known to cause multi-organ failure (including cardiovascular dysfunction). Additionally, diabetes has recently been shown to increase the risk of respiratory infection in diabetic patients. Thus, we here sought to describe the mechanisms underlying glucose dysregulation-derived organ dysfunction in several tissues (e.g., insulin-sensitive tissues, lamellae, and lung). While equine metabolic syndrome is well-known to be associated with endocrinopathic laminitis, the underlying cause of laminitic pathogenesis remains unknown. We determined that horses with laminitis induced by a 48-hour euglycemic hyperinsulinemic clamp had a significant upregulation of the insulin signaling pathway in the heart. Thus, horses with endocrinopathic laminitis were not insulin resistant. After proteomic analysis, we subsequently found an upregulation of heat shock protein 90, alpha-2-macroglobulin, and fibrinogen beta, and a downregulation of cadherin-13, vinculin, and talin-1 in lamellae of hyperinsulinemic horses. Separately, the regulation of glucose homeostasis in the lung, and how it may be affected during diabetes or during influenza infection, is under-investigated. We determined the protein and mRNA quantities of seven glucose transporter (GLUT) isoforms in the lung of healthy and diabetic mice. After infecting diabetic mice with H1N1 Influenza A (A/PR/8/34), infected and diabetic mice displayed an increased amount of glucose in BALF over control and non-infected counterparts. Insulin or metformin rescued these metabolic alterations in both non-infected and infected diabetic mice. While diabetes significantly altered protein expression of some GLUTs in the total lysate from the whole lung, influenza alone increased the cell-surface expression of insulin-sensitive GLUT4. Thus, overall, it can be concluded that alterations in glucose and insulin metabolism result in substantial alterations in the regulation of glucose transport in the lamellae of hyperinsulinemic horses, as well as in the lung of (type 1 and type 2) diabetic mice infected with influenza. Together, these findings underscore that glucose and insulin dysregulation contribute to multiple organ dysfunction during diabetes and metabolic syndrome. | |
