THIS GRANT IS A CONTINUATION OF N00014-14-1-0361 Characterization of a New Adiponectin Assay for the Assessment of Metabolic Syndrome in Bottlenose Dolphins
Abstract
The proposed research focuses on establishing a role for the adipocyte-derived, protein-based, hormone adiponectin, and a hormonal promoter of adiponectin, Fibroblast growth factor 21, in the monitoring of metabolic syndrome in dolphins (either metabolic perturbations or improvements). Adiponectin increases the sensitivity of target organs (e.g. liver, adipose, muscle, pancreas, etc.) to insulin in other animals. For example, in mice deletion of adiponectin has been shown to lead to an insulin resistant state, and low levels of adiponectin have been shown to be associated with a decrease in insulin sensitivity in monkeys and humans. A high iron diet or iron-overloading has been found to cause a significant reduction in adiponectin production in both mice and cells in culture. The link between adiponectin levels, insulin resistance, and high iron is very strong and could possibly underlie the cause of insulin resistance in Navy dolphins. As part of ONR funded research project N000141210294 “Determining the Risk Factors for Pathologic Insulin Resistance in Navy Bottlenose Dolphins (Tursiops truncates)”, a mass-spectrometry-based assay for measuring adiponectin in serum from dolphins with chronic iron-overload and insulin resistance was established that relies on the specific measurement of tryptic peptides of adiponectin by parallel reaction monitoring. Preliminary data obtained with the assay suggests that dolphins with iron-overload and insulin resistance don’t have different levels of total circulating adiponectin, but rather are unable to post-translationally modify the adiponectin to the same level as control healthy dolphins. In humans, it is known that post-translational modifications of adiponectin affect the variety of molecular weight forms of adiponectin that can form and that the amount of high molecular weight adiponectin, but not total adiponectin, correlates to improved insulin sensitivity in individuals with type 2 diabetes. Preliminary data with the adiponectin assay also showed a near perfect correlation with percent unmodified adiponectin and glucagon levels in healthy control dolphins 2 hours postprandially, but no correlation between percent unmodified adiponection and glucagon levels in dolphins with iron-overload 2 hours postprandially. Thus, a correlation between percent unmodified adiponectin and glucagon could be a marker for improvement of insulin resistance. The proposed studies will definitively determine whether the levels of high molecular complexes of adiponectin and the liver-derived, fasting, hormone fibroblast growth factor 21 (FGF21), a promoter of adiponectin, are decreased in dolphins with metabolic syndrome (i.e. high glucose, high insulin, high triglycerides). If so, the FGF21/adiponectin axis could be considered as a therapeutic target in dolphins. This hormonal axis has been targeted in humans, and FDA approved pharmaceuticals exist for treatment of type 2 diabetes. Administration of thiazolidinediones (TZDs), which are peroxisome proliferator activated receptor-gamma agonists, is known to elevate adiponectin levels in diabetic humans and correlate positively with improved glucose disposal rate while negatively correlating with fasting insulin. Although TZDs have known side effects, newer versions of peroxisome proliferator-activated receptor-gamma agonists promise the benefit of improved insulin sensitivity with fewer side effects. Furthermore, if adiponectin or FGF21 levels can be increased after therapeutic intervention, then these protein markers will be clinical tools to track the response to therapy and/or predict whether a dolphin is likely to become insulin-resistant in the near future.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jun 03, 2016
- Source ID
- N000141612160
Entities
People
- Michael G. Janech
Organizations
- Medical University of South Carolina
- Office of Naval Research
- United States Navy