DOI: 10.1507/endocrj.EJ18-0472
Keywords
1. GIP protein interaction
2. Incretin hormone therapy
3. Diabetes treatment advancement
4. Plasma binding proteins
5. Insulinotropic peptide research
A groundbreaking study conducted by a team of researchers from the Department of Endocrinology, Diabetes and Metabolism at Kitasato University School of Medicine, along with the Laboratory of Biomolecular Physics and Center for Disease Proteomics at Kitasato University School of Science, has identified the key plasma proteins that glucose-dependent insulinotropic polypeptide (GIP) binds to in the human body. This novel research, shedding new light on the fate and secretion of administered native GIP, has significant implications for the treatment of type 2 diabetes, where the search for more effective pharmacological interventions remains a high priority.
GIP is an incretin hormone secreted from the enteroendocrine K cells of the stomach and small intestine in response to the ingestion of nutrients. It plays a crucial role in the regulation of glucose homeostasis by stimulating insulin secretion from the pancreas. Unlike GIP, glucagon-like peptide-1 (GLP-1), another incretin hormone, has been successfully used in the treatment of type 2 diabetes due to its more potent biological effects. However, the potential of GIP as a therapeutic agent has been limited, partly due to a lack of comprehensive understanding of its interactions within the circulatory system.
The research, published in the ‘Endocrine Journal’, sought to determine the plasma binding partners of human GIP. This was achieved through a series of sophisticated experiments using fluorescent-labelled GIP added to fresh human plasma, followed by clear native polyacrylamide gel electrophoresis (CN-PAGE). The results were analyzed using in-gel trypsin digestion, followed by liquid chromatography tandem-mass spectrometry (LC-MS/MS). This innovative approach led to the identification of albumin, immunoglobulin G (IgG), and transferrin as the primary plasma binding proteins for GIP.
Dr. Ayako Hoshiyama of Kitasato University School of Medicine, the lead author of the study, highlighted the importance of this discovery by emphasizing that “understanding the interaction between GIP and these plasma proteins is crucial for realizing the full therapeutic potential of GIP in diabetes management. It could aid in the development of GIP analogs with enhanced biological activity or altered pharmacokinetics.”
In contrast to the findings concerning GIP, the study found that the binding of GLP-1 and glucagon to plasma protein fractions was minimal. This difference could be a contributing factor to the higher therapeutic success of GLP-1 analogs in treating diabetes.
The researchers conducted additional CN-PAGE analysis and western blot analysis to confirm the binding between synthetic GIP and human serum albumin, purified IgG, or transferrin. The consistency of the results supports the robustness of the study’s methodology and conclusions.
The identification of albumin as a binding partner is particularly noteworthy given its abundance and multifunctional nature in the bloodstream. Albumin’s role in transporting various substances, including hormones and drugs, suggests that GIP-bound albumin may influence the hormone’s half-life and bioavailability.
As for IgG, the most common type of antibody in blood circulation, its interaction with GIP could have implications for the immune response or represent a mechanism by which the body regulates the hormone’s activity.
Transferrin, which primarily binds and transports iron, is added to the intriguing mix of GIP interactors. This protein’s role in binding GIP raises questions about the interplay between iron metabolism and glucose homeostasis.
The study has been well-received within the scientific community, with Dr. Kazumi Fujimoto, another key member of the research team, noting, “Our findings have opened doors to new research pathways that could lead to improved treatments not just for diabetes but also for other metabolic disorders.”
The protein-binding data uncovered by the team’s comprehensive approach has substantial potential in refining peptide-based therapeutics. The study demonstrates the value of combining CN-PAGE with LC-MS/MS analysis in identifying protein interactions that can influence the physiological effects of bioactive peptides.
As a next step, the researchers advocate for further exploration into the impact of GIP interaction with these plasma proteins on incretin activity, the design of bioactive peptide analogs, and the pursuit of more effective diabetes treatments.
The research team’s innovative approach and findings represent a significant advancement in endocrinology and diabetes research. While opening new opportunities for therapeutic exploration, they also set the stage for deeper understanding and potentially revolutionizing the standard of care for individuals with type 2 diabetes.
References
Hoshiyama, A., Fujimoto, K., Konno, R., Sasaki, S., Momozono, A., Kodera, Y., & Shichiri, M. (2019). Identification of plasma binding proteins for glucose-dependent insulinotropic polypeptide. Endocrine Journal, 66(7), 621–628. DOI: 10.1507/endocrj.EJ18-0472
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