Oral Abstracts: GLP-1, GIP and Gut Hormones

Reviewed by Joelle Escoffery, PhD

New research addressing the potential mechanisms of action and toxicity concerns related to glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and dipeptidyl peptidase IV (DPP-IV) inhibitors was presented. A number of mechanisms by which these hormones function were investigated. Results from animal studies showed that pancreatic GLP-1 receptor action is important for enhanced acute glucose clearing,[1] and effects of GLP-1 on β-cell growth may be mediated by insulin receptor substrate 2 (IRS-2)[2] and phosphatidylinositol 3-kinaseγ (PI3-Kγ).[3] Additionally, one study showed preliminary cardiovascular benefits of GLP-1 in an animal model, suggesting that this class may have broader therapeutic implications.[4] An investigation of GIP found that exposure to high levels of glucose causes a down regulation of the GIP receptor. Two studies also addressed DPP-IV inhibitors, an emerging therapy for Type 2 diabetes that has the potential to prevent or reduce hypoglycemia and weight loss, as well as to prevent or reduce β-cell loss. The toxicity of DPP-IV inhibitors appears to be attenuated if highly selective DPP-IV inhibitors are used.  Toxic effects observed in previous work were found to be the result of off-target inhibition of DPP8/9.[5] Further, highly selective DPP-IV inhibitors do not have deleterious effects.

References

1. Li Y, Drucker D. Tissue-specific transgenic rescue experiments identify the pancreas as an essential site for the acute glucoregulatory actions of GLP-1. Diabetes. 2004;53(suppl 2):A1.
2. Park S, Dong X, White MF. Irs 2 is required for the long-term effects of glucagon-like peptide-1 and exendin-4 on β-cell growth, function and survival. Diabetes. 2004;53(suppl 2):A1.
3. Li L, Oudit G, Backx P, Brubaker P. The essential role of phosphatidylinositol 3-kinase γ. Diabetes. 2004;53 (suppl 2):A1.
4. Bose A, Mocanu MM, Mensah KN, et al. GLP-1 protects ischemic and reperfused myocardium via PI3 kinase and p42/p44 MAPK signaling pathways. Diabetes. 2004;53(suppl 2):A1.
5. Lankas G, Leiting B, Roy RS, et al. Inhibition of DPP8/9 results in toxicity in preclinical species: potential importance of selective dipeptidyl peptidase IV inhibitors for the treatment of type 2 DM. Diabetes. 2004;53 (suppl 2):A2.