Beta Cells Preservation in Diabetes using GLP-1 and Its Analog.
- Author:
Byung Joon KIM
1
Author Information
1. Division of Endocrinology and Metabolism, Department of Internal Medicine, Konyang University School of Medicine, Daejeon, Korea. kbjoon4u@hananet.net
- Publication Type:Original Article
- Keywords:
Pancreatic beta cell;
Apoptosis;
Glucagon like peptide-1;
Type 2 diabetes
- MeSH:
Amyloid Precursor Protein Secretases;
Apoptosis;
Asian Continental Ancestry Group;
Cell Death;
Cell Membrane;
Cell Proliferation;
Diabetes Mellitus;
Endoplasmic Reticulum;
Epithelium;
Glucagon;
Glucagon-Like Peptide 1;
Glucose;
Humans;
Hyperglycemia;
Insulin;
Insulin Resistance;
Insulin-Secreting Cells;
Islets of Langerhans;
Metabolic Diseases;
Models, Animal;
Pancreas;
Peptides;
Phosphorylation;
Promoter Regions, Genetic;
Receptors, Glucagon;
Stem Cells;
Venoms;
Glucagon-Like Peptide-1 Receptor
- From:Hanyang Medical Reviews
2009;29(2):140-147
- CountryRepublic of Korea
- Language:Korean
-
Abstract:
Diabetes Mellitus is a metabolic disease caused by impaired insulin secretion of pancreatic beta cells and increased insulin resistance of peripheral tissues. In Asian T2DM, progressive loss of beta cells mass and concomitant reduction of insulin secretion are more fundamental problems than peripheral insulin resistance. To solve this problem, research fields about investigation how stimulated islet cell growth and block the islet cell death is getting more important. Recently introduced drug, Glucagon like peptide-1 (GLP-1) has many beneficial roles in treatment of diabetes. GLP-1 stimulated glucose dependent insulin secretion and also can preserve beta cell mass through stimulation of beta cell growth and differentiation and protection of beta cell death from hyperglycemic stress. After treatment of GLP-1 or Exendin-4 (GLP-1 receptor agonist), beta cell mass is increased in animal models. This can be achieved through beta cell proliferation in islet or differentiation from intrapancreatic progenitor cells like ductal epithelium. The mechanism of beta cell proliferation is mediated by the PKA-CREB pathway. After activation of GLP-1 receptor, intracellular cAMP is elevated and then it activates PKA and CREB phosphorylation. Translocation of CREB into the nucleus up-regulates PDX-1 andIRS-2. Another pathway for beta cell proliferation is trans-activation of EGFR via c-Src after GLP-1 receptor activated. The notch pathway, major determinant of pancreas development in the embryonic stage, can be participate beta mass preservation through activation of gamma secretase in the beta cell membrane. Cleaved intracellular part of the notch translocates to the nucleus and binds to the pdx-1 promoter region. In hyperglycemia, oxidative and endoplasmic reticulum (ER) stress can be caused by apoptosis of the beta cell. Protection of apoptosis is another tool for beta cell mass preservation. After treatment of GLP-1 or exendin-4, beta cell apoptosis induced by oxidative and ER stress can be protected. GLP-1 can modulate JNK and GSK 3beta activation and ER chaperone and ER stress response. In treatment of diabetes, GLP-1 increases insulin secretion with glucose dependent manner and also preserves beta cell mass against progressive beta cell loss
