Glucagon-like peptide-1 enhances production of insulin in insulin-producing cells derived from mouse embryonic stem cells

Abstract

Embryonic stem cells (ESCs) can be differentiated into insulin-producing cells by a five-stage procedure involving altering culture conditions and addition of nicotinamide. The amounts of insulin in these cells are lower than those found in pancreatic cells. Glucagon-like peptide-1 (GLP-1) induces the differentiation of cells from ductal progenitor cells. We examined the possibility of GLP-1, and its long-acting agonist exendin-4, enhancing the differentiation of insulin-producing cells from mouse ESCs (mESCs). A five-stage culturing strategy starting with embryoid bodies (EBs) was used in this study. mRNA for pancreatic duodenal homeobox gene 1 (PDX-1) and neurogenic differentiation (NeuroD) was detected from stage 1, hepatocyte nuclear factor 3 beta (HNF3 ) and insulin 2 from stage 2, Ngn3 and glucose transporter 2 (GLUT2) from stage 3, and insulin 1 and other -cell markers, at stages 4-5. Cells at stage 5 secreted C-peptide, being 0·68 0·01 pmol/10 6 cells per 2 days, and had an immunoreactive insulin content of 13·5 0·7 pmol/10 6 cells. Addition of GLP-1 (100 nM) and nicotinamide (10 mM) at stage 5 resulted in a 50% and 48% increase in insulin content and C-peptide secretion respectively compared with nicotinamide alone. Glucose-induced insulin secretion was enhanced 4-fold by addition of both growth factors. The GLP-1 receptor was present at all five stages of the culture. Addition of exendin-4 to cells at stage 2 resulted in a 4·9-fold increase in expression of the gene for insulin 1 and a 2-fold increase in insulin content compared with the effect of nicotinamide alone at stage 5. It is concluded that both GLP-1 and exendin-4 enhance the level of expression of insulin in glucose-responsive insulinproducing cells derived from the R1 mESC line.

Glucagon-like Peptide-1 Activation of TCF7L2-dependent Wnt Signaling Enhances Pancreatic Beta Cell Proliferation

“…We have shown previously that clonal beta cell lines, including INS-1 cells, contain mixtures of undifferentiated and differentiated cells (95). The stimulation of Wnt signaling by GLP-1 agonists demonstrated here in INS-1 cells may be a clue to the findings of the expression of the GLP-1 receptor in embryonic stem cells (29) and the efficacy of GLP-1 agonists in differentiating embryonic stem cells into insulin-producing cells (30 -33) and in differentiating somatic tissue-derived cells into insulinproducing cells (27,96).…”

SH2B1 regulation of energy balance, body weight, and glucose metabolism

“…In line with these findings, PKO mice are more susceptible to STZ-induced β cell destruction, insulin deficiency, and glucose intolerance [86] . Mechanistically, SH2B1 directly enhances insulin and IGF-1 signaling in β cells [86] , and both insulin and IGF-1 potently increase β cell survival and proliferation [87][88][89][90][91] . Therefore, β cell SH2B1 cell-autonomously promotes β cell survival, proliferation, and expansion under stress conditions at least in part by enhancing insulin and IGF-1 signaling in β cells.…”

A feat of metabolic proportions: Pdx1 orchestrates islet development and function in the maintenance of glucose homeostasis

“…Based upon these studies, several mechanisms have been postulated: (a) increased β cell apoptosis via and Bcl-2), with resulting loss of downregulation of anti-apoptotic genes (Bcl XL functional cell mass [56,67], (b) loss of activity of key Pdx1 target genes whose products are involved in glucose-stimulated insulin transcription and secretion (including Glut2, glucokinase, MafA, Nkx6.1, insulin) [57,63,[68][69][70][71][72][73][74][75][76], and (d) loss of new β cell formation/regeneration [64,77]; in this regard, studies suggest that the action of glucagon-like peptide 1 (GLP1) in enhancing β cell growth and formation in the adult may rely upon activation of Pdx1 in β cells and potential precursor cell types, such as those residing within ducts [74,[78][79][80][81][82].…”