Co-culture of clonal beta cells with GLP-1 and glucagon-secreting cell line impacts on beta cell insulin secretion, proliferation and susceptibility to cytotoxins

Abstract

We investigated the direct effects on insulin releasing MIN6 cells of chronic exposure to GLP-1, glucagon or a combination of both peptides secreted from GLUTag L-cell and αTC1.9 alpha-cell lines in co-culture. MIN6, GLUTag and αTC1.9 cell lines exhibited high cellular hormone content and release of insulin, GLP-1 and glucagon, respectively. Co-culture of MIN6 cells with GLUTag cells significantly increased cellular insulin content, beta-cell proliferation, insulin secretory responses to a range of established secretogogues and afforded protection against exposure cytotoxic concentrations of glucose, lipid, streptozotocin or cytokines. Benefits of co-culture of MIN6 cells with αTC1.9 alphacells were limited to enhanced beta-cell proliferation with marginal positive actions on both insulin secretion and cellular protection. In contrast, co-culture of MIN6 with GLUTag cells plus αTC1.9 cells, markedly enhanced both insulin secretory responses and protection against beta-cell toxins compared with co-culture with GLUTag cells alone. These data indicate important long-term effects of conjoint GLP-1 and glucagon exposure on beta-cell function. This illustrates the possible functional significance of alpha-cell GLP-1 production as well as direct beneficial effects of dual agonism at beta-cell GLP-1 and glucagon receptors.

A Specific Gut Microbiota Dysbiosis of Type 2 Diabetic Mice Induces GLP-1 Resistance through an Enteric NO-Dependent and Gut-Brain Axis Mechanism

“…Additionally, reduced intestinal pH due to lactate from lacticacid bacteria (Lactobacillales) has been shown to promote NO production through non-enzymatic nitrite reduction (Tiso and Schechter, 2015). Another hypothesis is that the pro-and anti-inflammatory cytokines produced by the gut microbiota dysbiosis to host crosstalk would regulate glucose and GLP-1 effectiveness of the b cell (Green et al, 2016;Varin et al, 2016).…”

Glucagon Acting at the GLP-1 Receptor Contributes to β-Cell Regeneration Induced by Glucagon Receptor Antagonism in Diabetic Mice

“…However, whether glucagon can affect β-cell regeneration remains unclear. Coculture of α-TC1.9 cells (an α-cell line) with Min6 cells (a β-cell line) promoted β-cell proliferation ( 43 ). Impaired β-cell formation induced by Gcg knockdown could be restored by infusion of glucagon or GLP-1 analog in zebrafish, suggesting that the peptides encoded by Gcg were required for β-cell regeneration ( 44 ).…”

Dipeptidyl Peptidase (DPP)-IV Inhibitors with Antioxidant Potential Isolated from Natural Sources: A Novel Approach for the Management of Diabetes

“…The potency with which the DPP-IV enzyme cleaves neuropeptides, peptide hormones, or cyto-chemokine substrates suggests, a role for DPP-IV enzyme activity in body fluids and cellular systems in vitro or in vivo [ 27 , 29 , 60 ]. GLP-I is secreted from gut L cells that mostly contain an alanine amino acid at the second position of GLP-1 (9-36) or GLP-1 (9-37) amides [ 36 , 61 , 62 ]. In addition, DPP-IV inactivates GIP peptides secreted by gut K-cells and rapidly clears them from kidney circulation [ 63 ].…”