Protective Role of Glucagon-like Peptide-1 Against Glucosamine-induced Cytotoxicity in Pancreatic Beta Cells

Abstract

High doses of glucosamine have been known to induce apoptosis of pancreatic beta cells. The mechanism for this phenomenon has not been clearly elucidated. We aimed to explore the potential mechanisms for glucosamine toxicity in the rat insulinoma cell line INS-1 and in rat native beta cells. We also investigated whether glucagon-like peptide (GLP)-1 could be protective against glucosamine. Glucosamine exhibited dose-dependent inhibition of cell survival and an increase in the cell population at the sub-G1 phase. Glucosamine was revealed to inhibit cellular glucose uptake, resulting in the activation of AMP-activated protein kinase (AMPK). Accordingly, phosphorylation of P70S6K and ribosomal protein S6 (S6RP) was decreased. Protein glycosylation appeared not to be involved in this cytotoxicity. Pretreatment with GLP-1 alleviated glucosamine-mediated inhibition of glucose uptake and lessened AMPK activation, thus allowing recovery of the phosphorylation levels of P70S6K and S6RP.The effect of GLP-1 was blocked by the adenylyl cyclase inhibitor MDL12330A but not by the protein kinase A inhibitor H89. Taken together, these data demonstrate that glucosamine may inhibit beta-cell survival by diminishing cellular glucose uptake independent of glycosylation. This glucosamine toxicity can be blocked by GLP-1, which leads to recovery of the glucose uptake through a PKAindependent, cAMP-dependent mechanism.

Exendin‐4 ameliorates diabetic symptoms through activation of glucokinase

“…This improvement was substantiated by the observation that glucose‐stimulated insulin release from isolated islets was increased in the exendin‐4‐treated group. A previous study has suggested a protective effect for GLP‐1 against glucosamine‐induced cytotoxicity in pancreatic β‐cells 40 . Glucosamine is well known for its inhibitory effect on GK enzyme activity 41 .…”

“…A previous study has suggested a protective effect for GLP-1 against glucosamine-induced cytotoxicity in pancreatic b-cells. 40 Glucosamine is well known for its inhibitory effect on GK enzyme activity. 41 Consistent with these reports, we have observed that the beneficial effect of exendin-4 on glucose homeostasis involves increased pancreatic GK activity and expression.…”

Short-term treatment with glucosamine hydrochloride specifically downregulates hypoxia-inducible factor-1α at the protein level in YD-8 human tongue cancer cells

“…GS is a glucose deprivation mimetic and has been shown to inhibit glycolysis (39,40). It also has been demonstrated that both glucose and GS utilize the same glucose transporter system for import into the cells (41,42), and GS, through inhibition of glucose transporter, interferes with cellular glucose uptake (43). With this in mind, it is assumed that short-term GS-HCl exposure into YD-8 cells may hinder glucose uptake, inhibit glycolysis, and/or produce less (or no) glucose metabolites.…”

Glucagon-Like Peptide-1 Modulates Cholesterol Homeostasis by Suppressing the miR-19b-Induced Downregulation of ABCA1

“…Glucagon-like peptide 1 (GLP-1) as a novel anti-diabetic drug with multiple effects, not only has hypoglycaemic effects, but also relieves lipotoxicity at the cellular level [14,15,16]. GLP-1 has unique abilities to modulate lipid metabolism by affecting lipid assimilation and transport, fat formation and decomposition, hepatic lipid metabolism and reverse cholesterol transport [17,18,19].…”