Abstract
The significance of glucagon in the pathophysiology of diabetes mellitus is widely recognized, but the mechanisms underlying dysregulated glucagon secretion are still unclear. Here, we explored the molecular mechanisms of glucagon dysregulation, using an in vitro model. Hamster-derived glucagon-secreting InR1G cells were exposed to high glucose (25 mM) levels for 12 h before analyzing glucagon secretion and the activity of components involved in insulin signaling. High-glucose treatment induced increased glucagon secretion in InR1G cells, which represents a hallmark of diabetes mellitus. This treatment reduced the phosphorylation of Akt, indicating the deterioration of insulin signaling. Simultaneously, oxidative stress and JNK activity were shown to be increased. The inhibition of JNK signaling resulted in the amelioration of high-glucose level-induced glucagon secretion. Abnormally elevated glucagon secretion in diabetes can be reproduced by high-glucose treatment of InR1G cells, and the involvement of high glucose-oxidative stress-JNK-insulin signaling pathway axis has been demonstrated. These data elucidate, at least partly, the previously unclear mechanism of abnormal glucagon secretion, providing insights into a potential novel approach to diabetes treatment, targeting glucagon.
Highlights
The pathophysiological significance of glucagon is increasingly recognized, and glucagon is considered a potential new therapeutic target for diabetes mellitus treatment, since its dysregulated secretion in the diabetic state affects glycemic status [1]
Under regular culture conditions with 7 mM glucose which is similar to physiological blood glucose levels, glucagon secretion was not elevated after 25 mM glucose stimulation, whereas insulin secretion was significantly increased (Fig 1A and 1B)
Under regular culture conditions (11.1 mM glucose), glucagon secretion following the stimulation of cells with 25 mM glucose was comparable to that in the cells stimulated with different levels of glucose (Fig 1C)
Summary
The pathophysiological significance of glucagon is increasingly recognized, and glucagon is considered a potential new therapeutic target for diabetes mellitus treatment, since its dysregulated secretion in the diabetic state affects glycemic status [1]. Glucagon secretion is paradoxically increased, contributing to the exacerbation of the already existing hyperglycemia. Defective glucagon response in hypoglycemic states exacerbates clinical symptoms of hypoglycemia. A recent report demonstrated that the suppression of glucagon secretion and the enhancement of insulin secretion contribute to the glucose-lowering properties of glucagon-like peptide (GLP)-1 [2]. It is generally recognized that glucagon secretion is regulated by systemic glycemic status [3], the mechanisms underlying this regulation remain unclear.
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