Comparative effects of amino acids and glucose on insulin secretion from isolated rat or mouse islets

Abstract

Glucose and the combination of leucine and glutamine were used to stimulate insulin secretion from rat islets during a dynamic perifusion and the responses obtained were compared with those elicited from mouse islets under identical conditions. In rat islets, glucose (15 mM) or the amino acid combination of 10 mM glutamine plus 20 mM leucine were most efficacious and peak secondphase insulin release responses were 20-to 30-fold above prestimulatory rates. In contrast to rat islet responses, sustained second-phase insulin secretory responses to the same agonists were minimally increased 1-to 2-fold from mouse islets. Parallel studies demonstrated that phospholipase C (PLC) was markedly activated in rat, but not mouse, islets by both high glucose concentrations and the amino acid combination.Additional studies documented that glucose and amino acid responses of both rat and mouse islets were amplified by carbachol or forskolin. However, wortmannin, a phosphatidylinositol 3-kinase inhibitor, amplified only the responses to glucose leaving the responses to the amino acid mixture unaltered. These observations support the concept that mitochondrial metabolism alone is minimally effective in stimulating insulin secretion from islets. The activation of the supplementary second messenger systems (PLC and/or cAMP) appears essential for the emergence of their full secretory potential. The mechanism regulating the potency and specificity of wortmannin's impact on glucose-induced secretion remains to be identified; however a unique mechanism is supported by these findings.

GW8510 Increases Insulin Expression in Pancreatic Alpha Cells through Activation of p53 Transcriptional Activity

“…We show that in the donor tested, treatment with GW8510 and a general kinase inhibitor, staurosporine, potentiated both basal and the glucose-stimulated insulin secretion. In addition, a previous report indicates that wortmannin, a phosphatidylinositol 3-kinase inhibitor, augmented insulin secretion at 15 mM glucose [43]. Currently available methodology does not enable us to distinguish between the effects on insulin release from beta cells, which represent the majority of the islet endocrine cell population, and potential contributions from other islet cell types.…”

Insulin secretion in the conscious mouse is biphasic and pulsatile

“…Subsequent comparative studies between mouse and rat islets have established that stimulation of this pathway is less robust in mouse islets in vitro (4,23,26,42,56). This finding has led to several reports investigating the mechanisms underlying the different degrees of stimulation of second-phase secretion in mouse and rat islets, including glyceraldehyde (23), cAMP (26), protein kinase A (48), phospholipase C (53,56), and amino acids (25,55) and has even led to speculation that the mouse may not be a good model for examining insulin secretion as it relates to humans, which have a robust second phase (26).…”

Involvement of Ca2+/Calmodulin Kinase II (CaMK II) in Genistein-Induced Potentiation of Leucine/Glutamine-Stimulated Insulin Secretion

“…In general, activation of the insulin-signal cascade through activation of insulin receptor tyrosine kinase was thought to down-regulate GSIS. Studies using PI3 kinase inhibitors demonstrated that pharmacological blockage of the insulin-signaling pathway could potentiate GSIS (Eto et al, 2002;Zawalich et al, 2004). Diminished insulin signaling by reduced expression of the insulin receptor also showed enhanced GSIS (Ohsugi et al, 2005).…”