Insulin feedback action on pancreatic β‐cell function

Leibiger, Ingo B.; Leibiger, Barbara; Berggren, Per Olof

doi:10.1016/s0014-5793(02)03627-x

Cited by 107 publications

(87 citation statements)

References 62 publications

(177 reference statements)

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“…The concept that insulin inhibits its own secretion has been suggested for a long time (Best and Haist, 1941;Loreti et al, 1974). However, this autocrine effect of secreted insulin on β-cell function has been a matter of debate (Leibiger, 2002). Chronic administration of insulin or transplantation of insulinomas reduced pancreatic insulin content (Best and Haist, 1941;Koranyi et al, 1992).…”

Section: Discussionmentioning

confidence: 99%

Insulin Contributes to Fine-Tuning of the Pancreatic Beta-Cell Response to Glucagon-Like Peptide-1

Moon

Kim

Park

et al. 2011

Molecules and Cells

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Glucagon-like peptide-1 (GLP-1) stimulates insulin secretion from pancreatic β-cells in a glucose-dependent manner. However, factors other than glucose that regulate the β-cell response to GLP-1 remain poorly understood. In this study, we examined the possible involvement of insulin and receptor tyrosine kinase signaling in regulation of the GLP-1 responsiveness of β-cells. Pretreatment of β-cells with HNMPA, an insulin receptor inhibitor, and AG1478, an epidermal growth factor receptor inhibitor, further increased the cAMP level and Erk phosphorylation in the presence of exendin-4 (exe-4), a GLP-1 agonist. When β-cells were exposed to a high concentration of glucose (25 mM), which stimulates insulin secretion, exe-4-induced cAMP formation declined gradually as exposure time was increased. This decreased cAMP formation was not observed in the presence of HNMPA. HNMPA was able to further increase the exe-4-induced insulin secretion when β-cells were exposed to high glucose for 18 h. Treatment of β-cells with insulin significantly decreased exe-4-induced cAMP formation in a dose-dependent manner. Lowering the phospho-Akt level by HNMPA or LY294002, a PI3K inhibitor, further augmented exe-4-induced cAMP formation and Erk phosphorylation. These results suggest that insulin contributes to fine-tuning of the β-cell response to GLP-1.

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Section: Discussionmentioning

confidence: 99%

Insulin Contributes to Fine-Tuning of the Pancreatic Beta-Cell Response to Glucagon-Like Peptide-1

Moon

Kim

Park

et al. 2011

Molecules and Cells

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“…Since the integrity of the insulin signalling cascade in beta cells is responsible for preservation of beta cell mass and for insulin secretion [43], and since JNK inhibition affects IRS-1/AKT in peripheral tissues [13][14][15], we tested the effect of L-JNKI in human islet insulin pathway with our main focus on AKT and its substrates. Among those substrates, GSK-3B and p70S6K participate in the regeneration of beta cell mass via increased mitogenesis [44,45], while PRAS40 is also activated by insulin in peripheral tissues and is implicated in protection of neurons against ischaemic injury [46,47].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of c-jun N terminal kinase (JNK) improves functional beta cell mass in human islets and leads to AKT and glycogen synthase kinase-3 (GSK-3) phosphorylation

et al. 2007

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Aims/hypothesis Activation of c-jun N-terminal kinase (JNK) has been described in islet isolation and engraftment, making JNK a key target in islet transplantation. The objective of this study was to investigate if JNK inhibition with a cellpermeable TAT peptide inhibitor (L-JNKI) protects functional beta cell mass in human islets and affects AKT and its substrates in islet cells. Methods The effect of L-JNKI (10 μmol/l) on islet count, mitochondrial membrane potential, glucose-stimulated insulin release and phosphorylation of both AKT and its substrates, as well as on reversal of diabetes in immunodeficient diabetic Nu/Nu mice was studied. Results In vitro, L-JNKI reduced the islet loss in culture and protected from cell death caused by acute cytokine exposure. In vivo, treatment of freshly isolated human islets and diabetic Nu/Nu mice recipients of such islets resulted in improved functional beta cell mass. We showed that L-JNKI activates AKT and downregulates glycogen synthase kinase-3 beta (GSK-3B) in human islets exposed to cytokines, while other AKT substrates were unaffected, suggesting that a specific AKT/GSK-3B regulation by L-JNKI may represent one of its mechanisms of cytoprotection. Conclusions/interpretation In conclusion, we have demonstrated that targeting JNK in human pancreatic islets results in improved functional beta cell mass and in the regulation of AKT/GSK3B activity.

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“…In addition to its endocrine effects leading to glucose uptake in muscle and adipose tissue and glycogen storage in liver, insulin has autocrine effects on β-cells, regulating gene transcription (Leibiger et al, 1998;Xu and Rothenberg, 1998;Wu et al, 1999;da Silva Xavier et al, 2000), proliferation (Withers et al, 1998;Kulkarni et al, 1999a;Okada et al, 2007), glucose metabolism (Borelli et al, 2004;Nunemaker et al, 2004), insulin biosynthesis and secretion (reviewed in (Rutter, 1999) and (Leibiger et al, 2002). β-cells thus express insulin receptors (Verspohl and Ammon, 1980;Patel et al, 1982) as well as downstream adapter and signalling proteins, like insulin receptor substrate proteins IRS-1, -2, -3, -4, PI3-kinase and protein kinase B/Akt (Rothenberg et al, 1995;Velloso et al, 1995;Harbeck et al, 1996;Holst et al, 1998;Withers et al, 1998;Kulkarni et al, 1999b;Muller et al, 2006).…”

Section: Feedback Effect Of Insulin On Secretionmentioning

confidence: 99%

“…It is debated whether insulin stimulates, inhibits or does not influence insulin secretion (Leibiger et al, 2002). Arguments favouring a positive feedback effect include reduced insulin secretion from insulin receptor deficient mouse islets (Kulkarni et al, 1999a) and insulinoma cells (da Silva Xavier et al, 2004), increased insulin secretion in insulinpretreated and IRS-1-overexpressing cells (Xu et al, 2000) as well as a direct stimulatory effect of insulin or an insulin-mimetic compound on secretion from individual cells (Aspinwall et al, 1999) or islets (Westerlund et al, 2002).…”

Section: Feedback Effect Of Insulin On Secretionmentioning

confidence: 99%

Oscillatory control of insulin secretion

Tengholm

Gylfe

2009

Molecular and Cellular Endocrinology

163

169

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Pulsatile insulin secretionSince insulin is the only blood glucose-lowering hormone, its secretion is essential for glucose homeostasis, and disturbances are associated with glucose intolerance and diabetes.Glucose is the major stimulus for insulin release but secretion is enhanced also by other nutrients and is under stimulatory and inhibitory control by hormones and neurotransmitters.Although the external factors are essential determinants of insulin secretion, there are also input-independent variations in hormone release. Regular oscillations of the circulating insulin concentrations in normal subjects consequently occur without accompanying changes

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Insulin feedback action on pancreatic β‐cell function

Cited by 107 publications

References 62 publications

Insulin Contributes to Fine-Tuning of the Pancreatic Beta-Cell Response to Glucagon-Like Peptide-1

Insulin Contributes to Fine-Tuning of the Pancreatic Beta-Cell Response to Glucagon-Like Peptide-1

Inhibition of c-jun N terminal kinase (JNK) improves functional beta cell mass in human islets and leads to AKT and glycogen synthase kinase-3 (GSK-3) phosphorylation

Oscillatory control of insulin secretion

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