Proteasome Inhibition Alters Glucose-stimulated (Pro)insulin Secretion and Turnover in Pancreatic β-Cells

Kitiphongspattana, Kajorn; Mathews, Clayton E.; Leiter, Edward H.; Gaskins, H. Rex

doi:10.1074/jbc.m410876200

Cited by 67 publications

(51 citation statements)

References 66 publications

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“…Hence, the present data indicate that proteasome inhibition in the ␤-cell did not prevent but stimulated the degradation of iNOS, thus suggesting more complex control mechanisms regulating the cellular balance of this protein. A similar paradoxical effect of proteasome inhibition in the ␤-cell was previously reported with regard to (pro)insulin, the degradation of which was increased in the presence of the proteasome inhibitor lactacystin (21). A paradoxical effect of proteasome inhibition has also been reported (20) in rat vascular smooth muscle.…”

Section: Discussionmentioning

confidence: 50%

Expression of islet inducible nitric oxide synthase and inhibition of glucose-stimulated insulin release after long-term lipid infusion in the rat is counteracted by PACAP27

Qader

Jimenez-Feltström²,

Ekelund³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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Qader SS, Jimenez-Feltström J, Ekelund M, Lundquist I, Salehi A. Expression of islet inducible nitric oxide synthase and inhibition of glucose-stimulated insulin release after long-term lipid infusion in the rat is counteracted by PACAP27. Am J Physiol Endocrinol Metab 292: E1447-E1455, 2007. First published January 30, 2007; doi:10.1152/ajpendo.00172.2006.-Chronic exposure of pancreatic islets to elevated plasma lipids (lipotoxicity) can lead to ␤-cell dysfunction, with overtime becoming irreversible. We examined, by confocal microscopy and biochemistry, whether the expression of islet inducible nitric oxide synthase (iNOS) and the concomitant inhibition of glucose-stimulated insulin release seen after lipid infusion in rats was modulated by the islet neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP)27. Lipid infusion for 8 days induced a strong expression of islet iNOS, which was mainly confined to ␤-cells and was still evident after incubating islets at 8.3 mmol/l glucose. This was accompanied by a high iNOS-derived NO generation, a decreased insulin release, and increased cyclic GMP accumulation. No iNOS expression was found in control islets. Addition of PACAP27 to incubated islets from lipid-infused rats resulted in loss of iNOS protein expression, increased cyclic AMP, decreased cyclic GMP, and suppression of the activities of neuronal constitutive (nc)NOS and iNOS and increased glucose-stimulated insulin response. These effects were reversed by the PKA inhibitor H-89. The suppression of islet iNOS expression induced by PACAP27 was not affected by the proteasome inhibitor MG-132, which by itself induced the loss of iNOS protein, making a direct proteasomal involvement less likely. Our results suggest that PACAP27 through its cyclic AMP-and PKA-stimulating capacity strongly suppresses not only ncNOS but, importantly, also the lipid-induced stimulation of iNOS expression, possibly by a nonproteasomal mechanism. Thus PACAP27 restores the impairment of glucose-stimulated insulin release and additionally might induce cytoprotection against deleterious actions of iNOS-derived NO in ␤-cells. pancreatic islets; insulin secretion; isoforms of nitric oxide synthase; pituitary adenylate cyclase-activating polypeptide 27 THE SOLUTION USED for total parenteral nutrition (TPN) contains a high amount of lipids, which results in increased plasma levels of free fatty acid (FFA), triglycerides, and cholesterol (8,31,34,36). FFA has complex effects on pancreatic ␤-cells and insulin secretion (8,9,25,31,32,34,36,45,51). Hence, FFA acutely stimulates insulin secretion from isolated pancreatic islets (9), whereas long-term incubation (24 h) of islets in the presence of FFAs negatively modulates ␤-cell function and results in a markedly decreased glucose-stimulated release of insulin (51). Indeed, it has been known for a long time that chronic elevation of plasma FFA impairs the insulin-secreting response to glucose in both humans and animals (8,31,32,34,36,45,51), and this hyperlipidemia has been suggest...

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Section: Discussionmentioning

confidence: 50%

Expression of islet inducible nitric oxide synthase and inhibition of glucose-stimulated insulin release after long-term lipid infusion in the rat is counteracted by PACAP27

Qader

Jimenez-Feltström²,

Ekelund³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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“…Kalbe et al (47) also observed an increase in insulin secretion from fetal islets exposed to lactacystin. However, another recent report (48) demonstrates that lactacystin decreases insulin release from islets exposed to high glucose without affecting the total insulin content. The same work shows that lactacystin decreases insulin synthesis and favors its degradation.…”

Section: Discussionmentioning

confidence: 99%

Evidence for a Role of the Ubiquitin-Proteasome Pathway in Pancreatic Islets

López-Avalos

Duvivier‐Kali

et al. 2006

Diabetes

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The ubiquitin-proteasome pathway is crucial for protein turnover. Part of the pathway involves deubiquitination, which is carried out by cystein proteases known as ubiquitin COOH-terminal hydrolases. The isoform Uch-L1 was found to be present in large amounts in rat islets by immunostaining, Western blot analysis, and RT-PCR. Culturing islets in high glucose concentrations (16.7 mmol/l) for 24 h led to decreased gene expression. Exposure to chronic hyperglycemia following 90% partial pancreatectomy also led to reduced Uch-L1 expression. Expression of other members of the ubiquitin-proteasome pathway studied after culturing islets at high glucose concentrations revealed little change except for modest declines in parkin, human ubiquitin-conjugating enzyme 5 (UbcH5), and ␤-TRCP (transducin repeat-containing protein). With the pancreatectomy model, expression of polyubiquitin-B and c-Cbl were increased and E6-associated protein was reduced. Further insight about the proteasome pathway was obtained with the proteasome inhibitor lactacystin, which in short-term 2-h experiments enhanced glucose-induced insulin secretion. An important role for the ubiquitinproteasome pathways in ␤-cells is suggested by the findings that changes in glucose concentration influence expression of genes in the pathway and that blockade of the proteasome degradation machinery enhances glucose-stimulated insulin secretion.

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“…Despite this model's hypothetical nature, we suggest that it provides a useful platform for further investigation, On a more functional note, we suggest that regulation of UCP2 degradation by the ubiquitin-proteasome system serves to regulate it in line with other proteins. In the pancreatic b-cell, the proteasome is known to regulate proteins involved in the insulin secretion pathway such as ATP-sensitive potassium channels (Yan et al, 2005), voltage-dependent calcium channels (Kawaguchi et al, 2006) and proinsulin levels (Kitiphongspattana et al, 2005). In all these cases, proteasome inhibition leads to decreased glucose-stimulated insulin secretion, suggesting that proteasome dysfunction may be one of the molecular mechanisms of the b-cell impairment seen in type 2 diabetes mellitus.…”

Section: Discussionmentioning

confidence: 99%

Degradation of an intramitochondrial protein by the cytosolic proteasome

Azzu

Brand

2010

Journal of Cell Science

108

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Mitochondrial uncoupling protein 2 (UCP2) is implicated in a wide range of pathophysiological processes, including immunity and diabetes mellitus, but its rapid degradation remains uncharacterized. Using pharmacological proteasome inhibitors, immunoprecipitation, dominant negative ubiqbiquitiuitin mutants, cellular fractionation and siRNA techniques, we demonstrate the involvement of the ubiquitin-proteasome system in the rapid degradation of UCP2. Importantly, we resolve the issue of whether intramitochondrial proteins can be degraded by the cytosolic proteasome by reconstituting a cell-free system that shows rapid proteasome-inhibitor-sensitive UCP2 degradation in isolated, energised mitochondria presented with an ATP regenerating system, ubiquitin and 26S proteasome fractions. These observations provide the first demonstration that a mitochondrial inner membrane protein is degraded by the cytosolic ubiquitin-proteasome system.

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Proteasome Inhibition Alters Glucose-stimulated (Pro)insulin Secretion and Turnover in Pancreatic β-Cells

Abstract: Metabolic labeling studies were conducted in freshly isolated mouse islets and a ␤-cell line (MIN6) to examine the effects of proteasome inhibition on glucose-stimulated (pro)insulin synthesis and secretion. Glucose-stimulated (pro)insulin synthesis, as determined by the incorporation of

Cited by 67 publications

References 66 publications

Expression of islet inducible nitric oxide synthase and inhibition of glucose-stimulated insulin release after long-term lipid infusion in the rat is counteracted by PACAP27

Expression of islet inducible nitric oxide synthase and inhibition of glucose-stimulated insulin release after long-term lipid infusion in the rat is counteracted by PACAP27

Evidence for a Role of the Ubiquitin-Proteasome Pathway in Pancreatic Islets

Degradation of an intramitochondrial protein by the cytosolic proteasome

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