Modulation of insulin secretion by diazepam binding inhibitor and its processing products

Borboni, P.; Condorelli, Luigi; Stefanis, P. De; Sesti, Giorgio; Lauro, Renato

doi:10.1016/s0028-3908(11)80008-0

Cited by 43 publications

(26 citation statements)

References 17 publications

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“…Our results on insulin secretion are in agreement with a cytostatic effect of PK11195 reported in rodent islets (27), and with the inhibition of glucose-mediated insulin release associated with the incubation of rat islets with diazepam binding inhibitor (DBI), a putative endogenous PBR ligand (28). The mechanism(s) through which PK11195 exerts its inhibitory effect on insulin release was in part explored in the present study, and we showed that the cytostatic action was not due to grossly altered transcription of insulin or glucose-transporter GLUT-1 from the coding genes.…”

Section: Discussionsupporting

confidence: 90%

“…Moreover, a recently described molecule, peripheral benzodiazepine receptor-associated protein (PRAX)-1, has been reported to have several domains involved in protein -protein interaction at the PBR level (36). Whereas the possible direct effects of PIX, anthralin and PRAX-1 on islet cells has not been tested, DBI has been shown to inhibit insulin release (28). More recently, upon construction of a human pancreatic islet cDNA library, screening of sera from diabetic patients led to the observation that one of the generated clones was strongly related to DBI (37).…”

Section: Discussionmentioning

confidence: 99%

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The role of peripheral benzodiazepine receptors on the function and survival of isolated human pancreatic islets

Marselli

Trincavelli²,

Santangelo³

et al. 2004

European Journal of Endocrinology

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Objective: Peripheral benzodiazepine receptors (PBRs) are part of the mitochondrial permeability transition pore, and their activation may induce cell death. PBRs are expressed in human pancreatic islets, and cytokine-induced damage is accompanied by changes in their properties. We hypothesized that PBRs can have a role in human islet physiopathology, and evaluated the effects of prolonged exposure to two specific PBR ligands, PK11195 and Ro5-4864 on the function and survival of isolated human islets. Design: Isolated human islets were prepared from the pancreas of 25 multiorgan cadaveric donors and incubated for 12 h in the presence of PK11195 or Ro5-4864. Insulin secretion studies and apoptosis experiments were then performed, together with assessment of intracellular pathways involved in islet cell function and survival. Methods: Islets were prepared by enzymatic digestion and density gradient purification. Insulin secretion was assessed by the batch incubation method, and glucose oxidation was evaluated by the use of D-[U-14 C]glucose. Apoptosis was studied using the TUNEL technique, ELISA methods, and electron microscopy evaluation. PCR experiments were performed by the use of specific primers. Results: Glucose-stimulated insulin release was significantly lower after exposure to PK11195 than after exposure to Ro5-4864. This was accompanied by reduced glucose oxidation and no major change of insulin or GLUT-1 mRNA expression. Apoptosis was higher in PK11195-exposed islets, and electron microscopy demonstrated the involvement of beta-cells. The apoptotic effects were prevented by bongkrekic acid and low-dose cyclosporin A, which stabilize the mitochondrial membrane, and were associated with no evident change of inducible nitric oxide synthase (iNOS), B-cell leukemia/lymphoma-2 (Bcl-2) or Bcl-2-associated X protein (Bax) expression. Caspase inhibition markedly reduced the amount of apoptosis, and the role of these proteases was confirmed by the increased activity of caspase-3 and caspase-9. Conclusions: Prolonged binding to PBRs may cause human beta-cells functional damage and apoptosis, a phenomenon which is prevented by stabilizing the mitochondrial membrane; occurs without changes of iNOS, Bax and Bcl-2 mRNA expression; and involves caspase activation. These results suggest an involvement of PBRs in human pancreatic beta-cell function and survival.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

The role of peripheral benzodiazepine receptors on the function and survival of isolated human pancreatic islets

Marselli

Trincavelli²,

Santangelo³

et al. 2004

European Journal of Endocrinology

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“…ACBP is reported to play a role in a number of important physiological and biochemical functions, such as regulation of glucose-induced insulin secretion from pancreatic β-cells (32,33), stimulation of steroidogenesis through peripheral-type benzodiazepine receptor (PBR) (34)(35)(36), and modulation of cell proliferation (37). ACBP/DBI, originally described as a cytosolic protein and identified as stimulating the synthesis of pregnenolone in mitochondrial fractions, enhances steroidogenesis via PBRs.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of PGC-1α enhances cell proliferation and tumorigenesis of HEK293 cells through the upregulation of Sp1 and Acyl-CoA binding protein

Shin

Yun

Park

et al. 2015

International Journal of Oncology

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Abstract. Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a coactivator interacting with multiple transcription factors, regulates several metabolic processes. Although recent studies have focused on the role of PGC-1α in cancer, the underlying molecular mechanism has not been clarified. Therefore, we evaluated the role of PGC-1α in cell proliferation and tumorigenesis using human embryonic kidney (HEK)293 cells and colorectal cancer cells. We established stable HEK293 cell lines expressing PGC-1α and examined cell proliferation, anchorage-independent growth, and oncogenic potential compared to parental HEK293 cells. To identify the molecular PGC-1α targets for increased cell proliferation and tumorigenesis, the GeneFishing™ DEG (differentially expressed genes) screening system was used. Western blot analysis and immunofluorescence staining were performed for a regulated gene product to confirm the results. Forced expression of PGC-1α in HEK293 cells promoted cell proliferation and anchorage-independent growth in soft agar. In addition, HEK293 cells that highly expressed PGC-1α showed enhanced tumor formation when subcutaneously injected into the bilateral flanks of immunodeficient mice. The results of the GeneFishing DEG screening system identified one upregulated gene (Acyl-CoA binding protein; ACBP). Real-time RT-PCR, western blot analysis, and immunofluorescence staining showed that ACBP was markedly increased in HEK293 cells stably overexpressing PGC-1α (PGC-1α-HEK293 cells) compared to those expressing an empty vector. In PGC-1α, ACBP, and specificity protein 1 (Sp1) siRNA knockdown experiments in PGC-1α-HEK293 and SNU-C4 cells, we also observed inhibition of cell proliferation, reduced expression of antioxidant enzymes, and increased H 2 O 2 -induced reactive oxygen species production and apoptosis. These findings suggest that PGC-1α may promote cell proliferation and tumorigenesis through upregulation of ACBP. We provide evidence that increased Sp1 expression might contribute to enhanced ACBP expression by PGC-1α. The current results also suggest that PGC-1α, whose expression is related to enhanced cell proliferation and tumorigenesis, may be a good candidate molecular target for cancer therapy.

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“…Furthermore, elevated levels of a diazepam binding inhibitor-like immunoreactive compound have been reported in patients diagnosed with depression with concomitant anxiety (26). Diazepam binding inhibitor has been previously shown to inhibit glucose-stimulated insulin release from pancreatic islet > cells (28,29). Suk et al (30) demonstrated that cDNA related to diazepam binding inhi- bitor was expressed in most tissues including liver, lung, tonsil and thymus, in addition to pancreatic islet and sera, in diabetic patients.…”

Section: Discussionmentioning

confidence: 99%

Modification of the Effects of Benzodiazepines on the Exploratory Behaviors of Mice on a Hole-Board by Diabetes

Kamei

Ohsawa

Tsuji

et al. 2001

Japanese Journal of Pharmacology

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ABSTRACT-The effect of diabetes on the emotional behavior of mice was examined using an automatic hole-board apparatus. Changes in the emotional state of mice were evaluated in terms of changes in exploratory activity; i.e., total locomotor activity, numbers and duration of rearing and head-dipping, and latency to the first head-dipping. The number and duration of head-dipping in diabetic mice were less than those in non-diabetic mice. Diazepam (0.1 -0.56 mg/ kg, i.p.) dose-dependently increased the number and duration of head-dipping at doses that did not produce sedation in both diabetic and non-diabetic mice. In contrast, methyl->-carboline-3-carboxylate (1 and 2 mg/kg, i.p.) decreased the number and duration of head-dipping in non-diabetic mice, but not in diabetic mice. The number and duration of head-dipping in diabetic mice were increased by treatment with flumazenil (0.1 and 0.3 mg/ kg, i.v.). These doses of flumazenil did not affect the number or duration of head-dipping in non-diabetic mice. The present data indicate that diabetic mice exhibited anxiety in the hole-board test and that a benzodiazepine receptor antagonist affected the attenuated number and duration of head-dipping in diabetic mice. The heightened anxiety in diabetic mice may be due to the dysfunction of the benzodiazepine receptor and / or of central inhibitory systems.

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Modulation of insulin secretion by diazepam binding inhibitor and its processing products

Cited by 43 publications

References 17 publications

The role of peripheral benzodiazepine receptors on the function and survival of isolated human pancreatic islets

The role of peripheral benzodiazepine receptors on the function and survival of isolated human pancreatic islets

Overexpression of PGC-1α enhances cell proliferation and tumorigenesis of HEK293 cells through the upregulation of Sp1 and Acyl-CoA binding protein

Modification of the Effects of Benzodiazepines on the Exploratory Behaviors of Mice on a Hole-Board by Diabetes

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