RX871024 induces Ca2+ mobilization from thapsigargin-sensitive stores in mouse pancreatic beta-cells

Efanova, I. B.; Zaitsev, S. V.; Brown, G.; Berggren, P. O.; Efendic, S.

doi:10.2337/diabetes.47.2.211

Cited by 12 publications

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“…Some imidazoline compounds like idazoxan and phentolamine can activate caspase-3 [26]; however, the signal-transduction pathways of this effector caspase activation by imidazolines were not investigated. We have previously reported that RX871024 induces Ca 2+ mobilization from the endoplasmic reticulum (ER) in mouse pancreatic b-cells [41]. In contrast, efaroxan does not have such an activity [42].…”

Section: Discussionmentioning

confidence: 98%

“…The b-cell line MIN6 (passages [32][33][34][35][36][37][38][39][40][41][42] was cultured in DMEM containing 25 mM glucose supplemented with 10 % (vol/vol) fetal calf serum, 50 mM b-mercaptoethanol, 50 U/ml penicillin, and 50 mg/ml streptomycin as previously described [25]. MIN6 cells were exposed to imidazolines with or without a combination of cytokines (25 U/ml IL-1b, 100 U/ml IFN-g, 100 U/ml TNF-a) for 20 h and lactate dehydrogenase (LDH) release, nitrite production and activity of caspases-1, -3, -8 and -9 were measured.…”

Section: Methodsmentioning

confidence: 99%

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The imidazoline RX871024 induces death of proliferating insulin-secreting cells by activation of c-jun N-terminal kinase

Zaitseva

Størling

Mandrup-Poulsen

et al. 2008

Cell. Mol. Life Sci.

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An insufficient number of insulin-producing beta-cells is a major cause of defective control of blood glucose in both type 1 and type 2 diabetes. The aim of this study was to clarify whether the insulinotropic imidazolines can affect the survival of highly proliferating insulin-secreting cells, here exemplified by the MIN6 cell line. Our data demonstrate that RX871024, but not efaroxan, triggered MIN6 cell death and potentiated death induced by a combination of the pro-inflammatory cytokines interleukin-1beta, interferon- gamma and tumor necrosis factor-alpha. These effects did not involve changes in nitric oxide production but correlated with stimulation of c-jun N-terminal kinase (JNK) activity and activation of caspases-1, -3, -8 and -9. Our results suggest that the imidazoline RX871024 causes death of highly proliferating insulin-secreting cells, putatively via augmentation of JNK activity, a finding that may impact on the possibility of using compounds of similar activity in the treatment of diabetes.

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Section: Discussionmentioning

confidence: 98%

Section: Methodsmentioning

confidence: 99%

The imidazoline RX871024 induces death of proliferating insulin-secreting cells by activation of c-jun N-terminal kinase

Zaitseva

Størling

Mandrup-Poulsen

et al. 2008

Cell. Mol. Life Sci.

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“…Other intracellular cysteine proteases, such as calpains, can be initiated by Ca 2ϩ and are involved in apoptosis (32). It has also been reported that high glucose and tolbutamide can induce apoptosis in pancreatic ␤-cells in a Ca 2ϩ -dependent manner (35), and a calcium channel blocker can partially inhibit glibenclamide-induced ␤-cell apoptosis (33). In this study, we examined the effects of PANDER on Ca 2ϩ homeostasis in ␤-cells.…”

Section: Discussionmentioning

confidence: 99%

Pancreatic-Derived Factor (FAM3B), a Novel Islet Cytokine, Induces Apoptosis of Insulin-Secreting β-Cells

et al. 2003

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PANDER (PANcreatic DERived factor, FAM3B), a newly discovered secreted cytokine, is specifically expressed at high levels in the islets of Langerhans of the endocrine pancreas. To evaluate the role of PANDER in ␤-cell function, we investigated the effects of PANDER on rat, mouse, and human pancreatic islets; the ␤-TC3 cell line; and the ␣-TC cell line. PANDER protein was present in ␣-and ␤-cells of pancreatic islets, insulinsecreting ␤-TC3 cells, and glucagon-secreting ␣-TC cells. PANDER induced islet cell death in rat and human islets. Culture of ␤-TC3 cells with recombinant PANDER had a dose-dependent inhibitory effect on cell viability. This effect was also time-dependent. PANDER caused apoptosis of ␤-cells as assessed by electron microscopy, annexin V fluorescent staining, and flow-cytometric terminal deoxynucleotidyl transferase-mediated dUTP nickend labeling assay. PANDER did not affect cytosolic Ca 2؉ levels or nitric oxide levels. However, PANDER activated caspase-3. Hence, PANDER may have a role in the process of pancreatic ␤-cell apoptosis.

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“…Furthermore, the imidazoline clonidine inhibited insulin release when given alone, as a result of its ␣ 2 AR agonist action, but elicited insulin release through a nonadrenergic mechanism after ␣ 2 AR blockade. More recent studies have identified selective imidazoline agents that stimulate insulin release from the pancreas while lacking adrenergic actions (Efanova et al, 1998;Efanov et al, 2001). The mixed agent moxonidine facilitated glucose induced insulin secretion in isolated rat ␤-cells in a dose-dependent manner (Rosen et al, 1997).…”

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The Role of I1-Imidazoline and α2-Adrenergic Receptors in the Modulation of Glucose Metabolism in the Spontaneously Hypertensive Obese Rat Model of Metabolic Syndrome X

Velliquette

Ernsberger

2003

The Journal of Pharmacology and Experimental Therapeutics

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We examined glucose metabolism after I 1 -imidazoline (I 1 R) and ␣ 2 -adrenergic receptor (␣ 2 AR) activation in an animal model of metabolic syndrome X. Fasted spontaneously hypertensive obese rats (SHROB) were given the I 1 R/␣ 2 AR agonists moxonidine and rilmenidine or the ␣ 2 AR agonist guanabenz. Because of the dual specificity of moxonidine, its actions were split into adrenergic and nonadrenergic components by using selective antagonists: rauwolscine (␣ 2 AR) efaroxan (I 1 R/␣ 2 AR), or 2-endo-amino-3-exo-isopropylbicyclo[2.2.1.]heptane (AGN 192403) (I 1 R). Hyperglycemia induced by moxonidine, rilmenidine, and guanabenz resulted from inhibition of insulin secretion. Similar responses were observed after oral dosing and in lean littermates. Glucagon was reduced by the I 1 R agonists (moxonidine, 32 Ϯ 5%; rilmenidine, 24 Ϯ 7%) but elevated by guanabenz (71 Ϯ 32%). The hyperglycemic and hypoinsulinemic responses to moxonidine were blocked by rauwolscine. In contrast, rauwolscine potentiated the reduction in glucagon (39 Ϯ 6%). AGN 193402 blocked the glucagon response without affecting hyperglycemia and hypoinsulinemia. Efaroxan blocked all responses to moxonidine. When SHROB rats were treated with moxonidine 15 min before an oral glucose tolerance test, the glucose area under the curve (AUC) was increased. Antagonizing the ␣ 2 AR component of moxonidine's action with rauwolscine improved glucose AUC 3-fold and facilitated the insulin secretory response and reduced glucagon secretion. Testing fasting glucose and insulin during 3 weeks of oral moxonidine revealed early hyperglycemia that later faded, and a progressive drop in fasting insulin. The acute hyperglycemia and hypoinsulinemia elicited by moxonidine and rilmenidine was mediated by ␣ 2 AR, whereas I 1 R may reduce glucagon and increase insulin, particularly after a glucose load.

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RX871024 induces Ca2+ mobilization from thapsigargin-sensitive stores in mouse pancreatic beta-cells

Cited by 12 publications

References 0 publications

The imidazoline RX871024 induces death of proliferating insulin-secreting cells by activation of c-jun N-terminal kinase

The imidazoline RX871024 induces death of proliferating insulin-secreting cells by activation of c-jun N-terminal kinase

Pancreatic-Derived Factor (FAM3B), a Novel Islet Cytokine, Induces Apoptosis of Insulin-Secreting β-Cells

The Role of I1-Imidazoline and α2-Adrenergic Receptors in the Modulation of Glucose Metabolism in the Spontaneously Hypertensive Obese Rat Model of Metabolic Syndrome X

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