Nifedipine Protects INS-1 β-Cell from High Glucose-Induced ER Stress and Apoptosis

Wang, Yao; Gao, Lu; Li, Yuan; Chen, Hong; Sun, Zilin

doi:10.3390/ijms12117569

Cited by 41 publications

(43 citation statements)

References 55 publications

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“…[39][40][41][42] Execution of apoptosis was evident from a slight increase in caspase 3/7 activity after 72 h exposure which has also been observed in hyperglycemia treated INS-1 cells and isolated human islets. 43,44 In conclusion, this study has demonstrated multiple effects of glucotoxicity on gene expression and insulin secretory function in 1.1B4 cells, suggesting that this novel human-derived pancreatic β-cell line is useful for further investigations of β-cell dysfunction and its correction with novel therapeutic agents. …”

Section: Discussionmentioning

confidence: 99%

Cellular responses of novel human pancreatic β-cell line, 1.1B4 to hyperglycemia

Vasu

McClenaghan²,

McCluskey

et al. 2013

Islets

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Section: Discussionmentioning

confidence: 99%

Cellular responses of novel human pancreatic β-cell line, 1.1B4 to hyperglycemia

Vasu

McClenaghan²,

McCluskey

et al. 2013

Islets

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“…I NaL is linked to Ca 2+ homeostasis, which may thus be chronically perturbed by CHG-induced I NaL enhancement. Whereas acute increment of [Ca 2+ ] I is expected to stimulate insulin secretion [14], the only previous information on the effect of persistently elevated [Ca 2+ ] I levels concerned prevention of CHG-induced apoptosis by nifedipine [45]. The observation that RAN prevented β-cell loss in mice with streptozotocin-induced diabetes [32] is in line with this observation and conceptually reminiscent of myocardial response to persistent I NaL enhancement, i.e., transient increase in contractility followed by maladaptive remodeling [49].…”

Section: Effect Of Ran and Ttx On Membrane Potentialmentioning

confidence: 99%

“…Nevertheless, as in other tissues, pathophysiological significance of I NaL may require its enhancement under clinically relevant conditions [4,40], which in diabetes may be represented by chronic cell exposure to high glucose [45]. Thus, INS-1E cells incubated for 24 h in a medium containing 33 mM glucose (CHG) [45] were compared to cells incubated for the same period in 10 mM glucose (CNG) (Fig.…”

Section: Na -Dependent Modulation Of Intracellular Ca 2+mentioning

confidence: 99%

“…Chronic hyperglycemia (CHG) was simulated as described by Wang et al [45]. Briefly, after plating, INS-1E cells were kept in glucose-free medium overnight and then switched to complete medium containing either normal (10 mM) glucose (CNG group), high (33 mM) glucose (CHG group), 33 mM glucose+10 μM RAN (CHG+RAN group), or 33 mM glucose+0.5 μM TTX (CHG+TTX) for 24 h. Because potentially contributing to the effects of hyperglycemia, the osmolarity increment between CNG and CHG solutions was not compensated.…”

Section: Chronic Hyperglycemia Modelmentioning

confidence: 99%

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Late sodium current (INaL) in pancreatic β-cells

Rizzetto

Rocchetti

Sala

et al. 2014

Pflugers Arch - Eur J Physiol

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Recent evidence of beneficial effects of ranolazine (RAN) in type II diabetes motivates interest in the role of the late sodium current (INaL) in glucose-stimulated insulin secretion. In the present work, we characterize INaL and its function in rat INS-1E cells and human islets cells. INaL was identified as steady-state current blocked by 10 μM RAN (IRAN) or 0.5 μM tetrodotoxin (TTX) (ITTX). Veratridine (VERA, 40 μM) was used as INaL enhancer. Baseline INaL was similar between INS-1E and human islet cells. In INS-1E cells, activated by glucose or tolbutamide, TTX or RAN hyperpolarized membrane potential (V m). VERA-induced depolarization was countered by TTX or RAN. ITTX and IRAN reversal potentials were negative to Na(+) equilibrium one, but they approached it after Na(+) substitution with Li(+) or when K(+) channels were blocked. This revealed INaL coupling with Na(+)-activated K(+) current (IKNa); expression of IKNa channels (Slick/Slack) was confirmed by transcript analysis and Western blot. RAN or TTX blunted cytosolic Ca(2+) response to depolarization. Long-term incubation in high (33 mM) glucose (CHG) constitutively enhanced INaL. VERA immediately increased glucose-stimulated insulin secretion. CHG increased glucose-independent secretion instead and abolished the secretory response to glucose. RAN or TTX countered VERA- and CHG-induced changes in insulin secretion. Our study demonstrated that (1) INaL was expressed in insulin-secreting cells and coupled to IKNa; INaL affected cytosolic Ca(2+) but, unless enhanced, barely contributed to glucose-stimulated insulin secretion (GSIS); and (2) sustained hyperglycemic stress enhanced INaL, which contributed to the attending increase of glucose-independent insulin "leak" and GSIS impairment.

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“…49 Damaged mitochondria release cytochrome C and induce apoptosis via the activation of caspase 9 77 ; rs2020902 is located in the CASP9 gene. 49 Sustained demands on the endoplasmic reticulum (ER) during hyperglycemia result in cytoplasmic accumulation of calcium, 86,87 causing activation of the caspase cascade 86 and 57 regulates hepatic gluconeogenesis in mice 58 Where there is more than one candidate, the gene in closest proximity to the SNP was chosen (underlined). 48 In b cells, ER stress upregulates heat shock protein 40 expression; this correlates with increased apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Genetics of New-Onset Diabetes after Transplantation

McCaughan

McKnight²,

Maxwell

2014

Journal of the American Society of Nephrology

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New-onset diabetes after transplantation is a common complication that reduces recipient survival. Research in renal transplant recipients has suggested that pancreatic b-cell dysfunction, as opposed to insulin resistance, may be the key pathologic process. In this study, clinical and genetic factors associated with new-onset diabetes after transplantation were identified in a white population. A joint analysis approach, with an initial genome-wide association study in a subset of cases followed by de novo genotyping in the complete case cohort, was implemented to identify single-nucleotide polymorphisms (SNPs) associated with the development of new-onset diabetes after transplantation. Clinical variables associated with the development of diabetes after renal transplantation included older recipient age, female sex, and percentage weight gain within 12 months of transplantation. The genome-wide association study identified 26 SNPs associated with new-onset diabetes after transplantation; this association was validated for eight SNPs (rs10484821, rs7533125, rs2861484, rs11580170, rs2020902, rs1836882, rs198372, and rs4394754) by de novo genotyping. These associations remained significant after multivariate adjustment for clinical variables. Seven of these SNPs are associated with genes implicated in b-cell apoptosis. These results corroborate recent clinical evidence implicating b-cell dysfunction in the pathophysiology of newonset diabetes after transplantation and support the pursuit of therapeutic strategies to protect b cells in the post-transplant period. One-year graft survival after renal transplantation is now excellent, exceeding 93% for organs donated after brain death and 96% for those from living donors. 1-3 Technical advancements in surgery, improved understanding of immunology, and innovative developments in pharmacology have altered the landscape of renal transplantation. The goal of preventing early graft loss has largely been achieved and arguably the greatest challenge now is the avoidance of late graft failure. Although there has been a considerable improvement in 1-year renal transplant survival, the rate of graft attrition after the first year remains frustratingly constant. 2,4 New-onset diabetes after transplantation (NODAT) is a common and serious disorder that curtails recipient survival. [5][6][7] NODAT is associated with cardiovascular complications [8][9][10][11] and develops in 2%-50% 12 of renal transplant recipients. Approximately 50% of recipients with NODAT require insulin therapy. [6][7][8][13][14][15] A number of clinical variables have been associated with NODAT, including black ethnicity, older recipient age, female sex, obesity, immunosuppression, and viral infections. 5,6,8,13,16,17 Until recently, the pathophysiology of NODAT was considered to be analogous to type 2 diabetes mellitus. Renal transplant recipients have increased insulin resistance compared with transplant-naïve persons with normal renal function. 18 In a nondiabetic renal transplant population, the m...

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Nifedipine Protects INS-1 β-Cell from High Glucose-Induced ER Stress and Apoptosis

Cited by 41 publications

References 55 publications

Cellular responses of novel human pancreatic β-cell line, 1.1B4 to hyperglycemia

Cellular responses of novel human pancreatic β-cell line, 1.1B4 to hyperglycemia

Late sodium current (INaL) in pancreatic β-cells

Genetics of New-Onset Diabetes after Transplantation

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