Caspase-3-Dependent β-Cell Apoptosis in the Initiation of Autoimmune Diabetes Mellitus

Liadis, Nicole; Murakami, Kiichi; Eweida, Mohamed; Elford, Alisha R.; Sheu, Laura; Gaisano, Herbert Y.; Hakem, Razqallah; Ohashi, Pamela S.; Woo, Minna

doi:10.1128/mcb.25.9.3620-3629.2005

Cited by 130 publications

(121 citation statements)

References 59 publications

Supporting

Mentioning

111

Contrasting

Unclassified

Order By: Relevance

“…The explanation for this observation is provided by the experiments reported in Table 1, showing that the percentage of insulin-positive b-cells, which were in addition also positive for caspase 3 and for perforin 1, was approximately three times higher at the start of therapy, when blood glucose concentrations were .15 mmol/L, than at blood glucose concentrations below this threshold (Table 1). This demonstrates that with increasing blood glucose concentrations, the percentage of dying insulin-positive b-cells increases (47). This correlation is highly significant.…”

Section: Beneficial Effects Of Combination Therapymentioning

confidence: 49%

TNF-α Antibody Therapy in Combination With the T-Cell–Specific Antibody Anti-TCR Reverses the Diabetic Metabolic State in the LEW.1AR1-iddmRat

et al. 2015

View full text Add to dashboard Cite

Anti–tumor necrosis factor-α (TNF-α) therapy (5 mg/kg body weight), alone or combined with the T-cell–specific antibody anti–T-cell receptor (TCR) (0.5 mg/kg body weight), was performed over 5 days immediately after disease manifestation to reverse the diabetic metabolic state in the LEW.1AR1-iddm rat, an animal model of human type 1 diabetes. Only combination therapy starting at blood glucose concentrations below 15 mmol/L restored normoglycemia and normalized C-peptide. Increased β-cell proliferation and reduced apoptosis led to a restoration of β-cell mass along with an immune cell infiltration–free pancreas 60 days after the end of therapy. This combination of two antibodies, anti-TCR/CD3, as a cornerstone compound in anti–T-cell therapy, and anti–TNF-α, as the most prominent and effective therapeutic antibody in suppressing TNF-α action in many autoimmune diseases, was able to reverse the diabetic metabolic state. With increasing blood glucose concentrations during the disease progression, however, the proapoptotic pressure on the residual β-cell mass increased, ultimately reaching a point where the reservoir of the surviving β-cells was insufficient to allow a restoration of normal β-cell mass through regeneration. The present results may open a therapeutic window for reversal of diabetic hyperglycemia in patients, worthwhile of being tested in clinical trials.

show abstract

Section: Beneficial Effects Of Combination Therapymentioning

confidence: 49%

TNF-α Antibody Therapy in Combination With the T-Cell–Specific Antibody Anti-TCR Reverses the Diabetic Metabolic State in the LEW.1AR1-iddmRat

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Casp3 −/− mice have reduced apoptosis, which is tissue-and stimulusspecific [37,38] and have normal islet structure without any marked abnormality in islet baseline viability [39]. All animals were fed a diet containing 9% (wt/wt) fat (Purina #5021, LabDiet, Richmond, IN, USA).…”

Section: Methodsmentioning

confidence: 99%

Differences between amyloid toxicity in alpha and beta cells in human and mouse islets and the role of caspase-3

Law

Kieffer

et al. 2010

Diabetologia

View full text Add to dashboard Cite

Aims/hypothesis Type 2 diabetes is characterised by decreased beta cell mass and islet amyloid formation. Islet amyloid formed by aggregation of human islet amyloid polypeptide (hIAPP) is associated with beta cell apoptosis. We used human and transgenic mouse islets in culture to examine whether deletion of caspase-3 protects islets from apoptosis induced by endogenously produced and exogenously applied hIAPP and compared hIAPP toxicity in islet alpha and beta cells. Methods Human and wild-type or caspase-3 knockout mouse islet cells were treated with hIAPP. Rat insulinoma INS-1 cells were similarly cultured with hIAPP and the amyloid inhibitor Congo Red or caspase-3 inhibitor. Human and hIAPP-expressing caspase-3 knockout mouse islets were cultured to form amyloid fibrils and assessed for beta and alpha cell apoptosis, beta cell function and caspase-3 activation.Results hIAPP-treated INS-1 cells had increased caspase-3 activation and apoptosis, both of which were reduced by inhibitors of amyloid or caspase-3. Similarly, hIAPP-treated human and mouse islet beta cells had elevated active caspase-3-and TUNEL-positive cells, whereas mouse islet cells lacking caspase-3 had markedly lower beta cell but comparable alpha cell apoptosis. During culture, human islets that formed amyloid had higher active caspase-3-and TUNEL-positive beta cells than those without detectable amyloid. Finally, cultured hIAPP-expressing mouse islets lacking caspase-3 had markedly lower beta cell apoptosis than those expressing caspase-3, associated with an increase in islet beta cell/alpha cell ratio, insulin content and glucose response. Conclusions/interpretation Prevention of caspase-3 activation protects islet beta cells from apoptosis induced by fibrillogenesis of endogenously secreted and exogenously applied hIAPP. Islet beta cells are more susceptible to hIAPP toxicity than alpha cells cultured under the same conditions.

show abstract

“…Both pathways ultimately lead to the activation of executioner caspases, including caspase 3, which are responsible for the final steps of apoptosis [37]. Knockout of caspases 3 and 8 has been shown to protect mice from MLDS-induced islet destruction and hyperglycaemia [38,39]. Up-regulation of ROS is a common feature of both pathways [2,36,37].…”

Section: Discussionmentioning

confidence: 99%

TRPM2-mediated intracellular Zn2+ release triggers pancreatic β-cell death

Manna

Munsey

Abuarab

et al. 2015

Biochemical Journal

View full text Add to dashboard Cite

Reactive oxygen species (ROS) can cause pancreatic β-cell death by activating transient receptor potential (melastatin) 2 (TRPM2) channels. Cell death has been attributed to the ability of these channels to raise cytosolic Ca 2 + . Recent studies however revealed that TRPM2 channels can also conduct Zn 2 + , but the physiological relevance of this property is enigmatic. Given that Zn 2 + is cytotoxic, we asked whether TRPM2 channels can permeate sufficient Zn 2 + to affect cell viability. To address this, we used the insulin secreting (INS1) β-cell line, human embryonic kidney (HEK)-293 cells transfected with TRPM2 and pancreatic islets. H 2 O 2 activation of TRPM2 channels increases the cytosolic levels of both Ca 2 + and Zn 2 + and causes apoptotic cell death. Interestingly, chelation of Zn 2 + alone was sufficient to prevent β-cell death. The source of the cytotoxic Zn 2 + is intracellular, found largely sequestered in lysosomes. Lysosomes express TRPM2 channels, providing a potential route for Zn 2 + release. Zn 2 + release is potentiated by extracellular Ca 2 + entry, indicating that Ca 2 + -induced Zn 2 + release leads to apoptosis. Knockout of TRPM2 channels protects mice from β-cell death and hyperglycaemia induced by multiple low-dose streptozotocin (STZ; MLDS) administration. These results argue that TRPM2-mediated, Ca 2 + -potentiated Zn 2 + release underlies ROS-induced β-cell death and Zn 2 + , rather than Ca 2 + , plays a primary role in apoptosis.

show abstract

Caspase-3-Dependent β-Cell Apoptosis in the Initiation of Autoimmune Diabetes Mellitus

Cited by 130 publications

References 59 publications

TNF-α Antibody Therapy in Combination With the T-Cell–Specific Antibody Anti-TCR Reverses the Diabetic Metabolic State in the LEW.1AR1-iddmRat

TNF-α Antibody Therapy in Combination With the T-Cell–Specific Antibody Anti-TCR Reverses the Diabetic Metabolic State in the LEW.1AR1-iddmRat

Differences between amyloid toxicity in alpha and beta cells in human and mouse islets and the role of caspase-3

TRPM2-mediated intracellular Zn2+ release triggers pancreatic β-cell death

Contact Info

Product

Resources

About