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Updated: Aug 7, 2026
Assessing Replication and Beta Cell Function in Adenovirally-transduced Isolated Rodent Islets
Published on: June 25, 2012
Poly(ADP-ribose)polymerase activation determines strain sensitivity to streptozotocin-induced beta cell death in
J W Cardinal1, D J Allan, D P Cameron
1Department of Diabetes and Endocrinology, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Brisbane, 4102, Australia.
Abstract:
Streptozotocin (STZ) is believed to induce pancreatic beta cell death in mice by depleting the cell of NAD+NADH. The drug is known to cause a greater depletion of beta cell NAD+NADH in C57bl/6J mice than in Balb/c mice. To investigate the basis for this strain difference, we compared the effects of streptozotocin on poly(ADP-ribose)polymerase (PARP) activation - the major site of NAD consumption, and on mitochondrial activity - the major site of NAD production.%A significant strain difference was demonstrated in STZ-induced PARP activation (fmol NAD incorporated/min/microgram DNA+/-s.e.m.: Balb/c control 2.28+/-0.14, Balb STZ 3.11+/-0.25; C57bl/6J control 2.57+/-0.29, C57bl/6J STZ 4.17+/-0.24). In comparison, no strain difference could be demonstrated in hydrogen-peroxide-induced PARP activation. No strain differences could be detected in the activity of STZ-treated islet mitochondria as measured by determining ATP production (pmol/microgram protein/h+/-s. e.m.: Balb/c control 0.20+/-0.02, Balb/c STZ 0.15+/-0.02; C57bl/6J control 0.23+/- 0.03, C57bl/6J STZ 0.15+/-0.02) or by 3-[4, 5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) dye reduction (change in optical density/mg protein+/-s.e.m.: Balb/c control 10.19+/-0.62, Balb/c STZ 6.01+/-1.17; C57bl/6J control 6. 15+/-0.98, C57bl/6J STZ 5.81+/-0.96).% The strain difference in STZ-induced NAD depletion appears to be due to a difference in NAD consumption and not a difference in a mitochondrial process involved in replacing decreasing NAD concentrations. It is unlikely that a strain difference in the enzymic activity of PARP is responsible for strain differences in the effects of STZ, as no strain differences in hydrogen-peroxide-induced PARP activation could be detected. Thus the greater PARP activation, NAD depletion and beta cell death observed in C57bl/6J islets may be due to greater levels of DNA damage or differences in the DNA excision repair processes.
Insights
Streptozotocin (STZ) causes pancreatic beta cell death by depleting NAD+NADH. C57bl/6J mice show greater STZ-induced poly(ADP-ribose)polymerase (PARP) activation and NAD depletion than Balb/c mice, suggesting differences in DNA damage or repair.
Area of Science:
- Biochemistry
- Cell Biology
- Toxicology
Background:
- Streptozotocin (STZ) induces pancreatic beta cell death by depleting nicotinamide adenine dinucleotide (NAD+NADH).
- A significant difference exists in STZ-induced beta cell NAD+NADH depletion between C57bl/6J and Balb/c mouse strains.
- Poly(ADP-ribose)polymerase (PARP) activation is a major site of NAD consumption, while mitochondria are key sites of NAD production.
Purpose of the Study:
- To investigate the basis for strain-dependent differences in STZ-induced NAD depletion.
- To compare STZ effects on PARP activation and mitochondrial activity in C57bl/6J and Balb/c mice.
- To elucidate the mechanisms underlying differential beta cell vulnerability to STZ.
Main Methods:
- Quantification of STZ-induced poly(ADP-ribose)polymerase (PARP) activation in pancreatic islets.
- Measurement of mitochondrial activity via ATP production and MTT dye reduction in STZ-treated islets.
- Comparison of PARP activation in response to hydrogen peroxide to assess strain-specific enzyme activity.
Main Results:
- Significant strain difference observed in STZ-induced PARP activation, with higher activation in C57bl/6J mice.
- No strain difference in hydrogen-peroxide-induced PARP activation was detected.
- No strain differences were observed in mitochondrial ATP production or MTT dye reduction following STZ treatment.
Conclusions:
- The strain difference in STZ-induced NAD depletion is primarily due to differential NAD consumption via PARP activation, not altered mitochondrial NAD production.
- Differences in PARP enzyme activity are unlikely to explain the observed strain differences.
- Greater PARP activation and NAD depletion in C57bl/6J islets may stem from increased DNA damage or variations in DNA repair processes.
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