Insulin protects against amyloid β-peptide toxicity in brain mitochondria of diabetic rats

• Published in: Neurobiology of disease 2005-04, Vol.18 (3), p.628-637
• Main Authors: Moreira, Paula I., Santos, Maria S., Sena, Cristina, Seiça, Raquel, Oliveira, Catarina R.
• Format: Article
• Language: English
• Subjects: Amyloid beta-Peptides - toxicity; Amyloid β-peptide; Animals; Brain; Brain - drug effects; Brain - metabolism; Diabetes; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - metabolism; Glutathione - metabolism; Insulin; Insulin - pharmacology; Insulin - therapeutic use; Male; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Peptide Fragments - toxicity; Rats; Rats, Wistar
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2004.10.017

This study compared the status of brain mitochondria isolated from 12-week streptozotocin (STZ)-diabetic rats versus STZ-diabetic animals treated with insulin during a period of 4 weeks. Brain mitochondria isolated from 12-week citrate (vehicle)-treated rats were used as control. For that purpose, several mitochondrial parameters were evaluated: respiratory indexes (respiratory control ratio (RCR) and ADP/O ratio), transmembrane potential (ΔΨm), repolarization lag phase, repolarization level, ATP, glutathione and coenzyme Q (CoQ) contents, production of H 2O 2, ATPase activity, and the capacity of mitochondria to accumulate Ca 2+. Furthermore, the effect of Aβ 1–40 was also analyzed. We observed that STZ-induced diabetes promoted a significant decrease in mitochondrial CoQ9, ATPase activity, and a lower capacity of mitochondria to accumulate Ca 2+ when compared with control and insulin-treated diabetic rats. The presence of 4 μM Aβ 1–40 induced a significant decrease in RCR in the three groups of rats. However, this peptide induced a significant increase in the repolarization lag phase and a significant decrease in the repolarization level in control and diabetic animals without insulin treatment. Furthermore, this peptide exacerbated significantly the production of H 2O 2 in STZ-diabetic rats, this effect being avoided by insulin treatment. Our data show that although diabetes induces some alterations in brain mitochondrial activity, those alterations do not interfere significantly with mitochondria functional efficiency. Similarly, insulin does not affect basal mitochondria function. However, in the presence of amyloid β-peptide, insulin seems to prevent the decline in mitochondrial oxidative phosphorylation efficiency and avoids an increase in oxidative stress, improving or preserving the function of neurons under adverse conditions, such as Alzheimer's disease.