Euglycemia in Diabetic Rats Leads to Reduced Liver Weight via Increased Autophagy and Apoptosis through Increased AMPK and Caspase-3 and Decreased mTOR Activities

Figure 7

Proposed molecular mechanisms for (a) the loss or (b) the preservation of liver weight by glycemic levels in the presence of insulin deficiency. In the liver of euglycemic rats with insulin deficiency, AMPK is activated and the activity of Akt, a major insulin signaling molecule, decreases (the decreased Akt activity is also influenced by PTEN activation), compared with those in hyperglycemic rats with insulin deficiency. The increased AMPK and decreased Akt activities, in turn, decrease the activity of mTOR. As a result, excessive autophagy is induced not only by the activated AMPK but also by the inhibition of protective role of mTOR against autophagy through ERK-1 activation and caspase-3 inhibition. Then excessive autophagy leads to hepatic cell death, partially via apoptosis mediated by caspase-3 activation, resulting in the loss of liver weight in euglycemic rats with insulin deficiency. On the other hand, in the liver of hyperglycemic rats with insulin deficiency, AMPK is not activated while Akt and mTOR are activated, compared with those in euglycemic rats with insulin deficiency. Thus, excessive autophagy and hepatic cell death are prevented not only because of the protective role of mTOR against autophagy but also because of the low AMPK activity, resulting in the preservation of liver weight in hyperglycemic rats with insulin deficiency.

(a)

(b)