Hepatic Autophagy in Uncontrolled Experimental Diabetes and Its Relationships to Insulin and Glucagon

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Abstract

Exogenous glucagon is known to increase hepatic lysosomes, but the relationships between endogenous glucagon and insulin levels and hepatic lysosomes have not been examined. To determine if the hormones of the pancreatic islets influence the development of these organelles glycogenosomes, dense bodies, and autophagosomes were morphometrically quantitated in normal rats, in rats with mild streptozotocin diabetes with normal hormone levels, and in rats with severe streptozotocin diabetes with hyperglucagonemia, hypo-insulinemia, and clinical evidence of uncontrolled diabetes and ketoacidosis. In the latter volume density of lysosomes averaged 222.8×10-4 (SEM ±19.8×10-4), significantly above the control value of 75×10-4 (SEM ±7.0×10-4) (P<0.0005); glycogenosomes were absent in the diabetics, the increase being largely the result of increased autophagosomes. Insulin treatment corrected the hyperglucagonemia, hypoinsulinemia, and other manifestations of uncontrolled diabetes and reduced the volume density of lysosomes to 37.4×10-4 (SEM ±2.0×10-4), significantly below both the untreated diabetic rats and the nondiabetic controls (P<0.0025). In mild streptozotocin diabetes, in which hyperglucagonemia, hypoinsulinemia, and other evidence of uncontrolled diabetes were absent, lysosomes averaged 77.6×10-4 (SEM ±5.5×10-4), not different from the controls. A statistically significant correlation between all measurements of lysosomal volume density and plasma glucagon was observed (r=0.79; P<0.001). It is concluded that uncontrolled streptozotocin diabetes in rats is accompanied by hepatic autophagy which may be related to the increased plasma glucagon level and/or the decreased insulin and which is corrected by insulin therapy.

Authors

M. Amherdt, V. Harris, A. E. Renold, L. Orci, R. H. Unger