To evaluate whether catabolic levels of glucocorticoids activate the ubiquitin pathway in conjunction with their known proteolytic effect in skeletal muscle, rats were injected daily with corticosterone (CTC; 10 mg/100 g body wt) for 7 days. Two peaks of urinary excretion of 3-methylhistidine (3-MH), a specific marker of myofibrillar proteolysis, were observed at days 1 and 3 (165 and 295% of controls, respectively). Levels of ubiquitin pathway mRNAs in skeletal muscle were assessed around the 3-MH peaks. In the extensor digitorum longus, a first rise of two polyubiquitin (pUb) mRNAs was seen at day 1 (183 and 162% of control for the UbB and UbC transcripts, respectively, P < 0.01). An accumulation of both E2-14k mRNAs (140%, P < 0.02, and 157% of controls, P < 0.01) and proteasome C8 subunit mRNA (222% of control, P < 0.05) was seen at day 2. A second more important peak of induction of pUb mRNA was seen at day 3 (251 and 217% of controls for the UbB and UbC transcripts, respectively, P< 0.001). All transcripts returned to near control levels by day 4. In the soleus, induction of E2-14k mRNA started at day 3 and reached 216 and 208% of controls at day 4 (P < 0.001), whereas an increase of pUb mRNA was observed at days 3 (213 and 241%, P < 0.05) and 4 (211 and 221%, P < 0.001). A rise of proteasome C8 subunit mRNA accumulation was also seen in the soleus at days 3 (217%, P< 0.05) and 4 (157%, P < 0.05). Reduced ubiquitin conjugate levels, possibly due to their rapid degradation through increased proteasome activity, were observed in both muscle types at day 3. The parallel between the catabolic effects of CTC and activation of the ubiquitin pathway in muscles of CTC-treated rats strongly suggests the involvement of this system in glucocorticoid-induced muscular atrophy.
Diurnal variations in insulin-induced hypoglycemia and in plasma counterregulatory hormone concentrations were explored in eight insulin-dependent diabetic and six healthy subjects during a 100-min iv insulin infusion performed at 0300 h and 1500 h. In healthy subjects, plasma glucose concentrations (mean +/- SD) fell by 35 +/- 2% during the daytime test and by 26.5 +/- 2% during the nocturnal test (P less than 0.01). Plasma cortisol, GH, and epinephrine concentrations increased more during the daytime than during the nocturnal test. In contrast, plasma glucagon concentrations rose more during the nocturnal tests. In insulin-dependent diabetes mellitus patients, insulin infusion had to be interrupted in three subjects because plasma glucose fell below 1.9 mmol/L 80 min after the beginning of the test. In the other five patients plasma glucose fell by 34 +/- 5% during the daytime test while no significant decrease in plasma glucose was observed in any of the eight patients during the nighttime test. Counterregulatory hormone concentrations were consistent with the results of plasma glucose, with no change during the nocturnal test and significant increases in cortisol, GH, and epinephrine during the daytime test. These results show that insulin sensitivity is decreased at night in comparison to midafternoon in healthy subjects and that in insulin-dependent diabetes mellitus patients this phenomenon is exaggerated, even in patients with defective counterregulation to hypoglycemia.
In humans, sex steroid-binding protein (SBP) is a protein from the liver which binds with high affinity sex steroid hormones. The plasma concentration of SBP is regulated in part by hormonal factors. It has been shown that estrogens and/or thyroid hormones increase the production of SBP by hepatoma cell lines. It is therefore assumed that the increase in SBP levels in patients given oral estrogens or thyroid hormones is the consequence of a direct stimulation of the liver production of SBP by these hormones. The effects of androgen, progestagen and glucocorticoid hormones are unclear or still a matter of controversy. Moreover, the regulation of the metabolic clearance rate of SBP and the influence of nonhormonal factors on the production of SBP are still speculative. Changes in SBP have been described in a few nonendocrine diseases. A slight hormonal dysfunction may be either the primary or the sole cause of the changes in SBP occurring in these diseases. As an example, elevated SBP levels have been reported in men with liver cirrhosis together with testicular hypofunction and increased estrogen levels. It is therefore difficult to demonstrate that the increase in SBP is due to the liver dysfunction rather than to the endocrinological side effects of cirrhosis. The aim of this review is to present some aspects of the nonhormonal regulation of SBP. There is accumulating evidence in the literature for a relation between SBP levels and body weight and fat distribution, energy balance, diet and physical activity, and lipid metabolism. Therefore, it is tempting to propose that SBP is an index which reflects the status of endocrine, metabolic and nutritional functions. Measurement of SBP may be considered of interest in the light of previous epidemiological studies and the preventive approach to diseases such as hormone dependent tumors, cardiovascular diseases and osteoporosis.
