Regulation of the insulin-like growth factor system by acute acidosis.

Abstract

Many catabolic conditions are characterized by disturbances in acid-base balance and concomitant alterations in the insulin-like growth factor (IGF) system. However, the influence of acidosis per se on the various components of the IGF system has not been extensively examined. The purpose of the present study was to determine the effect of acute metabolic acidosis on the plasma and tissue concentrations of IGF-I and the various IGF-binding proteins (IGFBPs). Conscious unrestrained fasted rats were infused iv with either 0.2 N HCl or an equal volume of saline for 4 h. The arterial blood pH decreased within 60 min after starting the HCl infusion and remained lower than time-matched control values for the entire experimental protocol. Although the plasma IGF-I concentration fell gradually and was reduced by 30%, compared to time-matched control values, GH levels were unaltered. The IGF-I content of tissues collected at the conclusion of the experiment was increased in liver (35%) and kidney (63%), and unchanged in skeletal muscle. However, whereas acidosis moderately increased IGF-I messenger RNA abundance in liver, no significant alteration in IGF-I expression was detected in kidney. Acidosis also increased the plasma levels of IGFBP-1 and -2 as well as the IGFBP-1 content of liver and kidney. In contrast, the concentration of intact IGFBP-3 was decreased in acid-infused rats, and this reduction was associated with an increased rate of IGFBP-3 protease activity. Acidotic rats demonstrated unremarkable changes in the plasma concentrations of glucose and insulin, but corticosterone levels were elevated throughout the experiment. The results of the present study demonstrate that in the absence of underlying pathology, acute metabolic acidosis decreases circulating levels of IGF-I, probably by increasing renal clearance of the peptide, not by decreasing hepatic IGF-I synthesis.

Effect of IL-6 on IGF Binding Protein-3: A Study in IL-6 Transgenic Mice and in Patients with Systemic Juvenile Idiopathic Arthritis

“…In addition, we report that NSE/hIL-6 mice show shortened plasma IGF-I half-life and accelerated IGF-I clearance. The latter observation is in agreement with studies in animals showing that conditions with low levels of IGFBP-3 are associated with a marked decrease in IGF-I half-life and accelerated clearance leading to low IGF-I levels even in the presence of normal liver IGF-I production (24,44). Further supporting a direct relationship of IGFBP-3 levels with IGF-I, we found that IGFBP-3 levels were directly correlated with IGF-I levels both in NSE/hIL-6 mice and in patients with s-JIA.…”

Alcohol Withdrawal–Induced Change in Lipoprotein(a)

“…35 High NADH/NAD ratio is also characteristic for metabolic acidosis, a condition shown to increase plasma levels of IGFBP-1 and the IGFBP-1 content in the rat liver. 36 Theoretically, normalization of the redox state after alcohol withdrawal might have contributed to the observed reduction in IGFBP-1 levels. It is also possible that the removal of the hepatotoxic agent, ie, alcohol, allows the liver to resume its normal synthetic function and thus normalize IGFBP-1 and Lp(a) production.…”

Chronic Kidney Disease Causes Defects in Signaling through the Insulin Receptor Substrate/Phosphatidylinositol 3-Kinase/Akt Pathway

“…It seems unlikely, however, that low levels of insulin/IGF-1 are the sole cause of the signaling abnormalities that we identified. Uremia and acidosis typically have been associated with normal or high insulin levels (2,14,26,(31)(32)(33)(34). Moreover, it is unclear how low values of insulin/IGF-1 would raise the muscle levels of the IRS-2 and PI3-K p85 subunit or increase basal IRS-2-associated PI3-K activity.…”