Discordant, organ-specific regulation of insulin-like growth factor-I messenger ribonucleic acid in insulin-deficient diabetes in rats.
Linear growth retardation is common in uncontrolled insulin-deficient diabetes, but individual organs such as kidney may hypertrophy. To explore whether this heterogeneity of response might be mediated by differential local insulin-like growth factor-I (IGF-I) gene regulation, we injected rats with ip saline, 65, 120, or 175 mg/kg streptozotocin (STZ). Diabetics were untreated or received daily insulin. Animals were killed 24, 48, or 72 h after documentation of diabetes, and liver, kidney, and lung messenger RNA (mRNA) content analyzed by solution hybridization/RNase protection assay. Untreated diabetics had 10- to 100-fold reductions in hepatic IGF-I mRNA apparent as early as 24 h, and the magnitude of these changes varied directly with the severity of diabetes. In contrast, kidney IGF-I mRNA content increased by 400-500% at 24 h in untreated diabetics given 175 mg/kg STZ, and by 100-200% at 48 h in those given 120 mg/kg STZ, with return to control levels by 72 h. Renal IGF-I mRNA levels actually decreased by 250-350% at 24 h in rats injected with 65 mg/kg STZ, returning to supranormal values by 72 h. These results suggest that severity and/or duration of the metabolic abnormality qualitatively and quantitatively affect this response in the kidney. Liver and kidney IGF-I mRNA levels approached normal with insulin therapy and were similar to controls in rats which received STZ but did not develop diabetes. Lung IGF-I mRNA levels were minimally altered in all experimental groups. At the time point and STZ dosage at which liver IGF-I mRNA changes were most dramatic, little change in liver alpha-tubulin mRNA was noted. At the time point and STZ dosages at which kidney IGF-I mRNA induction was most dramatic, renal IGF-I receptor mRNA was only minimally changed, and renal alpha-tubulin mRNA was modestly reduced. In summary: 1) hepatic IGF-I mRNAs are dramatically reduced, and renal IGF-I mRNAs are significantly increased soon after the onset of insulin-deficient diabetes in STZ-treated rats; 2) insulin therapy restores IGF-I mRNA levels toward normal; and 3) these changes in IGF-I mRNA content are specific and are not the result of hepatic or renal STZ toxicity. These data suggest that IGF-I gene expression is regulated in a discordant, organ-specific manner in diabetes, and that metabolic factors in addition to GH may differentially modulate the endocrine and paracrine effects of IGF-I on growth.
Catanese
V M
VM
Department of Medicine, New York University School of Medicine, New York 10016.
Sciavolino
P J
PJ
Lango
M N
MN
D000818:Animals; D016375:Antisense Elements (Genetics); D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D005215:Fasting; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis / Q000235:genetics*; D007668:Kidney / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008168:Lung / Q000378:metabolism*; D008297:Male; D009928:Organ Specificity; D015347:RNA Probes; D012333:RNA, Messenger / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014404:Tubulin / Q000235:genetics
D016375:Antisense Elements (Genetics); D015347:RNA Probes; D012333:RNA, Messenger; D014404:Tubulin; D007334:Insulin-Like Growth Factor I