Adult rats prenatally exposed to ethanol have increased gluconeogenesis and impaired insulin response of hepatic gluconeogenic genes.
Rat offspring exposed to ethanol (EtOH rats) during pregnancy are insulin resistant, but it is unknown whether they have increased gluconeogenesis. To address this issue, we determined blood glucose and liver gluconeogenic genes, proteins, and enzyme activities before and after insulin administration in juvenile and adult EtOH rats and submitted adult EtOH rats to a pyruvate challenge. In juvenile rats, basal glucose; peroxisome proliferator-activated receptor-coactivator-1alpha protein and mRNA; and phosphoenolpyruvate carboxykinase enzyme activity, protein, and mRNA were similar between groups. After insulin injection, these parameters failed to decrease in EtOH rats, but glucose decreased by 30% and gluconeogenic enzymes, proteins, and mRNAs decreased by 50-70% in control rats. In adult offspring, basal peroxisome proliferator-activated receptor-coactivator-1alpha protein and mRNA levels were 40-80% higher in EtOH rats than in controls. Similarly, basal phosphoenolpyruvate carboxykinase activity, protein, and mRNA were approximately 1.8-fold greater in EtOH rats than in controls. These parameters decreased by approximately 50% after insulin injection in control rats, but they remained unchanged in EtOH rats. After insulin injection in the adult rats, glucose decreased by 60% in controls but did not decrease significantly in EtOH rats. A subset of adult EtOH rats had fasting hyperglycemia and an exaggerated glycemic response to pyruvate compared with controls. The data indicate that, after prenatal EtOH exposure, the expression of gluconeogenic genes is exaggerated in adult rat offspring and is insulin resistant in both juvenile and adult rats, explaining increased gluconeogenesis. These alterations persist through adulthood and may contribute to the pathogenesis of Type 2 diabetes after exposure to EtOH in utero.
Yao
Xing-Hai
XH
Diabetes Research Group, Univ. of Manitoba, 715 McDermot Ave. Rm. 834, Winnipeg, Manitoba, Canada R3E 3P4.
Chen
Li
L
Nyomba
B L Grégoire
BL
D000367:Age Factors; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D002492:Central Nervous System Depressants / Q000008:administration & dosage / Q000633:toxicity*; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology; D000431:Ethanol / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D005943:Gluconeogenesis; D018149:Glucose Intolerance / Q000097:blood / Q000201:enzymology / Q000209:etiology; D007328:Insulin / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D018811:Maternal Exposure; D008431:Maternal-Fetal Exchange; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D019289:Pyruvic Acid / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D001786:Blood Glucose; D002492:Central Nervous System Depressants; D007328:Insulin; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D000431:Ethanol; D019289:Pyruvic Acid; D010729:Phosphoenolpyruvate Carboxykinase (GTP)