title: Lethal hypoglycemia and hypothermia induced by administration of low doses of tumor necrosis factor to adrenalectomized rats.
abstract: An increased sensitivity of adrenalectomized (Adex) rats to intravenous (IV) injection of recombinant human tumor necrosis factor (rHuTNF) was manifested by a marked increase in the rate of mortality. The rats that died exhibited severe hypoglycemia and hypothermia. Administration of 2.5 or 10 micrograms/100 g body weight (3% or 12%) of the lethal dose in sham-operated rats (90 micrograms/100 g body weight) rHuTNF caused a mortality rate of 50% or 100%, respectively, within 4 hours of its injection. Pre-administration of dexamethasone or intermittent glucose infusion protected the animals from the lethal effect of rHuTNF. Indomethacin did not change the mortality rate in rHuTNF-treated Adex rats, but prevented it in sham-operated rats. The rats that died exhibited a marked decrease in body temperature, but only Adex rats developed hypoglycemia after low doses of TNF. Pretreatment with dexamethasone prevented the hypothermia in both Adex and sham-operated rats, while indomethacin was effective only in sham-operated rats and did not prevent the hypothermia or the hypoglycemia in Adex rats. In the surviving rHuTNF-treated Adex rats, a rapid increase in body temperature occurred, blood glucose decreased to 30 mg/dL, serum insulin concentration decreased to 6 microU/mL, liver glycogen content was reduced by 98%, and a significant reduction in liver phosphoeonolpyruvate carboxykinase (PEPCK) and liver microsomal glucose-6-phosphatase activities was observed. Repeated administration of glucose IV to rHuTNF-treated Adex rats caused an increase in blood glucose and insulin concentrations, and some repletion in liver glycogen content. Injection of rHuTNF, 2.5 to 10 micrograms/100 g body weight, to sham-operated rats caused a significant but slower increase in body temperature.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Internal Medicine, Hadassah University Hospital, Jerusalem, Israel.
authors.forename: T
authors.initials: T
authors.lastname: Chajek-Shaul
authors.forename: V
authors.initials: V
authors.lastname: Barash
authors.forename: J
authors.initials: J
authors.lastname: Weidenfeld
authors.forename: G
authors.initials: G
authors.lastname: Friedman
authors.forename: E
authors.initials: E
authors.lastname: Ziv
authors.forename: E
authors.initials: E
authors.lastname: Shohami
authors.forename: E
authors.initials: E
authors.lastname: Shiloni
mesh_terms: D000313:Adrenal Medulla / Q000502:physiology*; D000315:Adrenalectomy; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001833:Body Temperature Regulation / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D005947:Glucose / Q000008:administration & dosage / Q000378:metabolism; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D007003:Hypoglycemia / Q000139:chemically induced* / Q000378:metabolism / Q000401:mortality; D007035:Hypothermia / Q000139:chemically induced* / Q000378:metabolism / Q000401:mortality; D007213:Indomethacin / Q000494:pharmacology; D008071:Lipoprotein Lipase / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000008:administration & dosage; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage* / Q000633:toxicity
chemical_list: D001786:Blood Glucose; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D006003:Glycogen; D008071:Lipoprotein Lipase; D005952:Glucose-6-Phosphatase; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D005947:Glucose; D007213:Indomethacin