Evaluation of d,l-ethionine as a mechanism for pancreatic islet regeneration in dogs.
OBJECTIVE
To determine whether induction of pancreatic necrosis and islet proliferation by d,l-ethionine has potential for treating dogs with beta-cell insufficiency.


METHODS
Eighteen mixed breed dogs of both sexes were given d,l-ethionine at 100 mg/kg three times weekly for 2 weeks; 6 dogs were euthanased at 2, 14 and 28 d after the last dose.


METHODS
Clinical signs during administration and recovery were assessed. Routine biochemical analyses were performed before each ethionine dose and then once weekly. Faecal samples were examined weekly for malassimilated nutrients and blood. Blood coagulation screening tests (OSPT and APTT) were determined on four dogs after ethionine administration. Intravenous glucose tolerance tests were conducted before the first and after the last ethionine dose and then fortnightly. All dogs were necropsied and pancreas, liver, kidney and jejunum were examined microscopically.


RESULTS
During ethionine administration all animals displayed vomiting, inappetence, diarrhoea (often with blood), weight loss and depression. Three dogs were euthanased prematurely due to severe illness, but those allowed to recover were eating and brighter 7 d after cessation of ethionine administration. Serum concentrations of TLI, amylase and lipase increased initially, then decreased, during administration but retumed to normal during recovery. Concentrations of ALT, ALP, unconjugated and conjugated bilirubin increased during administration then decreased slowly. Histological examination revealed hepatic lipidosis and necrosis, but no renal or jejunal lesions. In most dogs, faecal examination demonstrated increased undigested starch and muscle, as well as increased digested and undigested fat, during ethionine administration or early during the recovery period, suggesting transient malassimilation. APTT was unchanged but OSPT was prolonged in all dogs. There was no impairment of insulin secretion or glucose intolerance and C-peptide concentrations were unaffected. Immediately after ethionine administration there was delayed insulin degradation and by day 43 there was evidence of increased insulin sensitivity.


CONCLUSIONS
d,l-ethionine administration in dogs appeared not to interfere with insulin secretion, but caused clinical signs and laboratory changes indicative of pancreatic exocrine necrosis, severe hepatobiliary disease and transient malassimilation. Pancreatic and hepatic dysfunction was severe but clinical recovery occurred after ethionine administration ceased. The severe side-effects observed with d,l-ethionine should preclude its potential use for treating diabetes mellitus in dogs.
Govendir
M
M
Faculty of Veterinary Science, The University of Sydney, New South Wales.
Canfield
P J
PJ
Emslie
D R
DR
Watson
A D J
AD
Church
D B
DB
D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000681:Amylases / Q000097:blood; D000818:Animals; D000963:Antimetabolites / Q000008:administration & dosage / Q000009:adverse effects*; D001663:Bilirubin / Q000097:blood; D001786:Blood Glucose; D002096:C-Peptide / Q000097:blood; D003404:Creatinine / Q000097:blood; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000662:veterinary*; D004283:Dog Diseases / Q000188:drug therapy*; D004285:Dogs; D005001:Ethionine / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D005951:Glucose Tolerance Test / Q000662:veterinary; D007275:Injections, Intravenous / Q000662:veterinary; D007328:Insulin / Q000097:blood; D007515:Islets of Langerhans / Q000187:drug effects; D007583:Jejunum / Q000473:pathology; D007668:Kidney / Q000473:pathology; D008049:Lipase / Q000097:blood; D008099:Liver / Q000473:pathology; D008111:Liver Function Tests / Q000662:veterinary; D008297:Male; D010179:Pancreas / Q000166:cytology / Q000187:drug effects; D014508:Urea / Q000097:blood
D000963:Antimetabolites; D001786:Blood Glucose; D002096:C-Peptide; D007328:Insulin; D014508:Urea; D003404:Creatinine; D000410:Alanine Transaminase; D008049:Lipase; D000469:Alkaline Phosphatase; D000681:Amylases; D001663:Bilirubin; D005001:Ethionine