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Supplement: Trans-HHS Workshop: Diet, DNA Methylation Processes and Health

Abnormal Methyl Metabolism in Pancreatic Toxicity and Diabetes¹

Department of Pathology, Dartmouth Medical School, Lebanon, NH 03756

²To whom correspondence should be addressed. E-mail: daniel.s.longnecker{at}dartmouth.edu.

Several experimental studies suggest that disturbed methylation can influence cellular differentiation in the pancreas and contribute to toxic injury in ways that enhance the pathogenesis of pancreatitis and carcinogenesis. In vitro development of fetal rat pancreas requires a basal level of methionine, but full differentiation requires a higher methionine level. Involvement of methylation in normal differentiation is supported by reports of development of hepatocyte-like cells in the pancreas of rats fed a choline-deficient diet. The administration of ethionine by feeding to mice in a choline-sufficient diet caused a lower incidence of acute hemorrhagic pancreatitis than in mice given a choline-deficient diet. Feeding or injections of ethionine in choline-sufficient diets induces low grade pancreatitis and pancreatic atrophy in rats. In the N-nitrosobis(2-oxopropyl)amine-induced model of ductal adenocarcinoma in hamsters, the latent period for induction of carcinomas has been dramatically reduced by the intermittent feeding of a choline-deficient diet combined with ethionine treatment. A recent epidemiologic study in smokers indicates that the risk of pancreatic carcinoma is inverse to serum levels of folate. These studies suggest that compromised methyl metabolism might be associated with pancreatic cancer risk in humans. Finally, it has recently been demonstrated that serum homocysteine and erythrocyte S-adenosylhomocysteine levels are elevated, and erythrocyte S-adenosylmethionine content is reduced in patients with diabetes mellitus and renal failure, likely reflecting disturbed methylation pathways. The latter may contribute to the pathogenesis of complicating lesions in diabetes. These studies suggest that disturbed methyl metabolism may contribute to the pathogenesis of several pancreatic diseases.

KEY WORDS: • hypomethylation • choline deficiency • pancreatitis • pancreatic carcinogenesis

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