Diabetes mellitus exacerbates citrin deficiency via glucose toxicity. (June 2020)

• Record Type: Journal Article
• Authors: Watanabe, Yoriko; Numakura, Chikahiko; Tahara, Toshiyuki; Fukui, Kaori; Torimura, Takuji; Hiromatsu, Yuji; Tomotsune, Ken; Yamakawa, Mitsunori; Hayasaka, Kiyoshi
• Is Part Of: Diabetes research and clinical practice. Volume 164(2020)
• Publication Date: 2020-06
• Subjects: Citrin deficiency -- Adult-onset type II citrullinemia (CTLN2) -- Glucose toxicity -- Diabetes mellitus; MCT medium-chain triglycerides -- AST aspartate aminotransferase -- ALT. alanine aminotransferase -- ALP alkaline phosphatase -- γ-GTP gamma-glutamyltranspeptidase -- ChE cholinesterase -- TG triglycerides.; Diabetes -- Periodicals; Diabetes Mellitus -- Periodicals; 616.462
• DOI: 10.1016/j.diabres.2020.108159
• Languages: English
• ISSNs: 0168-8227

Abstract

Abstract: Aims: Citrin is an aspartate/glutamate carrier that composes the malate-aspartate reduced nicotinamide adenine dinucleotide (NADH) shuttle in the liver. Citrin deficiency causes neonatal intrahepatic cholestasis (NICCD), failure to thrive and dyslipidemia (FTTDCD) and adult–onset type II citrullinemia (CTLN2). Hepatic glycolysis is essentially impaired in citrin deficiency and a low-carbohydrate diet was recommended. The lethal effect of infusion of glycerol- and fructose-containing osmotic agents was reported in these patients. Hyperalimentation was also reported to exacerbate CTLN2; however, glucose toxicity was unclear in citrin deficiency. Methods: We studied two CTLN2 patients complicated with type 2 diabetes mellitus (DM), Case 1 presented with hyperammonemic encephalopathy accompanied with DM, while Case 2 presented with hyperammonemic encephalopathy relapse upon the onset of DM after several years' remission following supplementation with medium-chain triglycerides (MCT) and adherence to a low-carbohydrate diet. Results: Insulin therapy with MCT supplementation and a low-carbohydrate diet improved hyperammonemia and liver function in Case 1. Additional insulin therapy improved hyperammonemia in Case 2. Conclusion: Glucose is not toxic for citrin deficiency in normoglycemia because glucose uptake and metabolism by hepatocytes are limited in normoglycemia. However, glucose becomes toxic during persistent hyperglycemia and antidiabetic therapy is indispensable for CTLN2 patients with DM.