Institute of Development, Aging and Cancer, Tohoku University

Research

Seminars and Symposia

IDAC Seminar, 20 April 2015

Secretariat, Alumni Association, IDAC
Date Monday,20 April 2015, 17:00~
Room Seminar-shitsu 1, IDAC Research building 7F
Title Hyperglycemia leading to elevated fumarate links Type-2 diabetes and colorectal cancer
Speaker Patrick J. Pollard
Affiliation Oxford Centre For Diabetes, Endocrinology & Metabolism,
(OCDEM) University Of Oxford
Person-in-charge Hozumi Motohashi Department of Gene Expression Regulation(ext.8550)
Abstract The Krebs cycle enzyme fumarate hydratase (FH) catalyzes the hydration of fumarate to malate. FH is a tumor suppressor, mutated in hereditary leiomyomatosis and renal cell cancer (HLRCC). Loss of FH activity results in the intracellular accumulation of fumarate, the stabilization of hypoxia-inducible factor (HIF1α) and activation of HIF dependent pathways including glucose metabolism. The high levels of fumarate that accumulate in FH-deficient cells also effect the post-translational modification of cysteine residues in proteins to form S-(2-succinyl)-cysteine (2SC) via succination. We explored the role of the FH in glucose homeostasis. Mice lacking FH in β-cells (Fh1βKO) develop progressive diabetes, ameliorated by expression of cytosolic FH, and impaired glucose-induced insulin secretion (GIIS), the latter defect rescued in vitro by glutamate. Elevated fumarate in Fh1βKO islets elicited succination of the antioxidant protein Park7 and the glycolytic enzyme Gapdh. Furthermore, protein succination was markedly increased in renal tubular cells and adipocytes of Fh1βKO mice, and in human islets and colorectal cancers from patients with type-2 diabetes. Intriguingly, Fh1βKO islets displayed diabetes-like glucagon secretion abnormalities, which were recapitulated by exogenous fumarate or high-glucose exposure. Our studies underscore the importance of glutamate in GIIS and indicate that diabetes, via hyperglycemia and elevated fumarate, impairs α-cell function. They also raise the exciting possibility that hyperglycemia-induced intracellular accumulation of the oncometabolite fumarate links diabetes and co-morbidities including renal failure and colorectal cancer.