Balancing glucose homeostasis is crucial to maintain appropriate energy and metabolic state. Chronic hyperglycemia with insulin resistance and development of type II diabetes mellitus is a growing health and health-economic threat. The unfolded protein response (UPR) is a mechanism by which the endoplasmic reticulum copes with diverse physiological and pathophysiological stress stimuli. Unresolved and chronic endoplasmic reticulum stress are important features in the development of diabetes mellitus. Understanding how the UPR impacts glucose balance and what disrupts this balance is critical for development of future therapies.
In pancreatic β-cells, evidence is growing that the single branches of the UPR work in concert to supply insulin in response to acute glucose availability. Chronic glucose stimulation disrupts these primarily adaptive changes into an overwhelming UPR, which leads to reduced insulin supply and β-cell mass due to apoptosis. In hepatocytes, the UPR interacts with key transcription factors to physiologically regulate glucose and lipid homeostasis. Prolonged endoplasmic reticulum stress disrupts these feedback loops and results in ongoing gluconeogenesis and steatosis.
Unraveling the molecular networks underlying the adaptive and contra-adaptive roles of the UPR in glucose metabolism will identify novel therapeutic approaches in the battle against diabetes mellitus.
aLaboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
bDepartment of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
Correspondence to David D. Moore, Department of Molecular and Cellular Biology, One Baylor Plaza, N610 Alkek Building, Baylor College of Medicine, Houston, Texas 77030, USA Tel: +1 713 798 3313; fax: +1 713 798 3017; e-mail: firstname.lastname@example.org