An imbalance of glucagon and insulin actions in type 2 diabetes (T2D) results in the dysregulation of glucose and lipid metabolism and metabolic stress throughout the body. Integrating gene expression data in multiple models of T2D and metabolic syndromes, we have identified a novel gene pair, that share the same bidirectional promoter, are coordinately upregulated by glucagon and downregulated by insulin in the liver in a variety of physiological and pathophysiological states. This gene pair consists of the long non-coding (lnc) RNA Gm15663 and the protein coding gene Tmtc2, an important regulator of endoplasmic reticulum (ER) Ca2+ flux. Gm15663/Tmtc2 are also upregulated when glucagon predominates insulin, such as during fasting, after high-fat or western diet and in ob/ob mice. Conversely, Gm15663/Tmtc2 are downregulated during feeding, when insulin predominates glucagon. This transcriptional regulation is mediated in part by the transcription factor Foxo1. Foxo1 binds with two promoter-distal enhancers, creating a spatial chromatin looping interaction with Gm15663/Tmtc2 promoter, which is involved in transcriptional regulation of this gene pair. Knockdown of Tmtc2 in hepatocytes results in a higher cytosolic Ca2+ level and lower ER Ca2+ level. This renders the cell more sensitive to both metabolic and ER stress, and impairs cell respiration, which is in part mediated by the increased cytosolic Ca2+ level and the activation of CaM kinase II (CamKII). In a unique mechanism, Gm15663 and Tmtc2 also cis-regulate the transcription of each other to maintain the homeostasis of their own expression levels. Thus, Gm15663/Tmtc2 gene pair are dynamically regulated by glucagon and insulin and serve as novel regulators of cell sensitivity to metabolic stress. This gene pair is also linked to a common subtype of T2D in GWAS studies, making them potential targets to treat or modify the development of T2D in these individuals.
X.Liu: None. C.Kahn: None.
