Abstract
Type 2 diabetes is a metabolic disorder associated with abnormal glucose homeostasis and is characterized by intrinsic defects in β-cell function and mass. Trimethylguanosine synthase 1 (TGS1) is an evolutionarily conserved enzyme that methylates small nuclear and nucleolar RNAs and that is involved in pre-mRNA splicing, transcription, and ribosome production. However, the role of TGS1 in β-cells and glucose homeostasis had not been explored. Here, we show that TGS1 is upregulated by insulin and upregulated in islets of Langerhans from mice exposed to a high-fat diet and in human β-cells from type 2 diabetes donors. Using mice with conditional (βTGS1KO) and inducible (MIP-CreERT-TGS1KO) TGS1 deletion, we determined that TGS1 regulates β-cell mass and function. Using unbiased approaches, we identified a link between TGS1 and endoplasmic reticulum stress and cell cycle arrest, as well as and how TGS1 regulates β-cell apoptosis. We also found that deletion of TGS1 results in an increase in the unfolded protein response by increasing XBP-1, ATF-4, and the phosphorylation of eIF2α, in addition to promoting several changes in cell cycle inhibitors and activators such as p27 and Cyclin D2. This study establishes TGS1 as a key player regulating β-cell mass and function. We propose that these observations can be used as a stepping-stone for the design of novel strategies focused on TGS1 as a therapeutic target for the treatment of diabetes.
Highlights
Type 2 diabetes (T2D) is a disease of epidemic proportions and a major public health problem with an estimated total cost of $673 billion [1]
We demonstrated that Trimethylguanosine synthase 1 (TGS1) is upregulated in β-cells in mouse and human models of T2D
The importance of TGS1 was further assessed in mice with constitutive and inducible inactivation of this gene in β-cells. These experiments showed that TGS1 inactivation in mouse β-cells results in hyperglycemia and glucose intolerance as a result of a reduction in β-cells mass
Summary
Type 2 diabetes (T2D) is a disease of epidemic proportions and a major public health problem with an estimated total cost of $673 billion [1]. TGS1 was elevated in cultured myoblasts stimulated with insulin and TGS1 overexpression in rat skeletal muscle and cultured myoblasts inhibited insulin-stimulated glucose uptake, further supporting the role of TGS1 in regulating insulin sensitivity [10]. These findings pointed towards an important role for TGS1 in regulating hepatic gluconeogenesis, insulin resistance and glucose homeostasis. Using mice with conditional TGS1 deletion in β-cells (βTGS1KO), the current studies show that TGS1 deficiency results in decreased β-cell function and mass due to increased ER stress, apoptosis, and cell cycle arrest. The current data demonstrate the importance of TGS1 levels in β-cells and suggest that controlling TGS1 levels could be a novel therapeutic target to control glucose levels in T2D
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