Diabetes is associated with beta cell mass loss and islet dysfunctions. mTORC1 regulates beta cell survival, proliferation and function in physiological and pathological conditions, such as pregnancy and pancreatectomy. Here we show that deletion of Raptor, which is an essential component of mTORC1, in insulin-expressing cells promotes hypoinsulinemia and glucose intolerance. Raptor-deficient beta cells display reduced glucose responsiveness and exhibit a glucose metabolic profile resembling fetal beta cells. Knockout islets have decreased expression of key factors of functional maturation and upregulation of neonatal markers and beta cell disallowed genes, resulting in loss of functional maturity. Mechanistically, Raptor-deficient beta cells show reduced expression of DNA-methyltransferase 3a and altered patterns of DNA methylation at loci that are involved in the repression of disallowed genes. The present findings highlight a novel role of mTORC1 as a core mechanism governing postnatal beta cell maturation and physiologic beta cell mass during adulthood.

Background The results of previous studies on the usefulness of free triiodothyronine (FT3) to free thyroxine (FT4) are controversial. We investigated the usefulness of FT3, FT4, and FT3/FT4 ratio in differentiating Graves' disease (GD) from destructive thyroiditis. Methods A total of 126 patients with untreated GD, 36 with painless thyroiditis, 18 with painful subacute thyroiditis, and 63 healthy controls, were recruited. The levels of FT3 and FT4 and the FT3/FT4 ratios for the different etiologies of thyrotoxicosis were evaluated separately by receiver operating characteristic (ROC) curve analysis. The expression levels of type 1 and type 2 deiodinase (DIO1 and DIO2) in thyroid tissues were also investigated. Results The optimal cut-off values were 7.215 pmol/L for FT3, 21.71 pmol/L for FT4, and 0.4056 for the FT3/FT4 ratio. The specificity and positive predictive value of the FT3/FT4 ratio were highest for values > 0.4056. DIO1 mRNA expression was significantly higher in the thyroid tissue of patients with GD (P = 0.013). Conclusions We demonstrated that the FT3/FT4 ratio was useful in differentiating GD from destructive thyroiditis. In addition, a relatively high expression of type 1 deiodinase in the thyroid might be responsible for the high FT3/FT4 ratio in patients with GD.

Compromised β-cell identity is emerging as an important contributor to β-cell failure in diabetes; however, the precise mechanism independent of hyperglycemia is under investigation. We have previously reported that mTORC1/Raptor regulates functional maturation in β-cells. In the present study, we find that diabetic β-cell specific Raptor-deficient mice (βRapKOGFP) show reduced β-cell mass, loss of β-cell identity and acquisition of α-cell features; which are not reversible upon glucose normalization. Deletion of Raptor directly impairs β-cell identity, mitochondrial metabolic coupling and protein synthetic activity, leading to β-cell failure. Moreover, loss of Raptor activates α-cell transcription factor MafB (via modulating C/EBPβ isoform ratio) and several α-cell enriched genes i.e. Etv1 and Tspan12, thus initiates β- to α-cell reprograming. The present findings highlight mTORC1 as a metabolic rheostat for stabilizing β-cell identity and repressing α-cell program at normoglycemic level, which might present therapeutic opportunities for treatment of diabetes.

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