Pancreatic βcells differentiate during fetal life, but only postnatally acquire the capacity for glucose-stimulated insulin secretion (GSIS). How this happens is not clear. In exploring what molecular mechanisms drive the maturation of βcell function, we found that the control of cellular signaling in βcells fundamentally switched from the nutrient sensor target of rapamycin (mTORC1) to the energy sensor 5'-adenosine monophosphate-activated protein kinase (AMPK), and that this was critical for functional maturation. Moreover, AMPK was activated by the dietary transition taking place during weaning, and this in turn inhibited mTORC1 activity to drive the adult βcell phenotype. While forcing constitutive mTORC1 signaling in adult βcells relegated them to a functionally immature phenotype with characteristic transcriptional and metabolic profiles, engineering the switch from mTORC1 to AMPK signaling was sufficient to promote βcell mitochondrial biogenesis, a shift to oxidative metabolism, and functional maturation. We also found that type 2 diabetes, a condition marked by both mitochondrial degeneration and dysregulated GSIS, was associated with a remarkable reversion of the normal AMPK-dependent adult βcell signature to a more neonatal one characterized by mTORC1 activation. Manipulating the way in which cellular nutrient signaling pathways regulate βcell metabolism may thus offer new targets to improve β cell function in diabetes.
Bibliographical noteFunding Information:
GAR was supported by a Wellcome Trust Senior Investigator (WT098424AIA) and Investigator Award (212625/Z/18/Z), by MRC Programme grants (MR/R022259/1, MR/J0003042/1, MR/L020149/1, and MR/R022259/1), an Experimental Challenge Grant (DIVA, MR/L02036X/1), and Project grants from the MRC (MR/N00275X/1), and Diabetes UK (BDA/11/0004210, BDA/15/0005275, and BDA 16/0005485). YD was supported by grants from the Human Islet Research Network (HIRN) and the DON foundation. This project was also supported by NIH/NIDDK grants, including DK108666 to MH, DK103175 and DK112304 to SKK, a Diabetes Research Center P30 grant (DK063720), and a Nutrition and Obesity Research Center P30 grant (DK098722).
© 2019, American Society for Clinical Investigation.