To act fast or to bide time? Adaptive exploration under competitive pressure

Competitive pressure affects a wide spectrum of decisions under uncertainty. It forces the individual to balance the value of gathering more information about the quality of potential choice alternatives against the risk that competitors will act first and claim the best options. Although this tradeoff between competition and exploration has long been recognized, little is known about how people adapt their exploration of uncertain options when facing competitive pressure. We examined how competitive pressure affects exploration in the “rivals-in-the-dark” game. Two players simultaneously learn about a set of choice options and compete to claim the best one. Across three studies, we show that people adapt their exploration in response to the structure of the choice environment (including the option set size and the relative number of gains and losses) and in response to repeated competition with the same opponent. Furthermore, we present a model-based analysis showing that their behavior is best described by a compensatory strategy under which the value of further exploration is weighed against the cost of being beaten to the punch by an opponent. The results point to a process of local adaptation whereby people learn to “act fast” based on their experience in a novel competitive environment

Aging-Dependent Demethylation of Regulatory Elements Correlates with Chromatin State and Improved β Cell Function

SummaryAging is driven by changes of the epigenetic state that are only partially understood. We performed a comprehensive epigenomic analysis of the pancreatic β cell, key player in glucose homeostasis, in adolescent and very old mice. We observe a global methylation drift resulting in an overall more leveled methylome in old β cells. Importantly, we discover targeted changes in the methylation status of β cell proliferation and function genes that go against the global methylation drift, are specific to β cells, and correlate with repression of the proliferation program and activation of metabolic regulators. These targeted alterations are associated with specific chromatin marks and transcription factor occupancy in young β cells. Strikingly, we find β cell function improved in aged mice, as predicted by the changes in methylome and transcriptome. Thus, aging of terminally differentiated cells in mammals is not always coupled to functional decline

Hyperglucagonaemia in diabetes: altered amino acid metabolism triggers mTORC1 activation, which drives glucagon production

Hyperglycaemia is associated with alpha cell dysfunction, leading to dysregulated glucagon secretion in type 1 and type 2 diabetes; however, the mechanisms involved are still elusive. The nutrient sensor mammalian target of rapamycin complex 1 (mTORC1) plays a major role in the maintenance of alpha cell mass and function. We studied the regulation of alpha cell mTORC1 by nutrients and its role in the development of hyperglucagonaemia in diabetes. Alpha cell mTORC1 activity was assessed by immunostaining for phosphorylation of its downstream target, the ribosomal protein S6, and glucagon, followed by confocal microscopy on pancreatic sections and flow cytometry on dispersed human and mouse islets and the alpha cell line, αTC1-6. Metabolomics and metabolic flux were studied by C glucose labelling in 2.8 or 16.7 mmol/l glucose followed by LC-MS analysis. To study the role of mTORC1 in mediating hyperglucagonaemia in diabetes, we generated an inducible alpha cell-specific Rptor knockout in the Akita mouse model of diabetes and tested the effects on glucose tolerance by IPGTT and on glucagon secretion. mTORC1 activity was increased in alpha cells from diabetic Akita mice in parallel to the development of hyperglycaemia and hyperglucagonaemia (two- to eightfold increase). Acute exposure of mouse and human islets to amino acids stimulated alpha cell mTORC1 (3.5-fold increase), whereas high glucose concentrations inhibited mTORC1 (1.4-fold decrease). The mTORC1 response to glucose was abolished in human and mouse diabetic alpha cells following prolonged islet exposure to high glucose levels, resulting in sustained activation of mTORC1, along with increased glucagon secretion. Metabolomics and metabolic flux analysis showed that exposure to high glucose levels enhanced glycolysis, glucose oxidation and the synthesis of glucose-derived amino acids. In addition, chronic exposure to high glucose levels increased the expression of Slc7a2 and Slc38a4, which encode amino acid transporters, as well as the levels of branched-chain amino acids and methionine cycle metabolites (~1.3-fold increase for both). Finally, conditional Rptor knockout in alpha cells from adult diabetic mice inhibited mTORC1, thereby inhibiting glucagon secretion (~sixfold decrease) and improving diabetes, despite persistent insulin deficiency. Alpha cell exposure to hyperglycaemia enhances amino acid synthesis and transport, resulting in sustained activation of mTORC1, thereby increasing glucagon secretion. mTORC1 therefore plays a major role in mediating alpha cell dysfunction in diabetes. All sequencing data are available from the Gene Expression Omnibus (GEO) repository (accession no. GSE154126; https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE154126 )