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Aims/hypothesisPancreatic beta cells secrete insulin to control glucose homeostasis. Beta cells can also adapt their function and mass when more insulin is required, especially in situations of insulin resistance (IR). Beta-cell mass adaptation can be achieved through either beta-cell proliferation or beta-cell neogenesis, a process that involves de novo beta-cell production from precursor cells. Signals and mechanisms that control adult beta-cell neogenesis and regulate the balance between beta-cell proliferation and/or beta-cell neogenesis still need to be fully deciphered. To do so, we previously developed a mouse model of pancreatic adaptation in response to a severe insulin resistance induced by a chronic glucocorticoid (GC) treatment. We observed a massive insulin production due to beta-cell adaptation by both proliferation and neogenesis. In the present study, we aimed at further characterizing beta-cell adaptation in response to mild or severe IR by studying various GC doses, along with other pharmacological or genetic models of IR. Further, we characterized the impact of aging on pancreatic adaptation in response to GC-induced IR. Finally, we precisely quantified adult beta-cell neogenesis by developing an original 3D method of beta-cell mass analysis in toto after organ clearing.MethodsGlucose metabolism, insulin secretion and pancreatic beta-cell adaptation were studied in mice rendered IR either by adipose tissue specific invalidation of SEIPIN, by chronic treatment with the insulin receptor antagonist S961 or by chronic treatment with several doses of GC both in young and aged mice. Moreover, we developed and used an unbiased-3D analysis of beta cells on whole cleared pancreas.ResultsWe demonstrated that beta-cell neogenesis - reflected by an increase in islet density - is constantly observed in response to genetically- or pharmacology-induced (S961 or GC) IR. Next, we observed that pancreatic adaptation mechanisms are closely defined by the level of IR. Indeed, mild IR induced by low dose of GC resulted in functional adaptation solely, while more severe IR induced by higher doses of GC resulted in an increase in both islet density and mean islet size, reflecting beta-cell neogenesis and proliferation, respectively. Then, we showed that in older mice, beta-cell adaptation through neogenesis is preserved in response to IR. Finally, using a new and unbiased 3D analysis, we confirmed the increase in islet density and mean islet size after GC’s treatment.Conclusions/interpretationOur results present evidence that beta-cell neogenesis is a preferential mechanism of pancreatic adaptation to increase insulin secretion in response to IR in mice. Moreover, aging does not preclude beta-cell neogenesis, suggesting that it could be triggered in elderly to compensate for IR. Finally, our innovative technique of 3D analysis of whole pancreas confirms the existence of adult beta-cell neogenesis and offers a new avenue to study islet cells and pancreas adaptation.Research in contextWhat is already known about this subject?Insulin resistance can be compensated by improved insulin secretion and increased beta-cell mass.New beta cells can be formed in the pancreas of adult mice through the differentiation of precursors, a process known as neogenesis.We previously demonstrated that glucocorticoid (GC) -induced insulin resistance leads to enhanced beta-cell proliferation and neogenesis.What is the key question?Is adaptive beta-cell neogenesis specific to GC-induced insulin resistance and persists in old mice ?What are the new findings?Insulin resistance, either genetically- or drug-induced, is a key driver to induce adaptive beta-cell neogenesis in the mouse pancreas.Aging does not prevent the induction of beta-cell neogenesis in response to insulin resistance.Three-dimension analysis on cleared pancreas confirms beta-cell neogenesis in mouse models of GC-induced insulin resistance.How might this impact on clinical practice in the foreseeable future?The mouse model of adaptive beta-cell neogenesis will be helpful to define new therapeutic targets to induce the formation of new beta cells and treat diabetes.

Increased sugar consumption is a risk factor for features of the metabolic syndrome including obesity, hypertriglyceridemia, insulin resistance, diabetes, and nonalcoholic fatty liver disease. The gut epithelium, which plays a central role in dietary sugar digestion, absorption and metabolism has emerged a key actor of metabolic disorders. While the transcription factor ChREBP (Carbohydrate response element binding protein) has been established as a key player of the adaptive reprograming of cellular metabolism in various tissues upon glucose or fructose challenge, its specific contribution to the regulation of blood glucose upon dietary sugar intake was not previously addressed.We demonstrate here that ChREBP is abundantly expressed in the proximal gut epithelium, where carbohydrate digestion and absorption primarily occur and in particular L cells, which produce the glucoincretin GLP-1. The inducible deletion of ChREBP specifically in the mouse gut epithelium (ChΔGUT mice) resulted in the reduction of early glycemic excursion upon oral glucose load. Surprisingly, despite being associated with reduced GLP-1 production, loss of gut ChREBP activity significantly dampened glucose transepithelial flux, and thereby delayed glucose distribution to peripheral tissues. Among the underlying mechanisms, we unveil that ChΔGUT mice show an impaired expression of key intestinal hexose (glucose, galactose, fructose) transporters and metabolic enzymes as well as brush border dissacharidases. In agreement, intestinal ChREBP deficiency was accompanied by a precocious intolerance to both high-lactose and high-sucrose diets concomitant with mild galactose and severe fructose malabsorption syndromes.Altogether, our study demonstrates that, by transcriptionally orchestrating local digestion and absorption of dietary sugars, ChREBP activity in the mouse gut epithelium controls glucose appearance rate into systemic circulation and prevents against intolerance to mono- and disaccharides.

SUMMARYIn mammalian cells, gene expression is rhythmic and sensitive to various environmental and physiological stimuli. A circadian clock system helps to anticipate and synchronize gene expression with daily stimuli including cyclic light and food intake, which control the central and peripheral clock programs, respectively. Food intake also regulates insulin secretion. How much insulin contributes to the effect of feeding on the entrainment of the clock and rhythmic gene expression remains to be investigated.An important component of insulin action is mediated by changes in insulin receptor (IR)-dependent gene expression. In the liver, insulin at high levels controls the transcription of hundreds of genes involved in glucose homeostasis to promote energy storage while repressing the expression of gluconeogenic genes. In type 2 diabetes mellitus (T2DM), selective hepatic insulin resistance impairs the inhibition of hepatic glucose production while promoting lipid synthesis. This pathogenic process promoting hyperlipidemia as well as non-alcoholic fatty liver diseases.While several lines of evidence link such metabolic diseases to defective control of circadian homeostasis, the hypothesis that IR directly synchronizes the clock has not been studied in vivo. Here, we used conditional hepatocyte-restricted gene deletion to evaluate the role of IR in the regulation and oscillation of gene expression as well as in the programming of the circadian clock in adult mouse liver.