Insulin resistance-driven beta-cell adaptation in mice: Mechanistic characterization and 3D analysis

Aims/hypothesis Pancreatic 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. Methods Glucose 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. Results We 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/interpretation Our 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 context What 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.