Generation and Characterization of a Novel Mouse Model That Allows Spatiotemporal Quantification of Pancreatic β-Cell Proliferation

Tokumoto, Shinsuke; Yabe, Daisuke; Tatsuoka, Hisato; Usui, Ryota; Fauzi, Muhammad; Botagarova, Ainur; Goto, Hisanori; Herrera, Pedro Luis; Ogura, Mariko; Inagaki, Nobuya

doi:10.2337/db20-0290

Cited by 10 publications

(10 citation statements)

References 15 publications

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“…We next investigated the proliferation rates of virgin and mature β-cells under challenged conditions, specifically, during pregnancy and in face of insulin resistance. These are conditions where mouse β-cells are known to expand via self-proliferation ( 26 , 27 ). We wanted to determine whether virgin β-cells would also increase their proliferation and contribute equally as mature β-cells during these challenged circumstances in order to meet the increased demand for insulin.…”

Section: Resultsmentioning

confidence: 99%

Virgin β-Cells at the Neogenic Niche Proliferate Normally and Mature Slowly

et al. 2021

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Proliferation of pancreatic b-cells has long been known to reach its peak in the neonatal stages and decline during adulthood. However, b-cell proliferation has been studied under the assumption that all b-cells constitute a single, homogenous population. It is unknown whether a subpopulation of b-cells retains the capacity to proliferate at a higher rate and thus contributes disproportionately to the maintenance of mature b-cell mass in adults. We therefore assessed the proliferative capacity and turnover potential of virgin b-cells, a novel population of immature b-cells found at the islet periphery. We demonstrate that virgin b-cells can proliferate but do so at rates similar to those of mature b-cells from the same islet under normal and challenged conditions. Virgin b-cell proliferation rates also conform to the agedependent decline previously reported for b-cells at large. We further show that virgin b-cells represent a long-lived, stable subpopulation of b-cells with low turnover into mature b-cells under healthy conditions. Our observations indicate that virgin b-cells at the islet periphery can divide but do not contribute disproportionately to the maintenance of adult b-cell mass. More than 30 million Americans currently have diabetes, which results from progressive b-cell loss caused by either autoimmune attack or lifestyle and genetic factors (1). Because b-cells are the only cells in the body capable of secreting insulin, a major therapeutic goal for diabetes has been to replace b-cells lost during disease. Islet or wholepancreas transplantation has had some success in achievement of insulin independence, but limited donor availability, immunological complications, and transplant survival make this process not a viable option for the majority of patients with diabetes (2). Thus, a great interest continues in strategies that promote the regeneration of b-cells from various cell sources (3,4). Despite these efforts, clinically meaningful restoration of b-cell mass has not yet been achieved, illustrating the ongoing need for strategies to regenerate b-cells. During late pancreas development, b-cell mass expands rapidly by self-replication of young b-cells. Seminal experiments by Dor et al. (5) established, by pulse-chase labeling of b-cells, that self-replication is the main mechanism to maintain b-cell mass-a conclusion that is noncontroversial (6,7). However, b-cell proliferation declines rapidly with age in mice (8-10), with even lower proliferation rates observed in human islets (11), which complicates the challenge of restoring b-cell mass secondary to diabetesassociated b-cell loss. Against this backdrop, numerous reports of insulin-positive multipotent precursors (12,13), transdifferentiation of aand d-cells to b-cells (14-16), transdifferentiation of exocrine cells to b-cells (17,18), and, most recently, the existence of a population of protein C receptor (ProCr)-positive islet-resident stem cells ( 19) continue to raise the prospect that alternative paths to generation of b-cells exist and coul...

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Section: Resultsmentioning

confidence: 99%

Virgin β-Cells at the Neogenic Niche Proliferate Normally and Mature Slowly

et al. 2021

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“…Pancreatic β-cell mass (BCM) plays an important role in the pathogenesis of type 2 diabetes ( 1 ); preservation and expansion of BCM in response to metabolic demands thus represents a key strategy for preventing and treating diabetes. Expansion of BCM is induced by obesity and several other conditions or interventions including pregnancy ( 2 – 4 ), partial pancreatectomy ( 5 ), and administration of insulin receptor antagonist S961 ( 6 ). Obese individuals without diabetes also exhibit increased BCM ( 7 ), and BCM positively correlates with body mass index in nondiabetic Caucasians ( 8 ).…”

Section: Introductionmentioning

confidence: 99%

Noninvasive Evaluation of GIP Effects on β-Cell Mass Under High-Fat Diet

et al. 2022

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Pancreatic β-cell mass (BCM) has an importance in the pathophysiology of diabetes mellitus. Recently, glucagon-like peptide-1 receptor (GLP-1R)-targeted imaging has emerged as a promising tool for BCM evaluation. While glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide (GIP) is known to be involved in high-fat diet (HFD)-induced obesity, the effect of GIP on BCM is still controversial. In this study, we investigated indium 111 (111In)-labeled exendin-4 derivative ([Lys12(111In-BnDTPA-Ahx)]exendin-4) single-photon emission computed tomography/computed tomography (SPECT/CT) as a tool for evaluation of longitudinal BCM changes in HFD-induced obese mice, at the same time we also investigated the effects of GIP on BCM in response to HFD using GIP-knockout (GIP-/-) mice. 111In-exendin-4 SPECT/CT was able to distinguish control-fat diet (CFD)-fed mice from HFD-fed mice and the pancreatic uptake values replicated the BCM measured by conventional histological methods. Furthermore, BCM expansions in HFD-fed mice were demonstrated by time-course changes of the pancreatic uptake values. Additionally, 111In-exendin-4 SPECT/CT demonstrated the distinct changes in BCM between HFD-fed GIP-/- (GIP-/-+HFD) and wild-type (WT+HFD) mice; the pancreatic uptake values of GIP-/-+HFD mice became significantly lower than those of WT+HFD mice. The different changes in the pancreatic uptake values between the two groups preceded those in fat accumulation and insulin resistance. Taken together with the finding of increased β-cell apoptosis in GIP-/-+HFD mice compared with WT+HFD mice, these data indicated that GIP has preferable effects on BCM under HFD. Therefore, 111In-exendin-4 SPECT/CT can be useful for evaluating increasing BCM and the role of GIP in BCM changes under HFD conditions.

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“…In C57BL6/J male mice, eight weeks of feeding a HFD increased the percentage of SA-β-Gal + cells in islets as well as expression of aging and SASP-related genes in islets ( 39 ). Similarly, administration of an insulin receptor antagonist S961 induced acute, severe insulin resistance in C57BL6/J mice ( 79 ), which was accompanied by increased SA-β-Gal + cells and increased mRNA levels of aging and SASP-related genes including p16 INK4a , p21 Cip1 , and Bambi in islets ( 39 , 70 ). Surprisingly, these changes under S961-induced insulin resistance are partially reversible.…”

Section: β Cell Senescence Under Metabolic Stressmentioning

confidence: 99%

Cellular Senescence in Diabetes Mellitus: Distinct Senotherapeutic Strategies for Adipose Tissue and Pancreatic β Cells

2022

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Increased insulin resistance and impaired insulin secretion are significant characteristics manifested by patients with type 2 diabetes mellitus (T2DM). The degree and extent of these two features in T2DM vary among races and individuals. Insulin resistance is accelerated by obesity and is accompanied by accumulation of dysfunctional adipose tissues. In addition, dysfunction of pancreatic β-cells impairs insulin secretion. T2DM is significantly affected by aging, as the β-cell mass diminishes with age. Moreover, both obesity and hyperglycemia-related metabolic changes in developing diabetes are associated with accumulation of senescent cells in multiple organs, that is, organismal aging. Cellular senescence is defined as a state of irreversible cell cycle arrest with concomitant functional decline. It is caused by telomere shortening or senescence-inducing stress. Senescent cells secrete proinflammatory cytokines and chemokines, which is designated as the senescence-associated secretory phenotype (SASP), and this has a negative impact on adipose tissues and pancreatic β-cells. Recent advances in aging research have suggested that senolysis, the removal of senescent cells, can be a promising therapeutic approach to prevent or improve aging-related diseases, including diabetes. The attenuation of a SASP may be beneficial, although the pathophysiological involvement of cellular senescence in diabetes is not fully understood. In the clinical application of senotherapy, tissue-context-dependent senescent cells are increasingly being recognized as an issue to be solved. Recent studies have observed highly heterogenic and complex senescent cell populations that serve distinct roles among tissues, various stages of disease, and different ages. For example, in high-fat-diet induced diabetes with obesity, mouse adipose tissues display accumulation of p21Cip1-highly-expressing (p21high) cells in the early stage, followed by increases in both p21high and p16INK4a-highly-expressing (p16high) cells in the late stage. Interestingly, elimination of p21high cells in visceral adipose tissue can prevent or improve insulin resistance in mice with obesity, while p16high cell clearance is less effective in alleviating insulin resistance. Importantly, in immune-deficient mice transplanted with fat from obese patients, dasatinib plus quercetin, a senolytic cocktail that reduces the number of both p21high and p16high cells, improves both glucose tolerance and insulin resistance. On the other hand, in pancreatic β cells, p16high cells become increasingly predominant with age and development of diabetes. Consistently, elimination of p16high cells in mice improves both glucose tolerance and glucose-induced insulin secretion. Moreover, a senolytic compound, the anti-Bcl-2 inhibitor ABT263 reduces p16INK4a expression in islets and restores glucose tolerance in mice when combined with insulin receptor antagonist S961 treatment. In addition, efficacy of senotherapy in targeting mouse pancreatic β cells has been validated not only in T2DM, but also in type 1 diabetes mellitus. Indeed, in non-obese diabetic mice, treatment with anti-Bcl-2 inhibitors, such as ABT199, eliminates senescent pancreatic β cells, resulting in prevention of diabetes mellitus. These findings clearly indicate that features of diabetes are partly determined by which or where senescent cells reside in vivo, as adipose tissues and pancreatic β cells are responsible for insulin resistance and insulin secretion, respectively. In this review, we summarize recent advances in understanding cellular senescence in adipose tissues and pancreatic β cells in diabetes. We review the different potential molecular targets and distinctive senotherapeutic strategies in adipose tissues and pancreatic β cells. We propose the novel concept of a dual-target tailored approach in senotherapy against diabetes.

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Generation and Characterization of a Novel Mouse Model That Allows Spatiotemporal Quantification of Pancreatic β-Cell Proliferation

Cited by 10 publications

References 15 publications

Virgin β-Cells at the Neogenic Niche Proliferate Normally and Mature Slowly

Virgin β-Cells at the Neogenic Niche Proliferate Normally and Mature Slowly

Noninvasive Evaluation of GIP Effects on β-Cell Mass Under High-Fat Diet

Cellular Senescence in Diabetes Mellitus: Distinct Senotherapeutic Strategies for Adipose Tissue and Pancreatic β Cells

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