WITHDRAWN AS DUPLICATE: Non-invasive evaluation of GPR119 agonist effects on β-cell mass in diabetic male mice using 111In-exendin-4 SPECT/CT

The IGF-1 receptor has become a therapeutic target for the treatment of cancer. The efficacy of OSI-906 (linstinib), a dual inhibitor of IGF-1 receptor and insulin receptor, for solid cancers has been examined in clinical trials. The effects of OSI-906, however, on the blood glucose levels and pancreatic β-cell functions have not yet been reported. We investigated the impact of OSI-906 on glycemic control, insulin secretion, β-cell mass, and β-cell proliferation in male mice. Oral administration of OSI-906 worsened glucose tolerance in a dose-dependent manner in the wild-type mice. OSI-906 at a dose equivalent to the clinical daily dose (7.5 mg/kg) transiently evoked glucose intolerance and hyperinsulinemia. Insulin receptor substrate (IRS)-2-deficient mice and mice with diet-induced obesity, both models of peripheral insulin resistance, exhibited more severe glucose intolerance after OSI-906 administration than glucokinase-haploinsufficient mice, a model of impaired insulin secretion. Phloridzin improved the hyperglycemia induced by OSI-906 in mice. In vitro, OSI-906 showed no effect on insulin secretion from isolated islets. After daily administration of OSI-906 for a week to mice, the β-cell mass and β-cell proliferation rate were significantly increased. The insulin signals in the β-cells were apparently unaffected in those mice. Taken together, the results suggest that OSI-906 could exacerbate diabetes, especially in patients with insulin resistance. On the other hand, the results suggest that the β-cell mass may expand in response to chemotherapy with this drug.

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Non-invasive Beta-cell Imaging: Visualization, Quantification, and Beyond

Frontiers in Endocrinology ◽

10.3389/fendo.2021.714348 ◽

2021 ◽

Vol 12 ◽

Author(s):

Takaaki Murakami ◽

Hiroyuki Fujimoto ◽

Nobuya Inagaki

Keyword(s):

Diabetes Mellitus ◽

Cell Imaging ◽

Diabetes Management ◽

Single Photon ◽

Cell Mass ◽

Photon Emission ◽

Emission Computed Tomography ◽

Β Cell ◽

Non Invasive

Pancreatic beta (β)-cell dysfunction and reduced mass play a central role in the development and progression of diabetes mellitus. Conventional histological β-cell mass (BCM) analysis is invasive and limited to cross-sectional observations in a restricted sampling area. However, the non-invasive evaluation of BCM remains elusive, and practical in vivo and clinical techniques for β-cell-specific imaging are yet to be established. The lack of such techniques hampers a deeper understanding of the pathophysiological role of BCM in diabetes, the implementation of personalized BCM-based diabetes management, and the development of antidiabetic therapies targeting BCM preservation and restoration. Nuclear medical techniques have recently triggered a major leap in this field. In particular, radioisotope-labeled probes using exendin peptides that include glucagon-like peptide-1 receptor (GLP-1R) agonist and antagonist have been employed in positron emission tomography and single-photon emission computed tomography. These probes have demonstrated high specificity to β cells and provide clear images accurately showing uptake in the pancreas and transplanted islets in preclinical in vivo and clinical studies. One of these probes, 111indium-labeled exendin-4 derivative ([Lys12(111In-BnDTPA-Ahx)]exendin-4), has captured the longitudinal changes in BCM during the development and progression of diabetes and under antidiabetic therapies in various mouse models of type 1 and type 2 diabetes mellitus. GLP-1R-targeted imaging is therefore a promising tool for non-invasive BCM evaluation. This review focuses on recent advances in non-invasive in vivo β-cell imaging for BCM evaluation in the field of diabetes; in particular, the exendin-based GLP-1R-targeted nuclear medicine techniques.

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Beta-cell specific insulin resistance promotes glucose-stimulated insulin hypersecretion

10.1101/2020.10.15.338160 ◽

2020 ◽

Author(s):

Søs Skovsø ◽

Evgeniy Panzhinskiy ◽

Jelena Kolic ◽

Derek A. Dionne ◽

Xiao-Qing Dai ◽

...

Keyword(s):

Insulin Resistance ◽

Glucose Tolerance ◽

Cell Mass ◽

Whole Body ◽

Calcium Oscillation ◽

Male Mice ◽

Β Cells ◽

Β Cell ◽

Specific Insulin

AbstractInsulin receptor (Insr) protein can be found at higher levels in pancreatic β-cells than in most other cell types, but the consequences of β-cell insulin resistance remain enigmatic. Ins1cre allele was used to delete Insr specifically in β-cells of both female and male mice which were compared to Ins1cre-containing littermate controls at multiple ages and on multiple diets. RNA-seq of recombined β-cells revealed significant differences in multiple pathways previously implicated in insulin secretion and cellular fate, including rewired Ras and NFκB signaling. Male, but not female, βInsrKO mice had reduced oxygen consumption rate, while action potential and calcium oscillation frequencies were increased in Insr knockout β-cells from female, but not male mice. Female βInsrKO and βInsrHET mice exhibited elevated insulin release in perifusion experiments, during hyperglycemic clamps, and following i.p. glucose challenge. Deletion of Insr did not reduce β-cell mass up to 9 months of age, nor did it impair hyperglycemia-induced proliferation. Based on our data, we adapted a mathematical model to include β-cell insulin resistance, which predicted that β-cell Insr knockout would improve glucose tolerance depending on the degree of whole-body insulin resistance. Indeed, glucose tolerance was significantly improved in female βInsrKO and βInsrHET mice when compared to controls at 9, 21 and 39 weeks. We did not observe improved glucose tolerance in adult male mice or in high fat diet-fed mice, corroborating the prediction that global insulin resistance obscures the effects of β-cell specific insulin resistance. We further validated our in vivo findings using the Ins1-CreERT transgenic line and found improved glucose tolerance 4 weeks after tamoxifen-mediated Insr deletion. Collectively, our data show that loss of β-cell Insr alone is sufficient to drive glucose-induced hyperinsulinemia, thereby improving glucose homeostasis in otherwise insulin sensitive dietary and age contexts.

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Incretin Therapies Do Not Expand β-Cell Mass or Alter Pancreatic Histology in Young Male Mice

Endocrinology ◽

10.1210/en.2017-00027 ◽

2017 ◽

Vol 158 (6) ◽

pp. 1701-1714 ◽

Cited By ~ 11

Author(s):

Aaron R. Cox ◽

Carol J. Lam ◽

Matthew M. Rankin ◽

Jacqueline S. Rios ◽

Julia Chavez ◽

...

Keyword(s):

Cell Mass ◽

Young Male ◽

Male Mice ◽

Β Cell ◽

Incretin Therapies

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Long-lived crowded-litter mice exhibit lasting effects on insulin sensitivity and energy homeostasis

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00031.2014 ◽

2014 ◽

Vol 306 (11) ◽

pp. E1305-E1314 ◽

Cited By ~ 23

Author(s):

Marianna Sadagurski ◽

Taylor Landeryou ◽

Manuel Blandino-Rosano ◽

Gillian Cady ◽

Lynda Elghazi ◽

...

Keyword(s):

Insulin Sensitivity ◽

Early Life ◽

Energy Homeostasis ◽

Cell Mass ◽

Adult Life ◽

Postnatal Growth ◽

Male Mice ◽

Β Cell ◽

Female Mice ◽

The Impact

The action of nutrients on early postnatal growth can influence mammalian aging and longevity. Recent work has demonstrated that limiting nutrient availability in the first 3 wk of life [by increasing the number of pups in the crowded-litter (CL) model] leads to extension of mean and maximal lifespan in genetically normal mice. In this study, we aimed to characterize the impact of early-life nutrient intervention on glucose metabolism and energy homeostasis in CL mice. In our study, we used mice from litters supplemented to 12 or 15 pups and compared those to control litters limited to eight pups. At weaning and then throughout adult life, CL mice are significantly leaner and consume more oxygen relative to control mice. At 6 mo of age, CL mice had low fasting leptin concentrations, and low-dose leptin injections reduced body weight and food intake more in CL female mice than in controls. At 22 mo, CL female mice also have smaller adipocytes compared with controls. Glucose and insulin tolerance tests show an increase in insulin sensitivity in 6 mo old CL male mice, and females become more insulin sensitive later in life. Furthermore, β-cell mass was significantly reduced in the CL male mice and was associated with reduction in β-cell proliferation rate in these mice. Together, these data show that early-life nutrient intervention has a significant lifelong effect on metabolic characteristics that may contribute to the increased lifespan of CL mice.

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