Dataset Information

Spontaneous restoration of functional ?-cell mass in obese SM/J mice.

ABSTRACT: Maintenance of functional ?-cell mass is critical to preventing diabetes, but the physiological mechanisms that cause ?-cell populations to thrive or fail in the context of obesity are unknown. High fat-fed SM/J mice spontaneously transition from hyperglycemic-obese to normoglycemic-obese with age, providing a unique opportunity to study ?-cell adaptation. Here, we characterize insulin homeostasis, islet morphology, and ?-cell function during SM/J's diabetic remission. As they resolve hyperglycemia, obese SM/J mice dramatically increase circulating and pancreatic insulin levels while improving insulin sensitivity. Immunostaining of pancreatic sections reveals that obese SM/J mice selectively increase ?-cell mass but not ?-cell mass. Obese SM/J mice do not show elevated ?-cell mitotic index, but rather elevated ?-cell mitotic index. Functional assessment of isolated islets reveals that obese SM/J mice increase glucose-stimulated insulin secretion, decrease basal insulin secretion, and increase islet insulin content. These results establish that ?-cell mass expansion and improved ?-cell function underlie the resolution of hyperglycemia, indicating that obese SM/J mice are a valuable tool for exploring how functional ?-cell mass can be recovered in the context of obesity.

SUBMITTER: Miranda MA

PROVIDER: S-EPMC7592878 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Spontaneous restoration of functional β-cell mass in obese SM/J mice.

Miranda Mario A MA Carson Caryn C St Pierre Celine L CL Macias-Velasco Juan F JF Hughes Jing W JW Kunzmann Marcus M Schmidt Heather H Wayhart Jessica P JP Lawson Heather A HA

Physiological reports 20201001 20

Maintenance of functional β-cell mass is critical to preventing diabetes, but the physiological mechanisms that cause β-cell populations to thrive or fail in the context of obesity are unknown. High fat-fed SM/J mice spontaneously transition from hyperglycemic-obese to normoglycemic-obese with age, providing a unique opportunity to study β-cell adaptation. Here, we characterize insulin homeostasis, islet morphology, and β-cell function during SM/J's diabetic remission. As they resolve hyperglyce ...[more]

PMID: 33113267

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Project description:One week of treatment with EGF and gastrin (EGF/G) was shown to restore normoglycemia and to induce islet regeneration in mice treated with the diabetogenic agent alloxan. The mechanisms underlying this regeneration are not fully understood. We performed genetic lineage tracing experiments to evaluate the contribution of beta cell neogenesis in this model. One day after alloxan administration, mice received EGF/G treatment for one week. The treatment could not prevent the initial alloxan-induced beta cell mass destruction, however it did reverse glycemia to control levels within one day, suggesting improved peripheral glucose uptake. In vitro experiments with C2C12 cell line showed that EGF could stimulate glucose uptake with an efficacy comparable to that of insulin. Subsequently, EGF/G treatment stimulated a 3-fold increase in beta cell mass, which was partially driven by neogenesis and beta cell proliferation as assessed by beta cell lineage tracing and BrdU-labeling experiments, respectively. Acinar cell lineage tracing failed to show an important contribution of acinar cells to the newly formed beta cells. No appearance of transitional cells co-expressing insulin and glucagon, a hallmark for alpha-to-beta cell conversion, was found, suggesting that alpha cells did not significantly contribute to the regeneration. An important fraction of the beta cells significantly lost insulin positivity after alloxan administration, which was restored to normal after one week of EGF/G treatment. Alloxan-only mice showed more pronounced beta cell neogenesis and proliferation, even though beta cell mass remained significantly depleted, suggesting ongoing beta cell death in that group. After one week, macrophage infiltration was significantly reduced in EGF/G-treated group compared to the alloxan-only group. Our results suggest that EGF/G-induced beta cell regeneration in alloxan-diabetic mice is driven by beta cell neogenesis, proliferation and recovery of insulin. The glucose-lowering effect of the treatment might play an important role in the regeneration process.

Dataset Information

Spontaneous restoration of functional ?-cell mass in obese SM/J mice.

Publications

Spontaneous restoration of functional β-cell mass in obese SM/J mice.

Similar Datasets

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