β-Cell adaptation in pregnancy

Maternal low-protein diets (LP) impair pancreatic β-cell development, resulting in later-life failure and susceptibility to type 2 diabetes (T2D). We hypothesized that intrauterine and/or postnatal developmental programming seen in this situation involve altered β-cell structure and relative time course of expression of genes critical to β-cell differentiation and growth. Pregnant Wistar rats were fed either control (C) 20% or restricted (R) 6% protein diets during pregnancy (1st letter) and/or lactation (2nd letter) in four groups: CC, RR, RC, and CR. At postnatal days 7 and 21, we measured male offspring β-cell fraction, mass, proliferation, aggregate number, and size as well as mRNA level for 13 key genes regulating β-cell development and function in isolated islets. Compared with CC, pre- and postnatal LP (RR) decreased β-cell fraction, mass, proliferation, aggregate size, and number and increased Hnf1a, Hnf4a, Pdx1, Isl1, Rfx6, and Slc2a2 mRNA levels. LP only in pregnancy (RC) also decreased β-cell fraction, mass, proliferation, aggregate size, and number and increased Hnf1a, Hnf4a, Pdx1, Rfx6, and Ins mRNA levels. Postnatal LP offspring (CR) showed decreased β-cell mass but increased β-cell fraction, aggregate number, and Hnf1a, Hnf4a, Rfx6, and Slc2a2 mRNA levels. We conclude that LP in pregnancy sets the trajectory of postnatal β-cell growth and differentiation, whereas LP in lactation has smaller effects. We propose that LP promotes differentiation through upregulation of transcription factors that stimulate differentiation at the expense of proliferation. This results in a decreased β-cell reserve, which can contribute to later-life predisposition to T2D.

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“Omics” and “epi-omics” underlying the β-cell adaptation to insulin resistance

Molecular Metabolism ◽

10.1016/j.molmet.2019.06.003 ◽

2019 ◽

Vol 27 ◽

pp. S42-S48 ◽

Cited By ~ 4

Author(s):

Dario F. De Jesus ◽

Rohit N. Kulkarni

Keyword(s):

Insulin Resistance ◽

Β Cell ◽

Cell Adaptation

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Lamin C Counteracts Glucose Intolerance in Aging, Obesity, and Diabetes Through β-Cell Adaptation

Diabetes ◽

10.2337/db19-0377 ◽

2020 ◽

Vol 69 (4) ◽

pp. 647-660 ◽

Cited By ~ 2

Author(s):

Marion de Toledo ◽

Isabel C. Lopez-Mejia ◽

Patricia Cavelier ◽

Marine Pratlong ◽

Célia Barrachina ◽

...

Keyword(s):

Glucose Intolerance ◽

Β Cell ◽

Cell Adaptation ◽

Obesity And Diabetes

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Reduction of islet pyruvate carboxylase activity might be related to the development of type 2 diabetes mellitus in Agouti-K mice

Journal of Endocrinology ◽

10.1677/joe-09-0391 ◽

2009 ◽

Vol 204 (2) ◽

pp. 143-152 ◽

Cited By ~ 19

Author(s):

J Han ◽

Y Q Liu

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Blood Glucose ◽

Protein Level ◽

Pyruvate Carboxylase ◽

Β Cell ◽

Cell Adaptation ◽

Type 2 Diabetic

Pyruvate carboxylase (PC) activity is enhanced in the islets of obese rats, but it is reduced in the islets of type 2 diabetic rats, suggesting the importance of PC in β-cell adaptation to insulin resistance as well as the possibility that PC reduction might lead to hyperglycemia. However, the causality is currently unknown. We used obese Agouti mice (AyL) as a model to show enhanced β-cell adaptation, and type 2 diabetic db/db mice as a model to show severe β-cell failure. After comparison of the two models, a less severe type 2 diabetic Agouti-K (AyK) mouse model was used to show the changes in islet PC activity during the development of type 2 diabetes mellitus (T2DM). AyK mice were separated into two groups: mildly (AyK-M, blood glucose <250 mg/dl) and severely (AyK-S, blood glucose >250 mg/dl) hyperglycemic. Islet PC activity, but not protein level, was increased 1.7-fold in AyK-M mice; in AyK-S mice, islet PC activity and protein level were reduced. All other changes including insulin secretion and islet morphology in AyK-M mice were similar to those observed in AyL mice, but they were worse in AyK-S mice where these parameters closely matched those in db/db mice. In 2-day treated islets, PC activity was inhibited by high glucose but not by palmitate. Our findings suggest that islet PC might play a role in the development of T2DM where reduction of PC activity might be a consequence of mild hyperglycemia and a cause for severe hyperglycemia.

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β−cell adaptation/dysfunction in an animal model of dyslipidemia and insulin resistance induced by the chronic administration of a sucrose-rich diet

Islets ◽

10.4161/isl.2.6.13869 ◽

2010 ◽

Vol 2 (6) ◽

pp. 367-373 ◽

Cited By ~ 6

Author(s):

Maria del Rosario Ferreira ◽

Yolanda B. Lombardo ◽

Adriana Chicco

Keyword(s):

Insulin Resistance ◽

Animal Model ◽

Chronic Administration ◽

Β Cell ◽

Cell Adaptation

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Adipose tissue macrophages orchestrate β cell adaptation in obesity through secreting miRNA-containing extracellular vesicles

10.1101/2020.06.12.148809 ◽

2020 ◽

Author(s):

Hong Gao ◽

Zhenlong Luo ◽

Zhongmou Jin ◽

Yudong Ji ◽

Wei Ying

Keyword(s):

Adipose Tissue ◽

Insulin Secretion ◽

Extracellular Vesicles ◽

Critical Role ◽

Β Cells ◽

Β Cell ◽

Cell Adaptation ◽

Cell Functions ◽

Cell Responses ◽

Adipose Tissue Macrophages

AbstractObesity induces an adaptive expansion of β cell mass and insulin secretion abnormality. Here, we explore a novel role of adipose tissue macrophages (ATMs) in mediating obesity-induced β cell function and proliferation through releasing miRNA-containing extracellular vesicles (EVs). ATM EVs derived from obese mice notably suppress insulin secretion in both in vivo and in vitro experiments, whereas there are more proliferating β cells in the islets treated with obese ATM EVs. Depletion of miRNAs blunts the ability of obese ATM EVs to regulate β cell responses. miR-155, a highly enriched miRNA within obese ATM EVs, exerts profound regulation on β cell functions, as evidenced by impaired insulin secretion and increased β cell proliferation after miR-155 overexpression in β cells. By contrast, knockout of miR-155 can attenuate the regulation of obese ATM EVs on β cell responses. We further demonstrate that the miR-155-Mafb axis plays a critical role in controlling β cell responses. Taken together, these studies show a novel mechanism by which ATM-derived EVs act as endocrine cargoes delivering miRNAs and subsequently mediating β cell adaptation and functional dysfunction in obesity.

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Oxytocin signal contributes to the adaptative growth of islets during gestation

Endocrine Connections ◽

10.1530/ec-21-0043 ◽

2021 ◽

Author(s):

Ping Gu ◽

Yuege Lin ◽

Qi Wan ◽

Dongming Su ◽

Qun Shu

Keyword(s):

Insulin Secretion ◽

Pregnant Women ◽

Cell Function ◽

Pancreatic Β Cell ◽

Β Cells ◽

Β Cell ◽

Pancreatic Β Cells ◽

Cell Adaptation ◽

Β Cell Function ◽

Insulinoma Cells

Background: Increased insulin production and secretion by pancreatic β-cells are important for ensuring the high insulin demand during gestation. However, the underlying mechanism of β-cell adaptation during gestation or in gestational diabetes mellitus (GDM) remains unclear. Oxytocin is an important physiological hormone in gestation and delivery, and it also contributes to the maintenance of β-cell function. The aim of this study was to investigate the role of oxytocin in β-cell adaptation during pregnancy. Methods: The relationship between the blood oxytocin level and pancreatic β-cell function in patients with GDM and healthy pregnant women was investigated. Gestating and non-gestating mice were used to evaluate the in vivo effect of oxytocin signal on β-cells during pregnancy. In vitro experiments were performed on INS-1 insulinoma cells. Results: The blood oxytocin levels were lower in patients with GDM than in healthy pregnant women and were associated with impaired pancreatic β-cell function. Acute administration of oxytocin increased insulin secretion in both gestating and non-gestating mice. A three-week oxytocin treatment promoted the proliferation of pancreatic β-cells and increased the β-cell mass in gestating but not non-gestating mice. Antagonism of oxytocin receptors by atosiban impaired insulin secretion and induced GDM in gestating but not non-gestating mice. Oxytocin enhanced glucose-stimulated insulin secretion, activated the mitogen-activated protein kinase pathway, and promoted cell proliferation in INS-1 cells. Conclusions: These findings provide strong evidence that oxytocin is needed for β-cell adaptation during pregnancy to maintain β-cell function, and lack of oxytocin could be associated with the risk of GDM.

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