Neonatal Stimulation of β-cells Reduces the Incidence and Delays the Onset of Diabetes in a Barrier-protected Breeding Colony of BB Rats

OBJECTIVE: Changes in the functional state of beta cells by neonatal stimulation or adolescent suppression have reduced the incidence of type 1 diabetes mellitus in animal models. The aim of this study was to evaluate the effect of manipulation of the activity of the thyroid gland by neonatal stimulation or by adolescent suppression on the prevalence of spontaneous autoimmune thyroiditis (AIT) in rats. METHODS: Bio-Breeding/Worcester (BB) rats were treated neonatally with sodium iodine (NaI) or thyroid stimulating hormone (TSH), or during adolescence by triiodothyronine (T(3)), and the lymphocytic infiltration in the thyroid gland was evaluated. RESULTS: Neonatal treatment with NaI decreased the prevalence of AIT to 32+/-9% compared with 66+/-5% in the controls (P<0.002), mainly caused by a reduction among the female rats (13+/-9% vs 52+/-8%, P<0.006). TSH had no effect. Post neonatal suppression of the thyroid gland by T(3) had a biphasic response. Early in adolescence the overall prevalence was 14+/-7% compared with 66+/-5% in the controls (P<10(-5)); for female rats AIT was prevented (0+/-0%) compared with 52+/-8% in the controls (P<0.0003) and in male rats the values were 29+/-13% compared with 80+/-6% in the controls (P<0.001). Treatment with T(3) later in adolescence increased the overall prevalence to 81+/-7% compared with 66+/-5% in the controls (not significant). For female rats the prevalence increased to 78+/-9% compared with 52+/-8% in the controls (P=0.04). The degree of thyroiditis among the affected animals was similar in all groups. CONCLUSION: Neonatal stimulation of the thyroid gland by iodine or early adolescent suppression by T(3) reduced the prevalence of AIT whereas T(3) given later increased the prevalence of thyroiditis in rats. Thyroid activity at various ages seems to be of importance for the development of autoimmune thyroiditis.

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Time course of the lymphopenia in BB rats. Relation to the onset of diabetes

Diabetes ◽

10.2337/diabetes.34.10.955 ◽

1985 ◽

Vol 34 (10) ◽

pp. 955-959 ◽

Cited By ~ 7

Author(s):

J. F. Yale ◽

M. Grose ◽

E. B. Marliss

Keyword(s):

Time Course ◽

Bb Rats ◽

Onset Of Diabetes

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Mitochondrial–Endoplasmic Reticulum Interplay: A Lifelong On–Off Relationship?

Contact ◽

10.1177/2515256419861227 ◽

2019 ◽

Vol 2 ◽

pp. 251525641986122 ◽

Cited By ~ 3

Author(s):

Corina T. Madreiter-Sokolowski ◽

Roland M. Malli ◽

Wolfgang F. Graier

Keyword(s):

Endoplasmic Reticulum ◽

Adenosine Triphosphate ◽

Therapeutic Strategies ◽

Mitochondrial Activity ◽

Β Cells ◽

Pancreatic Β Cells ◽

Potential Target ◽

Pathological Conditions ◽

Elevated Glucose ◽

Stimulation Of

This article comments recent publications that highlight an intriguing importance of specific settings in the interaction between the mitochondria and the endoplasmic reticulum to ensure cell-specific functions like the responsiveness to elevated glucose in pancreatic β-cells. Hence, alterations of the mitochondria–endoplasmic reticulum communications under various pathological conditions like aging or cancer often come with enhanced Ca2+ transfer that, in turn, yields stimulation of basal mitochondrial activity to meet the increasing adenosine triphosphate demand of the very cell. Such observations identify mitochondria-associated membranes as potential target for new therapeutic strategies against aging or cancer.

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The Stimulation of Neurogenesis Improves the Cognitive Status of Aging Rats Subjected to Gestational and Perinatal Deficiency of B9–12 Vitamins

International Journal of Molecular Sciences ◽

10.3390/ijms21218008 ◽

2020 ◽

Vol 21 (21) ◽

pp. 8008

Author(s):

Grégory Pourié ◽

Nicolas Martin ◽

Jean-Luc Daval ◽

Jean-Marc Alberto ◽

Rémy Umoret ◽

...

Keyword(s):

Body Weight ◽

Cognitive Status ◽

Vitamin Deficiency ◽

Developmental Defects ◽

Rat Pups ◽

Vitamin Status ◽

Neonatal Stimulation ◽

B Vitamin ◽

In The Beginning ◽

Stimulation Of

A deficiency in B-vitamins is known to lead to persistent developmental defects in various organs during early life. The nervous system is particularly affected with functional retardation in infants and young adults. In addition, even if in some cases no damage appears evident in the beginning of life, correlations have been shown between B-vitamin metabolism and neurodegenerative diseases. However, despite the usual treatment based on B-vitamin injections, the neurological outcomes remain poorly rescued in the majority of cases, compared with physiological functions. In this study, we explored whether a neonatal stimulation of neurogenesis could compensate atrophy of specific brain areas such as the hippocampus, in the case of B-vitamin deficiency. Using a physiological mild transient hypoxia within the first 24 h after birth, rat-pups, submitted or not to neonatal B-vitamin deficiency, were followed until 330-days-of-age for their cognitive capacities and their hippocampus status. Our results showed a gender effect since females were more affected than males by the deficiency, showing a persistent low body weight and poor cognitive performance to exit a maze. Nevertheless, the neonatal stimulation of neurogenesis with hypoxia rescued the maze performance during adulthood without modifying physiological markers, such as body weight and circulating homocysteine. Our findings were reinforced by an increase of several markers at 330-days-of-age in hypoxic animals, such as Ammon’s Horn 1hippocampus (CA1) thickness and the expression of key actors of synaptic dynamic, such as the NMDA-receptor-1 (NMDAR1) and the post-synaptic-density-95 (PSD-95). We have not focused our conclusion on the neonatal hypoxia as a putative treatment, but we have discussed that, in the case of neurologic retardation associated with a reduced B-vitamin status, stimulation of the latent neurogenesis in infants could ameliorate their quality of life during their lifespan.

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The Metabolic Availability of Vitamin A Is Decreased at the Onset of Diabetes in BB Rats

Journal of Nutrition ◽

10.1093/jn/130.8.1958 ◽

2000 ◽

Vol 130 (8) ◽

pp. 1958-1962 ◽

Cited By ~ 24

Author(s):

Jing Lu ◽

Walter T. Dixon ◽

Andrew T. C. Tsin ◽

Tapan K. Basu

Keyword(s):

Vitamin A ◽

Bb Rats ◽

Onset Of Diabetes

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A Sustained Activation of Pancreatic NMDARs Is a Novel Factor of β-Cell Apoptosis and Dysfunction

Endocrinology ◽

10.1210/en.2017-00366 ◽

2017 ◽

Vol 158 (11) ◽

pp. 3900-3913 ◽

Cited By ~ 13

Author(s):

Xiao-Ting Huang ◽

Shao-Jie Yue ◽

Chen Li ◽

Yan-Hong Huang ◽

Qing-Mei Cheng ◽

...

Keyword(s):

Type 2 Diabetes ◽

Cell Apoptosis ◽

Cell Function ◽

Cell Mass ◽

Nuclear Factor Κb ◽

Β Cells ◽

Β Cell ◽

Stimulation Of ◽

Sustained Activation

Abstract Type 2 diabetes, which features β-cell failure, is caused by the decrease of β-cell mass and insulin secretory function. Current treatments fail to halt the decrease of functional β-cell mass. Strategies to prevent β-cell apoptosis and dysfunction are highly desirable. Recently, our group and others have reported that blockade of N-methyl-d-aspartate receptors (NMDARs) in the islets has been proposed to prevent the progress of type 2 diabetes through improving β-cell function. It suggests that a sustained activation of the NMDARs may exhibit deleterious effect on β-cells. However, the exact functional impact and mechanism of the sustained NMDAR stimulation on islet β-cells remains unclear. Here, we identify a sustained activation of pancreatic NMDARs as a novel factor of apoptotic β-cell death and function. The sustained treatment with NMDA results in an increase of intracellular [Ca2+] and reactive oxygen species, subsequently induces mitochondrial membrane potential depolarization and a decrease of oxidative phosphorylation expression, and then impairs the mitochondrial function of β-cells. NMDA specifically induces the mitochondrial-dependent pathway of apoptosis in β-cells through upregulation of the proapoptotic Bim and Bax, and downregulation of antiapoptotic Bcl-2. Furthermore, a sustained stimulation of NMDARs impairs β-cell insulin secretion through decrease of pancreatic duodenal homeobox-1 (Pdx-1) and adenosine triphosphate synthesis. The activation of nuclear factor–κB partly contributes to the reduction of Pdx-1 expression induced by overstimulation of NMDARs. In conclusion, we show that the sustained stimulation of NMDARs is a novel mediator of apoptotic signaling and β-cell dysfunction, providing a mechanistic insight into the pathological role of NMDARs activation in diabetes.

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Potentiation of insulin secretion by phorbol esters is mediated by PKC-α and nPKC isoforms

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00474.2001 ◽

2002 ◽

Vol 283 (5) ◽

pp. E880-E888 ◽

Cited By ~ 19

Author(s):

Gordon C. Yaney ◽

Jamison M. Fairbanks ◽

Jude T. Deeney ◽

Helen M. Korchak ◽

Keith Tornheim ◽

...

Keyword(s):

Insulin Secretion ◽

Membrane Potential ◽

Phorbol Esters ◽

Myristate Acetate ◽

Β Cells ◽

Kinase C ◽

Pkc Isoforms ◽

Enhanced Secretion ◽

Intracellular Ca ◽

Stimulation Of

Culturing clonal β-cells (HIT-T15) overnight in the presence of phorbol ester [phorbol myristate acetate (PMA)] enhanced insulin secretion while causing downregulation of some protein kinase C (PKC) isoforms and most PKC activity. We show here that this enhanced secretion required the retention of PMA in the cell. Hence, it could not be because of long-lived phosphorylation of cellular substrates by the isoforms that were downregulated, namely PKC-α, -βII, and -ε, but could be because of the continued activation of the two remaining diacylglycerol-sensitive isoforms δ and μ. The enhanced secretion did not involve changes in glucose metabolism, cell membrane potential, or intracellular Ca2+handling, suggesting a distal effect. PMA washout caused the loss of the enhanced response, but secretion was then stimulated by acute readdition of PMA or bombesin. The magnitude of this restimulation appeared dependent on the mass of PKC-α, which was rapidly resynthesized during PMA washout. Therefore, stimulation of insulin secretion by PMA, and presumably by endogenous diacylglycerol, involves the activation of PKC isoforms δ and/or μ, and also PKC-α.

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