scholarly journals Gfi1 Loss Protects against Two Models of Induced Diabetes

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 2805
Author(s):  
Tiziana Napolitano ◽  
Fabio Avolio ◽  
Serena Silvano ◽  
Sara Forcisi ◽  
Anja Pfeifer ◽  
...  
Keyword(s):  
Acinar Cells ◽  
Conditional Knockout ◽  
Mutant Mice ◽  
High Dose ◽  
Diabetes Research ◽  
High Fat ◽  
Β Cells ◽  
High Sugar ◽  
Deficient Mice

Background: Although several approaches have revealed much about individual factors that regulate pancreatic development, we have yet to fully understand their complicated interplay during pancreas morphogenesis. Gfi1 is transcription factor specifically expressed in pancreatic acinar cells, whose role in pancreas cells fate identity and specification is still elusive. Methods: In order to gain further insight into the function of this factor in the pancreas, we generated animals deficient for Gfi1 specifically in the pancreas. Gfi1 conditional knockout animals were phenotypically characterized by immunohistochemistry, RT-qPCR, and RNA scope. To assess the role of Gfi1 in the pathogenesis of diabetes, we challenged Gfi1-deficient mice with two models of induced hyperglycemia: long-term high-fat/high-sugar feeding and streptozotocin injections. Results: Interestingly, mutant mice did not show any obvious deleterious phenotype. However, in depth analyses demonstrated a significant decrease in pancreatic amylase expression, leading to a diminution in intestinal carbohydrates processing and thus glucose absorption. In fact, Gfi1-deficient mice were found resistant to diet-induced hyperglycemia, appearing normoglycemic even after long-term high-fat/high-sugar diet. Another feature observed in mutant acinar cells was the misexpression of ghrelin, a hormone previously suggested to exhibit anti-apoptotic effects on β-cells in vitro. Impressively, Gfi1 mutant mice were found to be resistant to the cytotoxic and diabetogenic effects of high-dose streptozotocin administrations, displaying a negligible loss of β-cells and an imperturbable normoglycemia. Conclusions: Together, these results demonstrate that Gfi1 could turn to be extremely valuable for the development of new therapies and could thus open new research avenues in the context of diabetes research.

scholarly journals Nrf2 Regulates β-cell Mass by Suppressing Cell Death and Promoting Proliferation

2021 ◽  
Author(s):  
Sharon Baumel-Alterzon ◽  
Liora S. Katz ◽  
Gabriel Brill ◽  
Clairete Jean-Pierre ◽  
Yansui Li ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
High Fat Diet ◽  
Ex Vivo ◽  
Cell Mass ◽  
Conditional Knockout ◽  
Diabetes Research ◽  
Loss Of Function ◽  
High Fat ◽  
Β Cells ◽  
Β Cell

SUMMARYFinding therapies that can protect and expand functional β-cell mass is a major goal of diabetes research. Here we generated β-cell-specific conditional knockout and gain-of-function mouse models and used human islet transplant experiments to examine how manipulating Nrf2 levels affects β-cell survival, proliferation and mass. Depletion of Nrf2 in β-cells resulted in decreased glucose-stimulated β-cell proliferation ex vivo and decreased adaptive β-cell proliferation and β-cell mass expansion after a high fat diet in vivo. Nrf2 protects β-cells from apoptosis after a high fat diet. Nrf2 loss-of-function decreases Pdx1 abundance and insulin content. Activating Nrf2 in a β-cell-specific manner increases β-cell proliferation and β-cell mass. Human islets transplanted under the kidney capsule of immunocompromised mice and treated systemically with CDDO-Me, an Nrf2 activator, display increased β-cell proliferation. Thus, Nrf2 regulates β-cell mass and is an exciting therapeutic target for expanding β-cell mass in diabetes.

scholarly journals Growth factors and medium hyperglycemia induce Sox9+ ductal cell differentiation into β cells in mice with reversal of diabetes

2016 ◽  
Vol 113 (3) ◽  
pp. 650-655 ◽  
Author(s):  
Mingfeng Zhang ◽  
Qing Lin ◽  
Tong Qi ◽  
Tiankun Wang ◽  
Ching-Cheng Chen ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Low Dose ◽  
Mixed Chimerism ◽  
High Dose ◽  
Β Cells ◽  
Β Cell ◽  
Ductal Cells ◽  
Ductal Cell ◽  
Term Administration

We previously reported that long-term administration of a low dose of gastrin and epidermal growth factor (GE) augments β-cell neogenesis in late-stage diabetic autoimmune mice after eliminating insulitis by induction of mixed chimerism. However, the source of β-cell neogenesis is still unknown. SRY (sex-determining region Y)-box 9+ (Sox9+) ductal cells in the adult pancreas are clonogenic and can give rise to insulin-producing β cells in an in vitro culture. Whether Sox9+ ductal cells in the adult pancreas can give rise to β cells in vivo remains controversial. Here, using lineage-tracing with genetic labeling of Insulin- or Sox9-expressing cells, we show that hyperglycemia (>300 mg/dL) is required for inducing Sox9+ ductal cell differentiation into insulin-producing β cells, and medium hyperglycemia (300–450 mg/dL) in combination with long-term administration of low-dose GE synergistically augments differentiation and is associated with normalization of blood glucose in nonautoimmune diabetic C57BL/6 mice. Short-term administration of high-dose GE cannot augment differentiation, although it can augment preexisting β-cell replication. These results indicate that medium hyperglycemia combined with long-term administration of low-dose GE represents one way to induce Sox9+ ductal cell differentiation into β cells in adult mice.

Milk from dams fed an obesogenic diet combined with a high-fat/high-sugar diet induces long-term abnormal mammary gland development in the rabbit1

2015 ◽  
Vol 93 (4) ◽  
pp. 1641-1655 ◽  
Author(s):  
C. Hue-Beauvais ◽  
E. Koch ◽  
P. Chavatte-Palmer ◽  
L. Galio ◽  
S. Chat ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Mammary Gland Development ◽  
High Fat ◽  
High Sugar ◽  
Obesogenic Diet ◽  
Gland Development

scholarly journals Congenital Anomalies Programmed by Maternal Diabetes and Obesity on Offspring of Rats

2021 ◽  
Vol 12 ◽  
Author(s):  
Vanessa Caruline Araujo-Silva ◽  
Alice Santos-Silva ◽  
Andressa Silva Lourenço ◽  
Cristielly Maria Barros-Barbosa ◽  
Rafaianne Queiroz Moraes-Souza ◽  
...  
Keyword(s):  
Maternal Diabetes ◽  
Diabetic Rats ◽  
Female Rats ◽  
Gravid Uterus ◽  
Oral Glucose ◽  
Standard Diet ◽  
High Fat ◽  
High Sugar ◽  
Obesity And Diabetes

Embryo-fetal exposure to maternal disorders during intrauterine life programs long-term consequences for the health and illness of offspring. In this study, we evaluated whether mild diabetic rats that were given high-fat/high-sugar (HF/HS) diet presented maternal and fetal changes at term pregnancy. Female rats received citrate buffer (non-diabetic-ND) or streptozotocin (diabetic-D) after birth. According to the oral glucose tolerance test (OGTT), the experimental groups (n = 11 animals/group) were composed of non-diabetic and diabetic receiving standard diet (S) or HF/HS diet. High-fat/high-sugar diet (30% kcal of lard) in chow and water containing 5% sucrose and given 1 month before mating and during pregnancy. During and at the end of pregnancy, obesity and diabetes features were determined. After laparotomy, blood samples, periovarian fat, and uterine content were collected. The diabetic rats presented a higher glycemia and percentage of embryonic losses when compared with the NDS group. Rats DHF/HS presented increased obesogenic index, caloric intake, and periovarian fat weight and reduced gravid uterus weight in relation to the other groups. Besides, this association might lead to the inflammatory process, confirmed by leukocytosis. Obese rats (NDHF/HS and DHF/HS) showed higher triglyceride levels and their offspring with lower fetal weight and ossification sites, indicating intrauterine growth restriction. This finding may contribute to vascular alterations related to long-term hypertensive disorders in adult offspring. The fetuses from diabetic dams showed higher percentages of skeletal abnormalities, and DHF/HS dams still had a higher rate of anomalous fetuses. Thus, maternal diabetes and/or obesity induces maternal metabolic disorders that contribute to affect fetal development and growth.

scholarly journals STAT3 Regulates Mitochondrial Gene Expression in Pancreatic β-Cells and its Deficiency Induces Glucose Intolerance in Obesity

2021 ◽  
Author(s):  
Anaïs Schaschkow ◽  
Lokman Pang ◽  
Valerie Vandenbempt ◽  
Bernat Elvira ◽  
Sara A. Litwak ◽  
...  
Keyword(s):  
Gene Expression ◽  
Glucose Intolerance ◽  
High Fat Diet ◽  
Cell Function ◽  
Mitochondrial Gene ◽  
High Fat ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function ◽  
Deficient Mice

Most obese and insulin-resistant individuals do not develop diabetes. This is the result of the capacity of β-cells to adapt and produce enough insulin to cover the needs of the organism. The underlying mechanism of β-cell adaptation in obesity, however, remains unclear. Previous studies have suggested a role for STAT3 in mediating β-cell development and human glucose homeostasis, but little is known about STAT3 in β-cells in obesity. We observed enhanced cytoplasmic expression of STAT3 in severely obese and diabetic subjects. To address the functional role of STAT3 in adult β-cells, we generated mice with tamoxifen-inducible partial or full deletion of STAT3 in β-cells and fed them a high-fat diet before analysis. Interestingly, β-cell heterozygous and homozygous STAT3-deficient mice showed glucose intolerance when fed a high-fat diet. Gene expression analysis by RNA-Seq showed reduced expression of mitochondrial genes in STAT3 knocked down human EndoC-βH1 cells and was confirmed in FACS-purified β-cells from obese STAT3-deficient mice. Moreover, silencing of STAT3 impaired mitochondria activity in EndoC-βH1 cells and human islets, suggesting a mechanism for STAT3-modulated β-cell function. We propose STAT3 as a regulator of β-cell function, improving glucose-induced insulin secretion in obesity.

scholarly journals Muscle-Specific Myosin Heavy Chain Shifts in Response to a Long-Term High Fat/High Sugar Diet and Resveratrol Treatment in Nonhuman Primates

2016 ◽  
Vol 7 ◽  
Author(s):  
Jon-Philippe K. Hyatt ◽  
Lisa Nguyen ◽  
Allison E. Hall ◽  
Ashley M. Huber ◽  
Jessica C. Kocan ◽  
...  
Keyword(s):  
Myosin Heavy Chain ◽  
Heavy Chain ◽  
Nonhuman Primates ◽  
High Fat ◽  
High Sugar ◽  
Resveratrol Treatment ◽  
Chain Shifts

scholarly journals STAT3 Regulates Mitochondrial Gene Expression in Pancreatic β-Cells and its Deficiency Induces Glucose Intolerance in Obesity

2021 ◽  
Author(s):  
Anaïs Schaschkow ◽  
Lokman Pang ◽  
Valerie Vandenbempt ◽  
Bernat Elvira ◽  
Sara A. Litwak ◽  
...  
Keyword(s):  
Gene Expression ◽  
Glucose Intolerance ◽  
High Fat Diet ◽  
Cell Function ◽  
Mitochondrial Gene ◽  
High Fat ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function ◽  
Deficient Mice

Most obese and insulin-resistant individuals do not develop diabetes. This is the result of the capacity of β-cells to adapt and produce enough insulin to cover the needs of the organism. The underlying mechanism of β-cell adaptation in obesity, however, remains unclear. Previous studies have suggested a role for STAT3 in mediating β-cell development and human glucose homeostasis, but little is known about STAT3 in β-cells in obesity. We observed enhanced cytoplasmic expression of STAT3 in severely obese and diabetic subjects. To address the functional role of STAT3 in adult β-cells, we generated mice with tamoxifen-inducible partial or full deletion of STAT3 in β-cells and fed them a high-fat diet before analysis. Interestingly, β-cell heterozygous and homozygous STAT3-deficient mice showed glucose intolerance when fed a high-fat diet. Gene expression analysis by RNA-Seq showed reduced expression of mitochondrial genes in STAT3 knocked down human EndoC-βH1 cells and was confirmed in FACS-purified β-cells from obese STAT3-deficient mice. Moreover, silencing of STAT3 impaired mitochondria activity in EndoC-βH1 cells and human islets, suggesting a mechanism for STAT3-modulated β-cell function. We propose STAT3 as a regulator of β-cell function, improving glucose-induced insulin secretion in obesity.

scholarly journals Retrospective lifetime dietary patterns are associated with demographic and cardiovascular health variables in an older community-dwelling Australian population

2013 ◽  
Vol 110 (11) ◽  
pp. 2069-2083 ◽  
Author(s):  
Diane Hosking ◽  
Vanessa Danthiir
Keyword(s):  
Dietary Patterns ◽  
Hdl Cholesterol ◽  
Later Life ◽  
Community Dwelling ◽  
High Fat ◽  
Lower Odds ◽  
Dietary Recall ◽  
High Sugar ◽  
Cholesterol Levels

Dietary patterns derived from factor analytic procedures have been demonstrated to predict demographic and health outcomes across a wide range of populations. To examine the potential utility of long-term dietary recall, in the present study, we examined associations between dietary patterns from across the lifespan and demographic and later-life cardiovascular-related health variables, using the Lifetime Diet Questionnaire (LDQ). The LDQ is a self-administered, non-quantitative, retrospective FFQ designed to assess dietary intake from childhood to older age. Participants (n 352) from the Older People, Omega-3 and Cognitive Health trial, aged 65–91 years, completed the LDQ. Exploratory factor analysis was conducted on the LDQ and plausible dietary patterns were derived. As a result, three patterns were extracted from each life period, with five distinct patterns overall; these were ‘traditional Australian’ and ‘non-traditional Australian’, ‘high-sugar and high-fat’, ‘vegetable’ and ‘fruit and vegetable’ patterns. In separate adjusted regression models, age, sex, education, income, parental background and childhood physical activity all significantly predicted dietary patterns across the lifespan. A ‘traditional Australian’ pattern in childhood predicted higher HDL-cholesterol levels and lower odds of cholesterol medication use; lower HDL-cholesterol levels were predicted by the adult ‘processed, high-sugar and high-fat’ pattern, and higher intake of a ‘non-traditional Australian’ pattern in adulthood also predicted lower odds of using cardiac medications. Lifetime dietary recall, as instantiated by the LDQ, provides a hitherto untapped source of long-term dietary information in older adults that may contribute to greater understanding of the impact exerted by early-life and cumulative dietary choices on later-life health.

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