scholarly journals Gastrin induces ductal cell dedifferentiation and β-cell neogenesis after 90% pancreatectomy

2014 ◽  
Vol 223 (1) ◽  
pp. 67-78 ◽  
Author(s):  
Noèlia Téllez ◽  
Eduard Montanya
Keyword(s):  
Cell Mass ◽  
Β Cell ◽  
Neurogenin 3 ◽  
Glucose Levels ◽  
Ductal Cells ◽  
Blood Glucose Levels ◽  
Morphometric Analyses ◽  
Underlying Mechanisms ◽  
Mass Expansion

Induction of β-cell mass regeneration is a potentially curative treatment for diabetes. We have recently found that long-term gastrin treatment results in improved metabolic control and β-cell mass expansion in 95% pancreatectomised (Px) rats. In this study, we investigated the underlying mechanisms of gastrin-induced β-cell mass expansion after Px. After 90%-Px, rats were treated with gastrin (Px+G) or vehicle (Px+V), pancreatic remnants were harvested on days 1, 3, 5, 7, and 14 and used for gene expression, protein immunolocalisation and morphometric analyses. Gastrin- and vehicle-treated Px rats showed similar blood glucose levels throughout the study. Initially, after Px, focal areas of regeneration, showing mesenchymal cells surrounding ductal structures that expressed the cholecystokinin B receptor, were identified. These focal areas of regeneration were similar in size and cell composition in the Px+G and Px+V groups. However, in the Px+G group, the ductal structures showed lower levels of keratin 20 and β-catenin (indicative of duct dedifferentiation) and higher levels of expression of neurogenin 3 and NKX6-1 (indicative of endocrine progenitor phenotype), as compared with Px+V rats. In Px+G rats, β-cell mass and the number of scattered β-cells were significantly increased compared with Px+V rats, whereas β-cell replication and apoptosis were similar in the two groups. These results indicate that gastrin treatment-enhanced dedifferentiation and reprogramming of regenerative ductal cells in Px rats, increased β-cell neogenesis and fostered β-cell mass expansion.

scholarly journals Dissecting the Brain/Islet Axis in Metabesity

Genes ◽  
2019 ◽  
Vol 10 (5) ◽  
pp. 350 ◽  
Author(s):  
Esther Fuente-Martín ◽  
Jose M. Mellado-Gil ◽  
Nadia Cobo-Vuilleumier ◽  
Alejandro Martín-Montalvo ◽  
Silvana Y. Romero-Zerbo ◽  
...  
Keyword(s):  
Common Factor ◽  
Critical Role ◽  
Cell Mass ◽  
Cell Types ◽  
Β Cell ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
High Prevalence ◽  
The Central Nervous System ◽  
Metabolic Dysfunctions

The high prevalence of type 2 diabetes mellitus (T2DM), together with the fact that current treatments are only palliative and do not avoid major secondary complications, reveals the need for novel approaches to treat the cause of this disease. Efforts are currently underway to identify therapeutic targets implicated in either the regeneration or re-differentiation of a functional pancreatic islet β-cell mass to restore insulin levels and normoglycemia. However, T2DM is not only caused by failures in β-cells but also by dysfunctions in the central nervous system (CNS), especially in the hypothalamus and brainstem. Herein, we review the physiological contribution of hypothalamic neuronal and glial populations, particularly astrocytes, in the control of the systemic response that regulates blood glucose levels. The glucosensing capacity of hypothalamic astrocytes, together with their regulation by metabolic hormones, highlights the relevance of these cells in the control of glucose homeostasis. Moreover, the critical role of astrocytes in the response to inflammation, a process associated with obesity and T2DM, further emphasizes the importance of these cells as novel targets to stimulate the CNS in response to metabesity (over-nutrition-derived metabolic dysfunctions). We suggest that novel T2DM therapies should aim at stimulating the CNS astrocytic response, as well as recovering the functional pancreatic β-cell mass. Whether or not a common factor expressed in both cell types can be feasibly targeted is also discussed.

scholarly journals Combining sitagliptin/metformin with a functional fiber delays diabetes progression in Zucker rats

2014 ◽  
Vol 220 (3) ◽  
pp. 361-373 ◽  
Author(s):  
Raylene A Reimer ◽  
Gary J Grover ◽  
Lee Koetzner ◽  
Roland J Gahler ◽  
Michael R Lyon ◽  
...  
Keyword(s):  
Cell Mass ◽  
Primary Objective ◽  
Zucker Rats ◽  
Β Cell ◽  
Dipeptidyl Peptidase 4 ◽  
Glucose Levels ◽  
Combination Treatments ◽  
Blood Glucose Levels ◽  
Obese Zucker Rat ◽  
Zdf Rats

Our primary objective was to determine whether administering the viscous and fermentable polysaccharide PolyGlycopleX (PGX) with metformin (MET) or sitagliptin/metformin (S/MET) reduces hyperglycemia in Zucker diabetic fatty (ZDF) rats more so than monotherapy of each. Glucose tolerance, adiposity, satiety hormones and mechanisms related to dipeptidyl peptidase 4 activity, gut microbiota and, hepatic and pancreatic histology were examined. Male ZDF rats (9–10 weeks of age) were randomized to: i) cellulose/vehicle (control, C); ii) PGX (5% wt/wt)/vehicle (PGX); iii) cellulose/metformin (200 mg/kg) (MET); iv) cellulose/S/MET (10 mg/kg+200 mg/kg) (S/MET); v) PGX (5%)+MET (200 mg/kg) (PGX+MET); vi) cellulose/sitagliptin/MET (5%)+(10 mg/kg+200 mg/kg) (PGX+S/MET) for 6 weeks. PGX+MET and PGX+S/MET reduced glycemia compared with C and singular treatments (P=0.001). Weekly fasted and fed blood glucose levels were lower in PGX+MET and PGX+S/MET compared with all other groups at weeks 4, 5, and 6 (P=0.001). HbA1c was lower in PGX+S/MET than C, MET, S/MET, and PGX at week 6 (P=0.001). Fat mass was lower and GLP1 was higher in PGX+S/MET compared with all other groups (P=0.001). β-cell mass was highest and islet degeneration lowest in PGX+S/MET. Hepatic lipidosis was significantly lower in PGX+S/MET compared with PGX or S/MET alone. When combined with PGX, both MET and S/MET markedly reduce glycemia; however, PGX+S/MET appears advantageous over PGX+MET in terms of increased β-cell mass and reduced adiposity. Both combination treatments attenuated diabetes in the obese Zucker rat.

scholarly journals Loss of β-cell identity and diabetic phenotype in mice caused by disruption of CNOT3-dependent mRNA deadenylation

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Dina Mostafa ◽  
Akiko Yanagiya ◽  
Eleni Georgiadou ◽  
Yibo Wu ◽  
Theodoros Stylianides ◽  
...  
Keyword(s):  
Cell Function ◽  
Cell Mass ◽  
Cell Maturation ◽  
Β Cells ◽  
Β Cell ◽  
Cell Identity ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Β Cell Function ◽  
And Function

AbstractPancreatic β-cells are responsible for production and secretion of insulin in response to increasing blood glucose levels. Defects in β-cell function lead to hyperglycemia and diabetes mellitus. Here, we show that CNOT3, a CCR4–NOT deadenylase complex subunit, is dysregulated in islets in diabetic db/db mice, and that it is essential for murine β cell maturation and identity. Mice with β cell-specific Cnot3 deletion (Cnot3βKO) exhibit impaired glucose tolerance, decreased β cell mass, and they gradually develop diabetes. Cnot3βKO islets display decreased expression of key regulators of β cell maturation and function. Moreover, they show an increase of progenitor cell markers, β cell-disallowed genes, and genes relevant to altered β cell function. Cnot3βKO islets exhibit altered deadenylation and increased mRNA stability, partly accounting for the increased expression of those genes. Together, these data reveal that CNOT3-mediated mRNA deadenylation and decay constitute previously unsuspected post-transcriptional mechanisms essential for β cell identity.

scholarly journals Glucokinase is required for high‐starch diet‐induced β‐cell mass expansion in mice

2021 ◽  
Author(s):  
Kazuhisa Tsuchida ◽  
Akinobu Nakamura ◽  
Hideaki Miyoshi ◽  
Kelaier Yang ◽  
Yuki Yamauchi ◽  
...  
Keyword(s):  
Cell Mass ◽  
Β Cell ◽  
High Starch ◽  
Mass Expansion ◽  
Starch Diet

scholarly journals Adaptive β-cell proliferation increases early in high-fat feeding in mice, concurrent with metabolic changes, with induction of islet cyclin D2 expression

2013 ◽  
Vol 305 (1) ◽  
pp. E149-E159 ◽  
Author(s):  
Rachel E. Stamateris ◽  
Rohit B. Sharma ◽  
Douglas A. Hollern ◽  
Laura C. Alonso
Keyword(s):  
Cell Proliferation ◽  
Cell Mass ◽  
Extended Period ◽  
Time Frame ◽  
High Fat ◽  
Β Cells ◽  
Β Cell ◽  
Cyclin D2 ◽  
Mass Expansion

Type 2 diabetes (T2D) is caused by relative insulin deficiency, due in part to reduced β-cell mass ( 11 , 62 ). Therapies aimed at expanding β-cell mass may be useful to treat T2D ( 14 ). Although feeding rodents a high-fat diet (HFD) for an extended period (3–6 mo) increases β-cell mass by inducing β-cell proliferation ( 16 , 20 , 53 , 54 ), evidence suggests that adult human β-cells may not meaningfully proliferate in response to obesity. The timing and identity of the earliest initiators of the rodent compensatory growth response, possible therapeutic targets to drive proliferation in refractory human β-cells, are not known. To develop a model to identify early drivers of β-cell proliferation, we studied mice during the first week of HFD exposure, determining the onset of proliferation in the context of diet-related physiological changes. Within the first week of HFD, mice consumed more kilocalories, gained weight and fat mass, and developed hyperglycemia, hyperinsulinemia, and glucose intolerance due to impaired insulin secretion. The β-cell proliferative response also began within the first week of HFD feeding. Intriguingly, β-cell proliferation increased before insulin resistance was detected. Cyclin D2 protein expression was increased in islets by day 7, suggesting it may be an early effector driving compensatory β-cell proliferation in mice. This study defines the time frame and physiology to identify novel upstream regulatory signals driving mouse β-cell mass expansion, in order to explore their efficacy, or reasons for inefficacy, in initiating human β-cell proliferation.

scholarly journals Insulin secretion in health and disease: nutrients dictate the pace

2015 ◽  
Vol 75 (1) ◽  
pp. 19-29 ◽  
Author(s):  
Romano Regazzi ◽  
Adriana Rodriguez-Trejo ◽  
Cécile Jacovetti
Keyword(s):  
Fatty Acids ◽  
Insulin Secretion ◽  
Cell Mass ◽  
Insulin Biosynthesis ◽  
Β Cells ◽  
Β Cell ◽  
Altered Expression ◽  
Cell Dysfunction ◽  
Dietary Nutrients ◽  
Underlying Mechanisms

Insulin is a key hormone controlling metabolic homeostasis. Loss or dysfunction of pancreatic β-cells lead to the release of insufficient insulin to cover the organism needs, promoting diabetes development. Since dietary nutrients influence the activity of β-cells, their inadequate intake, absorption and/or utilisation can be detrimental. This review will highlight the physiological and pathological effects of nutrients on insulin secretion and discuss the underlying mechanisms. Glucose uptake and metabolism in β-cells trigger insulin secretion. This effect of glucose is potentiated by amino acids and fatty acids, as well as by entero-endocrine hormones and neuropeptides released by the digestive tract in response to nutrients. Glucose controls also basal and compensatory β-cell proliferation and, along with fatty acids, regulates insulin biosynthesis. If in the short-term nutrients promote β-cell activities, chronic exposure to nutrients can be detrimental to β-cells and causes reduced insulin transcription, increased basal secretion and impaired insulin release in response to stimulatory glucose concentrations, with a consequent increase in diabetes risk. Likewise, suboptimal early-life nutrition (e.g. parental high-fat or low-protein diet) causes altered β-cell mass and function in adulthood. The mechanisms mediating nutrient-induced β-cell dysfunction include transcriptional, post-transcriptional and translational modifications of genes involved in insulin biosynthesis and secretion, carbohydrate and lipid metabolism, cell differentiation, proliferation and survival. Altered expression of these genes is partly caused by changes in non-coding RNA transcripts induced by unbalanced nutrient uptake. A better understanding of the mechanisms leading to β-cell dysfunction will be critical to improve treatment and find a cure for diabetes.

Development of β-cell mass in fetuses of rats deprived of protein and/or energy in last trimester of pregnancy

2002 ◽  
Vol 283 (3) ◽  
pp. R623-R630 ◽  
Author(s):  
Eric Bertin ◽  
Marie-Noëlle Gangnerau ◽  
Georges Bellon ◽  
Danièle Bailbé ◽  
Annick Arbelot De Vacqueur ◽  
...  
Keyword(s):  
Control Diet ◽  
Cell Mass ◽  
Energy Restriction ◽  
Protein Diet ◽  
Low Protein Diet ◽  
Restricted Diet ◽  
Β Cell ◽  
Fetal Plasma ◽  
Low Protein

Fetal malnutrition is now proposed as a risk factor of later obesity and type II diabetes. We previously analyzed the long-term impact of reduced protein and/or energy intake strictly limited to the last week of pregnancy in Wistar rats. Three protocols of gestational malnutrition were used: 1) low-protein isocaloric diet (5 instead of 15%) with pair feeding to the mothers receiving the control diet, 2) restricted diet (50% of control diet), and 3) low protein-restricted diet (50% of low-protein diet). Only isolated protein restriction induced a long-term β-cell mass decrease. In the present study, we used the same protocols of food restriction to analyze their short-term impact (on day 21.5 of pregnancy) on β-cell mass development. A 50% β-cell mass decrease was present in the three restricted groups, but low-protein diet, either associated or not to energy restriction, increased fetal β-cell insulin content. Among all the parameters analyzed to further explain our results, we found that the fetal plasma level of taurine was lowered by low-protein diet and was the main predictor of the fetal plasma insulin level ( r = 0.63, P < 0.01). In conclusion, rat fetuses exposed to protein and/or energy restriction during the third part of pregnancy have a similar dramatic decrease in β-cell mass, and their ability to recover β-cell mass development retardation depends on the type of malnutrition used. Moreover, our results support the hypothesis that taurine might play an important role in fetal β-cell mass function.

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.

scholarly journals Oreocnide integrifoliaFlavonoids Augment Reprogramming for Islet Neogenesis andβ-Cell Regeneration in Pancreatectomized BALB/c Mice

2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Ansarullah ◽  
Bhavna Bharucha ◽  
Malati Umarani ◽  
Mitesh Dwivedi ◽  
Naresh C. Laddha ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Blood Glucose ◽  
Brdu Incorporation ◽  
Cell Regeneration ◽  
Mice Model ◽  
Islet Neogenesis ◽  
Glucose Levels ◽  
Ductal Cells ◽  
Blood Glucose Levels

Agents which can either trigger proliferation ofβ-cells or induce neogenesis ofβ-cells from precursors would be of pivotal role in reversing diabetic manifestations. We examined the role of flavonoid rich fraction (FRF) ofOreocnide integrifolialeaves using a mice model of experimental regeneration. BALB/c mice were subjected to ~70% pancreatectomy (Px) and supplemented with FRF for 7, 14, and 21 days after pancreatectomy. Px animals displayed increased blood glucose levels and decreased insulin titres which were ameliorated by FRF supplementation. FRF-treated mice demonstrated prominent newly formed islets budding off from ducts and depicting increased BrdU incorporation. Additionally, transcripts levels of Ins1/2, Reg-3α/γ, Ngn-3, and Pdx-1 were upregulated during the initial 1 week. The present study provides evidence of a nutraceutical contributing to islet neogenesis from ductal cells as the mode ofβ-cell regeneration and a potential therapeutic for clinical trials in management of diabetic manifestations.

scholarly journals Prevention of Diabetes in db/db Mice by Dietary Soy Is Independent of Isoflavone Levels

Endocrinology ◽  
2012 ◽  
Vol 153 (11) ◽  
pp. 5200-5211 ◽  
Author(s):  
Céline Zimmermann ◽  
Christopher R. Cederroth ◽  
Lucie Bourgoin ◽  
Michelangelo Foti ◽  
Serge Nef
Keyword(s):  
Glucose Homeostasis ◽  
Cell Function ◽  
Hepatic Glucose Production ◽  
Cell Mass ◽  
Glucose Production ◽  
Metabolic Effects ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Glucose Levels ◽  
Hepatic Glucose

Abstract Recent evidence points towards the beneficial use of soy proteins and isoflavones to improve glucose control and slow the progression of type 2 diabetes. Here, we used diabetic db/db mice fed a high soy-containing diet (SD) or a casein soy-free diet to investigate the metabolic effects of soy and isoflavones consumption on glucose homeostasis, hepatic glucose production, and pancreatic islet function. Male db/db mice fed with a SD exhibited a robust reduction in hyperglycemia (50%), correlating with a reduction in hepatic glucose production and preserved pancreatic β-cell function. The rapid decrease in fasting glucose levels resulted from an inhibition of gluconeogenesis and an increase in glycolysis in the liver of db/db mice. Soy consumption also prevented the loss of pancreatic β-cell mass and thus improved glucose-stimulated insulin secretion (3-fold), which partly accounted for the overall improvements in glucose homeostasis. Comparison of SD effects on hyperglycemia with differing levels of isoflavones or with purified isoflavones indicate that the beneficial physiological effects of soy are not related to differences in their isoflavone content. Overall, these findings suggest that consumption of soy is beneficial for improving glucose homeostasis and delaying the progression of diabetes in the db/db mice but act independently of isoflavone concentration.

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