scholarly journals Early administration of keratinocyte growth factor improves β-cell regeneration in rat with streptozotocin-induced diabetes

2007 ◽  
Vol 195 (2) ◽  
pp. 333-340 ◽  
Author(s):  
Jamileh Movassat ◽  
Bernard Portha
Keyword(s):  
Body Weight ◽  
Growth Factor ◽  
Wistar Rats ◽  
Keratinocyte Growth Factor ◽  
Cell Mass ◽  
Duct Cell ◽  
Cell Regeneration ◽  
Cell Replication ◽  
Β Cell ◽  
Old Rats

The aim of our study was to investigate the ability of keratinocyte growth factor (KGF; palifermin) in regulating β-cell growth in normal newborn rats and in rats with neonatal diabetes. Wistar rats were injected with streptozotocin (STZ) to induce diabetes on the dayof birth. From days 2 to 6 after birth, animals received a daily s.c. injection of KGF (STZ/KGF group) and at the dose of 3 mg/kg body weight or saline solution (STZ groups). A group of non-diabetic Wistar rats was treated either with saline (Wistar group) or with KGF from days 2 to 6 after birth at the dose of 3 mg/kg body weight (Wistar/KGF group). β-cell mass was measured at day 7 after birth in all groups. β- and ductal cells replication were measured in all groups and apoptosis was assessed in the pancreas of 2-, 4-, and 7-day-old STZ and STZ/KGF rats. The total β-cell mass of the 7-day-old KGF/STZ neonates was significantly increased compared with that of age-matched STZ rats. β-cell replication rate was decreased at day 2 in the STZ/KGF group and was similar in the 4- and 7-day-old rats from STZ and STZ/KGF groups. Duct cell replication was significantly increased in the pancreas of 2- and 4-day-old KGF/STZ neonates when compared with that of age-matched rats from STZ control group. The rate of apoptosis in the neonatal pancreases of STZ and KGF/STZ groups was not significantly different. In non-diabetic Wistar rats, KGF treatment led to a slight but significant increase in duct cell proliferation at day 2 without significant changes in the total β-cell mass in the 7-day-old rats. We provide evidence for a growth-promoting effect of KGF during β-cell regeneration in neonatal diabetic rats. KGF exerts strong mitogenic effect on the pancreatic duct cells, thus expanding the population of precursor cells that subsequently differentiate into insulin-producing β-cells.

scholarly journals Increased β-Cell Replication and β-Cell Mass Regeneration in Syngeneically Transplanted Rat Islets Overexpressing Insulin-Like Growth Factor II

2012 ◽  
Vol 21 (10) ◽  
pp. 2119-2129 ◽  
Author(s):  
Elisabet Estil·les ◽  
Noèlia Téllez ◽  
Jessica Escoriza ◽  
Eduard Montanya
Keyword(s):  
Growth Factor ◽  
Cell Mass ◽  
Insulin Like Growth Factor ◽  
Cell Replication ◽  
Β Cell ◽  
Rat Islets ◽  
Factor Ii

scholarly journals Dynamics of β-cell turnover: evidence for β-cell turnover and regeneration from sources of β-cells other than β-cell replication in the HIP rat

2009 ◽  
Vol 297 (2) ◽  
pp. E323-E330 ◽  
Author(s):  
Erica Manesso ◽  
Gianna M. Toffolo ◽  
Yoshifumi Saisho ◽  
Alexandra E. Butler ◽  
Aleksey V. Matveyenko ◽  
...  
Keyword(s):  
Cell Mass ◽  
Cell Formation ◽  
Cell Regeneration ◽  
Cell Turnover ◽  
Cell Replication ◽  
Wild Type ◽  
Β Cells ◽  
Β Cell ◽  
Islet Amyloid

Type 2 diabetes is characterized by hyperglycemia, a deficit in β-cells, increased β-cell apoptosis, and islet amyloid derived from islet amyloid polypeptide (IAPP). These characteristics are recapitulated in the human IAPP transgenic (HIP) rat. We developed a mathematical model to quantify β-cell turnover and applied it to nondiabetic wild type (WT) vs. HIP rats from age 2 days to 10 mo to establish 1) whether β-cell formation is derived exclusively from β-cell replication, or whether other sources of β-cells (OSB) are present, and 2) to what extent, if any, there is attempted β-cell regeneration in the HIP rat and if this is through β-cell replication or OSB. We conclude that formation and maintenance of adult β-cells depends largely (∼80%) on formation of β-cells independent from β-cell duplication. Moreover, this source adaptively increases in the HIP rat, implying attempted β-cell regeneration that substantially slows loss of β-cell mass.

scholarly journals β-Cell dedifferentiation, reduced duct cell plasticity, and impaired β-cell mass regeneration in middle-aged rats

2016 ◽  
Vol 311 (3) ◽  
pp. E554-E563 ◽  
Author(s):  
Noèlia Téllez ◽  
Marina Vilaseca ◽  
Yasmina Martí ◽  
Arturo Pla ◽  
Eduard Montanya
Keyword(s):  
Cell Mass ◽  
Duct Cell ◽  
Cell Regeneration ◽  
Aged Rats ◽  
Cell Plasticity ◽  
Middle Aged ◽  
Β Cell ◽  
Partial Pancreatectomy ◽  
Cell Dedifferentiation ◽  
Increased Risk

Limitations in β-cell regeneration potential in middle-aged animals could contribute to the increased risk to develop diabetes associated with aging. We investigated β-cell regeneration of middle-aged Wistar rats in response to two different regenerative stimuli: partial pancreatectomy (Px + V) and gastrin administration (Px + G). Pancreatic remnants were analyzed 3 and 14 days after surgery. β-Cell mass increased in young animals after Px and was further increased after gastrin treatment. In contrast, β-cell mass did not change after Px or after gastrin treatment in middle-aged rats. β-Cell replication and individual β-cell size were similarly increased after Px in young and middle-aged animals, and β-cell apoptosis was not modified. Nuclear immunolocalization of neurog3 or nkx6.1 in regenerative duct cells, markers of duct cell plasticity, was increased in young but not in middle-aged Px rats. The pancreatic progenitor-associated transcription factors neurog3 and sox9 were upregulated in islet β-cells of middle-aged rats and further increased after Px. The percentage of chromogranin A+/hormone islet cells was significantly increased in the pancreases of middle-aged Px rats. In summary, the potential for compensatory β-cell hyperplasia and hypertrophy was retained in middle-aged rats, but β-cell dedifferentiation and impaired duct cell plasticity limited β-cell regeneration.

scholarly journals Insulin Stimulates Primary β-Cell Proliferation via Raf-1 Kinase

Endocrinology ◽  
2008 ◽  
Vol 149 (5) ◽  
pp. 2251-2260 ◽  
Author(s):  
Jennifer L. Beith ◽  
Emilyn U. Alejandro ◽  
James D. Johnson
Keyword(s):  
Cell Proliferation ◽  
Dominant Role ◽  
Cell Mass ◽  
Diabetes Type 2 ◽  
Dominant Negative ◽  
Cell Replication ◽  
Β Cell ◽  
Physiological Control ◽  
Primary Mouse

A relative decrease in β-cell mass is key in the pathogenesis of type 1 diabetes, type 2 diabetes, and in the failure of transplanted islet grafts. It is now clear that β-cell duplication plays a dominant role in the regulation of adult β-cell mass. Therefore, knowledge of the endogenous regulators of β-cell replication is critical for understanding the physiological control of β-cell mass and for harnessing this process therapeutically. We have shown that concentrations of insulin known to exist in vivo act directly on β-cells to promote survival. Whether insulin stimulates adult β-cell proliferation remains unclear. We tested this hypothesis using dispersed primary mouse islet cells double labeled with 5-bromo-2-deoxyuridine and insulin antisera. Treating cells with 200-pm insulin significantly increased proliferation from a baseline rate of 0.15% per day. Elevating glucose from 5–15 mm did not significantly increase β-cell replication. β-Cell proliferation was inhibited by somatostatin as well as inhibitors of insulin signaling. Interestingly, inhibiting Raf-1 kinase blocked proliferation stimulated by low, but not high (superphysiological), insulin doses. Insulin-stimulated mouse insulinoma cell proliferation was dependent on both phosphatidylinositol 3-kinase/Akt and Raf-1/MAPK kinase pathways. Overexpression of Raf-1 was sufficient to increase proliferation in the absence of insulin, whereas a dominant-negative Raf-1 reduced proliferation in the presence of 200-pm insulin. Together, these results demonstrate for the first time that insulin, at levels that have been measured in vivo, can directly stimulate β-cell proliferation and that Raf-1 kinase is involved in this process. These findings have significant implications for the understanding of the regulation of β-cell mass in both the hyperinsulinemic and insulin-deficient states that occur in the various forms of diabetes.

scholarly journals Short-Term High-Starch, Low-Protein Diet Induces Reversible Increase in β-cell Mass Independent of Body Weight Gain in Mice

Nutrients ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 1045 ◽  
Author(s):  
Atsushi Masuda ◽  
Yusuke Seino ◽  
Masatoshi Murase ◽  
Shihomi Hidaka ◽  
Megumi Shibata ◽  
...  
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Body Weight Gain ◽  
Cell Mass ◽  
Protein Diet ◽  
Β Cell ◽  
Short Term ◽  
Insulin Levels ◽  
Low Protein ◽  
High Starch

Long-term exposure to a high starch, low-protein diet (HSTD) induces body weight gain and hyperinsulinemia concomitantly with an increase in β-cell mass (BCM) and pancreatic islets number in mice; however, the effect of short-term exposure to HSTD on BCM and islet number has not been elucidated. In the present study, we investigated changes in body weight, plasma insulin levels, BCM and islet number in mice fed HSTD for 5 weeks followed by normal chow (NC) for 2 weeks. BCM and islet number were increased in mice fed HSTD for 5 weeks compared with those in mice fed NC. On the other hand, mice fed HSTD for 5 weeks followed by NC for 2 weeks (SN) showed decreased BCM and insulin levels, compared to mice fed HSTD for 7 weeks, and no significant differences in these parameters were observed between SN and the control NC at 7 weeks. No significant difference in body weight was observed among HSTD, NC and SN fed groups. These results suggest that a high-starch diet induces an increase in BCM in a manner independent of body weight gain, and that 2 weeks of NC feeding is sufficient for the reversal of the morphological changes induced in islets by HSTD feeding.

scholarly journals Differential Effects of Prenatal and Postnatal Nutritional Environment on β-Cell Mass Development and Turnover in Male and Female Rats

Endocrinology ◽  
2010 ◽  
Vol 151 (12) ◽  
pp. 5647-5656 ◽  
Author(s):  
Aleksey V. Matveyenko ◽  
Inderroop Singh ◽  
Bo-Chul Shin ◽  
Senta Georgia ◽  
Sherin U. Devaskar
Keyword(s):  
Type 2 Diabetes ◽  
Cell Mass ◽  
Growth Restriction ◽  
Female Rats ◽  
Cell Replication ◽  
Β Cell ◽  
Male And Female ◽  
Fractional Area ◽  
Mass Development

Fetal nutrient and growth restriction is associated with development of type 2 diabetes. Although the exact mechanisms responsible for this association remain debated, intrauterine and/or postnatal maldevelopment of β-cell mass has been proposed as a potential mechanism. To address this hypothesis, β-cell mass development and turnover was assessed in rats exposed to either intrauterine and/or postnatal caloric/growth restriction. In total, four groups of male and female Sprague Dawley rats (n = 69) were developed and studied: 1) control rats, i.e. control mothers rearing control pups; 2) intrauterine calorically and growth-restricted rats, i.e. 50% prenatal calorically restricted pups cross-fostered to control mothers; 3) postnatal calorically and growth-restricted rats, i.e. 50% calorically restricted mothers rearing pups born to control mothers; and 4) prenatal and postnatal calorically and growth restricted rats, i.e. 50% calorically restricted mothers rearing intrauterine 50% calorically restricted pups. Intrauterine growth restriction resulted in approximately 45% reduction of postnatal β-cell fractional area and mass characterized by reduced rate of β-cell replication and decreased evidence of neogenesis. In contrast, β-cell fractional area and weight-adjusted β-cell mass in postnatal growth restriction was approximately 30% higher than in control rats. Rats exposed to both intrauterine and postnatal caloric and growth restriction demonstrated approximately 80% decrease in β-cell mass, reduction in β-cell replication, and decreased evidence of neogenesis compared with control. Neither intrauterine nor postnatal caloric restriction significantly affected the rate of β-cell apoptosis. These data support the hypothesis that intrauterine maldevelopment of β-cell mass may predict the increased risk of type 2 diabetes in adult life.

scholarly journals Mechanisms involved in the beta-cell mass increase induced by chronic sucrose feeding to normal rats

2002 ◽  
Vol 174 (2) ◽  
pp. 225-231 ◽  
Author(s):  
H Del Zotto ◽  
CL Gomez Dumm ◽  
S Drago ◽  
A Fortino ◽  
GC Luna ◽  
...  
Keyword(s):  
Body Weight ◽  
Beta Cell ◽  
Beta Cells ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Serum Glucose ◽  
Beta Cell Apoptosis ◽  
Cell Replication ◽  
Replication Rate ◽  
Endocrine Tissue

The aim of the present study was to clarify the mechanisms by which a sucrose-rich diet (SRD) produces an increase in the pancreatic beta-cell mass in the rat. Normal Wistar rats were fed for 30 weeks either an SRD (SRD rats; 63% wt/wt), or the same diet but with starch instead of sucrose in the same proportion (CD rats). We studied body weight, serum glucose and triacylglycerol levels, endocrine tissue and beta-cell mass, beta-cell replication rate (proliferating cell nuclear antigen; PCNA), islet neogenesis (cytokeratin immunostaining) and beta-cell apoptosis (propidium iodide). Body weight (g) recorded in the SRD rats was significantly (P<0.05) larger than that of the CD group (556.0+/-8.3 vs 470.0+/-13.1). Both serum glucose and triacylglycerol levels (mmol/l) were also significantly higher (P<0.05) in SRD than in CD rats (serum glucose, 8.11+/-0.14 vs 6.62+/-0.17; triacylglycerol, 1.57+/-0.18 vs 0.47+/-0.04). The number of pancreatic islets per unit area increased significantly (P<0.05) in SRD rats (3.29+/-0.1 vs 2.01+/-0.2). A significant increment (2.6 times) in the mass of endocrine tissue was detected in SRD animals, mainly due to an increase in the beta-cell mass (P=0.0025). The islet cell replication rate, measured as the percentage of PCNA-labelled beta cells increased 6.8 times in SRD rats (P<0.03). The number of apoptotic cells in the endocrine pancreas decreased significantly (three times) in the SRD animals (P=0.03). The cytokeratin-positive area did not show significant differences between CD and SRD rats. The increase of beta-cell mass induced by SRD was accomplished by an enhanced replication of beta cells together with a decrease in the rate of beta-cell apoptosis, without any evident participation of islet neogenesis. This pancreatic reaction was unable to maintain serum glucose levels of these rats at the level measured in CD animals.

scholarly journals Monosodium Glutamate Dietary Consumption Decreases Pancreatic β-Cell Mass in Adult Wistar Rats

PLoS ONE ◽  
2015 ◽  
Vol 10 (6) ◽  
pp. e0131595 ◽  
Author(s):  
Piyanard Boonnate ◽  
Sakda Waraasawapati ◽  
Wiphawi Hipkaeo ◽  
Supattra Pethlert ◽  
Amod Sharma ◽  
...  
Keyword(s):  
Wistar Rats ◽  
Monosodium Glutamate ◽  
Cell Mass ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Dietary Consumption

scholarly journals Impaired islet turnover in human donor pancreata with aging

2009 ◽  
Vol 160 (2) ◽  
pp. 185-191 ◽  
Author(s):  
Christina Reers ◽  
Saskia Erbel ◽  
Irene Esposito ◽  
Bruno Schmied ◽  
Markus W Büchler ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Cell Volume ◽  
Cell Apoptosis ◽  
Cell Function ◽  
Cell Mass ◽  
Pancreatic Tissue ◽  
Human Pancreas ◽  
Cell Replication ◽  
Β Cell ◽  
Islet Neogenesis

ObjectiveThe prevalence of type 2 diabetes mellitus escalates with aging although β-cell mass, a primary parameter of β-cell function, is subject to compensatory regulation. So far it is unclear whether the proliferative capacity of pancreatic islets is restricted by senescence.Materials and methodsHuman pancreatic tissue from n=20 non-diabetic organ donors with a mean age of 50.2±3.5 years (range 7–66 years) and mean body mass index of 25.7±0.9 kg/m2 (17.2–33.1 kg/m2) was morphometrically analyzed to determine β-cell volume, β-cell replication, β-cell apoptosis, islet neogenesis, and pancreatic duodenal homeobox-1 (PDX-1) expression.ResultsRelative β-cell volume in human pancreata (mean 2.3±0.2%) remains constant with aging (r=0.26, P=ns). β-cell replication (r=0.71, P=0.0004) decreases age-dependently, while β-cell apoptosis does not change significantly (r=0.42, P=0.08). Concomitantly, PDX-1 expression is downregulated with age in human pancreatic tissue (r=0.65, P=0.002). The rate of islet neogenesis is not affected by aging (r=0.13, P=ns).ConclusionsIn non-diabetic humans, aging is linked with impaired islet turnover possibly due to reduced PDX-1 expression. As β-cell replication is considered to be the main mechanism responsible for β-cell regeneration, these changes restrict the flexibility of the aging human pancreas to adapt to changing demands for insulin secretion and increase the risk for the development of diabetes mellitus in older subjects.

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