The Pdx1-Bound Swi/Snf Chromatin Remodeling Complex Regulates Pancreatic Progenitor Cell Proliferation and Mature Islet β-Cell Function

ABSTRACTThe melastatin subfamily of the transient receptor potential channels (TRPM) are regulators of pancreatic β-cell function. TRPM7 is the most abundant islet TRPM channel; however, the role of TRPM7 in β-cell function has not been determined. Here, we utilized various spatiotemporal transgenic mouse models to investigate how TRPM7 knockout influences pancreatic endocrine development, proliferation, and function. Ablation of TRPM7 within pancreatic progenitors reduced pancreatic size, as well as α-cell and β-cell mass. This resulted in impaired glucose tolerance due to decreased serum insulin levels. However, ablation of TRPM7 following endocrine specification or in adult mice did not impact endocrine expansion or glucose tolerance. As TRPM7 regulates cell proliferation, we assessed how TRPM7 influences β-cell hyperplasia under insulin resistant conditions. β-cell proliferation induced by high-fat diet was significantly decreased in TRPM7 deficient β-cells. The endocrine roles of TRPM7 may be influenced by cation flux through the channel, and indeed we find that TRPM7 ablation alters β-cell intracellular Mg2+. Together, these findings reveal that TRPM7 controls pancreatic progenitor expansion and β-cell proliferation, which is likely due to regulation of Mg2+ homeostasis.SummaryThis manuscript identifies a critical developmental role for TRPM7 channels in pancreatic progenitor cells. The manuscript also determines that TRPM7 plays a key role in β-cell proliferation under insulin-resistant conditions.

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TRPM7 is a critical regulator of pancreatic endocrine development and high-fat diet-induced β-cell proliferation

Development ◽

10.1242/dev.194928 ◽

2021 ◽

Author(s):

Molly K. Altman ◽

Charles M. Schaub ◽

Matthew T. Dickerson ◽

Karolina E. Zaborska ◽

Prasanna K. Dadi ◽

...

Keyword(s):

Cell Proliferation ◽

Glucose Tolerance ◽

High Fat Diet ◽

Transient Receptor Potential ◽

Cell Function ◽

Cell Mass ◽

Transient Receptor Potential Channels ◽

High Fat ◽

Β Cell ◽

Β Cell Function

The melastatin subfamily of the transient receptor potential channels (TRPM) are regulators of pancreatic β-cell function. TRPM7 is the most abundant islet TRPM channel; however, the role of TRPM7 in β-cell function has not been determined. Here, we utilized various spatiotemporal transgenic mouse models to investigate how TRPM7 knockout influences pancreatic endocrine development, proliferation, and function. Ablation of TRPM7 within pancreatic progenitors reduced pancreatic size, α-cell and β-cell mass. This resulted in modestly impaired glucose tolerance. However, TRPM7 ablation following endocrine specification or in adult mice did not impact endocrine expansion or glucose tolerance. As TRPM7 regulates cell proliferation, we assessed how TRPM7 influences β-cell hyperplasia under insulin resistant conditions. β-cell proliferation induced by high-fat diet was significantly decreased in TRPM7-deficient β-cells. The endocrine roles of TRPM7 may be influenced by cation flux through the channel, and indeed we find that TRPM7 ablation alters β-cell Mg2+ and reduces the magnitude of elevation in β-cell Mg2+ during proliferation. Together, these findings reveal that TRPM7 controls pancreatic development and β-cell proliferation, which is likely due to regulation of Mg2+ homeostasis.

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Exercise improves glucose homeostasis that has been impaired by a high-fat diet by potentiating pancreatic β-cell function and mass through IRS2 in diabetic rats

Journal of Applied Physiology ◽

10.1152/japplphysiol.00434.2007 ◽

2007 ◽

Vol 103 (5) ◽

pp. 1764-1771 ◽

Cited By ~ 36

Author(s):

Sunmin Park ◽

Sang Mee Hong ◽

Ji Eun Lee ◽

So Ra Sung

Keyword(s):

Cell Proliferation ◽

High Fat Diet ◽

Cell Function ◽

Cell Mass ◽

Diabetic Rats ◽

Pancreatic Β Cell ◽

High Fat ◽

Β Cell ◽

Igf I ◽

Β Cell Function

In this study, we investigated the effects of a high-fat diet and exercise on pancreatic β-cell function and mass and its molecular mechanism in 90% pancreatectomized male rats. The pancreatectomized diabetic rats were given control diets (20% energy) or a high-fat (HF) diet (45% energy) for 12 wk. Half of each group was given regular exercise on an uphill treadmill at 20 m/min for 30 min 5 days/wk. HF diet lowered first-phase insulin secretion with glucose loading, whereas exercise training reversed this decrease. However, second-phase insulin secretion did not differ among the groups. Exercise increased pancreatic β-cell mass. This resulted from stimulated β-cell proliferation and reduced apoptosis, which is associated with potentiated insulin or IGF-I signaling through insulin receptor substrate-2 (IRS2) induction. Although the HF diet resulted in decreased proliferation and accelerated apoptosis by weakened insulin and IGF-I signaling from reduction of IRS2 protein, β-cell mass was maintained in HF rats just as much as in control rats via increased individual β-cell size and neogenesis from precursor cells. Consistent with the results of β-cell proliferation, pancreas duodenal homeobox-1 expression increased in the islets of rats in the exercise groups, and it was reduced the most in rats fed the HF diet. In conclusion, exercise combined with a moderate fat diet is a good way to maximize β-cell function and mass through IRS2 induction to alleviate the diabetic condition. This study suggests that dietary fat contents and exercise modulate β-cell function and mass to overcome insulin resistance in two different pathways.

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SMAD7 enhances adult β-cell proliferation without significantly affecting β-cell function in mice

Journal of Biological Chemistry ◽

10.1074/jbc.ra119.011011 ◽

2020 ◽

Vol 295 (15) ◽

pp. 4858-4869 ◽

Cited By ~ 2

Author(s):

Anuradha Sehrawat ◽

Chiyo Shiota ◽

Nada Mohamed ◽

Julia DiNicola ◽

Mohamed Saleh ◽

...

Keyword(s):

Cell Proliferation ◽

Transforming Growth Factor ◽

Cell Function ◽

Therapeutic Option ◽

Transforming Growth Factor Β ◽

Vital Role ◽

Negative Effects ◽

Β Cells ◽

Β Cell ◽

Β Cell Function

The interplay between the transforming growth factor β (TGF-β) signaling proteins, SMAD family member 2 (SMAD2) and 3 (SMAD3), and the TGF-β–inhibiting SMAD, SMAD7, seems to play a vital role in proper pancreatic endocrine development and also in normal β-cell function in adult pancreatic islets. Here, we generated conditional SMAD7 knockout mice by crossing insulin1Cre mice with SMAD7fx/fx mice. We also created a β cell–specific SMAD7-overexpressing mouse line by crossing insulin1Dre mice with HPRT-SMAD7/RosaGFP mice. We analyzed β-cell function in adult islets when SMAD7 was either absent or overexpressed in β cells. Loss of SMAD7 in β cells inhibited proliferation, and SMAD7 overexpression enhanced cell proliferation. However, alterations in basic glucose homeostasis were not detectable following either SMAD7 deletion or overexpression in β cells. Our results show that both the absence and overexpression of SMAD7 affect TGF-β signaling and modulates β-cell proliferation but does not appear to alter β-cell function. Reversible SMAD7 overexpression may represent an attractive therapeutic option to enhance β-cell proliferation without negative effects on β-cell function.

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GLP-1 signaling suppresses menin’s transcriptional block by phosphorylation in β cells

The Journal of Cell Biology ◽

10.1083/jcb.201805049 ◽

2019 ◽

Vol 218 (3) ◽

pp. 855-870 ◽

Cited By ~ 1

Author(s):

Bowen Xing ◽

Jian Ma ◽

Zongzhe Jiang ◽

Zijie Feng ◽

Sunbin Ling ◽

...

Keyword(s):

Cell Proliferation ◽

Gene Transcription ◽

Histone Deacetylases ◽

Cell Function ◽

Β Cells ◽

Β Cell ◽

Histone Modifiers ◽

Β Cell Function ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Both menin and glucagon-like peptide 1 (GLP-1) pathways play central yet opposing role in regulating β cell function, with menin suppressing, and GLP-1 promoting, β cell function. However, little is known as to whether or how GLP-1 pathway represses menin function. Here, we show that GLP-1 signaling–activated protein kinase A (PKA) directly phosphorylates menin at the serine 487 residue, relieving menin-mediated suppression of insulin expression and cell proliferation. Mechanistically, Ser487-phosphorylated menin gains increased binding affinity to nuclear actin/myosin IIa proteins and gets sequestrated from the Ins1 promoter. This event leads to reduced binding of repressive epigenetic histone modifiers suppressor variegation 3–9 homologue protein 1 (SUV39H1) and histone deacetylases 1 (HDAC1) at the locus and subsequently increased Ins1 gene transcription. Ser487 phosphorylation of menin also increases expression of proproliferative cyclin D2 and β cell proliferation. Our results have uncovered a previously unappreciated physiological link in which GLP-1 signaling suppresses menin function through phosphorylation-triggered and actin/myosin cytoskeletal protein–mediated derepression of gene transcription.

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Glucocorticoid-Induced Suppression of β-Cell Proliferation Is Mediated by Mig6

Endocrinology ◽

10.1210/en.2012-1923 ◽

2013 ◽

Vol 154 (3) ◽

pp. 1039-1046 ◽

Cited By ~ 21

Author(s):

E. Scott Colvin ◽

Hong-Yun Ma ◽

Yi-Chun Chen ◽

Angelina M. Hernandez ◽

Patrick T. Fueger

Keyword(s):

Cell Proliferation ◽

Epidermal Growth Factor Receptor ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Cell Function ◽

Cell Mass ◽

Growth Factor Receptor ◽

Β Cell ◽

Β Cell Function ◽

Epidermal Growth

Abstract Glucocorticoids can cause steroid-induced diabetes or accelerate the progression to diabetes by creating systemic insulin resistance and decreasing functional β-cell mass, which is influenced by changes in β-cell function, growth, and death. The synthetic glucocorticoid agonist dexamethasone (Dex) is deleterious to functional β-cell mass by decreasing β-cell function, survival, and proliferation. However, the mechanism by which Dex decreases β-cell proliferation is unknown. Interestingly, Dex induces the transcription of an antiproliferative factor and negative regulator of epidermal growth factor receptor signaling, Mig6 (also known as gene 33, RALT, and Errfi1). We, therefore, hypothesized that Dex impairs β-cell proliferation by increasing the expression of Mig6 and thereby decreasing downstream signaling of epidermal growth factor receptor. We found that Dex induced Mig6 and decreased [3H]thymidine incorporation, an index of cellular replication, in mouse, rat, and human islets. Using adenovirally delivered small interfering RNA targeted to Mig6 in rat islets, we were able to limit the induction of Mig6 upon exposure to Dex, compared with islets treated with a control virus, and completely rescued the Dex-mediated impairment in replication. We demonstrated that both Dex and overexpression of Mig6 attenuated the phosphorylation of ERK1/2 and blocked the G1/S transition of the cell cycle. In conclusion, Mig6 functions as a molecular brake for β-cell proliferation during glucocorticoid treatment in β-cells, and thus, Mig6 may be a novel target for preventing glucocorticoid-induced impairments in functional β-cell mass.

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Elevated Circulating LINC-P21 Serves as a Diagnostic Biomarker of Type 2 Diabetes Mellitus and Regulates Pancreatic β-cell Function by Sponging miR-766-3p to Upregulate NR3C2

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/a-1247-4978 ◽

2020 ◽

Author(s):

Zhibin Cao ◽

Fuwang Yao ◽

Yuqin Lang ◽

Xueqiang Feng

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Cell Proliferation ◽

Type 2 Diabetes Mellitus ◽

Insulin Secretion ◽

Cell Function ◽

Β Cell ◽

Β Cell Function ◽

Glucose Stimulated Insulin Secretion

Abstract Objective The purpose of this study was to evaluate the clinical value and biological function of long non-coding RNA (lncRNA) LINC-P21 in type 2 diabetes mellitus (T2DM), and explore the underlying mechanisms. Methods The expression of LINC-P21 was estimated using quantitative real-time PCR. The functional role of LINC-P21 was explored by gain- and loss-of-function experiments. INS-1 cell proliferation was analyzed using a cell counting kit-8 (CCK-8)assay, and the glucose-stimulated insulin secretion was measured using an ELISA kit. The miRNAs that might be sponged by LINC-P21 were analyzed, and the subsequent target genes were predicted and assessed in INS-1 cells. Results Serum expression of LINC-P21 was elevated in T2DM patients, which was correlated with fasting blood glucose levels and disease diagnosis. The glucose-stimulated insulin secretion and the proliferation of INS-1 cells were enhanced by LINC-P21 knockdown, but the overexpression of LINC-P21 led to opposite effects. miR-766-3p could be directly inhibited by LINC-P21 in INS-1 cells and reverse the effects of LINC-P21 on β-cell function. Additionally, NR3C2 was determined as a target of miR-766-3p, which could be positively regulated by LINC-P21 and had same effects with LINC-P21 on INS-1 cell proliferation and insulin secretion. Conclusion All the data demonstrated that serum elevated LINC-P21 and decreased miR-766-3p serve as candidate diagnostic biomarkers in T2DM patients. LINC-P21 acts as a potential regulator in insulin secretion and proliferation of pancreatic β-cells through targeting miR-766-3p to upregulate NR3C2.

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Genistein Induces Pancreatic β-Cell Proliferation through Activation of Multiple Signaling Pathways and Prevents Insulin-Deficient Diabetes in Mice

Endocrinology ◽

10.1210/en.2009-1294 ◽

2010 ◽

Vol 151 (7) ◽

pp. 3026-3037 ◽

Cited By ~ 124

Author(s):

Zhuo Fu ◽

Wen Zhang ◽

Wei Zhen ◽

Hazel Lum ◽

Jerry Nadler ◽

...

Keyword(s):

Cell Proliferation ◽

Cell Function ◽

Herbal Medicines ◽

Human Islets ◽

Pancreatic Β Cell ◽

Diabetic Mice ◽

Β Cell ◽

Β Cell Function ◽

17Β Estradiol ◽

Multiple Signaling

Genistein, a flavonoid in legumes and some herbal medicines, has various biological actions. However, studies on whether genistein has an effect on pancreatic β-cell function are very limited. In the present study, we investigated the effect of genistein on β-cell proliferation and cellular signaling related to this effect and further determined its antidiabetic potential in insulin-deficient diabetic mice. Genistein induced both INS1 and human islet β-cell proliferation after 24 h of incubation, with 5 μm genistein inducing a maximal 27% increase. The effect of genistein on β-cell proliferation was neither dependent on estrogen receptors nor shared by 17β-estradiol or a host of structurally related flavonoid compounds. Pharmacological or molecular intervention of protein kinase A (PKA) or ERK1/2 completely abolished genistein-stimulated β-cell proliferation, suggesting that both molecules are essential for genistein action. Consistent with its effect on cell proliferation, genistein induced cAMP/PKA signaling and subsequent phosphorylation of ERK1/2 in both INS1 cells and human islets. Furthermore, genistein induced protein expression of cyclin D1, a major cell-cycle regulator essential for β-cell growth. Dietary intake of genistein significantly improved hyperglycemia, glucose tolerance, and blood insulin levels in streptozotocin-induced diabetic mice, concomitant with improved islet β-cell proliferation, survival, and mass. These results demonstrate that genistein may be a natural antidiabetic agent by directly modulating pancreatic β-cell function via activation of the cAMP/PKA-dependent ERK1/2 signaling pathway.

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Bee Pollen Polysaccharide From Rosa rugosa Thunb. (Rosaceae) Promotes Pancreatic β-Cell Proliferation and Insulin Secretion

Frontiers in Pharmacology ◽

10.3389/fphar.2021.688073 ◽

2021 ◽

Vol 12 ◽

Author(s):

Siwen Yang ◽

Yunhe Qu ◽

Jiyu Chen ◽

Si Chen ◽

Lin Sun ◽

...

Keyword(s):

Cell Proliferation ◽

Cell Function ◽

Therapeutic Potential ◽

Liver Fat ◽

Pancreatic Β Cell ◽

Diabetic Mice ◽

Β Cell ◽

Bee Pollen ◽

Insulin Synthesis ◽

Β Cell Function

Insufficient pancreatic β-cell or insulin-producing β-cell are implicated in all types of diabetes mellitus. Our previous studies showed bee pollen polysaccharide RBPP-P improves insulin resistance in type 2 diabetic mice by inhibiting liver fat deposition. However, its potential of regulating β-cell function and integrity is not fully known. Herein, we observed that β-cell proliferation (n = 10), insulin synthesis (n = 5, p = 0.01684) and insulin incretion (n = 5, p = 0.02115) were intensely activated in MIN6 cells when treatment with RBPP-P. In alloxan-induced diabetic mice, oral administration of RBPP-P (n = 10) effectively decreased the blood glucose (p = 0.0326), drink intake (p < 0.001) and urine (p < 0.001). It directly stimulated phosphorylation of p38 (p = 0.00439), ERK (p = 0.02951) and AKT (p = 0.0072) to maintain the islet function and mass. Thus, our data suggest that RBPP-P is a natural compound to regulate β-cell proliferation and function, indicating it might have therapeutic potential against type 1 diabetes.

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Connective tissue growth factor is critical for proper β-cell function and pregnancy-induced β-cell hyperplasia in adult mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00194.2016 ◽

2016 ◽

Vol 311 (3) ◽

pp. E564-E574 ◽

Cited By ~ 7

Author(s):

Raymond C. Pasek ◽

Jennifer C. Dunn ◽

Joseph M. Elsakr ◽

Mounika Aramandla ◽

Anveetha R. Matta ◽

...

Keyword(s):

Cell Proliferation ◽

Insulin Secretion ◽

Growth Factor ◽

Gestational Diabetes ◽

Cell Function ◽

Tissue Growth ◽

Β Cells ◽

Β Cell ◽

Β Cell Function ◽

Glucose Stimulated Insulin Secretion

During pregnancy, maternal β-cells undergo compensatory changes, including increased β-cell mass and enhanced glucose-stimulated insulin secretion. Failure of these adaptations to occur results in gestational diabetes mellitus. The secreted protein connective tissue growth factor (CTGF) is critical for normal β-cell development and promotes regeneration after partial β-cell ablation. During embryogenesis, CTGF is expressed in pancreatic ducts, vasculature, and β-cells. In adult pancreas, CTGF is expressed only in the vasculature. Here we show that pregnant mice with global Ctgf haploinsufficiency (CtgfLacZ/+) have an impairment in maternal β-cell proliferation; no difference was observed in virgin CtgfLacZ/+ females. Using a conditional CTGF allele, we found that mice with a specific inactivation of CTGF in endocrine cells (CtgfΔEndo) develop gestational diabetes during pregnancy, but this is due to a reduction in glucose-stimulated insulin secretion rather than impaired maternal β-cell proliferation. Moreover, virgin CtgfΔEndo females also display impaired GSIS with glucose intolerance, indicating that underlying β-cell dysfunction precedes the development of gestational diabetes in this animal model. This is the first time a role for CTGF in β-cell function has been reported.

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