scholarly journals DYRK1A Kinase Inhibitors Promote β-Cell Survival and Insulin Homeostasis

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2263
Author(s):  
Agata Barzowska ◽  
Barbara Pucelik ◽  
Katarzyna Pustelny ◽  
Alex Matsuda ◽  
Alicja Martyniak ◽  
...  

The rising prevalence of diabetes is threatening global health. It is known not only for the occurrence of severe complications but also for the SARS-Cov-2 pandemic, which shows that it exacerbates susceptibility to infections. Current therapies focus on artificially maintaining insulin homeostasis, and a durable cure has not yet been achieved. We demonstrate that our set of small molecule inhibitors of DYRK1A kinase potently promotes β-cell proliferation, enhances long-term insulin secretion, and balances glucagon level in the organoid model of the human islets. Comparable activity is seen in INS-1E and MIN6 cells, in isolated mice islets, and human iPSC-derived β-cells. Our compounds exert a significantly more pronounced effect compared to harmine, the best-documented molecule enhancing β-cell proliferation. Using a body-like environment of the organoid, we provide a proof-of-concept that small–molecule–induced human β-cell proliferation via DYRK1A inhibition is achievable, which lends a considerable promise for regenerative medicine in T1DM and T2DM treatment.

2019 ◽  
Author(s):  
Hans E. Hohmeier ◽  
Lu Zhang ◽  
Brandon Taylor ◽  
Samuel Stephens ◽  
Peter McNamara ◽  
...  

AbstractA key event in the development of both major forms of diabetes is the loss of functional pancreatic islet β-cell mass. Strategies aimed at enhancing β-cell regeneration have long been pursued, but methods for reliably inducing human β-cell proliferation with full retention of key functions such as glucose-stimulated insulin secretion (GSIS) are still very limited. We have previously reported that overexpression of the homeobox transcription factor Nkx6.1 stimulates β-cell proliferation, while also enhancing GSIS and providing protection against β-cell cytotoxicity through induction of the VGF prohormone. We developed an Nkx6.1 pathway screen by stably transfecting 832/13 rat insulinoma cells with a VGF promoter-luciferase reporter construct, using the resultant cell line to screen a 630,000 compound chemical library. We isolated three compounds with consistent effects to stimulate human islet cell proliferation. Further studies of the most potent of these compounds, GNF-9228, revealed that it selectively activates human β-cell relative to α-cell proliferation and has no effect on δ-cell replication. In addition, pre-treatment, but not short term exposure of human islets to GNF-9228 enhances GSIS. GNF-9228 also protects 832/13 insulinoma cells against ER stress- and inflammatory cytokine-induced cytotoxicity. In contrast to recently emergent Dyrk1a inhibitors that stimulate human islet cell proliferation, GNF-9228 does not activate NFAT translocation. These studies have led to identification of a small molecule with pleiotropic positive effects on islet biology, including stimulation of human β-cell proliferation and insulin secretion, and protection against multiple agents of cytotoxic stress.


2016 ◽  
Vol 5 (10) ◽  
pp. 988-996 ◽  
Author(s):  
Kevin Vivot ◽  
Valentine S. Moullé ◽  
Bader Zarrouki ◽  
Caroline Tremblay ◽  
Arturo D. Mancini ◽  
...  

PLoS ONE ◽  
2020 ◽  
Vol 15 (3) ◽  
pp. e0224344 ◽  
Author(s):  
Hans E. Hohmeier ◽  
Lu Zhang ◽  
Brandon Taylor ◽  
Samuel Stephens ◽  
Danhong Lu ◽  
...  

2008 ◽  
Vol 22 (12) ◽  
pp. 2716-2728 ◽  
Author(s):  
Jeremy A. Lavine ◽  
Philipp W. Raess ◽  
Dawn Belt Davis ◽  
Mary E. Rabaglia ◽  
Brent K. Presley ◽  
...  

PLoS Genetics ◽  
2016 ◽  
Vol 12 (12) ◽  
pp. e1006466 ◽  
Author(s):  
Mark P. Keller ◽  
Pradyut K. Paul ◽  
Mary E. Rabaglia ◽  
Donnie S. Stapleton ◽  
Kathryn L. Schueler ◽  
...  

2020 ◽  
Vol 12 (541) ◽  
pp. eaay0455
Author(s):  
Joon Ho Moon ◽  
Hyeongseok Kim ◽  
Hyunki Kim ◽  
Jungsun Park ◽  
Wonsuk Choi ◽  
...  

Pregnancy imposes a substantial metabolic burden on women through weight gain and insulin resistance. Lactation reduces the risk of maternal postpartum diabetes, but the mechanisms underlying this benefit are unknown. Here, we identified long-term beneficial effects of lactation on β cell function, which last for years after the cessation of lactation. We analyzed metabolic phenotypes including β cell characteristics in lactating and non-lactating humans and mice. Lactating and non-lactating women showed comparable glucose tolerance at 2 months after delivery, but after a mean of 3.6 years, glucose tolerance in lactated women had improved compared to non-lactated women. In humans, the disposition index, a measure of insulin secretory function of β cells considering the degree of insulin sensitivity, was higher in lactated women at 3.6 years after delivery. In mice, lactation improved glucose tolerance and increased β cell mass at 3 weeks after delivery. Amelioration of glucose tolerance and insulin secretion were maintained up to 4 months after delivery in lactated mice. During lactation, prolactin induced serotonin production in β cells. Secreted serotonin stimulated β cell proliferation through serotonin receptor 2B in an autocrine and paracrine manner. In addition, intracellular serotonin acted as an antioxidant to mitigate oxidative stress and improved β cell survival. Together, our results suggest that serotonin mediates the long-term beneficial effects of lactation on female metabolic health by increasing β cell proliferation and reducing oxidative stress in β cells.


2004 ◽  
Vol 167 (6) ◽  
pp. 1123-1135 ◽  
Author(s):  
Thierry Brun ◽  
Isobel Franklin ◽  
Luc St-Onge ◽  
Anna Biason-Lauber ◽  
Eugene J. Schoenle ◽  
...  

The mechanism by which the β-cell transcription factor Pax4 influences cell function/mass was studied in rat and human islets of Langerhans. Pax4 transcripts were detected in adult rat islets, and levels were induced by the mitogens activin A and betacellulin. Wortmannin suppressed betacellulin-induced Pax4 expression, implicating the phosphatidylinositol 3-kinase signaling pathway. Adenoviral overexpression of Pax4 caused a 3.5-fold increase in β-cell proliferation with a concomitant 1.9-, 4-, and 5-fold increase in Bcl-xL (antiapoptotic), c-myc, and Id2 mRNA levels, respectively. Accordingly, Pax4 transactivated the Bcl-xL and c-myc promoters, whereas its diabetes-linked mutant was less efficient. Bcl-xL activity resulted in altered mitochondrial calcium levels and ATP production, explaining impaired glucose-induced insulin secretion in transduced islets. Infection of human islets with an inducible adenoviral Pax4 construct caused proliferation and protection against cytokine-evoked apoptosis, whereas the mutant was less effective. We propose that Pax4 is implicated in β-cell plasticity through the activation of c-myc and potentially protected from apoptosis through Bcl-xL gene expression.


2015 ◽  
Vol 308 (7) ◽  
pp. E573-E582 ◽  
Author(s):  
Rockann E. Mosser ◽  
Matthew F. Maulis ◽  
Valentine S. Moullé ◽  
Jennifer C. Dunn ◽  
Bethany A. Carboneau ◽  
...  

Both short- (1 wk) and long-term (2–12 mo) high-fat diet (HFD) studies reveal enhanced β-cell mass due to increased β-cell proliferation. β-Cell proliferation following HFD has been postulated to occur in response to insulin resistance; however, whether HFD can induce β-cell proliferation independent of insulin resistance has been controversial. To examine the kinetics of HFD-induced β-cell proliferation and its correlation with insulin resistance, we placed 8-wk-old male C57Bl/6J mice on HFD for different lengths of time and assayed the following: glucose tolerance, insulin secretion in response to glucose, insulin tolerance, β-cell mass, and β-cell proliferation. We found that β-cell proliferation was significantly increased after only 3 days of HFD feeding, weeks before an increase in β-cell mass or peripheral insulin resistance was detected. These results were confirmed by hyperinsulinemic euglycemic clamps and measurements of α-hydroxybutyrate, a plasma biomarker of insulin resistance in humans. An increase in expression of key islet-proliferative genes was found in isolated islets from 1-wk HFD-fed mice compared with chow diet (CD)-fed mice. These data indicate that short-term HFD feeding enhances β-cell proliferation before insulin resistance becomes apparent.


2013 ◽  
Vol 135 (5) ◽  
pp. 1669-1672 ◽  
Author(s):  
Weijun Shen ◽  
Matthew S. Tremblay ◽  
Vishal A. Deshmukh ◽  
Weidong Wang ◽  
Christophe M. Filippi ◽  
...  

Endocrinology ◽  
2010 ◽  
Vol 151 (7) ◽  
pp. 3026-3037 ◽  
Author(s):  
Zhuo Fu ◽  
Wen Zhang ◽  
Wei Zhen ◽  
Hazel Lum ◽  
Jerry Nadler ◽  
...  

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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