Cyclin D2 Is Essential for the Compensatory β-Cell Hyperplastic Response to Insulin Resistance in Rodents

Georgia, Senta; Hinault, Charlotte; Kawamori, Dan; Hu, Jiang; Meyer, John Stirling; Kanji, Murtaza; Bhushan, Anil; Kulkarni, Rohit

doi:10.2337/db09-0838

Cited by 61 publications

(65 citation statements)

References 58 publications

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“…Moreover, we observed increased insulin-positive cells in the ductal epithelium and a significant enhancement in the number of duct-associated small islet-like clusters (ICCs) (Lee et al, 2010). In addition, several recent studies have underscored the important roles of other cell cycle regulators in  cell biology (Annicotte et al, 2009;Cozar-Castellano et al, 2006;Fajas et al, 2004;Fiaschi-Taesch et al, 2009;Georgia and Bhushan, 2004;Georgia et al, 2010;Krishnamurthy et al, 2006;Kushner et al, 2005;Rachdi et al, 2006;Uchida et al, 2005;Zhang et al, 2005).…”

Section: Introductionmentioning

confidence: 62%

The Cdk4-E2f1 pathway regulates early pancreas development by targeting Pdx1+ progenitors and Ngn3+ endocrine precursors

Kim

Rane

2011

Development

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SUMMARYCell division and cell differentiation are intricately regulated processes vital to organ development. Cyclin-dependent kinases (Cdks) are master regulators of the cell cycle that orchestrate the cell division and differentiation programs. Cdk1 is essential to drive cell division and is required for the first embryonic divisions, whereas Cdks 2, 4 and 6 are dispensable for organogenesis but vital for tissue-specific cell development. Here, we illustrate an important role for Cdk4 in regulating early pancreas development. Pancreatic development involves extensive morphogenesis, proliferation and differentiation of the epithelium to give rise to the distinct cell lineages of the adult pancreas. The cell cycle molecules that specify lineage commitment within the early pancreas are unknown. We show that Cdk4 and its downstream transcription factor E2f1 regulate mouse pancreas development prior to and during the secondary transition. Cdk4 deficiency reduces embryonic pancreas size owing to impaired mesenchyme development and fewer Pdx1 + pancreatic progenitor cells. Expression of activated Cdk4 R24C kinase leads to increased Nkx2.2 + and Nkx6.1 + cells and a rise in the number and proliferation of Ngn3 + endocrine precursors, resulting in expansion of the  cell lineage. We show that E2f1 binds and activates the Ngn3 promoter to modulate Ngn3 expression levels in the embryonic pancreas in a Cdk4-dependent manner. These results suggest that Cdk4 promotes  cell development by directing E2f1-mediated activation of Ngn3 and increasing the pool of endocrine precursors, and identify Cdk4 as an important regulator of early pancreas development that modulates the proliferation potential of pancreatic progenitors and endocrine precursors.KEY WORDS: Cdk4, E2f1, Ngn3 (Neurog3), Pancreas development, Pdx1, Mouse

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Section: Introductionmentioning

confidence: 62%

The Cdk4-E2f1 pathway regulates early pancreas development by targeting Pdx1+ progenitors and Ngn3+ endocrine precursors

Kim

Rane

2011

Development

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“…These pathways include protein kinase A pathways, mitogen-activated protein kinase (MAPK) pathways, janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways, phosphatidyl inositol-3 (PI3) kinase/protein kinase B (AKT) pathways and insulin-receptor-substrate pathways [36]. These signalling cascades lead to G 1 /S transition, mainly by stimulating the activity of the cyclin-dependent-kinase 4-cyclin D complex [8,[37][38][39]. The EGFR has been shown to activate the RAS-and SHC-activated MAPK pathway and the PI3 kinase-activated AKT pathway [40].…”

Section: Discussionmentioning

confidence: 99%

“…During metabolic syndrome and the associated insulin resistance, the normal pancreatic beta cell response is compensatory insulin hypersecretion in order to maintain normoglycaemia. This compensation involves the expansion of the beta cell mass and enhanced insulin synthesis and secretion [5,[8][9][10][11][12]. The same is probably true in obese non-diabetic humans, although the increase in beta cell mass (about 50%) is less than that seen in mice [13].…”

Section: Introductionmentioning

confidence: 97%

“…In adulthood the beta cell mass remains quite constant under normal physiological circumstances, with very low rates of beta cell replication [3,4]. However, beta cells adaptively compensate for both physiological and pathophysiological states of insulin resistance, including pregnancy and metabolic syndrome [5][6][7][8][9][10]. During metabolic syndrome and the associated insulin resistance, the normal pancreatic beta cell response is compensatory insulin hypersecretion in order to maintain normoglycaemia.…”

Section: Introductionmentioning

confidence: 99%

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Epidermal growth factor (EGF)-receptor signalling is needed for murine beta cell mass expansion in response to high-fat diet and pregnancy but not after pancreatic duct ligation

et al. 2011

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Aims/hypothesis Epidermal growth factor receptor (EGFR) signalling is essential for the proper fetal development of pancreatic islets and in the postnatal formation of an adequate beta cell mass. In this study we investigated the role of EGFR signalling in the physiological states of beta cell mass expansion in adults during metabolic syndrome and pregnancy, as well as in regeneration after pancreatic duct ligation. Methods Heterozygous Pdx1-EGFR-dominant-negative (E1-DN) mice, which have a kinase-negative EGFR under the Pdx1 promoter, and wild-type mice were both subjected to a high-fat diet, pregnancy and pancreatic duct ligation. Results The beta cell mass of wild-type mice fed the highfat diet increased by 70% and the mice remained normoglycaemic; the E1-DN mice became diabetic and failed to show any compensatory beta cell mass expansion. Similarly, pregnant wild-type mice had four times more proliferating beta cells and a 75% increase in beta cell mass at mid-gestation, in contrast to the pregnant E1-DN mice, which did not show any significant beta cell compensation and were hyperglycaemic in an intraperitoneal glucose tolerance test. However, after pancreatic duct ligation, both the wild-type and E1-DN mice showed similar expression of Ngn3 (also known as Neurog3) and beta cell proliferation increased to a similar level in the ligated part of pancreas. Conclusions/interpretations EGFR signalling is essential in beta cell mass expansion during a high-fat diet and pregnancy where replication is the primary mechanism for compensatory beta cell mass expansion. In contrast, EGFR signalling appears not to be crucial to increased beta cell proliferation after pancreatic duct ligation.

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“…Mechanistically, it has been shown that GLIS3 controls β cell proliferation in response to HFD feeding partly by direct regulation of Ccnd2 mRNA transcription . CCND2 is essential for postnatal pancreatic β cell growth (Georgia & Bhushan 2004, Kushner et al 2005 and compensatory mass expansion in response to insulin resistance (Georgia et al 2010). Interestingly, GWAS identified that the variant rs11063069 G in CCND2 confers susceptibility to T2D (Morris et al 2012), whereas the variant rs76895963 G in CCND2 reduces risk of T2D by half and is correlated with increased CCND2 expression (Steinthorsdottir et al 2014).…”

Section: Glis3 Is Required For Obesity-induced β Cell Proliferation Amentioning

confidence: 99%

Emerging roles of GLIS3 in neonatal diabetes, type 1 and type 2 diabetes

Wen

Yang

2017

Journal of Molecular Endocrinology

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GLI-similar 3 (GLIS3), a member of the Krüppel-like zinc finger protein subfamily, is predominantly expressed in the pancreas, thyroid and kidney. Glis3 mRNA can be initially detected in mouse pancreas at embryonic day 11.5 and is largely restricted to β cells, pancreatic polypeptide-expressing cells, as well as ductal cells at later stage of pancreas development. Mutations in GLIS3 cause a neonatal diabetes syndrome, characterized by neonatal diabetes, congenital hypothyroidism and polycystic kidney.

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Cyclin D2 Is Essential for the Compensatory β-Cell Hyperplastic Response to Insulin Resistance in Rodents

Cited by 61 publications

References 58 publications

The Cdk4-E2f1 pathway regulates early pancreas development by targeting Pdx1+ progenitors and Ngn3+ endocrine precursors

The Cdk4-E2f1 pathway regulates early pancreas development by targeting Pdx1+ progenitors and Ngn3+ endocrine precursors

Epidermal growth factor (EGF)-receptor signalling is needed for murine beta cell mass expansion in response to high-fat diet and pregnancy but not after pancreatic duct ligation

Emerging roles of GLIS3 in neonatal diabetes, type 1 and type 2 diabetes

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