Professional Documents
Culture Documents
ae
Current Diabetes Reviews, 2016, 12, 000-000
Himadri Singh
Himadri Singh
Many factors enhance beta-cell mass by beta-cell proliferation, neogenesis. and inhibition of apoptosis. These factors could be identified using high throughput technologies
like whole genome microarrays [49]. Analysis of gene expression profile between islets of obese diabetic and non
diabetic obese mice revealed a module of genes that comprises of cell cycle regulatory genes that predicts type 2 diabetes and correlate with beta-cell proliferation.[50]. These
lists of genes are accessible as searchable database
(http://diabetes.wisc.edu). Using a consensus expression
status, a gene signature was also derived which seem to have
a role in beta-cell survival and prevent type 2 diabetes in
obese C57BL/6J ob/ob mice [3]. Many candidate genes have
been identified which are essential for proliferation/survival
of the beta-cell in animal models, to successfully compensate
for metabolic stress.
Himadri Singh
Function(s)
Reference(s)
[51,52]
Regeneration
Neurog-3
[70]
Dad1
Anti-apoptotic gene
[3]
INGAP
Islet neogenesis
[52]
Pdx1
[66]
Survivin
Proliferation/inhibition of apoptosis
[53]
HIP-14
[58]
Exendin-4
[44,45]
Betatrophin
[5]
Betacellulin
[42]
GLP1
Beta-cell function
[43]
[46]
[73]
MiR-7a
[73]
[73]
Proliferation/anti-apoptotic
[73]
Genes
Growth
factors
MiRNAs
cause of defect in beta-cell function and reduced pdx1 levels.Tshz1 levels were also reduced in islets of type 2 diabetic
patients [69]
Ngn3 is a master-regulator of islet development [70]. Direct cell lineage tracing reveals that ngn3 positive cells are
islet progenitors and give rise to all endocrine islet cells during the mouse embryogenesis and in adults [71]. In ngn3
knockout mice, endocrine cells fail to form. When ngn3
positive cells were sorted and implanted into pancreatic buds
of ngn3 knockout mice. These ngn3 positive cells differentiated into other endocrine cells. In response to pancreatic
injury, ngn3 has an important role in neogenesis of beta-cells
[68]. Many genes in the beta-cell differentiation pathway are
also involved in transdifferentiation/neogenesis of beta-cells.
The combination of many of these genes are useful for invitro production of surrogate beta-cells, such as the combination of MafA, Pdx-1 and NeuroD can efficiently induce nonbeta-cell to insulin-producing surrogate beta-cells. [72].
Table 1 outlines the key genes involved in successful adaptation of beta-cells.
7. MicroRNAs
Pancreatic development, islet adaptation to metabolic
stress and insulin secretion is not only regulated by transcription factors but also by non-coding RNAs like microRNAs.
MicroRNAs are approx 19 to 23 nucleotides long. MicroR-
Fig. (1). Different factors outlined in this review are implicated in increased beta-cell adaptation.
CONCLUSION
Animal studies point to increased functional beta-cell
mass in response to increased metabolic load. Beta-cells require many intrinsic and extrinsic factors for successful adaptation in metabolic stress Table 1. These factors are implicated in designing new therapeutic strategies for increasing
beta-cell proliferation, survival, and function Figure 1.
CONFLICT OF INTEREST
The author confirm that this article content has no conflict of interest.
ACKNOWLEDGEMENTS
Declared none.
REFERENCES
[1]
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
Srinivasan K, Ramarao P. Animal models in type 2 diabetes research: an overview. Indian J Med Res 2007; 125(3): 45172.
Singh H, Ganneru S, Malakapalli V, et al. Islet adaptation to obesity and insulin resistance in WNIN / GR-Ob rats. Islets 2015; 5-6:
e998099.
Singh H, Farouk M, Bose BB, Singh P. Novel genes underlying
beta cell survival in metabolic stress. Bioinformation 2013; 9: 37
41.
Aleixandre de Artiano A, Miguel Castro M. Experimental rat
models to study the metabolic syndrome. Br J Nutr 2009; 102:
124653.
Ahnfelt-Rnne J, Madsen OD. Betatrophin: The long awaited circulating factor from the liver promoting -cell replication? Islets
2014; 6: 14.
Pagliuca FW, Melton D How to make a functional -cell. Development 2013; 140: 247283.
Montane J, Cadavez L, Novials A. Stress and the inflammatory
process: a major cause of pancreatic cell death in type 2 diabetes. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2014; 7: 25-34.
Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity
to insulin resistance and type 2 diabetes. Nature. 2006; 444: 8406.
Rieck S, Kaestner KH. Expansion of beta-cell mass in response to
pregnancy. Trends in Endocrinology and Metabolism. 2010; 21:
151-8
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
Meier JJ, Bonadonna RC. Role of reduced -cell mass versus impaired -cell function in the pathogenesis of type 2 diabetes. Diabetes Care 2013; 36: S1139.
Ogihara T, Mirmira RG. An islet in distress: cell failure in type 2
diabetes. J Diabetes Investig 2010; 1: 12333.
Rorsman P, Braun M. Regulation of insulin secretion in human
pancreatic islets. Annu Rev Physiol 2013; 75: 15579.
Fu Z, Gilbert ER, Liu D. Regulation of insulin synthesis and secretion and pancreatic Beta-cell dysfunction in diabetes. Curr Diabetes
Rev 2013; 9: 2553.
Seino S, Shibasaki T, Minami K. Review series Dynamics of insulin secretion and the clinical implications for obesity and diabetes. J
Clin Investig 2011; 121: 211825.
Weir GC, Aguayo-Mazzucato C, Bonner-Weir S. B-cell dedifferentiation in diabetes is important, but what is it. Islets 2013; 5: 233-7.
Jonas JC, Sharma A, Hasenkamp W, et al. Chronic hyperglycemia
triggers loss of pancreatic cell differentiation in an animal model
of diabetes. J Biol Chem 1999; 274: 1411221.
Ferrannini E. The stunned beta cell: a brief history. Cell Metab
2010; 11: 34952.
Cerf ME. Beta cell dysfunction and insulin resistance. Front Endocrinol (Lausanne) 2013; 4: 37.
Chen ZF, Li YB, Han JY, et al. The double-edged effect of autophagy in pancreatic beta cells and diabetes. Autophagy 2011; 7: 126
Stienstra R, Haim Y, Riahi Y, Netea M, Rudich A, Leibowitz G.
Autophagy in adipose tissue and the beta cell: Implications for obesity and diabetes. Diabetologia 2014; 57: 1505-16
Bonner-Weir S, Li W-C, Ouziel-Yahalom L, Guo L, Weir GC,
Sharma A. Beta-cell growth and regeneration: replication is only
part of the story. Diabetes 2010; 59: 23408.
Brennand K, Huangfu D, Melton D. All beta-cells contribute
equally to islet growth and maintenance. PLoS Biol 2007; 5: 1520
9.
Blandino-Rosano M, Alejandro EU, Sathyamurthy A, et al. Enhanced beta cell proliferation in mice overexpressing a constitutively active form of Akt and one allele of p21 Cip. Diabetologia
2012; 55: 13809.
Butler PC, Meier JJ, Butler AE, Bhushan A. The replication of beta
cells in normal physiology, in disease and for therapy. Nat Clin
Pract Endocrinol Metab 2007; 3: 75868.
Rankin MM, Kushner JA. Adaptive beta-cell proliferation is
severely restricted with advanced age. Diabetes. 2009; 58: 1365
72.
Maedler K, Schumann DM, Schulthess F, et al. Aging correlates
with decreased beta-cell proliferative capacity and enhanced sensitivity to apoptosis: a potential role for Fas and pancreatic duodenal
homeobox-1. Diabetes 2006; 55: 245562.
Bhushan A, Itoh N, Kato S, et al. Fgf10 is essential for maintaining
the proliferative capacity of epithelial progenitor cells during early
pancreatic organogenesis. Development. 2001; 128: 510917.
Deltour L, Leduque P, Paldi A, Ripoche MA, Dubois P, Jami J.
Polyclonal origin of pancreatic islets in aggregation mouse chimaeras. Development 1991; 112: 111521.
Ackermann AM, Gannon M. Molecular regulation of pancreatic
beta-cell mass development, maintenance, and expansion. J Mol
Endocrinol 2007; 38: 193206.
Wang Z, York NW, Nichols CG, Remedi MS. Pancreatic beta-cell
dedifferentiation in diabetes and redifferentiation following insulin
therapy. Cell Metab 2014; 19: 87282.
Bar Y, Russ HA, Sintov E, Anker-Kitai L, Knoller S, Efrat S.
Redifferentiation of expanded human pancreatic beta-cell-derived
cells by inhibition of the NOTCH pathway. J Biol Chem 2012; 287:
1726980.
Puri S, Folias AE, Hebrok M. Plasticity and Dedifferentiation
within the Pancreas: Development, Homeostasis, and Disease. Cell
Stem Cell 2015; 16: 1831
Ye L, Robertson M, Hesselson D, Stainier DYR, Anderson RM.
Glucagon Is Essential for Alpha Cell Transdifferentiation and Beta
Cell Neogenesis. Development 2015; 142: 140717.
Gu D, Sarvetnick N. Epithelial cell proliferation and islet neogenesis in IFN-g transgenic mice. Development 1993; 118: 3346.
Peters J, Jrgensen A, Klppel G. Ontogeny, differentiation and
growth of the endocrine pancreas. Virchows Archiv 2000; 436:
527-38
Himadri Singh
[36]
[37]
[38]
[39]
[40]
[41]
[42]
[43]
[44]
[45]
[46]
[47]
[48]
[49]
[50]
[51]
[52]
[53]
[54]
[55]
[56]
[57]
[58]
[61]
[62]
[63]
[64]
[65]
[66]
[67]
Heit JJ, Karnik SK, Kim SK. Intrinsic regulators of pancreatic betacell proliferation. Annu Rev Cell Dev Biol 2006; 22: 31138.
Rane SG, Dubus P, Mettus R V, et al. Loss of Cdk4 expression
causes insulin-deficient diabetes and Cdk4 activation results in
beta-islet cell hyperplasia. Nat Genet 1999; 22: 4452.
Georgia S, Bhushan A. Beta cell replication is the primary mechanism for maintaining postnatal beta-cell mass. J Clin Invest 2004;
114: 9638.
Kushner JA, Ciemerych MA, Sicinska E, et al. Cyclins D2 and D1
are essential for postnatal pancreatic beta-cell growth. Mol Cell
Biol 2005; 25(9): 375262.
Davis DB, Lavine JA, Suhonen JI, et al. FoxM1 is up-regulated by
obesity and stimulates beta-cell proliferation. Mol Endocrinol
2010; 24: 182234.
Lejonklou MH, Barbu A, Stlberg P, Skogseid B. Accelerated
proliferation and differential global gene expression in pancreatic
islets of five-week-old heterozygous Men1 mice: Men1 is a haploinsufficient suppressor. Endocrinology 2012; 153: 258898.
Jonsson J, Carlsson L, Edlund T, Edlund H. Insulin-promoterfactor 1 is required for pancreas development in mice. Nature 1994;
371: 6069.
Ashizawa S, Brunicardi FC, Wang X-P. PDX-1 and the pancreas.
Pancreas 2004; 28: 10920.
Wilson ME, Scheel D, German MS. Gene expression cascades in
pancreatic development. Mechanisms of Development 2003; 120:
65-80
[68]
[69]
[70]
[71]
[72]
[73]
[74]
[75]
[76]
Bernardo AS, Hay CW, Docherty K. Pancreatic transcription factors and their role in the birth, life and survival of the pancreatic
beta- cell. Molecular and Cellular Endocrinology 2008; 294: 1-9
Raum JC, Soleimanpour SA, Groff DN, et al. Tshz1 regulates
pancreatic beta cell maturation. Diabetes 2015; db141443.
Rukstalis JM, Habener JF. Neurogenin3: a master regulator of
pancreatic islet differentiation and regeneration. Islets 2009; 1:
177-84.
Desgraz R, Herrera PL. Pancreatic neurogenin 3-expressing cells
are unipotent islet precursors. Development 2009; 136: 356774.
Kaneto H, Matsuoka T, Katakami N, Matsuhisa M. Combination of
MafA, PDX-1 and NeuroD is a useful tool to efficiently induce insulin-producing surrogate beta-cells. Curr Med Chem 2009; 16:
314451.
Plaisance V, Waeber G, Regazzi R, Abderrahmani A. Role of microRNAs in islet beta-cell compensation and failure during diabetes. Journal of Diabetes Research 2014; 618652
Haumaitre C. Epigenetic regulation of pancreatic islets. Curr Diab
Rep 2013; 13: 62432.
Yang BT, Dayeh TA, Volkov PA, et al. Increased DNA Methylation and Decreased Expression of PDX-1 in Pancreatic Islets from
Patients with Type 2 Diabetes. Mol Endocrinol 2012; 26: 110.
Volkmar M, Dedeurwaerder S, Cunha DA,et al. DNA methylation
profiling identifies epigenetic dysregulation in pancreatic islets
from type 2 diabetic patients. The EMBO Journal 2012; 31: 140526.