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Diabetologia

Erschienen in:

01.02.2011 | Article

Alx3-deficient mice exhibit decreased insulin in beta cells, altered glucose homeostasis and increased apoptosis in pancreatic islets

verfasst von: M. Mirasierra, A. Fernández-Pérez, N. Díaz-Prieto, M. Vallejo

Erschienen in: Diabetologia | Ausgabe 2/2011

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Abstract

Aims/hypothesis

Homeodomain transcription factors play an important role in the regulation of pancreatic islet function. In previous studies we determined that aristaless-like homeobox 3 (ALX3) is produced in islet cells, binds to the promoter of the insulin gene and regulates its expression. The purpose of the present study was to investigate the functional role of ALX3 in pancreatic islets and its possible involvement in the regulation of glucose homeostasis in vivo.

Methods

Alx3-knockout mice were used. Glucose and insulin tolerance tests were carried out, and serum insulin concentrations were determined. Isolated islets were used to test insulin secretion and gene expression. The pancreatic islets were also studied using both confocal and conventional microscopy.

Results

ALX3 deficiency resulted in increased blood glucose levels and impaired glucose tolerance in the presence of normal serum insulin concentrations. Insulin, glucagon and glucokinase expression were reduced in Alx3-null pancreatic islets. Reduced insulin content was reflected by decreased insulin secretion from isolated islets. Alx3-deficient islets also showed increased apoptosis, and morphometric analyses indicated that they were, on average, of smaller size than islets from control mice. ALX3 deficiency resulted in reduced beta cell mass. Finally, mature Alx3-null mice developed age-dependent insulin resistance due to impaired peripheral insulin receptor signalling.

Conclusions/interpretation

ALX3 participates in the regulation of the expression of essential genes for the function of pancreatic islets, and its deficiency alters the regulation of glucose homeostasis in vivo. We suggest that ALX3 constitutes a potential candidate to consider in the aetiopathogenesis of diabetes mellitus.

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Song B, Scheuner D, Ron D, Pennathur S, Kaufman RJ (2008) Chop deletion reduces oxidative stress, improves beta cell function, and promotes cell survival in multiple mouse models of diabetes. J Clin Invest 118:3378–3389CrossRefPubMed

Hashimoto N, Kido Y, Uchida T et al (2006) Ablation of PDK1 in pancreatic β cells induces diabetes as a result of loss of β cell mass. Nature Genet 38:589–593CrossRefPubMed

Lee JW, Kim WH, Lim JH et al (2009) Mitochondrial dysfunction: glucokinase downregulation lowers interaction of glucokinase with mitochondria, resulting in apoptosis of pancreatic β-cells. Cell Signal 21:69–78CrossRefPubMed

Bernardo AS, Hay CW, Docherty K (2008) Pancreatic transcription factors and their role in the birth, life and survival of the pancreatic β cell. Mol Cell Endocrinol 294:1–9CrossRefPubMed

Naya FJ, Huang HP, Qiu Y et al (1997) Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BETA2/NeuroD-deficient mice. Genes Dev 11:2323–2334CrossRefPubMed

Johnson JD, Ahmed NT, Luciani DS et al (2003) Increased islet apoptosis in Pdx1^+/− mice. J Clin Invest 111:1147–1160PubMed

Du A, Hunter CS, Murray J et al (2009) Islet-1 is required for the maturation, proliferation and survival of the endocrine pancreas. Diabetes. doi:10.2337/db08-0987

Wobser H, Dussmann H, Kogel D et al (2002) Dominant-negative suppression of HNF-1 alpha results in mitochondrial dysfunction, INS-1 cell apoptosis, and increased sensitivity to ceramide-, but not glucose-induced cell death. J Biol Chem 277:6413–6421CrossRefPubMed

Malecki MT, Jhala U, Antonellis A et al (1999) Mutations in NEUROD1 are associated with the development of type 2 diabetes. Nat Genet 23:323–328CrossRefPubMed

10.

Stoffers DA, Ferrer J, Clarke WL, Habener JF (1997) Early-onset type-II diabetes mellitus (MODY4) linked to IPF1. Nature Genet 17:138–141CrossRefPubMed

11.

Hani EH, Stofers DA, Chevre JC et al (1999) Defective mutations in the insulin promoter factor-1 (IPF-1) gene in late-onset type 2 diabetes mellitus. J Clin Invest 104:41–48CrossRef

12.

Barat-Houari M, Clement K, Vatin V et al (2002) Positional candidate gene analysis of Lim homeobox gene (Isl-1) on chroosome 5q11-q13 in a French morbidly obese population suggests indication for association with type 2 diabetes. Diabetes 51:1640–1643CrossRefPubMed

13.

Shimomura H, Sanke T, Hanabusa T, Tsunoka K, Furuta H, Nanjo K (2000) Nonsense mutation of islet-1 gene (Q310X) found in a type 2 diabetic patient with a strong family history. Diabetes 49:1597–1600CrossRefPubMed

14.

Yamagata K, Oda N, Kaisaki PJ et al (1996) Mutations in the hepatocyte nuclear factor-1 alpha gene in maturity-onset diabetes of the young (MODY3). Nature 384:455–458CrossRefPubMed

15.

Servitja JM, Pignatelli M, Maestro MA et al (2009) Hnf1α (MODY3) controls tissue-specific transcriptional programs and exerts opposed effects on cell growth in pancreatic islets and liver. Mol Cell Biol 29:2945–2959CrossRefPubMed

16.

Oliver-Krasinski JM, Kasner MT, Yang J et al (2009) The diabetes gene Pdx1 regulates the transcriptional network of pancreatic endocrine progenitor cells in mice. J Clin Invest 119:1888–1898CrossRefPubMed

17.

Servitja JM, Ferrer J (2004) Transcriptional networks controlling pancreatic development and beta cell function. Diabetologia 47:597–613CrossRefPubMed

18.

Ten Berge D, Brouwer A, El Bahi S, Guenet JL, Robert B, Meijlink F (1998) Mouse Alx3: an aristaless-like homeobox gene expressed during embryogenesis in ectomesenchyme and lateral plate mesoderm. Dev Biol 199:11–25CrossRefPubMed

19.

Mirasierra M, Vallejo M (2006) The homeoprotein Alx3 expressed in pancreatic β-cells regulates insulin gene transcription by interacting with the basic helix-loop-helix protein E47. Mol Endocrinol 20:2876–2889CrossRefPubMed

20.

Beverdam A, Brouwer A, Reijnen M, Korving J, Meijlink F (2001) Severe nasal clefting and abnormal embryonic apoptosis in Alx3/Alx4 double mutant mice. Development 128:3975–3986PubMed

21.

González-Rodríguez A, Escribano O, Alba J, Rondinone CM, Benito M, Valverde AM (2007) Levels of protein tyrosine phosphatase 1B determine susceptibility to apoptosis in serum-deprived hepatocytes. J Cell Physiol 212:76–88CrossRefPubMed

22.

Moates JM, Nanda S, Cissell MA, Tsai MJ, Stein R (2003) BETA2 activates transcription from the upstream glucokinase gene promoter in islet β-cells and gut endocrine cells. Diabetes 52:403–408CrossRefPubMed

23.

Artner I, Hang Y, Guo M, Gu G, Stein R (2008) MafA is a dedicated activator of the insulin gene in vivo. J Endocrinol 198:271–279CrossRefPubMed

24.

Andrali SS, Sampley ML, Vanderford NL, Ozcan S (2008) Glucose regulation of insulin gene expression in pancreatic β-cells. Biochem J 415:1–10CrossRefPubMed

25.

Postic C, Shiota M, Magnuson MA (2001) Cell-specific roles of glucokinase in glucose homeostasis. Recent Prog Horm Res 56:195–217CrossRefPubMed

26.

Zelent D, Najafi H, Odili S et al (2005) Glucokinase and glucose homeostasis: proven concepts and new ideas. Biochem Soc Trans 33:306–310CrossRefPubMed

27.

Byrne MM, Sturis J, Clement K et al (1994) Insulin secretory abnormalities in subjects with hyperglycemia due to glucokinase mutations. J Clin Invest 93:1120–1130CrossRefPubMed

28.

Pearson ER, Velho G, Clark P et al (2001) β-Cell genes and diabetes: quantitative and qualitative differences in the pathophysiology of hepatic nuclear factor-1α and glucokinase mutations. Diabetes 50:S101–S107CrossRefPubMed

29.

Velho G, Blanch H, Vaxillaire M et al (1997) Identification of 14 new glucokinase mutations and description of the clinical profile of 42 MODY-2 families. Diabetologia 40:217–224CrossRefPubMed

30.

Terauchi Y, Sakura H, Yasuda K et al (1995) Pancreatic β-cell-specific targeted disruption of glucokinase gene. Diabetes mellitus due to defective insulin secretion to glucose. J Biol Chem 270:30253–30256CrossRefPubMed

31.

Johnson JD, Ford EL, Bernal-Mizrachi E et al (2006) Suppressed insulin signaling and increased apoptosis in Cd38-null islets. Diabetes 55:2737–2746CrossRefPubMed

32.

Sachdeva MM, Claiborn KC, Khoo C et al (2009) Pdx1 (MODY4) regulates pancreatic beta cell susceptibility to ER stress. Proc Natl Acad Sci USA 106:19090–19095CrossRefPubMed

33.

Kim WH, Lee JW, Suh YH et al (2005) Exposure to chronic high glucose induces β-cell apoptosis through decreased interaction of glucokinase with mitochondria. Downregulation of glucokinase in pancreatic β-cells. Diabetes 54:2602–2611CrossRefPubMed

34.

Danial NN, Walensky LD, Zhang CY et al (2008) Dual role of proapoptotic BAD in insulin secretion and beta cell survival. Nat Med 14:144–153CrossRefPubMed

35.

Lakhwani S, Garcia-Sanz P, Vallejo M (2010) Alx3-deficient mice exhibit folic acid-resistant craniofacial midline and neural tube closure defects. Dev Biol 344:869–880CrossRefPubMed

36.

Matveyenko AV, Butler PC (2006) Beta cell deficit due to increased apoptosis in the human islet amyloid polypeptide transgenic (HIP) rat recapitulates the metabolic defects present in type 2 diabetes. Diabetes 55:2106–2114CrossRefPubMed

37.

Matveyenko AV, Veldhuis JD, Butler PC (2006) Mechanisms of impaired fasting glucose and glucose intolerance induced by 50% pancreatectomy. Diabetes 55:2347–2356CrossRefPubMed

38.

Kahn SE, Hull RL, Utzschmeider KM (2006) Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 444:840–846CrossRefPubMed

39.

Matveyenko AV, Butler PC (2008) Relationship between β-cell mass and diabetes onset. Diabetes Obes Metab 10:23–31CrossRefPubMed

40.

Prentki M, Nolan CJ (2006) Islet β cell failure in type 2 diabetes. J Clin Invest 116:1802–1812CrossRefPubMed

41.

Holmkvist J, Almgren P, Lyssenko V et al (2008) Common variants in maturity-onset diabetes of the young genes and future risk of type 2 diabetes. Diabetes 57:1738–1744CrossRefPubMed

42.

Shih DQ, Heimesaat M, Kuwajima S, Stein R, Wright C, Stoffel M (2002) Profound defects in pancreatic β-cell function in mice with combined heterozygous mutations in Pdx-1, Hnf-1α, and Hnf-3β. Proc Natl Acad Sci USA 99:3818–3823CrossRefPubMed

43.

Neve B, Fernandez-Zapico ME, Ashkenazi-Katalan V et al (2005) Role of transcription factor KLF11 and its diabetes-associated gene variants in pancreatic beta cell function. Proc Natl Acad Sci USA 102:4807–4812CrossRefPubMed

44.

Wallace KJ, Wallis RH, Collins SC et al (2004) Quantitative trait locus dissection in congenic strains of the Goto-Kakizaki rat identifies a region conserved with diabetes loci in human chromosome 1q. Physiol Genomics 19:1–10CrossRefPubMed

45.

Wallis RH, Wang K, Marandi L et al (2009) Type 1 diabetes in the BB rat: a polygenic disease. Diabetes 58:1007–1017CrossRefPubMed

46.

Gao P, Jiao Y, Xiong Q, Wang CY, Gerling I, Gu W (2008) Genetic and molecular basis of QTL of diabetes in mouse: genes and polymorphisms. Curr Genomics 9:324–337CrossRefPubMed

Titel: Alx3-deficient mice exhibit decreased insulin in beta cells, altered glucose homeostasis and increased apoptosis in pancreatic islets
verfasst von: M. Mirasierra
A. Fernández-Pérez
N. Díaz-Prieto
M. Vallejo
Publikationsdatum: 01.02.2011
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 2/2011
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-010-1975-6

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