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

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.

A study of the consequences of early gestational ethanol and/or nicotine exposure in the mouse

“…The presence of genes with known roles in growth in our list provided assurance that the filtering conducted was valid, and that the resultant gene list was likely to be involved in the growth phenotype. A number of genes (Ddr2, Insm1, Sst, and Alx3) were also involved in metabolism, with reported roles in glucose and insulin homeostasis or pancreas development (Cordoba-Chacon et al, 2013;Gierl et al, 2006;Mirasierra et al, 2011;Zurakowski et al, 2007). Table 5.3: Genes identified to be both differentially expressed in the nicotine-exposed embryos and correlated in control embryos with crownrump length normalised to somite number (|r 2 | ≥ 0.5).…”

Thearistaless-like homeobox protein Alx3 as an etiopathogenic factor for diabetes mellitus

“…This question is important for three reasons: (1) The predictive power of mouse models in the identification of etiopathogenic factors causing some types of monogenic diabetes; [1][2][3][4] (2) The appreciation that the majority of maturity-onset diabetes of the young (MODY) cases, the most frequent form of monogenic diabetes, may remain undetected or misdiagnosed; 5 [6][7][8] The proposal that the aristaless-like homeobox ALX3 gene is a candidate to consider for predisposition to diabetes in humans is based on studies showing that the inactivation of the murine homolog results in a relatively mild alteration of glucose homeostasis accompanied by decreased islet cell mass due to excessive apoptosis. 9 In addition, a proportion of mature Alx3-deficient mice develop a defect in the insulin receptor signaling in liver and muscle that results in peripheral insulin resistance as they age. 9 The main phenotypic feature of young Alx3-deficient mice, mild glucose intolerance and fasting hyperglycemia in the presence of normal levels of serum insulin, resembles the alterations observed in MODY2 patients, caused by lossof-function mutations in the glucokinase gene, as well as in mouse models for this disease.…”

“…9 In addition, a proportion of mature Alx3-deficient mice develop a defect in the insulin receptor signaling in liver and muscle that results in peripheral insulin resistance as they age. 9 The main phenotypic feature of young Alx3-deficient mice, mild glucose intolerance and fasting hyperglycemia in the presence of normal levels of serum insulin, resembles the alterations observed in MODY2 patients, caused by lossof-function mutations in the glucokinase gene, as well as in mouse models for this disease. 10,11 This is consistent with the observation that Alx3 is important for maintaining adequate levels of glucokinase gene expression in pancreatic islets.…”

“…10,11 This is consistent with the observation that Alx3 is important for maintaining adequate levels of glucokinase gene expression in pancreatic islets. 9 However, important differences exist. The main one is that Alx3-deficient mice develop age-dependent insulin resistance, which together with the concomitant β-cell loss due to abnormal apoptosis could lead to overt diabetes.…”

“…In contrast, elevation in plasma glucose due to glucokinase mutations in humans is not sufficient for increased risk to develop type 2 diabetes. 7 This may be related to the circumstance that Alx3 also controls the expression of the insulin and glucagon genes, 9,12 and is likely to regulate the expression of ©2 0 1 1 L a n d e s B i o s c i e n c e .…”