A positive effect of a β-adrenergic agonist on RAF-1 and PDX-1, reduction in β-cell apoptosis and improved insulin contents can help to understand the pathogenesis of diabetes and to develop novel approaches for the β-cell dysfunction in diabetes.
All of the five known MODY genes, HNF-4alpha, glucokinase, HNF-1alpha, HNF-1beta, and IPF1, were previously excluded as being the cause of diabetes in these families.
Generation of a human induced pluripotent stem cell (iPSC) line from a patient with family history of diabetes carrying a C18R mutation in the PDX1 gene.
Here we examined these questions by testing the ability of hBMSCs genetically modified to transiently express vascular endothelial growth factor (VEGF) or pancreatic-duodenal homeobox 1 (PDX1) to reverse diabetes and whether these cells were differentiated into β-cells or mediated recovery through alternative mechanisms.
Heterozygous mutations in the gene result in impaired glucose tolerance and symptoms of diabetes as seen in MODY4 and late-onset Type II (non-insulin-dependent) diabetes mellitus.
Interestingly, it also modulated the expression of peroxisome proliferator-activated receptor γ (PPARγ) and pancreatic and duodenal homeobox 1 (PDX-1).Our findings showed that <i>A. annulatum</i> and its bioactive compounds are capable of improving insulin secretion by pancreatic β-cells.This suggests that <i>A. annulatum</i> can be used as a therapeutic agent to treat diabetes.
It should be emphasized that MODY comprises two discrete clinical syndromes: glucokinase diabetes and transcription factor diabetes, the latter of which results from mutations in the genes encoding hepatocyte nuclear factor (HNF)-1alpha, HNF-1beta, HNF-4alpha and insulin promoter factor-1.
Mutations in pancreatic duodenal homeobox 1 (PDX-1) can cause a monogenic form of diabetes (maturity onset diabetes of the young 4) in humans, and silencing Pdx-1 in pancreatic β-cells of mice causes diabetes.
Mutations in transcription factors that play a role in the development of the endocrine pancreas, such as insulin promoter factor-1 and NeuroD1/BETA2, have been associated with diabetes.
Our data provide stage-specific target genes of PDX1 during in vitro differentiation of stem cells into pancreatic progenitors that could be useful to identify pathways and molecular targets that predispose for diabetes.
Our results reveal mechanistic details of how common coding mutations in PDX1 impair human pancreatic endocrine lineage formation and β-cell function and contribute to the predisposition for diabetes.
Several studies showed that stress can stimulate autophagy in β-cells: the number of autophagosomes is increased in different in vivo models for diabetes, such as db/db mice, mice fed high-fat diet, pdx-1 knockout mice, as well as in in vitro models of glucotoxicity and lipotoxicity.
The D76N variant of PDX1 does not significantly alter insulin secretion or act as a high-risk susceptibility allele for late-onset type 2 diabetes as proposed previously, although we cannot exclude a minor role in increasing risk of diabetes.
The identification of mutations in hepatocyte nuclear factors-1alpha, -4alpha, -1beta and insulin promoter factor-1 in maturity onset diabetes of the young (MODY) has highlighted the role that transcription factors may have in the development of diabetes.
The significance of the P2 promoter was shown by the identification of a mutation in the IPF-1 binding site of the alternative promoter which cosegregated with diabetes in a large MODY family.
The unusual presentation in this Brazilian family enabled expansion upon a rare disease phenotype, demonstrating the possibility of detecting pancreatic malformation even in cases of PDX1 -related diabetes diagnosed after the first year of life.