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.
We found that MST1 is strongly activated in a diabetic beta cell and induces not only its death but also directly impairs insulin secretion through promoting proteasomal degradation of key beta cell transcription factor, pancreatic and duodenal homeobox 1 (PDX1), which is critical for insulin production.Pre-clinical studies in various animal models of diabetes have reported that MST1 deficiency remarkably restores normoglycaemia and beta cell function and prevents the development of diabetes.
We demonstrate the significance of this alternative promoter in a large MODY family where a mutated IPF-1 binding site in the P2 promoter of the HNF-4alpha gene co-segregates with diabetes (LOD score 3.25).
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.
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.
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.
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.
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.
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.