Abstract
Genetic Predisposition for Type 1 Diabetes Mellitus - The Role of Endoplasmic Reticulum Stress in Human Disease EtiopathogenesisThe increasing incidence of diabetes mellitus worldwide has prompted a rapid growth in the pace of scientific discovery of the mechanisms involved in the etiopathogenesis of this multifactorial disease. Accumulating evidence suggests that endoplasmic reticulum stress plays a role in the pathogenesis of diabetes, contributing to pancreatic beta cell loss and insulin resistance. Wolfram syndrome is an autosomal recessive neurodegenerative disorder accompanied by insulin-dependent diabetes mellitus and progressive optic atrophy. The pathogenesis of this rare neurodegenerative genetic disease is unknown. A Wolfram gene (WFS1 locus) has recently been mapped to chromosome 4p16.1, but there is evidence for locus heterogeneity, including the mitochondrial genome deletion. Recent positional cloning led to identification of the second WFS locus, a mutation in the CISD2 gene, which encodes an endoplasmic reticulum intermembrane small protein. Our results were obtained by the analysis of a families belonging to specific population, affected by Wolfram syndrome. We have identified the newly diagnosed genetic alteration of WFS1 locus, a double non-synonymous and frameshift mutation, providing further evidence for the genetic heterogeneity of this syndrome. Newly identified mutations may contribute to the further elucidation of the pathogenesis of Wolfram syndrome, as well as of the complex mechanisms involved in diabetes mellitus development.
Highlights
Karmen StankovUnlike type 2 diabetes mellitus, a late onset disease, resulting from the interaction of two mechanisms: 1) abnormal insulin secretion due to pancreatic beta cell defects and 2) insulin resistance in skeletal, muscle, liver, and adipose tissue, Type 1 diabetes mellitus (T1D) typically presents in childhood and has a much stronger genetic component
Summary: The increasing incidence of diabetes mellitus worldwide has prompted a rapid growth in the pace of scientific discovery of the mechanisms involved in the etiopathogenesis of this multifactorial disease
Our study of 408 nuclear families from Lebanon, which had been ascertained through a patient with insulin-dependent juvenile-onset diabetes mellitus (JOD), with a total of 455 JOD patients, including nonsyndromic and syndromic cases, shows evidence that some WFS1 mutations may result in nonsyndromic JOD, and that WFS1 mutations are responsible for a large proportion of JOD in some population subgroups, reaching 12.1% of probands in Lebanese consanguineous families [68]
Summary
Unlike type 2 diabetes mellitus, a late onset disease, resulting from the interaction of two mechanisms: 1) abnormal insulin secretion due to pancreatic beta cell defects and 2) insulin resistance in skeletal, muscle, liver, and adipose tissue, T1D typically presents in childhood and has a much stronger genetic component. It primarily arises as a consequence of autoimmune destruction of pancreatic beta cells, resulting in insufficient production of insulin; in addition, syndromes of insulin-requiring beta cell failure in the absence of clinically evident autoimmunity fall under the definition of T1D.
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