Endocrine Abstracts

Pancreatic β cell dysfunction and death are central in the pathogenesis of type 2 diabetes but the underlying mechanisms are not well understood. Genetic factors predispose to type 2 diabetes but, despite very large scale genome-wide association studies, the heritability of the disease remains largely unexplained. Environmental and lifestyle factors contribute to the pathogenesis of type 2 diabetes and likely explain its rapidly increasing prevalence. Elevated levels of s...

Background and aim: Loss-of-function mutations in TRMT10A, a transfer RNA (tRNA) methyltransferase, cause early onset diabetes and microcephaly. tRNAs play a crucial role in cellular homeostasis and post-transcriptional modifications modulate tRNA function and fragmentation. tRNA-derived halves (tiRNAs, 29-50 nt) and fragments (tRFs, 14-30 nt) are a new class of functional small noncoding RNAs, involved in cellular stress responses. Here we set out to investigate the ...

Background and aims: Diabetes currently affects 425 million people worldwide. Pancreatic β-cell failure is central in the development and progression of type 1 and type 2 diabetes. Diabetes research is slowed by the difficulty to study the diseased tissue, i.e. human islet bcells: these are only available in a few donor organ transplantation centers worldwide. β-cells differentiated from human induced pluripotent stem cells (hiPSCs) represent a novel cell source. Cur...

Background and aims: Wolfram syndrome is a rare autosomal recessive orphan disease. The clinical manifestations are young onset diabetes, optic nerve atrophy and deafness. Most Wolfram patients carry mutations in WFS1. WFS1 deficiency results in endoplasmic reticulum (ER) stress, leading to neurodegeneration and pancreatic β-cell dysfunction and death. Glucagon-like peptide-1 (GLP-1) analogs and the cAMP inducer forskolin have been shown to protect β-cells f...

Aim of the work: Diabetes is characterized by progressive loss of functional pancreatic beta cells. None of the therapeutic agents used to treat diabetes arrest this process and preventing beta cell loss remains a major unmet need. We have previously shown that serum from 8 young healthy males who exercised for 8 weeks protects human islets and human insulin-producing EndoC-βH1 cells from apoptosis induced by pro-inflammatory cytokines or the endoplasmic reticulum (ER) st...

Background and aims: MEHMO is an X-linked syndrome comprising Mental retardation, Epilepsy, Hypogenitalism, Microcephaly and Obesity. It is caused by a damaging p.Ile465Serfs frameshift mutation in EIF2S3 that encodes the □ subunit of eukaryotic translation initiation factor 2 (eIF2), essential for protein synthesis and regulation of the integrated stress response. Patients with this EIF2S3 mutation also have neonatal hypoglycemia, early onset insulin-...

Background and aims: Neonatal diabetes diagnosed before 6 months is caused by mutations that reduce. β cell number (reduced formation or increased destruction) or impair β cell function. We investigated the genetic cause of a syndrome characterised by neonatal diabetes, microcephaly and epilepsy.Materials and methods: We performed whole genome sequencing for two unrelated patients with neonatal diabetes, epilepsy and microcephaly. Replication s...

Objective: Neonatal diabetes is caused by single gene mutations reducing pancreatic β-cell number or impairing β-cell function. Understanding the genetic underpinnings of rare diabetes subtypes highlights fundamental biological processes in β-cells. Our aim was to explore the genetic basis of a syndrome characterized by neonatal diabetes, microcephaly and epilepsy.Methods: We performed whole genome sequencing for 2 unrelated patients with ...