Abstract
Diabetes mellitus is a heterogeneous disease characterized by hyperglycemia due to impaired insulin secretion and/or action. All diabetes types have a strong genetic component. The most frequent forms, type 1 diabetes (T1D), type 2 diabetes (T2D) and gestational diabetes mellitus (GDM), are multifactorial syndromes associated with several genes’ effects together with environmental factors. Conversely, rare forms, neonatal diabetes mellitus (NDM) and maturity onset diabetes of the young (MODY), are caused by mutations in single genes. Large scale genome screenings led to the identification of hundreds of putative causative genes for multigenic diabetes, but all the loci identified so far explain only a small proportion of heritability. Nevertheless, several recent studies allowed not only the identification of some genes as causative, but also as putative targets of new drugs. Although monogenic forms of diabetes are the most suited to perform a precision approach and allow an accurate diagnosis, at least 80% of all monogenic cases remain still undiagnosed. The knowledge acquired so far addresses the future work towards a study more focused on the identification of diabetes causal variants; this aim will be reached only by combining expertise from different areas. In this perspective, model organism research is crucial. This review traces an overview of the genetics of diabetes and mainly focuses on Drosophila as a model system, describing how flies can contribute to diabetes knowledge advancement.
Highlights
Diabetes is a chronic metabolic disease affecting more than 450 million people worldwide
The first indication that Drosophila could be exploited as model for diabetes came from studies of Rulifson and collaborators [112] showing that ablation of insulin producing cells (IPCs) increased the level of circulating sugars; this phenotype was rescued by Drosophila insulin-like peptides (DILPs) expression
It was shown that high sugar diet (HSD)-fed mutants of the TRP 2,3-dioxygenase (TDO) enzyme—required for the conversion of tryptophan in kynurenine—displayed reduced insulin resistance, reinforcing the hypothesis that associates tryptophan metabolism with diabetes [139]
Summary
Diabetes is a chronic metabolic disease affecting more than 450 million people worldwide. Insulin secretion depends on the open or closed status of the ATP-dependent potassium channels (K+ ATP channels); when blood glucose levels are high, pancreatic beta cells promote glycolysis, a process leading to increased intracellular ATP concentration, and K+ ATP channel inhibition and cellular membrane depolarization. This event opens the voltage-dependent calcium channels and the entering of Ca2+ ions enables insulin release into the bloodstream (Figure 1). Rare forms of diabetes, including neonatal (NDM) and maturity onset diabetes of the young (MODY) are, instead, due to single gene mutations
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