The Genetics of Diabetes: What We Can Learn from Drosophila

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.

A polygenic score for type 2 diabetes risk is associated with both the acute and sustained response to sulfonylureas

There is a limited understanding of how genetic loci associated with glycemic traits and type 2 diabetes (T2D) influence the response to anti-diabetes medications. Polygenic scores provide increasing power to detect patterns of disease predisposition that might benefit from a targeted pharmacologic intervention. In the Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH), we constructed weighted polygenic scores using known genome-wide significant associations for T2D, fasting glucose (FG), and fasting insulin (FI), comprised of 65, 43, and 13 single nucleotide polymorphisms, respectively. Multiple linear regression tested for associations between scores and glycemic traits as well as pharmacodynamic endpoints, adjusting for age, sex, race, and body mass index (BMI). A higher T2D score was nominally associated with a shorter time to insulin peak, greater glucose area over the curve, shorter time to glucose trough, and steeper slope to glucose trough after glipizide. In replication, a higher T2D score was associated with a greater 1-year HbA1c reduction to sulfonylureas in the Genetics of Diabetes Audit and Research, Tayside and Scotland (GoDARTS) study (<i>p</i>=0.02). Our findings suggest that individuals with a higher genetic burden for T2D experience a greater acute and sustained response to sulfonylureas.<b> </b>

A polygenic score for type 2 diabetes risk is associated with both the acute and sustained response to sulfonylureas

There is a limited understanding of how genetic loci associated with glycemic traits and type 2 diabetes (T2D) influence the response to anti-diabetes medications. Polygenic scores provide increasing power to detect patterns of disease predisposition that might benefit from a targeted pharmacologic intervention. In the Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH), we constructed weighted polygenic scores using known genome-wide significant associations for T2D, fasting glucose (FG), and fasting insulin (FI), comprised of 65, 43, and 13 single nucleotide polymorphisms, respectively. Multiple linear regression tested for associations between scores and glycemic traits as well as pharmacodynamic endpoints, adjusting for age, sex, race, and body mass index (BMI). A higher T2D score was nominally associated with a shorter time to insulin peak, greater glucose area over the curve, shorter time to glucose trough, and steeper slope to glucose trough after glipizide. In replication, a higher T2D score was associated with a greater 1-year HbA1c reduction to sulfonylureas in the Genetics of Diabetes Audit and Research, Tayside and Scotland (GoDARTS) study (<i>p</i>=0.02). Our findings suggest that individuals with a higher genetic burden for T2D experience a greater acute and sustained response to sulfonylureas.<b> </b>