The Effect of Variants in Five Genes in the Glucagon Pathway on Type 2 Diabetes Risk and Diabetes-Related Traits
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The Effect of Variants in 5 Genes in the Glucagon Pathway on Type 2 Diabetes Risk and Diabetes-Related TraitsAbstract
The CDC estimates that 29.1 million Americans have type 2 diabetes, which is currently the seventh leading cause of death in the US. It has been proposed that disordered glucagon regulation is a major contributor to the diabetic phenotype. We hypothesized that variants in five genes in the glucagon pathway are associated with response of diabetes-related glucose, insulin, and body composition traits to three antidiabetic interventions in the DPP and that rare coding variants would be enriched compared to other populations and associated with type 2 diabetes and diabetes-related traits in the Old Order Amish (OOA). We have discovered an association between the GCG variant, rs5649, that is predicted to modify the consensus splice site, with increased baseline-adjusted fasting glucose at one year in the metformin and placebo groups but not in the other two treatment groups, suggesting that it may change the structure of glucagon and decrease the ability of metformin to reduce glucagon signaling. We have performed the only known study of a PCSK2 coding variant common in any population. We found this variant, R430W, and the GCGR variant D458H to be twice as common among OOA individuals with diabetes as those with normal or impaired glucose tolerance, although this difference is not statistically significant. In addition, we examined the relationship between the GCGR coding variant G40S and type 2 diabetes risk that has been previously reported and did not see an association despite being better powered than previous studies because of the increased allele frequency of 14% in the OOA population. Finally, we described the only reported GCGR G40S homozygotes, none of whom have type 2 diabetes. In sum, we have provided data on the effects of variants in five genes in the glucagon pathway that can be used in future work to understand the contribution of the glucagon pathway to type 2 diabetes and to inform the development of antidiabetic treatments targeting this pathway.Description
University of Maryland, Baltimore. Epidemiology and Preventive Medicine. Ph.D. 2016Keyword
diabetes prevention programOld Order Amish
prohormone convertase 2
Amish
Diabetes Mellitus, Type 2
Glucagon
Proprotein Convertases
Receptors, Glucagon
Identifier to cite or link to this item
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Development of autoimmune diabetes with severe diabetic ketoacidosis and immune-related thyroiditis secondary to durvalumab: a case report.Immune-mediated endocrinopathies are among the most frequent immune-related adverse events (irAEs) with immune checkpoint inhibitors (ICIs) targeting programmed death-ligand 1 (PDL1)/PD-1. However, the development of auto-immune diabetes is an uncommon event during PD(L)-1 blockade, either as monotherapy or in combination therapy. Here we report a case of a 75-year-old male with a mediastinal recurrence from a stage IA squamous cell carcinoma of the lung previously treated with stereotactic body radiotherapy (SBRT) who early developed a severe diabetic ketoacidosis (DKA) caused by new-onset auto-immune diabetes, with positive glutamic acid decarboxylase (GAD65) autoantibodies, during durvalumab consolidation therapy after concurrent chemoradiation. The patient had no personal or family history of diabetes or auto-immune diseases and was admitted after the second cycle of durvalumab to the intensive care unit (ICU) with severe DKA. During his hospitalization, insulin and fluid therapy were started and the patient had a favorable clinical course. Durvalumab treatment was interrupted and thyroiditis was verified during follow-up, without anti-thyroid antibodies, that progressed to subsequent hypothyroidism with need of thyroid hormone replacement therapy. This case highlights the rare irAE of autoimmune type 1 diabetes during anti-PD(L)-1 therapy, which can be life-threatening and requires adequate patient education and prompt medical treatment within a multidisciplinary team, including endocrinology and emergency medicine. Besides its low incidence, this case show how irAE must be taken in account about decision of ICI treatment, especially in curative setting, as they can be potentially fatal and impair overall survival. Furthermore, as reported in the present case, multiple endocrine irAEs can occur in the same patient either simultaneously or sequentially, suggesting that active surveillance is needed in those who develop endocrinopathies as a result of ICI treatment. Immune-mediated endocrinopathies are generally irreversible and cause life-long morbidity, which must be taken into consideration when deciding on further lines of treatment.
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