The Effect of Variants in Five Genes in the Glucagon Pathway on Type 2 Diabetes Risk and Diabetes-Related Traits
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Other TitlesThe Effect of Variants in 5 Genes in the Glucagon Pathway on Type 2 Diabetes Risk and Diabetes-Related Traits
AbstractThe 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.
DescriptionUniversity of Maryland, Baltimore. Epidemiology and Preventive Medicine. Ph.D. 2016
Keyworddiabetes prevention program
Old Order Amish
prohormone convertase 2
Diabetes Mellitus, Type 2
Identifier to cite or link to this itemhttp://hdl.handle.net/10713/5464
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Screening Adults with Type II Diabetes in Primary Care for Diabetes DistressLaird, Jordan E.; Watson, Melissa D.N.P., C.R.N.A.; Regan, Claire (2023-05)Problem & Purpose: Diabetes remains a prevalent issue in the United States as one of the top ten leading causes of death and contributing to significant healthcare expenditures. At a primary care clinic in suburban Maryland, one-third of adults with type II diabetes (T2DM) had a glycated hemoglobin A1C (HbA1c) greater than or equal to 7%, above the current clinical guideline recommendations. Diabetes distress (DD) is directly linked to poor glycemic control and worse clinical and psychological outcomes but is not often assessed by clinicians. The short-form Problem Areas in Diabetes Scale (PAID-5) has been shown to detect DD in adult patients effectively. The purpose of this quality improvement (QI) project was to identify whether DD exists in this patient population and could be a contributor to poorly controlled T2DM. Methods: Screening adults with T2DM for DD was implemented in a suburban primary care clinic. A medical assistant educated in the screening process offered the self-administered PAID-5 survey to eligible adults. Exclusion criteria were pregnancy, acute visits, and patients not previously diagnosed with T2DM. The percentages of patients offered the survey and those who completed it were calculated. HbA1c levels were paired with each participant’s PAID-5 score. Results: A total of 105 eligible patients were seen over 14 weeks. Of those, 49% were offered the PAID-5, and 36% completed it. Significant DD was indicated in 18%, and of those, 100% endorsed the item, “Worrying about the future and the possibility of serious complications”. Mean HbA1c for all patients, those with and without DD were 7.2%, 7.5%, and 7.1%, respectively. Conclusion: DD exists in the clinic and patients with DD have higher mean HbA1c levels. Limiting factors include staff absences and time constraints. Future QI projects should aim to minimize DD by using PAID responses to identify barriers, guide patient discussions, and make needed referrals.