Single gene mutations cause approximately 1% of all cases of diabetes and up to 10% of cases diagnosed at less than 35 years of age. However, the vast majority of cases of monogenic diabetes are misdiagnosed as type 1 or type 2 diabetes. Here we propose to evaluate the consequences of a diagnosis of monogenic diabetes and to develop and validate new cost-effective methods to improve diagnosis and treatment. We and others have suggested that a precise genetic diagnosis of diabetes enables targeted therapy, leads to improved quality of life, and aids in diagnosis of diabetes in other family members including earlier diagnosis in children. Despite this, the overwhelming majority of patients with these forms of diabetes remain undiagnosed and most often inappropriately treated. Those with diabetes due to mutations in KCNJ11, ABCC8, HNF1A and HNF4A may be effectively managed with sulfonylurea therapy instead of suboptimal insulin injections, while individuals with GCK-related diabetes generally do not require drug treatment. However, the best treatment of several other forms of monogenic diabetes remains poorly understood. Furthermore, the variables predicting failure of monotherapy in sulfonylurea-responsive forms and the best choices for second-line agents is not known. Using a simulation model of diabetes costs and complications, we have demonstrated the potential cost-effectiveness of genetic testing for the diagnosis of neonatal diabetes and MODY. The development of targeted next-generation sequencing approaches that facilitate testing of the more than 40 genes known to cause monogenic diabetes will allow us to efficiently examine the true cost-effectiveness of genetic testing. With genetic testing for diabetes slowly becoming more readily available, the impact of testing results - positive, negative and inconclusive - have not been fully assessed. We propose to 1) Determine the efficiency of next-generation sequencing in monogenic diabetes and impact on the cost-effectiveness of genetic testing leading to targeted treatment and 2) Determine the impact of positive genetic testing results on treatment and quality of life while also assessing th impact of indeterminate results. The overall goal of this proposal is to determine the benefits of routine testing for monogenic forms of diabetes in appropriately selected individuals and promote the resulting improvements in treatment through guidance and support of patients, families and physicians.

Public Health Relevance

Diabetes mellitus is a complex metabolic disease affecting over 29 million Americans with serious and costly complications. A major cause of this disease is progressive decline in function of the insulin secreting beta- cells. This study is designed to establish the role of genetic testing for single gene causes of diabetes that cause beta cell dysfunction, are generally undiagnosed and often incorrectly treated in 250-300,000 Americans with monogenic diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK104942-03
Application #
9406480
Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Pawlyk, Aaron C
Project Start
2016-01-08
Project End
2020-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Lanning, Monica S; Carmody, David; Szczerbi?ski, ?ukasz et al. (2018) Hypoglycemia in sulfonylurea-treated KCNJ11-neonatal diabetes: Mild-moderate symptomatic episodes occur infrequently but none involving unconsciousness or seizures. Pediatr Diabetes 19:393-397
Greeley, Siri Atma W; Letourneau, Lisa R; Philipson, Louis H (2018) Precision medicine in KCNJ11 permanent neonatal diabetes. Lancet Diabetes Endocrinol 6:594-595
Harris, Anastasia G; Letourneau, Lisa R; Greeley, Siri Atma W (2018) Monogenic diabetes: the impact of making the right diagnosis. Curr Opin Pediatr 30:558-567
Lemelman, Michelle Blanco; Letourneau, Lisa; Greeley, Siri Atma W (2018) Neonatal Diabetes Mellitus: An Update on Diagnosis and Management. Clin Perinatol 45:41-59
Dickens, Laura T; Naylor, Rochelle N (2018) Clinical Management of Women with Monogenic Diabetes During Pregnancy. Curr Diab Rep 18:12
Sanyoura, May; Jacobsen, Laura; Carmody, David et al. (2018) Pancreatic Histopathology of Human Monogenic Diabetes Due to Causal Variants in KCNJ11, HNF1A, GATA6, and LMNA. J Clin Endocrinol Metab 103:35-45
Letourneau, Lisa R; Greeley, Siri Atma W (2018) Congenital Diabetes: Comprehensive Genetic Testing Allows for Improved Diagnosis and Treatment of Diabetes and Other Associated Features. Curr Diab Rep 18:46
Sanyoura, May; Philipson, Louis H; Naylor, Rochelle (2018) Monogenic Diabetes in Children and Adolescents: Recognition and Treatment Options. Curr Diab Rep 18:58
Letourneau, Lisa R; Greeley, Siri Atma W (2018) Congenital forms of diabetes: the beta-cell and beyond. Curr Opin Genet Dev 50:25-34
Hwang, Jessica L; Park, Soo-Young; Ye, Honggang et al. (2018) FOXP3 mutations causing early-onset insulin-requiring diabetes but without other features of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Pediatr Diabetes 19:388-392

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