Lisa R. Letourneau

Diabetes Presentation in Infancy: High Risk of Diabetic Ketoacidosis

Diabetes in childhood has been associated with increased morbidity and mortality, but the risks for diabetes in infancy remain unclear. Cases with onset of hyperglycemia in the first 6 months of life consist predominantly of monogenic diabetes, whereas type 1 autoimmune diabetes accounts for the majority of cases beyond this threshold. Regardless of etiology, diabetes symptoms tend to be difficult to recognize in an infant, putting patients at increased risk for delays in diagnosis, which may lead to higher blood glucose levels and diabetic ketoacidosis (DKA) at presentation. Here, we report a high degree of morbidity among a cohort of subjects with infancy-onset diabetes.nnWe examined diagnosis records from 88 cases with diabetes onset ≤13 months of age collected through the University of Chicago Monogenic Diabetes Registry (1). We assessed laboratory values and sign/symptoms, and if a causal mutation for diabetes was detected, participants were subdivided by similar mutation subtypes. Data were managed using REDCap electronic data capture tools and analyzed using Stata version 14 (StataCorp, 2015).nnThe majority of participants were male ( n = 46, …

Patients with KCNJ11-related diabetes frequently have neuropsychological impairments compared with sibling controls.

KCNJ11‐related diabetes is the most common form of permanent neonatal diabetes and has been associated with a spectrum of neurodevelopmental problems. We compared neurodevelopmental outcomes in patients with KCNJ11 mutations and their sibling controls.

Hypoglycemia in sulfonylurea-treated KCNJ11-neonatal diabetes: Mild-moderate symptomatic episodes occur infrequently but none involving unconsciousness or seizures

Neonatal diabetes mellitus (NDM) caused by mutations in KCNJ11 can be successfully treated with high dose oral sulfonylureas; however, little data is available on the risk of hypoglycemia.

Early Intensive Insulin Use May Preserve β-Cell Function in Neonatal Diabetes Due to Mutations in the Proinsulin Gene

Although mutations in the proinsulin gene (INS) are the second most common cause of neonatal diabetes mellitus, the natural history of β-cell death and the most appropriate treatments remains unknown. We describe the management and outcome of two sisters with INS-mediated diabetes (S1 and S2) and suggest that more intensive insulin treatment of S2 may have resulted in better clinical outcomes. S1 was diagnosed with diabetes after presenting with serum glucose of 404 mg/dL (22.4 mmol/L) and started multiple daily insulin injections at age 4 months, followed by continuous subcutaneous insulin infusion (CSII) at age 42 months. S1 had positive genetic testing at age 4 months for the GlyB8Ser or Gly32Ser mutation in proinsulin. S2 had positive research-based genetic testing, age 1 month, before she had consistently elevated blood glucose levels. Continuous glucose monitoring revealed abnormal excursions to 200 mg/dL. Low-dose insulin therapy was initiated at age 2.5 months via CSII. At age-matched time points, S2 had higher C-peptide levels, lower hemoglobin A1c values, and lower estimated doses of insulin as compared with S1. Earlier, more intensive insulin treatment was associated with higher C-peptide levels, decreased insulin dosing, and improved glycemic control. Initiating exogenous insulin before overt hyperglycemia and maintaining intensive insulin management may reduce the demand for endogenous insulin production and may preserve β-cell function. Studies accumulating data on greater numbers of participants will be essential to determine whether these associations are consistent for all INS gene mutations.

Neonatal Diabetes Mellitus: An Update on Diagnosis and Management

Neonatal diabetes mellitus is likely to be due to an underlying monogenic defect when it occurs at less than 6xa0months of age. Early recognition and urgent genetic testing are important for predicting the clinical course and raising awareness of possible additional features. Early treatment of sulfonylurea-responsive types of neonatal diabetes may improve neurologic outcomes. It is important to distinguish neonatal diabetes mellitus from other causes of hyperglycemia in newborns. Other causes include infection, stress, inadequate pancreatic insulin production in preterm infants, among others. This review explores the diagnostic approach, mutation types, management, and clinical course of neonatal diabetes.

Clinical Utility of the T1D Genetic Risk Score—Examples from the U.S. Monogenic Diabetes Registry

Monogenic forms of diabetes are often difficult to distinguish from type 1 (T1D) and type 2 diabetes due to overlapping clinical features. As a result, a growing majority of patients remain misdiagnosed and often inappropriately treated. We used a T1D genetic risk score (T1D-GRS), generated from 10 T1D-associated common genetic variants, to help identify patients with a low T1D-GRS, and thus a potential monogenic etiology. We genotyped 798 probands from the U.S. Monogenic Diabetes Registry: 37% (n=293) had a known monogenic cause and 63% (n=505) had an unknown cause or were not exhaustively sequenced. To improve the discriminatory power of the T1D-GRS, participants were categorized using a T1D-GRS equivalent to the 5th, 25th, 50th, 75th, and 95th centile of the UK T1D cohort. 45% (132) of the registry participants with a confirmed monogenic cause had a T1D-GRS below the 5 th percentile, 35% (103) had a T1D-GRS between the 5-25 th percentile, 12% (35) between the 25-50 th percentile, 5% (15) between the 50-75 th percentile, and 2% (7) between the 75-95 th percentile. Of the participants with an unknown cause, 24% (n=108) had a T1D-GRS below the 5 th percentile, 30% (n=137) had a T1D-GRS between the 5-25 th percentile, 16% (72) between the 25-50 th percentile, 15% (67) between the 50-75 th percentile, and 15% (69) between the 75-95 th percentile. We sequenced a total of 124 participants with a T1D-GRS below the 25 th percentile using a targeted next-generation sequencing library that includes more than 140 genes known to be associated with diabetes. 21% (n=24) were found to have a pathogenic variant in a known diabetes gene. Further tests are ongoing. Our results show that the T1D-GRS is a useful discriminatory tool between diabetes types and a strong predictor of whether a monogenic cause is likely. More importantly, patients with a low T1D-GRS and negative for all known monogenic subtypes should be prioritized for exome or whole genome sequencing to maximize the chance of novel gene discoveries. Disclosure M. Sanyoura: None. L.R. Letourneau: Other Relationship; Self; Novo Nordisk Inc.. R.N. Naylor: None. L.H. Philipson: Research Support; Self; Novo Nordisk Inc.. Speaker9s Bureau; Self; Merck & Co., Inc.. Research Support; Self; JAEB Center For Health Research, JDRF, Janssen Pharmaceuticals, Inc., Medtronic MiniMed, Inc.. M.N. Weedon: None. R.A. Oram: Other Relationship; Self; Randox. S.W. Greeley: Research Support; Self; Novo Nordisk Inc..

Congenital forms of diabetes: the beta-cell and beyond

The majority of patients diagnosed with diabetes less than 6 months of age, and many cases diagnosed between 6 and 12 months of age, have a gene mutation that causes permanent or transient hyperglycemia. Recent research advances have allowed for the discovery of new causes of congenital diabetes, including genes involved in pancreatic development (GATA4, NKX2-2, MNX1) and monogenic causes of autoimmune dysregulation (STAT3, LRBA). Ongoing follow-up of patients with KCNJ11 and ABCC8 mutations has supported the safety and efficacy of sulfonylureas, as well as the use of insulin pumps and continuous glucose monitors in infants with insulin-requiring forms of monogenic diabetes. Future studies are needed to improve clinical care and outcomes for these patients and their families.

Congenital Diabetes: Comprehensive Genetic Testing Allows for Improved Diagnosis and Treatment of Diabetes and Other Associated Features

Purpose of ReviewThe goal of this review is to provide updates on congenital (neonatal) diabetes from 2011 to present, with an emphasis on publications from 2015 to present.Recent FindingsThere has been continued worldwide progress in uncovering the genetic causes of diabetes presenting within the first year of life, including the recognition of nine new causes since 2011. Management has continued to be refined based on underlying molecular cause, and longer-term experience has provided better understanding of the effectiveness, safety, and sustainability of treatment. Associated conditions have been further clarified, such as neurodevelopmental delays and pancreatic insufficiency, including a better appreciation for how these “secondary” conditions impact quality of life for patients and their families.SummaryWhile continued research is essential to understand all forms of congenital diabetes, these cases remain a compelling example of personalized genetic medicine.