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. We 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). The majority of participants were male (n = 46, 52%), Caucasian (n = 55, 63%), and living in the United States (n = 83, 94%). There was no significant difference across mutation subtypes based on socioeconomic status (P = 0.19), race/ethnicity (P = 0.36), or sex (P = 0.07). KCNJ11-related diabetes was the most common form of infancy-onset diabetes (37.5%, n = 33), followed by "Unknown" (likely type 1 diabetes) (21.6%, n = 19); 14% (n = 12) had transient neonatal diabetes. Median age at diabetes diagnosis was 10.4 weeks and was significantly different by mutation subtype (Table 1). When grouped into permanent versus transient diabetes, diagnosis age was significantly lower in the transient group (median 15.2 weeks vs. 0.43 weeks, P < 0.001). The most commonly reported signs/symptoms were polyuria (n = 32), tachypnea (n = 31), flu-like symptoms (n = 30), tiredness/weakness (n = 28), dehydration (n = 27), and "not acting right" (n = 26). Blood glucose, pH, bicarbonate, HbA1c, and DKA were dependent on mutation subtype (Table 1). Overall frequency of DKA was 66.2% (Table 1), and odds of DKA increased with age at diagnosis (odds ratio per 1 month increase 1.23 95% CI 1.04, 1.45).
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.
Introduction: Transient neonatal diabetes mellitus (TNDM) is a heterogeneous subtype of neonatal diabetes that usually presents within the first days or weeks of life, spontaneously remits in ...infancy, but can recur in childhood or adolescence as a permanent form of diabetes. Approximately 70% of TNDM cases are due to overexpression of genes at chromosome 6q24 caused by one of three potential mechanisms: uniparental disomy (UPD6), paternal duplication, or hypomethylation of the maternal allele. Our aim was to further elucidate clinical characteristics of a relatively large group of individuals with this rare condition.
Methods: Participants with a confirmed or suspected diagnosis of 6q24 TNDM were identified through the University of Chicago Monogenic Diabetes Registry. Research based genetic testing was provided. Clinical information was extracted from survey responses and medical records.
Results: There were thirty-three participants with 6q24-TNDM (58% male). Eight (24%) had hypomethylation of the maternal allele, seven (21%) had paternal duplication, seventeen (52%) had UPD6, and one had UPD6 vs. hypomethylation of the maternal allele. The mean age of initial diabetes presentation was 4.6 days (n=33). Remission occurred at a mean age of 4.5 months (n=28). Nine participants reported having relapse of diabetes, with a mean age of relapse of 17.4 years (range 12 - 31 years). There were six participants who reported umbilical hernia (22%, n=27), fifteen participants reported macroglossia (54%, n=27), and ten (36%, n=28) indicated speech therapy was required. No significant differences in clinical characteristics were identified across the three mechanisms (UPD6, paternal duplication, hypomethylation).
Conclusions: Clinical characteristics were not different across mechanism groups, suggesting that genetic testing is required to definitively determine a mechanism and diagnosis of 6q24 TNDM. Early assessment for speech therapy should be considered for this patient population.
Disclosure
M.Mccullough: None. L.R.Letourneau-freiberg: None. T.L.Bowden: Stock/Shareholder; Procter & Gamble, OPKO Biologics, Ltd. B.Kandasamy: None. D.Del gaudio: None. L.H.Philipson: Advisory Panel; Nevro Corp., Research Support; Novo Nordisk, Dompé, Provention Bio, Inc., Imcyse, Novo Nordisk Foundation. S.W.Greeley: None.
Funding
National Institutes of Health (R01DK104942, P30DK020595)
Mitochondrial diabetes (MD) results from pathogenic variants in mitochondrial (MT) genes. MT disease is associated with neuromuscular disease. MD may occur either alone or with other conditions. The ...most common MD genetic variant is MT-TL1 m.3243 A>G, associated with Maternally Inherited Diabetes and Deafness and Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes. The incidence, variability and optimum treatment are uncertain. We describe clinical characteristics of participants in the Univ. of Chicago Monogenic Diabetes Registry with MD variants. Participants enrolled in the Univ. of Chicago Monogenic Diabetes Registry (IRB 6858,15617B). Clinical and genetic information was collected. As of February 2023, 18 participants from 13 families had a known MT variant. Clinical characteristics are in Table 1. Clinicians should consider MD when the patient is negative for T1D antibodies, is non-obese, has high frequency bilateral hearing loss, and has a strong maternal family history of diabetes. However, the features are variable and can include multiple organs and tissues. Genetic testing panels should include MT variants because MD can be misdiagnosed and the prevalence is uncertain. Clinical phenotypes are heterogenous among family members. Cascade testing and screening for related conditions is encouraged. Our data shows that MD is misdiagnosed as T1 or T2DM (16/16).
Disclosure
T. L. Bowden: Stock/Shareholder; Procter & Gamble, OPKO Biologics, Ltd. B. Kandasamy: None. L. R. Letourneau-freiberg: None. K. Rodriguez: None. M. Mccullough: None. S. W. Greeley: None. L. H. Philipson: Advisory Panel; Nevro Corp., Research Support; Novo Nordisk, Dompé, Provention Bio, Inc., Imcyse, Novo Nordisk Foundation.
Funding
National Institutes of Health (R01DK104942, P30DK020595, K23DK094866, UL1TR000430)
Although insulin resistance consistently occurs with type 1 diabetes, its predominant driver is uncertain. We therefore determined the relative contributions of hyperglycemia and iatrogenic ...hyperinsulinemia to insulin resistance using hyperinsulinemic-euglycemic clamps in three participant groups (
= 10/group) with differing insulinemia and glycemia: healthy control subjects (euinsulinemia and euglycemia), glucokinase-maturity-onset diabetes of the young (GCK-MODY; euinsulinemia and hyperglycemia), and type 1 diabetes (hyperinsulinemia and hyperglycemia matching GCK-MODY). We assessed the contribution of hyperglycemia by comparing insulin sensitivity in control and GCK-MODY and the contribution of hyperinsulinemia by comparing GCK-MODY and type 1 diabetes. Hemoglobin A
was normal in control subjects and similarly elevated for type 1 diabetes and GCK-MODY. Basal insulin levels in control subjects and GCK-MODY were nearly equal but were 2.5-fold higher in type 1 diabetes. Low-dose insulin infusion suppressed endogenous glucose production similarly in all groups and suppressed nonesterified fatty acids similarly between control subjects and GCK-MODY, but to a lesser extent for type 1 diabetes. High-dose insulin infusion stimulated glucose disposal similarly in control subjects and GCK-MODY but was 29% and 22% less effective in type 1 diabetes, respectively. Multivariable linear regression showed that insulinemia-but not glycemia-was significantly associated with muscle insulin sensitivity. These data suggest that iatrogenic hyperinsulinemia predominates in driving insulin resistance in type 1 diabetes.
To determine the mechanism of reduced pancreas size in type 1 diabetes and the significance of islet-derived insulin in pancreatic growth.
Using a validated and standardized MRI protocol, we measured ...pancreas volume and shape in a family with an autosomal-dominant insulin gene mutation that results in insulin deficiency similar in severity to that of type 1 diabetes but without autoimmunity. DNA sequencing confirmed the mutation in all four affected individuals and none of the four control family members. Insulin secretory capacity was determined by measuring postprandial urinary C-peptide.
Family members with this form of monogenic diabetes had a markedly smaller pancreas and a severely impaired postprandial C-peptide level than family members without diabetes.
These results suggest that severe insulin deficiency, rather than islet-directed autoimmunity, leads to reduced pancreas size in type 1 diabetes and that insulin is a major trophic factor for the exocrine pancreas.
Background: Neonatal diabetes is rare, but most commonly caused by activating heterozygous mutations in either of the KATP channel genes KCNJ11or ABCC8. While a large fraction of those with KATP-NDM ...exhibit a spectrum of neurodevelopmental difficulties, patients and families also describe difficulties with sleep that has not been well-characterized.
Methods: To assess sleep duration and quality, all participants wore an actigrapher (Actiwatch® 2) for at least 7 full days and completed sleep questionnaires based on age: parents of 0-11 years old participants completed the Children’s Sleep Habits Questionnaire (CSHQ), while participants 12+ years completed the Pittsburgh Sleep Quality Index (PSQI) themselves.
Results: 12 affected individuals and 5 sibling controls completed all components of the study: 0-11 yo: 7 affected, 3 controls; 12+ yo: 5 affected, 2 controls. Affected participants had significantly less total sleep time of 433.4 minutes/night, compared to 506.2 minutes/night in controls (p = 0.003). All affected 0-11 yo individuals exhibited sleep disturbance on CSHQ (qualified as a score greater than 41). In contrast, affected 12+ yo individuals did not report significantly greater global sleep scores on the PSQI compared to controls; however, those with R201H/C mutations reported a sleep disturbance score that trended towards being significantly greater than those with V59M/A mutations (55 vs. 46; p = 0.0525).
Conclusion: Objective total sleep time was reduced in KATP-NDM, with parents reporting greater sleep difficulties than self-reported measures by older affected individuals. Neurodevelopmental supports in individuals with KATP-NDM should include assessment of sleep, but more study is required to further characterize specific disruptions that may depend on age and/or specific mutations.
Disclosure
P. Tian: None. S. Choppara: None. A. Harris: None. L.R. Letourneau-Freiberg: None. S.W. Greeley: None.
Funding
American Diabetes Association (1-17-JDF-008 to S.A.W.G.); National Institute of Diabetes and Digestive and Kidney Diseases (R01DK104942, P30DK0205950); National Center for Advancing Translational Sciences (UL1TR002389)
Background: Activating mutations in KCNJ11 or ABCC8 cause neonatal diabetes (NDM) as well as neurodevelopmental difficulties, related to expression of mutated KATP channels in pancreatic beta cells ...as well as brain. Even individuals with more mildly activating KCNJ11 mutations underperform on many neurodevelopmental measures compared to sibling controls; however, very little information has been available about those with ABCC8 mutations.
Methods: Surveys were used to assess attention-deficit hyperactivity disorder (ADHD), learning and behavioral challenges, sleep disturbances, and other related medical conditions in participants with ABCC8-related NDM from the University of Chicago Monogenic Diabetes Registry.
Results: Baseline data including diagnosis and treatment information, and relevant medical records, were available for 19 of 20 participants with ABCC8-NDM (10 permanent, 9 transient), while 10 completed the ADHD/behavior/sleep survey. Participants with ABCC8-related NDM showed a range of neurodevelopmental and behavioral challenges (Table 1).
Conclusions: Our results suggest that individuals with ABCC8-NDM have a high prevalence of neurodevelopmental, behavioral and sleep challenges and should therefore receive relevant ongoing evaluation and support to address these challenges.
Disclosure
N. Brown: None. S. Berry: None. A. Harris: None. L.R. Letourneau-Freiberg: None. S.W. Greeley: None.
Funding
American Diabetes Association (1-17-JDF-008 to S.A.W.G.); National Institute of Diabetes and Digestive and Kidney Diseases (R01DK104942, P30DK0205950); National Center for Advancing Translational Sciences (UL1TR002389)
Introduction: Maturity onset diabetes of the young (MODY) may represent 2-5% of diabetes under 30-35 years. Rarely MODY may be due to mutation in the INS gene. HNF1A mutations are well described ...causes of MODY and may be treated with low dose sulfonylurea. Our aim was to compare clinical features and treatment of INS-MODY with HNF1A-MODY cohort population.
Methods: Participants enrolled through the U.S. Monogenic Diabetes Registry, with Sanger or next-generation sequencing completed with causal mutations found in INS or HNF1A, diagnosed after 13 months of age. Those with neonatal diabetes due to INS were excluded.
Results: Each group shared similar demographics (Table 1). Common presenting symptoms in each group included polyuria, polydipsia, weight loss, fatigue (Table 1). In the INS cohort, all showed residual c-peptide. None reported DKA. The majority had used insulin, though there were a variety of treatment modalities, even among those with the same mutation (Figure 1). For HNF1A cohort, over 60% had been on insulin or sulfonylurea, with 40% having discontinued insulin.
Conclusion: Review of treatments in INS cohort consist of multiple agents with majority using insulin at some point. If clinical suspicion of MODY, genetic testing may help inform treatment. It appears that some variants of INS-MODY lead to a progressive disease eventually requiring insulin therapy and early insulin may improve outcomes.
Disclosure
M. McCauley: None. S. Korkmaz: None. L.R. Letourneau-Freiberg: None. R.N. Naylor: None. S.W. Greeley: None.
Funding
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK104942, P30DK0205950); National Center for Advancing Translational Sciences (UL1TR002389)
Purpose of Review
The goal of this review is to provide updates on the safety and efficacy of long-term sulfonylurea use in patients with
KCNJ11
-related diabetes. Publications from 2004 to the ...present were reviewed with an emphasis on literature since 2014.
Recent Findings
Sulfonylureas, often taken at high doses, have now been utilized effectively in
KCNJ11
patients for over 10 years. Mild–moderate hypoglycemia can occur, but in two studies with a combined 975 patient-years on sulfonylureas, no severe hypoglycemic events were reported. Improvements in neurodevelopment and motor function after transition to sulfonylureas continue to be described.
Summary
Sulfonylureas continue to be an effective, sustainable, and safe treatment for
KCNJ11
-related diabetes. Ongoing follow-up of patients in research registries will allow for deeper understanding of the facilitators and barriers to long-term sustainability. Further understanding of the effect of sulfonylurea on long-term neurodevelopmental outcomes, and the potential for adjunctive therapies, is needed.
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