Precision treatment of beta-cell monogenic diabetes: a systematic review.

BACKGROUND: Beta-cell monogenic forms of diabetes have strong support for precision medicine. We systematically analyzed evidence for precision treatments for GCK-related hyperglycemia, HNF1A-, HNF4A- and HNF1B-diabetes, and mitochondrial diabetes (MD) due to m.3243 A > G variant, 6q24-transient neonatal diabetes mellitus (TND) and SLC19A2-diabetes. METHODS: The search of PubMed, MEDLINE, and Embase for individual and group level data for glycemic outcomes using inclusion (English, original articles written after 1992) and exclusion (VUS, multiple diabetes types, absent/aggregated treatment effect measures) criteria. The risk of bias was assessed using NHLBI study-quality assessment tools. Data extracted from Covidence were summarized and presented as descriptive statistics in tables and text. RESULTS: There are 146 studies included, with only six being experimental studies. For GCK-related hyperglycemia, the six studies (35 individuals) assessing therapy discontinuation show no HbA1c deterioration. A randomized trial (18 individuals per group) shows that sulfonylureas (SU) were more effective in HNF1A-diabetes than in type 2 diabetes. Cohort and case studies support SU's effectiveness in lowering HbA1c. Two cross-over trials (each with 15-16 individuals) suggest glinides and GLP-1 receptor agonists might be used in place of SU. Evidence for HNF4A-diabetes is limited. Most reported patients with HNF1B-diabetes (N = 293) and MD (N = 233) are on insulin without treatment studies. Limited data support oral agents after relapse in 6q24-TND and for thiamine improving glycemic control and reducing/eliminating insulin requirement in SLC19A2-diabetes. CONCLUSION: There is limited evidence, and with moderate or serious risk of bias, to guide monogenic diabetes treatment. Further evidence is needed to examine the optimum treatment in monogenic subtypes.

Monogenic diabetes is a type of diabetes caused by changes in genes that affect how the body makes or responds to insulin. Precision medicine (where knowledge of the gene change directs the selection of treatment) is available for some forms of monogenic diabetes. This study evaluated the published literature for several forms of monogenic diabetes to assess the level of evidence supporting specific precision treatments. Among the 146 small studies that we reviewed, only six compared different treatments. However, we found evidence supporting oral medications for some types of monogenic diabetes, and evidence that treatment is not needed for one particular type. Based on our results, we provide treatment recommendations for certain forms of monogenic diabetes and identify future directions for research to help us optimize precision medicine in monogenic diabetes.

High Prevalence of A-ß+ Ketosis-Prone Diabetes in Children with Type 2 Diabetes and Diabetic Ketoacidosis at Diagnosis: Evidence from the Rare and Atypical Diabetes Network (RADIANT).

Background: A-ß+ ketosis-prone diabetes (KPD) in adults is characterized by presentation with diabetic ketoacidosis (DKA), negative islet autoantibodies, and preserved ß-cell function in persons with a phenotype of obesity-associated type 2 diabetes (T2D). The prevalence of KPD has not been evaluated in children. We investigated children with DKA at "T2D" onset and determined the prevalence and characteristics of pediatric A-ß+ KPD within this cohort. Methods: We reviewed the records of 716 children with T2D at a large academic hospital and compared clinical characteristics of those with and without DKA at onset. In the latter group, we identified patients with A-ß+ KPD using criteria of the Rare and Atypical Diabetes Network (RADIANT) and defined its prevalence and characteristics. Results: Mean age at diagnosis was 13.7 ± 2.4 years: 63% female; 59% Hispanic, 29% African American, 9% non-Hispanic White, and 3% other. Fifty-six (7.8%) presented with DKA at diagnosis and lacked islet autoantibodies. Children presenting with DKA were older and had lower C-peptide and higher glucose concentrations than those without DKA. Twenty-five children with DKA (45%) met RADIANT A-ß+ KPD criteria. They were predominantly male (64%), African American or Hispanic (96%), with substantial C-peptide (1.3 ± 0.7 ng/mL) at presentation with DKA and excellent long-term glycemic control (HbA1c 6.6% ± 1.9% at follow-up (median 1.3 years postdiagnosis)). Conclusions: In children with a clinical phenotype of T2D and DKA at diagnosis, approximately half meet criteria for A-ß+ KPD. They manifest the key characteristics of obesity, preserved ß-cell function, male predominance, and potential to discontinue insulin therapy, similar to adults with A-ß+ KPD.

Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine.

Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.

Systematic Review of Treatment of Beta-Cell Monogenic Diabetes.

Background: Beta-cell monogenic forms of diabetes are the area of diabetes care with the strongest support for precision medicine. We reviewed treatment of hyperglycemia in GCK-related hyperglycemia, HNF1A-HNF4A- and HNF1B-diabetes, Mitochondrial diabetes (MD) due to m.3243A>G variant, 6q24-transient neonatal diabetes (TND) and SLC19A2-diabetes. Methods: Systematic reviews with data from PubMed, MEDLINE and Embase were performed for the different subtypes. Individual and group level data was extracted for glycemic outcomes in individuals with genetically confirmed monogenic diabetes. Results: 147 studies met inclusion criteria with only six experimental studies and the rest being single case reports or cohort studies. Most studies had moderate or serious risk of bias.For GCK-related hyperglycemia, six studies (N=35) showed no deterioration in HbA1c on discontinuing glucose lowering therapy. A randomized trial (n=18 per group) showed that sulfonylureas (SU) were more effective in HNF1A-diabetes than in type 2 diabetes, and cohort and case studies supported SU effectiveness in lowering HbA1c. Two crossover trials (n=15 and n=16) suggested glinides and GLP-1 receptor agonists might be used in place of SU. Evidence for HNF4A-diabetes was limited. While some patients with HNF1B-diabetes (n=301) and MD (n=250) were treated with oral agents, most were on insulin. There was some support for the use of oral agents after relapse in 6q24-TND, and for thiamine improving glycemic control and reducing insulin requirement in SLC19A2-diabetes (less than half achieved insulin-independency). Conclusion: There is limited evidence to guide the treatment in monogenic diabetes with most studies being non-randomized and small. The data supports: no treatment in GCK-related hyperglycemia; SU for HNF1A-diabetes. Further evidence is needed to examine the optimum treatment in monogenic subtypes.

Enrollment of underrepresented racial and ethnic groups in the Rare and Atypical Diabetes Network (RADIANT).

Introduction: Diabetes mellitus in underrepresented racial and ethnic groups (URG) is rapidly increasing in incidence and has worse outcomes than diabetes in non-Hispanic White individuals. Rare and Atypical Diabetes Network (RADIANT) established recruitment targets based on the racial and ethnic distribution of the USA to enroll a diverse study population. We examined participation of URG across RADIANT study stages and described strategies to enhance recruitment and retention of URG. Materials and Methods: RADIANT is a multicenter NIH-funded study of people with uncharacterized forms of atypical diabetes. RADIANT participants consent online and progress through three sequential study stages, as eligible. Results: We enrolled 601 participants with mean age 44 ± 16.8 years, 64.4% female. At Stage 1, 80.6% were White, 7.2% African American (AA), 12.2% other/more than one race, and 8.4% Hispanic. Enrollment of URG was significantly below preset targets across most stages. Referral sources differed by race (p < 0.001) but not ethnicity (p = 0.15). Most AA participants were referred by RADIANT investigators (58.5% vs. 24.5% in Whites), whereas flyers, news, social media, and family or friends were more frequent referral sources for White individuals (26.4% vs. 12.2% in AA). Ongoing initiatives to increase enrollment of URG in RADIANT include engaging with clinics/hospitals serving URG, screening electronic medical records, and providing culturally competent study coordination and targeted advertisement. Conclusions: There is low participation of URG in RADIANT, potentially limiting the generalizability of its discoveries. Investigations into barriers and facilitators for recruitment and retention of URG in RADIANT, with implications for other studies, are ongoing.

Diagnosis, treatment and disclosure: A qualitative exploration of participant challenges in a Monogenic Diabetes Registry.

PURPOSE: Maturity-onset diabetes of the young (MODY) represents a heterogenous group of monogenic diabetes. Despite its autosomal dominant inheritance, many MODY participants in the University of Chicago Monogenic Diabetes Registry have no family members enrolled. We aimed to gather data on the Registry participants' experiences in (1) receipt of an accurate diagnosis, (2) decisions regarding disclosure of their MODY genetic test results with biological relatives, and (3) recommendations toward our Registry's processes and outreach. METHODS: We conducted 20 one-on-one semistructured interviews with adult Registry participants. RESULTS: All participants found navigating the health care system challenging because of the providers' unfamiliarity with MODY and dismissal of its importance post diagnosis. All had shared their results with at least 1 relative, however many found their relatives resistant to engaging with their providers. Participants wanted to receive targeted information on their condition and connect with other participants who have faced similar diagnostic and treatment challenges. CONCLUSION: Our results demonstrate that our probands faced resistance to reclassification of their diabetes from both health care providers and relatives. In an effort to improve cascade testing, the Registry is designing a portal to facilitate participant-research team communication and provide additional supports for participants to involve family members in testing.

Objective and Subjective Sleep Patterns in Adults With Maturity-Onset Diabetes of the Young (MODY).

OBJECTIVE: To examine sleep patterns in adults with maturity-onset diabetes of the young (MODY). RESEARCH DESIGN AND METHODS: Adults with glucokinase (GCK)-MODY and transcription factor (TF)-related MODY (HNF1A, HNF1B, HNF4A) were recruited (n = 24; age 46.0 years, 79% women, BMI 24.7 kg/m2) from The University of Chicago's Monogenic Diabetes Registry. Sleep patterns were assessed by 2-week wrist actigraphy (total 315 nights), one night of a home sleep apnea test, and validated surveys. RESULTS: Overall, compared with established criteria, 29% of participants had sleep latency ≥15 min, 38% had sleep efficiency ≤85%, 46% had wake after sleep onset >40 min, all indicating poor objective sleep quality. Among all participants, 54% had a sleep duration below the recommended minimum of 7 h, 88% reported poor sleep quality, 58% had obstructive sleep apnea, and 71% reported insomnia. Compared with GCK-MODY, participants with TF-related MODY had poorer objective sleep quality and increased night-to-night variability in sleep patterns. CONCLUSIONS: Sleep disturbances appear to be common in adults with MODY despite absent traditional risk factors for sleep disorders. Future research investigating the sleep-diabetes relationship is warranted in this population.

Investigator and participant expectations for returning non-genetic results: insights from the Rare and Atypical Diabetes Network (RADIANT) study.

Objectives/Goals: The Rare and Atypical DIAbetes NeTwork (RADIANT) aims to discover the underlying pathoetiology of atypical diabetes by conducting both genotyping and non-genetic deep phenotyping. While the return of genetic test results in research settings has been investigated, the return of non-genetic results (RoR-NG) has received less attention. We explore the RoR-NG with RADIANT investigators and participants. Methods/Study Population: We conducted one-on-one interviews with 10 adult RADIANT participants and 10 RADIANT investigators. Participants also completed two health literacy screening tools and a survey on perspectives regarding return of results (RoR). Investigators completed one survey on experience and confidence in explaining clinical tests utilized in the RADIANT study and another survey on perspectives regarding RoR. Results: Most participants were non-Hispanic White. All participants had high scores on health literacy screens. Both RADIANT participants and investigators expressed strong support for RoR-NG. RADIANT participants and investigators acknowledged the different roles and responsibilities between research and clinical care for interpreting and acting on non-genetic results. However, the lines between clinical care and research in returning and acting on results were often blurred by both participants and investigators. Discussion/Significance: Our study provides important insight into how both investigators and participants simultaneously distinguish and blur clinical and research roles and responsibilities when discussing non-genetic research results and the return of these results. Further study should engage individuals from diverse racial and ethnic backgrounds and with varying levels of health literacy to understand how best to support all participants when returning research results.

Insight on Diagnosis and Treatment From Over a Decade of Research Through the University of Chicago Monogenic Diabetes Registry.

Monogenic diabetes is a category of diabetes mellitus caused by a single gene mutation or chromosomal abnormality, usually sub-classified as either neonatal diabetes or maturity-onset diabetes of the young (MODY). Although monogenic diabetes affects up to 3.5% of all patients with diabetes diagnosed before age 30, misdiagnosis and/or improper treatment occurs frequently. The University of Chicago Monogenic Diabetes Registry, established in 2008, offers insight into the diagnosis, treatment, and natural history of individuals known or suspected to have monogenic diabetes. Those interested in participating in the Registry begin by completing a secure web-based registration form found on our website (http://monogenicdiabetes.uchicago.edu/registry/). Participants are then screened for eligibility and consented either by phone, video call, or in person. Relevant medical and family history is collected at baseline and then annually via surveys through our secure Research Electronic Data Capture (REDCap) database. The University of Chicago Monogenic Diabetes Registry has enrolled over 3800 participants from over 2000 families. Participants represent all 50 states and more than 20 different countries. To date, over 1100 participants have a known genetic cause of diabetes. While many Registry participants reported being referred through their diabetes care provider (54%), a large portion also learned about the Registry through web searching (24%), friends/family (18%), or other sources (13%). Around two-thirds of those with a known genetic cause had research-based genetic testing completed rather than clinical testing due to insurance coverage difficulties. Of those who were found to have monogenic diabetes, significant delays in diagnosis were identified, which highlights the need for increased access to clinical genetic testing covered by insurance companies specifically within the United States. Among genes that cause a MODY phenotype, GCK mutations were the most common (59%) followed by HNF1A mutations (28%), while mutations in KCNJ11 were the most common among genes that cause neonatal diabetes (35%) followed by INS (16%). Over the last decade, improvements in data collection for the University of Chicago Monogenic Diabetes Registry have resulted in increased knowledge of the natural history of monogenic diabetes, as well as a better understanding of the most effective treatments. The University of Chicago Monogenic Diabetes Registry serves as a valuable resource that will continue to provide evidence to support improved clinical care and patient outcomes in monogenic diabetes.

Using a Do-It-Yourself Artificial Pancreas: Perspectives from Patients and Diabetes Providers.

BACKGROUND: A growing number of people with diabetes are choosing to adopt do-it-yourself artificial pancreas system (DIYAPS) despite a lack of approval from the US Food and Drug Administration.We describe patients' experiences using DIYAPS, and patient and diabetes providers' perspectives on the use of such technology. METHODS: We distributed surveys to patients and diabetes providers to assess each group's perspectives on the use of DIYAPS. The patient survey also assessed glycemic control and impact on sleep. The patient survey was distributed in February 2019 via Facebook and Twitter (n = 101). The provider survey was distributed via the American Association of Diabetes Educators' e-mail newsletter in April 2019 and the Pediatric Endocrine Society membership e-mail list in May 2019 (n = 152). RESULTS: Patients overwhelmingly described improvements in glycemic control and sleep quality: 94% reported improvement in time in range, and 64% reported improvement in all five areas assessed. Eighty-nine percent of patients described DIYAPS as "Safe" or "Very Safe," compared to only 27% of providers. Most felt encouraged by their diabetes provider to continue using DIYAPS, but few described providers as knowledgeable regarding its use. Providers cited a lack of experience with such systems and an inability to troubleshoot them as their most significant challenges. CONCLUSIONS: Despite evidence that DIYAPS usage is increasing, our surveys suggest that patients' adoption of this technology and trust in it is outpacing that of diabetes providers. Providers must be aware of this growing population of patients and familiarize themselves with DIYAPS to support patients using this technology.

The Impact of Biomarker Screening and Cascade Genetic Testing on the Cost-Effectiveness of MODY Genetic Testing.

OBJECTIVE: In the U.S., genetic testing for maturity-onset diabetes of the young (MODY) is frequently delayed because of difficulty with insurance coverage. Understanding the economic implications of clinical genetic testing is imperative to advance precision medicine for diabetes. The objective of this article is to assess the cost-effectiveness of genetic testing, preceded by biomarker screening and followed by cascade genetic testing of first-degree relatives, for subtypes of MODY in U.S. pediatric patients with diabetes. RESEARCH DESIGN AND METHODS: We used simulation models of distinct forms of diabetes to forecast the clinical and economic consequences of a systematic genetic testing strategy compared with usual care over a 30-year time horizon. In the genetic testing arm, patients with MODY received treatment changes (sulfonylureas for HNF1A- and HNF4A-MODY associated with a 1.0% reduction in HbA1c; no treatment for GCK-MODY). Study outcomes included costs, life expectancy (LE), and quality-adjusted life years (QALY). RESULTS: The strategy of biomarker screening and genetic testing was cost-saving as it increased average quality of life (+0.0052 QALY) and decreased costs (-$191) per simulated patient relative to the control arm. Adding cascade genetic testing increased quality-of-life benefits (+0.0081 QALY) and lowered costs further (-$735). CONCLUSIONS: A combined strategy of biomarker screening and genetic testing for MODY in the U.S. pediatric diabetes population is cost-saving compared with usual care, and the addition of cascade genetic testing accentuates the strategy's benefits. Widespread implementation of this strategy could improve the lives of patients with MODY while saving the health system money, illustrating the potential population health benefits of personalized medicine.

Pediatric Monogenic Diabetes: A Unique Challenge and Opportunity.

Monogenic diabetes affects approximately 120,000 people in the United States but continues to be misdiagnosed. Within the pediatric population, 1% to 3% of diabetes is monogenic, and early diagnosis and genetically targeted management of congenital diabetes and maturity onset diabetes of the young (MODY) can have a tremendous impact on future health outcomes and quality of life. In some of the more common monogenic diabetes types, patients can switch from insulin therapy to sulfonylureas or even discontinue glucose-lowering therapy with stable glycemic control. Advancements in the field have identified tools and resources to aid in distinguishing patients likely to have monogenic diabetes from the more common forms of type 1 and type 2 diabetes. However, genetic testing with accurate interpretation of results is necessary to confirm a diagnosis and direct treatment selection and disease management. This article discusses challenges and opportunities in monogenic diabetes in the pediatric population. [Pediatr Ann. 2019;48(8):e319-e325.].

Iatrogenic Hyperinsulinemia, Not Hyperglycemia, Drives Insulin Resistance in Type 1 Diabetes as Revealed by Comparison With GCK-MODY (MODY2).

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 (n = 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 A1c 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.

GCK-MODY in the US Monogenic Diabetes Registry: Description of 27 unpublished variants.

We report on 134 unique GCK variants in 217 families, including 27 unpublished variants, identified in the US Monogenic Diabetes Registry in the last decade. Using ACMG guidelines, 26% were pathogenic, 56% likely pathogenic and 18% were of uncertain significance. Those with pathogenic variants had clinical features consistent with GCK-MODY.

Management and pregnancy outcomes of women with GCK-MODY enrolled in the US Monogenic Diabetes Registry.

AIMS: GCK-MODY is characterized by mild hyperglycemia. Treatment is not required outside of pregnancy. During pregnancy, insulin treatment is recommended if second trimester fetal ultrasound monitoring shows macrosomia, suggesting the fetus has not inherited the GCK gene. There are limited data about GCK-MODY management in pregnancy. The aim of this study was to examine clinical management and pregnancy outcomes amongst women with a known diagnosis of GCK-MODY. METHODS: In this observational, cross-sectional study, a survey was distributed via Redcap to women ≥ 18 years enrolled in the University of Chicago Monogenic Diabetes Registry (n = 94). All or part of the survey was completed by 54 women (128 pregnancies). RESULTS: There were 78 term births (61%), 15 pre-term births (12%), and 24 miscarriages (19%). Of the 39 pregnancies where insulin was given, 22 (56%) had occasional or frequent hypoglycemia including 9 with severe hypoglycemia. Average birth weight for full-term GCK-affected infants was significantly less in cases of maternal insulin treatment versus no treatment (2967 and 3725 g, p = 0.005). For GCK-unaffected infants, conclusions are limited by small sample size but large for gestational age (LGA) was common with maternal insulin treatment (56%) and no treatment (33%), p = 0.590. CONCLUSIONS: The observed miscarriage rate was comparable to the background US population rate (15-20%). Patients treated with insulin experienced a 23% incidence of severe hypoglycemia and lower birth weights were observed in the insulin-treated, GCK-affected neonates. These data support published guidelines of no treatment if the fetus is suspected to have inherited GCK-MODY and highlight the importance of additional studies to determine optimal pregnancy management for GCK-MODY, particularly among unaffected fetuses.

Clinical Management of Women with Monogenic Diabetes During Pregnancy.

PURPOSE OF REVIEW: Monogenic diabetes accounts for 1-2% of all diabetes cases, but is frequently misdiagnosed as type 1, type 2, or gestational diabetes. Accurate genetic diagnosis directs management, such as no pharmacologic treatment for GCK-MODY, low-dose sulfonylureas for HNF1A-MODY and HNF4A-MODY, and high-dose sulfonylureas for KATP channel-related diabetes. While diabetes treatment is defined for the most common causes of monogenic diabetes, pregnancy poses a challenge to management. Here, we discuss the key issues in pregnancy affected by monogenic diabetes. RECENT FINDINGS: General recommendations for pregnancy affected by GCK-MODY determine need for maternal insulin treatment based on fetal mutation status. However, a recent study suggests macrosomia and miscarriage rates may be increased with this strategy. Recent demonstration of transplacental transfer of sulfonylureas also raises questions as to when insulin should be initiated in sulfonylurea-responsive forms of monogenic diabetes. Pregnancy represents a challenge in management of monogenic diabetes, where factors of maternal glycemic control, fetal mutation status, and transplacental transfer of medication must all be taken into consideration. Guidelines for pregnancy affected by monogenic diabetes will benefit from large, prospective studies to better define the need for and timing of initiation of insulin treatment.

Individualized Glycemic Control for U.S. Adults With Type 2 Diabetes: A Cost-Effectiveness Analysis.

Background: Intensive glycemic control in type 2 diabetes (glycated hemoglobin [HbA1c] level <7%) is an established, cost-effective standard of care. However, guidelines recommend individualizing goals on the basis of age, comorbidity, diabetes duration, and complications. Objective: To estimate the cost-effectiveness of individualized control versus uniform intensive control (HbA1c level <7%) for the U.S. population with type 2 diabetes. Design: Patient-level Monte Carlo-based Markov model. Data Sources: National Health and Nutrition Examination Survey 2011-2012. Target Population: The approximately 17.3 million persons in the United States with diabetes diagnosed at age 30 years or older. Time Horizon: Lifetime. Perspective: Health care sector. Intervention: Individualized versus uniform intensive glycemic control. Outcome Measures: Average lifetime costs, life-years, and quality-adjusted life-years (QALYs). Results of Base-Case Analysis: Individualized control saved $13 547 per patient compared with uniform intensive control ($105 307 vs. $118 854), primarily due to lower medication costs ($34 521 vs. $48 763). Individualized control decreased life expectancy (20.63 vs. 20.73 years) due to an increase in complications but produced more QALYs (16.68 vs. 16.58) due to fewer hypoglycemic events and fewer medications. Results of Sensitivity Analysis: Individualized control was cost-saving and generated more QALYs compared with uniform intensive control, except in analyses where the disutility associated with receiving diabetes medications was decreased by at least 60%. Limitation: The model did not account for effects of early versus later intensive glycemic control. Conclusion: Health policies and clinical programs that encourage an individualized approach to glycemic control for U.S. adults with type 2 diabetes reduce costs and increase quality of life compared with uniform intensive control. Additional research is needed to confirm the risks and benefits of this strategy. Primary Funding Source: National Institute of Diabetes and Digestive and Kidney Diseases.

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

BACKGROUND: 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. OBJECTIVE: To determine the frequency, severity, and clinical significance of hypoglycemia in KCNJ11-related NDM. METHODS: Utilizing the University of Chicago Monogenic Diabetes Registry, parents completed an online questionnaire addressing hypoglycemia. Continuous glucose monitoring (CGM) data was available for 7 subjects. RESULTS: Thirty subjects with KCNJ11-related permanent NDM (166 patient-years on sulfonylurea) had median sulfonylurea dose of 0.39 mg/kg/day (0.24-0.88 IQR, interquartile range) with median HbA1c 5.7% (39 mmol/mol) (5.5-6.1 IQR, 37-43 mmol/mol). Hypoglycemia (<70 mg/dL) was reported monthly once or less frequently in 89.3% of individuals, but 3 (10.7%) reported once weekly or more. Of all hypoglycemic episodes reported, none involved seizures or unconsciousness and thus did not meet the current ISPAD definition of severe hypoglycemia. Seven individuals wore a CGM for a total of 912 hours with blood sugars falling below 70 mg/dL for 5.8% of the time recorded, similar to ranges reported for people without diabetes. CONCLUSIONS: In our cohort of KCNJ11-related permanent NDM, hypoglycemia is infrequent and mild despite the high doses of sulfonylurea used and near-normal level of glycemic control. Long-term follow-up on larger numbers will be required to clarify the incidence and determinants of hypoglycemia in this unique population.

GCK-MODY in the US National Monogenic Diabetes Registry: frequently misdiagnosed and unnecessarily treated.

AIMS: GCK-MODY leads to mildly elevated blood glucose typically not requiring therapy. It has been described in all ethnicities, but mainly in Caucasian Europeans. Here we describe our US cohort of GCK-MODY. METHODS: We examined the rates of detection of heterozygous mutations in the GCK gene in individuals referred to the US Monogenic Diabetes Registry with a phenotype consistent with GCK-MODY. We also assessed referral patterns, treatment and demography, including ethnicity, of the cohort. RESULTS: Deleterious heterozygous GCK mutations were found in 54.7 % of Registry probands selected for GCK sequencing for this study. Forty-nine percent were previously unnecessarily treated with glucose-lowering agents, causing hypoglycemia and other adverse effects in some of the subjects. The proportion of probands found to have a GCK mutation through research-based testing was similar across each ethnic group. However, together African-American, Latino and Asian subjects represented only 20.5 % of screened probands and 17.2 % of those with GCK-MODY, despite higher overall diabetes prevalence in these groups. CONCLUSIONS: Our data show that a high detection rate of GCK-MODY is possible based on clinical phenotype and that prior to genetic diagnosis, a large percentage are inappropriately treated with glucose-lowering therapies. We also find low minority representation in our Registry, which may be due to disparities in diagnostic diabetes genetic testing and is an area needing further investigation.