Uncommon Presentations of Diabetes: Zebras in the Herd.

The majority of patients with diabetes are diagnosed as having either type 1 or type 2 diabetes. However, when encountered in clinical practice, some patients may not match the classic diagnostic criteria or expected clinical presentation for either type of the disease. Latent autoimmune, ketosis-prone, and monogenic diabetes are nonclassical forms of diabetes that are often misdiagnosed as either type 1 or type 2 diabetes. Recognizing the distinguishing clinical characteristics and understanding the diagnostic criteria for each will lead to appropriate treatment, facilitate personalized medicine, and improve patient outcomes.

Precision Medicine: Long-Term Treatment with Sulfonylureas in Patients with Neonatal Diabetes Due to KCNJ11 Mutations.

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. 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.

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

PURPOSE OF REVIEW: The 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 FINDINGS: There 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. While continued research is essential to understand all forms of congenital diabetes, these cases remain a compelling example of personalized genetic medicine.

Monogenic diabetes: the impact of making the right diagnosis.

PURPOSE OF REVIEW: Monogenic forms of diabetes have received increased attention and genetic testing is more widely available; however, many patients are still misdiagnosed as having type 1 (T1D) or type 2 diabetes. This review will address updates to monogenic diabetes prevalence, identification, treatment, and genetic testing. RECENT FINDINGS: The creation of a T1D genetic risk score and the use of noninvasive urinary C-peptide creatinine ratios have provided new tools to aid in the discrimination of possible monogenic diabetes from likely T1D. Early, high-dose sulfonylurea treatment in infants with a KCNJ11 or ABCC8 mutation continues to be well tolerated and effective. As the field moves towards more comprehensive genetic testing methods, there is an increased opportunity to identify novel genetic causes. Genetic testing results continue to allow for personalized treatment but should provide patient information at an appropriate health literacy level. SUMMARY: Although there have been clinical and genetic advances in monogenic diabetes, patients are still misdiagnosed. Improved insurance coverage of genetic testing is needed. The majority of data on monogenic diabetes has been collected from Caucasian populations, therefore, research studies should endeavor to include broader ethnic and racial diversity to provide comprehensive information for all populations.

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.

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.

Trisomy 21 Is a Cause of Permanent Neonatal Diabetes That Is Autoimmune but Not HLA Associated.

Identifying new causes of permanent neonatal diabetes (PNDM) (diagnosis <6 months) provides important insights into ß-cell biology. Patients with Down syndrome (DS) resulting from trisomy 21 are four times more likely to have childhood diabetes with an intermediate HLA association. It is not known whether DS can cause PNDM. We found that trisomy 21 was seven times more likely in our PNDM cohort than in the population (13 of 1,522 = 85 of 10,000 observed vs. 12.6 of 10,000 expected) and none of the 13 DS-PNDM patients had a mutation in the known PNDM genes that explained 82.9% of non-DS PNDM. Islet autoantibodies were present in 4 of 9 DS-PNDM patients, but DS-PNDM was not associated with polygenic susceptibility to type 1 diabetes (T1D). We conclude that trisomy 21 is a cause of autoimmune PNDM that is not HLA associated. We propose that autoimmune diabetes in DS is heterogeneous and includes coincidental T1D that is HLA associated and diabetes caused by trisomy 21 that is not HLA associated.

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.

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.

Early Intensive Insulin Use May Preserve ß-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 ß-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 ß-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.