Stress hyperglycemia as first sign of asymptomatic type 1 diabetes: an instructive case

Background Stress hyperglycemia (SH) is considered a transient manifestation and routine diagnostic evaluation was thought to be unnecessary due to the lack of definite correlation with diabetes mellitus (DM). Although SH was usually benign and long-term treatment was superfluous, it might be the first sign of insulinopenic status such as type 1 DM (T1DM). Case presentation We reported a boy with acute asthma attack presented incidentally with high blood glucose levels exceeding 300 mg/dL and obvious glycemic variability. A prolonged hyperglycemic duration of more than 48 h was also noticed. To elucidate his unique situation, glucagon test and insulin autoantibody survey were done which showed insulinopenia with positive anti-insulin antibody and glutamic acid decarboxylase antibody despite the absence of overt DM symptoms and signs. Conclusions This case highlights that SH might be a prodromal presentation in T1DM children, especially when accompanied simultaneously with extreme hyperglycemia, apparent glucose variability, as well as prolonged hyperglycemic duration.

Neonatal Hypo-Ketotic Hypoglycemia Secondary to Transient Hyperinsulinism: Diazoxide Responsiveness and Experience With Fasting Test After Treatment Withdrawal

Introduction:: Transient neonatal hyperinsulinism (TNH) is frequently reported in neonates with stress factors (intrauterine growth restriction (IUGR), large for gestational age (LGA), perinatal asphyxia, infants of diabetic mother, etc.). Early recognition and treatment are prioritary to avoid neurological morbidity. Objective: Clinical, molecular characterization and treatment response in neonates with hypoglycemia due to transient hyperinsulinism admitted to a tertiary hospital Neonatal Unit from January 2015 to August 2020. Materials and Methods: Prospective cohort study. Newborns older than 7 days of age, with diagnostic criteria of hyperinsulinism: non ketotic hypoglycemia with detectable insulin, low free fatty acids, glucose infusion rate > 10mg/kg/min, and positive response to glucagon test, were recruited. Results: Out of 5374 patients admitted, 46 (0.85%) presented hypoglycemia secondary to TNH (57% males and 43% females). 78% were delivered by Cesarean section, 59% were European, 17% Latino-Americans, 11% Asians, 9% Africans, and 4% Arabs. 78% were preterm newborns (median 33 weeks gestational age), 70% had birth weights or heights <-1.6 SDS (medians: -1.8 SDS and -2 SDS, respectively). Median age at diagnosis was 22 days (IQE 10–29 days), and feeding was exclusively enteral. Median blood glucose at diagnosis was 37mg/dl (IQE 31-44mg/dl), median insulin: 3mu/ml, median ketonemia: 0.2mmol/L, GH: 15 ng/ml, Cortisol: 16 ug/dl and AAL: 75mg/dl. 90% received diazoxide (dose ranged between 5-10mg/kg/day), presenting as most prevalent side effects hypertrichosis (80%) and edema (13%). Diazoxide median treatment duration was 83 days (IQE 41–110). Response was positive in 100%, with fasting tests response yielding a glycemia > 60mg / dl after 10 hours of fasting post treatment withdrawal. Molecular analysis was carried out with help of a custom NGS panel (MonDIAB.V3; 385 genes) in 80% of the patients. No mutations were identified in known genes implicated in the etiology of congenital hyperinsulinism (ABCC8, KCNJ11, HNF4A, GLUD1, HADH, SLC16A1, GCK, UCP2, HNF1A, AKT2, INSR, CACNA1D), however, predicted deleterious variants were found in other candidate genes such as G6PC2, TH, PMM2, and APPL1, implicated in insulin secretion or glycemic homeostasis. Conclusions: TNH is a prevalent entity to be considered in neonates with risk factors. In our series, TNH is also present in term newborns (22% of patients) and in newborns with weight and/or height appropriate for gestational age (30%). Treatment with diazoxide at low doses is effective in the resolution of these hypoglycemias. The fasting test could be useful for a safe treatment withdrawal when resolution is suspected. No monogenic cause explaining the TNH was identified. Most of the cases molecularly examined presented with 2 or more predicted deleterious variants, suggesting a multifactorial genetic component.

Stress Hyperglycemia as First Sign of Asymptomatic Type 1 Diabetes: An Instructive Case and Literature Review

Background:Stress hyperglycemia (SH) is considered a transient manifestation and routine diagnostic evaluation was thought to be unnecessary due to the lack of definite correlation with diabetes mellitus (DM). Although SH was usually benign and long-term treatment was superfluous, it might be the first sign of insulinopenic status such as type 1 DM (T1DM). Case presentation:We reported a boy with acute asthma attack presented incidentally with high blood glucose levels exceeding 300 mg/dL and obvious glycemic variability. Sustained hyperglycemic duration lasting longer than 48 hours was also noticed. To elucidate his unique situation, glucagon test and insulin autoantibody survey were done which showed insulinopenia with positive anti-insulin antibody and glutamic acid decarboxylase antibody despite the absence of overt DM symptoms and signs. Conclusions:This case highlights that SH might be a prodromal presentation in T1DM children, especially when accompanied simultaneously with extreme hyperglycemia, apparent glucose variability, as well as prolonged hyperglycemic duration.

Comparative study of glucagon and insulin tests for diagnostics of secondary adrenal insufficiency and growth hormone deficiency in children and adolescents

BACKGROUND: Diagnostics of growth hormone deficiency (GHD) and secondary adrenal insufficiency (SAI) is based on estimation of peak GH and cortisol concentrations in provocation tests. Russian consensus on diagnostics and treatment of hypopituitarism in children and adolescences recommends to measure GH and cortisol concentrations in every time-point of insulin test (IT). Glucagon test (GT) is discussed in literature as alternative to IT.AIMS: To estimate the possibility to use provocation GT for diagnostics of SAI and GHD in children and adolescents.MATERIALS AND METHODS: We investigated blood and urine cortisol levels, IT, and GT in 20 patients 6.5–17.8 years (Me 13.0 (10.4; 15.3)) after surgery and/or radiology and/or chemical therapy of head and neck tumors; remission for 0.4–7.5 years (Ме 2.1 (1.5; 5.2)).RESULTS: With cut-off point 550 nmol/L sensitivity and specifity of IT was 100% and 60%, GT — 100% and 53% respectively. Minimal cortisol cut-off level for GT with sensitivity 100% was 500 nmol/L, maximal with specifity 100% — 400 nmol/L.Early morning cortisol levels did not exceed 250 nmol/l in 2 patients with SAI; and were above 500 nmol/l in 8 patients without SAI while primary or repeated examination.GHD was reviled by IT in all patients. Maximal GH concentrations in GT and IT did not differ significantly (p>0.05) but GT results of 4 patients exceeded or met cut-off for this test (7 ng/ml).GT was characterized by less severity compared with IT.CONCLUSIONS: For diagnostics of SAI by GT we can advise cut-off points of cortisol level 500 (sensitivity 100%, specifty 53%) and 400 nmol/L (sensitivity 80%, specifity 100%). Measuring of cortisol levels in 2–3 early morning blood samples allows to exclude or to suspect SAI in half of patients before tests. GH peaks in GT can exceed similarly data in IT that needs future investigation.

Neonatal hyperinsulinemic hypoglycemia: case report of kabuki syndrome due to a novel KMT2D splicing-site mutation

Background Persistent neonatal hypoglycemia, owing to the possibility of severe neurodevelopmental consequences, is a leading cause of neonatal care admission. Hyperinsulinemic hypoglycemia is often resistant to dextrose infusion and needs rapid diagnosis and treatment. Several congenital conditions, from single gene defects to genetic syndromes should be considered in the diagnostic approach. Kabuki syndrome type 1 (MIM# 147920) and Kabuki syndrome type 2 (MIM# 300867), can be associated with neonatal hyperinsulinemic hypoglycemia. Patient presentation We report a female Italian (Sicilian) child, born preterm at 35 weeks gestation, with persistent hypoglycemia. Peculiar facial dysmorphisms, neonatal hypotonia, and cerebellar vermis hypoplasia raised suspicion of Kabuki syndrome. Hyperinsulinemic hypoglycemia was confirmed with glucagon test and whole-exome sequencing (WES) found a novel heterozygous splicing-site mutation (c.674-1G > A) in KMT2D gene. Hyperinsulinemic hypoglycemia was successfully treated with diazoxide. At 3 months corrected age for prematurity, a mild global neurodevelopmental delay, postnatal weight and occipitofrontal circumference growth failure were reported. Conclusions Kabuki syndrome should be considered when facing neonatal persistent hypoglycemia. Diazoxide may help to improve hyperinsulinemic hypoglycemia. A multidisciplinary and individualized follow-up should be carried out for early diagnosis and treatment of severe pathological associated conditions.

Changes in glucose tolerance after pancreatectomy in patients with pancreatic ductal adenocarcinoma.

668 Background: Diabetes mellitus (DM) is reported to be related to pancreatic ductal adenocarcinoma (PDAC). Long-standing DM is a risk factor for PDAC, meanwhile, quite a few patients with PDAC develop DM as a paraneoplastic disorder and some papers reported that DM affected prognosis for PDAC. In this study, we investigated pre- and post-operative glucose tolerance in patients with pancreatectomy for PDAC or other disease. Methods: This single-center prospective study included 69 patients with pancreatectomy (40 pancreaticoduodenectomy (PD) and 29 distal pancreatectomy (DP) ) who received 75-g oral glucose tolerance test (OGTT) and glucagon test pre- and one month postoperatively. Plasma glucose, insulin, and C-peptide (CPR) at 0-, 30-, 60-, and 120-min during OGTT; and 0- and 6-min during glucagon test were obtained. These data and survival outcomes were analyzed. Results: There were 20 (29%) PDAC patients: 12 (30%) in PD group and eight (28%) in DP group. Nine patients with PDAC (45%) and seven patients (18%) without PDAC demonstrated DM type in preoperative OGTT. After pancreatectomy, 11 patients (55%) with PDAC and seven patients (15%) without PDAC experienced improvement in OGTT (P=0.0005). Greater improvement in homeostasis model assessment insulin resistance that were obtained by OGTT and used to measure insulin resistance, was noted after surgery in PDAC patients compared with non-PDAC patients (-1.4 vs -0.5 in PD group, P=0.07; -0.8 vs +0.06 P=0.05 in DP group). Delta CPRs obtained by glucagon test were significantly decreased postoperatively (3.0 to 1.1 ng/mL, P<0.0001 in PD group; 3.3 to 1.8 ng/mL, P<0.0001 in DP group). In survival analysis, fasting plasma glucose >110 mg/dL (HR 3.9, 95%CI 1.5-10, P=0.005) and the average of plasma insulin > 25 µIU/mL during OGTT (HR 0.36, 95%CI 0.14-0.93, P=0.035) were significant prognostic factor for PDAC. Conclusions: Pancreatectomy impaired insulin secretion and improve insulin resistance especially in PDAC patients. About half of PDAC patients demonstrated the improvement of glucose tolerance after surgery. Of note, glucose tolerance differed between PDAC and other disease, and affect the survival outcome for PDAC patients.

The glucagon test in diagnosis of secondary adrenal insufficiency after craniospinal irradiation: the feasibility of application, the features of performing the test, and its diagnostic informativity

BACKGROUND: The glucagon test (GT) is a promising alternative to the insulin hypoglycemia test (IHT) in diagnosis of secondary adrenal insufficiency (SAI). AIM: To study the feasibility of using the GT in patients after craniospinal irradiation and to determine the cut-off value to rule out SAI. METHODS: A total of 28 patients (14 males and 14 females) with the median age of 19 years (17; 23) who had undergone combination treatment (surgery, craniospinal irradiation (35 Gy) with boost to the tumor bed, and polychemotherapy) of extrapituitary brain tumors no later than 2 years before study initiation and 10 healthy volunteers of matching sex and age were examined. All the subjects underwent the GT and IHT with an interval of at least 57 days. The cortisol, ACTH, and glucose levels were measured. RESULTS: Twelve out of 28 patients were diagnosed with SAI according to the IHT results. ROC analysis revealed that cortisol release during the GT 499 nmol/L ruled out SAI [100% sensitivity (Se); 62% specificity (Sp)], while the absence of a rise 340 nmol/l verified SAI (Sp 100%; 55% Se). For GT, the area under a curve (AUC) was 93.6%, which corresponds to a very good diagnostic informativity. In 19 patients, the IHT and GT results were concordant (in ten patients, the release of cortisol occurred above the cut-off value in both tests; no release was detected in nine patients). In nine cases, the results were discordant: the maximum cortisol level detected in the GT was 500 nmol/l, but the IHT results ruled out SAI (the GT yielded a false positive outcome). Contrariwise, in three (10.7%) patients the release of cortisol detected in the GT was adequate, while being insufficient in the IHT test. Adverse events (nausea) were reported during the GT test in 9 (25%) subjects; one patient had hypoglycemia (1.8 mmol/l). CONCLUSION: GT is highly informative and can be used as a first-level stimulation test for ruling out SAI in patients exposed to craniospinal irradiation performed to manage brain tumors. The cortisol level of 500 nmol/L is the best cut-off value for ruling out SAI according to the GT results. The insulin hypoglycemia test is used as the second-level supporting test in patients with positive GT results.

Cortisol Levels in Glucagon Stimulation Test in Children Assessed for Short Stature: Clinical and Laboratorial Correlations

To assess total cortisol levels in children being evaluating for short stature with normal cortisol reserve and to correlate this response to clinical and laboratory data. Children assessed with glucagon test in our department were recruited in this study retrospectively. Inclusion criteria were: i) age>1 year, ii) absence of chronic illness or medication interfering with ACTH-cortisol axis, iii) GH stimulation levels>3ng/mL at least in one provocation test (glucagon or clonidine), iv) absence of multiple pituitary growth hormone deficiencies, v) normal short Synacthen test in cases of low cortisol response in glucagon test.Two hundred and thirty-seven subjects (160 males, 67.5%) with a mean age of 9.02±3.19 years, were finally included in the analysis. Cortisol peak levels but not cortisol AUC were significantly increased in females compared to males (26.83±7.31 μg/dl vs. 24.04±7.20 μg/dl). When linear correlations were studied, both cortisol peak levels and cortisol AUC were linearly but inversely correlated to age (r=−0.234, p<0.001 and r=−0.315, p<0.001, respectively). Finally, cortisol AUC was inversely correlated to weight Z-scores (r=−0.160, p=0.014). When our analysis was limited only to subjects with intact GH response (GH peak> 7 ng/mL), age was still inversely correlated to cortisol AUC (r=−0.312, p<0.001), and cortisol AUC was linearly correlated to GH AUC assessed with clonidine test (r=0.223, p=0.013). Girls, younger and thinner children exhibit higher cortisol response to glucagon test.