Arginine Stimulation Test Research Articles

Insulin Resistance in Long COVID-19 Syndrome.

Background: The COVID-19 pandemic has caused severe health issues worldwide and contributed to huge financial losses. Key comorbidities linked to an increased risk of severe COVID-19 and higher mortality rates include cardio-metabolic disorders such as type 1 and type 2 diabetes mellitus (T1DM and T2DM), atherosclerotic cardiovascular disease, chronic kidney disease, hypertension, heart failure, and obesity. The persistence of symptoms even after the acute phase is over is termed long COVID-19 syndrome. This study aimed to evaluate the relationship between long COVID-19 syndrome and the development of insulin resistance in previously non-diabetic patients. Methods: A prospective observational study was performed on 143 non-diabetic patients who had tested positive for SARS-CoV-2 infection by a PCR test and were hospitalized in our hospital between January 2020 and December 2022. The clinical and para-clinical data at 0, 4, and 12 months of hospital admission for post-COVID-19 infection follow-up was collected and labeled as t0, t4, and t12. Blood glucose, insulin, and C-peptide levels were measured at the beginning and further at 2, 5, 10, and 30 min after the intravenous arginine stimulation test. Similarly, BMI was calculated, and hs-CRP and ESR levels were noted. The results obtained were statistically analyzed. Results: More than one-third (30.7%) of the included patients developed long COVID-19 syndrome. It was found that 75% of patients with long COVID-19 hospitalized in our clinic developed diabetes within a year of acute infection with COVID-19; therefore, it can be said that the presence of long COVID-19 is a major risk for an altered metabolic status, which can cause diabetes. When comparing the glycemia levels (106 mg/dL) with the BMI at t0, t4, and t12 time intervals, the p-values were found to be 0.214, 0.042, and 0.058, respectively. Almost 62% of the patients having BMI > 30 kg/m2 were found to have an increase in blood glucose levels at 1 year. Similarly, insulin resistance was noted during this interval. A negative correlation of 0.40 for hsCRP and 0.38 for ESR was noted when compared with acute infection with COVID-19. Conclusions: The association between long COVID-19 and insulin resistance highlights the varied and widespread impacts of SARS-CoV-2 infection. Addressing the complexities of long COVID-19 requires a holistic strategy that encompasses both respiratory and metabolic considerations, which is crucial for enhancing the well-being of those enduring this persistent condition.

Bone Quality Indices Correlate with Growth Hormone Secretory Capacity in Women Affected by Weight Excess: A Cross-Sectional Study.

Background/Objectives: Obesity can be associated with impaired growth hormone (GH) secretion, with possible negative repercussions on bone health. We aimed to investigate the relationships between GH secretory capacity, evaluated with GHRH + arginine stimulation test, and bone parameters, assessed with a dual-energy X-ray absorptiometer, in a population of adult female patients affected by overweight and obesity. Methods: We assessed 276 women affected by overweight or obesity referred to the High-Specialization Center for the Care of Obesity, Umberto I Polyclinic, between 2014 and 2019 with signs or symptoms of growth hormone deficiency (GHD). Results: A total of 97 patients were diagnosed with GHD, and 179 patients with normal GH secretion were considered our control group. GHD patients showed a significantly reduced trabecular bone score (TBS) (p = 0.01). Bone quality parameters corrected for body mass index (BMI) had a positive and significant linear correlation with stimulated GH secretory capacity. Conclusions: In conclusion, bone quality, evaluated by TBS and hip structural analysis, correlates with GH-stimulated secretory capacity. GHD may act as an additive factor in the alteration of bone microarchitecture in patients affected by obesity, who are already at a higher risk of fractures.

Diabetes Insipidus: Types, Diagnosis and Management

Diabetes insipidus (DI) is an acquired or hereditary water imbalance disorder characterized by polydipsia and polyuria. It is a condition that involves the excretion of dilute urine in large volumes. The illness can strike at any age, with males and females have identical rates of occurrence of the disease. The two main mechanisms responsible for diabetes insipidus are either insufficient release or production of ADH (antidiuretic hormone) from the hypothalamus (central diabetes insipidus) or ADH resistance in which the kidneys are unable to respond to ADH (nephrogenic diabetes insipidus). Another form of DI is transient diabetes insipidus commonly known as gestational diabetes insipidus that occurs in the second/third trimester of pregnancy due to increased levels of placental vasopressinase that occurs progressively during pregnancy and increases metabolic clearance of vasopressin. The fourth type of DI is primary polydipsia, characterized by elevated levels of water intake that physiologically lower vasopressin and may be psychogenic, iatrogenic or dipsogenic. Signs and symptoms of DI often include water electrolyte-imbalance, excessive or severe thirst, frequent and excessive urination, fatigue, dehydration, and weight loss. Diabetes insipidus (DI) should be distinguished from primary polydipsia, and whether it is caused by a central, nephrogenic, or gestational cause. This distinction is critical since incorrect treatment can result in serious repercussions. Diagnosis of DI includes measurement of plasma sodium and osmolality, baseline copeptin, hypertonic saline stimulation and arginine stimulation test. The treatment for DI includes the use of drugs such as desmopressin, thiazide diuretics, indomethacin and amiloride.

The diagnostic role of arginine-stimulated copeptin in the differential diagnosis of polyuria-polydipsia syndrome (PPS) in pediatric age.

In recent years, copeptin stimulation through arginine administration has been evaluated as a new potential tool in the differential diagnosis of polyuria-polydipsia syndrome (PPS) in adults; to date very few data, all retrospective, exist in pediatric age. The aim of this prospective study is to evaluate the diagnostic performance of the arginine-stimulation test for copeptin in a cohort of pediatric patients affected by PPS. All children (<18 years) referred to the Department of Pediatric Endocrinology of the Regina Margherita Children Hospital for polyuria-polydipsia in the period January 2021-June 2023 were enrolled. The Arginine-stimulation test for copeptin was performed in all patients presenting PPS after water deprivation test (WDT). Patients with polyuria-polydipsia were then classified as having primary polyuria (PP), complete and partial central diabetes insipidus (CDI), according to the standardized interpretation. Arginine-stimulation test for copeptin was also performed in a control cohort. A significant difference in arginine-stimulated copeptin values was observed at baseline (p = 0.005), at 60 min (p = 0.01), and at 90 min (p = 0.005) in 7 subjects presenting PP, 6 patients affected by CDI and 50 subjects of the control cohort. Plasma osmolality values remained stable at all measurements. The arginine-stimulated copeptin test demonstrated sensitivity and specificity of 100%, whereas the sensitivity of the WDT test was 83.3% and the specificity was 85.7%. Given the reliability and the minor adverse effects and costs, the copeptin level after arginine administration could replace the WDT in the diagnostic workup of these in pediatric age.

THU074 Plasma Spexin In Metabolic Syndrome Related To Adult Growth Hormone Deficiency: A Cross-sectional Study

Abstract Disclosure: E. Vergani: None. A. Oliva: None. C. Bruno: None. D. Currò: None. A. Mancini: None. Adult growth hormone deficiency (aGHD) shares with metabolic syndrome some clinical features such as higher fat mass percentage, increased total cholesterol, LDL, triglycerides, reduced HDL, and higher risk of developing type 2 diabetes mellitus and cardiovascular complications. Spexin, also known as neuropeptide Q, is a 14-aminoacid polypeptide, related to the galanin-kisspeptin family, produced in several human tissues. It is also secreted along with insulin by pancreatic beta cells; via paracrine effects they blunted reciprocal secretion. In type 2 diabetes mellitus spexin is closely correlated to fasting and post prandial glucose, glycosylated hemoglobin and HOMA index. Moreover, spexin infusion seems to ameliorate ALT and AST levels in non-alcoholic fatty liver disease. Given its controversial role in condition of metabolic impairment, we aimed to evaluate spexin plasmatic levels in aGHD. Thirty-eight subjects were included in the study, 18 aGHD patients (7 females and 11 males) and 20 healthy controls (12 females and 8 males). aGHD was diagnosed by a GHRH plus arginine test. Etiologies of GHD were as follows: 7 empty sellas, 5 post-surgical hypopituitarism, and 6 idiopathic with negative MRI scans. GHRH plus arginine stimulation tests were repeated twice in idiopathic aGHD to confirm the diagnosis. They were evaluated for glucose and insulin, HOMA and QUICKI index, total/LDL/HDL cholesterol, triglycerides, uric acid and IGF-1. Spexin was measured by ELISA, according to manufacturers’ protocols. Fat mass percentage was evaluated by DXA. Mean±SEM age of aGHD group was 59.7±2.7 years, while BMI was 30.2±2.2 kg/m2; control group aged 47.1±2.5 years, while BMI was 24.5±0.9 kg/m2. As expected, aGHD patients showed higher HOMA index, triglycerides and lower HDL than controls. Furthermore mean±SEM fat mass percentage was significantly higher in aGHD than controls (44.41±3.15 vs 32.2±3.64). Spexin levels were similar in the two groups (aGHD 1.17±0.21 vs controls 1.25±0.10 ng/ml). significant correlations were found in both populations. These results, although preliminary, seem to exclude a possible role of spexin in aGHD; however, spexin could represent another possible element of differentiation between aGHD and metabolic syndrome. Such controversial topic requires further evaluations. Presentation: Thursday, June 15, 2023

Visceral fat correlates with insulin secretion and sensitivity independent of BMI and subcutaneous fat in Chinese with type 2 diabetes.

Clinical heterogeneity exists in overall obesity and abdominal obesity in terms of insulin secretion and sensitivity. Further, the impact of visceral fat (VF) on the first- and second-phase insulin secretion (FPIS and SPIS) is controversial. We aim to investigate insulin secretion and sensitivity in Chinese patients with T2DM according to different BMI and VF levels. This study enrolled 300 participants. A dual bioelectrical impedance analyzer was used to assess the visceral and subcutaneous fat area (VFA and SFA). VF levels were categorized as normal or high, with the cutoff value of 100 cm2. FPIS and SPIS were evaluated by arginine stimulation test and standardized steamed bread meal tolerance test, respectively. β-cell function (HOMA2-β), insulin resistance (HOMA2-IR), and Gutt's insulin sensitivity index (Gutt-ISI) were also calculated. Spearman's correlation analysis and multivariate linear regression analysis were adopted for statistical analysis. Participants were categorized into four groups: normal weight-normal VF, normal weight-high VF, overweight/obese-normal VF and overweight/obese-high VF. Multivariate linear regression showed that both VFA and SFA were correlated with FPIS, HOMA2-IR and Gutt-ISI after controlling for gender and diabetes duration. After further adjustment for BMI and VFA, some associations of SFA with insulin secretion and sensitivity disappeared. After adjustment for gender, diabetes duration, BMI and SFA, VFA was positively correlated with FPIS, SPIS and HOMA2-IR. Subjects with overweight/obese-high VF were more likely to have higher FPIS, HOMA2-IR and lower Gutt-ISI (all p < 0.05). VF affects both FPIS and SPIS, and worsens insulin sensitivity independent of BMI and subcutaneous fat in Chinese patients with T2DM. http://www.chictr.org.cn, identifier ChiCTR2200062884.

Growth hormone responses during arginine and clonidine stimulation test: Correlations with patients' auxological and metabolic parameters in a single centre study

BackgroundChildren with auxological parameters defining a ‘short stature’ is routinely subjected to various blood tests and, if necessary, to growth hormone stimulation test (GHST) for differentiating GH deficiency (GHD) and other causes of stunted growth. AimThis retrospective monocentric study aimed to evaluate any correlations between GH peaks during GHST in children assessed for short stature and their auxological/metabolic parameters, highlighting differences between GHD and idiopathic short stature. Patients and methodsWe reviewed the medical records of 74 children with short stature (height lower than the third percentile according to standardized growth curves for the Italian population) managed at the Pediatric Day Hospital of our Department of Life Sciences and Public Health in Università Cattolica Sacro Cuore, Rome, who performed at least two GHSTs, using arginine and clonidine as stimulants, for assessment of GH secretion. The results of a total number of 161 GHSTs, performed in 42 children diagnosed with GHD and in 32 children with other causes of short stature, were analyzed. ResultsWe found significantly lower serum levels of insulin growth factor-1 (IGF-1) and increased levels of thyroid-stimulating hormone (TSH) in children with GHD, without other metabolic differences in comparison to children with other causes of short stature. There was also a correlation between triglycerides and GH peak during arginine test, while fT4 and LDL concentrations correlated with GH peak during the third test, if performed. Pre-test BMI (rho −0.274, p = 0.01) and weight (rho −0.251, p = 0.03) have influenced GH peak during clonidine stimulation test. Metabolic and auxological parameters could influence GH peak during clonidine and arginine stimulation tests and must be taken into account when interpreting GHST results.

The effect of glucose dynamics on plasma copeptin levels upon glucagon, arginine, and macimorelin stimulation in healthy adults

PurposeNon-osmotic stimulation tests using glucagon, arginine, or macimorelin were recently evaluated for their ability to assess posterior pituitary function. Glucagon and arginine, but not macimorelin, stimulated copeptin secretion (a surrogate marker of vasopressin) and, therefore, provide novel tests to assess the posterior pituitary. The exact underlying mechanism behind their stimulatory effect remains elusive.MethodsThis analysis combined data from three diagnostic studies conducted at the University Hospital Basel, Switzerland. In total, 80 healthy adults underwent the glucagon (n = 22), arginine (n = 30), or macimorelin (n = 28) stimulation tests. The primary objective was to investigate glucose course upon glucagon, arginine, and macimorelin stimulation tests and its effect on plasma copeptin release.ResultsUpon glucagon stimulation, the median [IQR] glucose level at baseline was 5.0 [4.6, 5.2] mmol/l, peaked at 8.1 [7.2, 9.4] mmol/l after 30 min and decreased to a minimum of 3.8 [3.5, 4.5] mmol/l after 120 min. The median copeptin increase upon glucagon stimulation was 7.7 [2.6, 28.0] pmol/l. Upon arginine, the glucose level at baseline was 4.9 [4.8, 5.5] mmol/l, peaked at 6.0 [5.2, 6.4] mmol/l after 30 min and decreased to a minimum of 4.3 [3.8, 4.8] mmol/l after 60 min. The median copeptin increase upon arginine stimulation was 4.5 [2.9, 7.5] pmol/l. Upon macimorelin, glucose levels showed no notable dynamics over the 120 min, and no major change in copeptin was observed.In the pooled dataset, a decrease in glucose levels was significantly correlated with copeptin increase (ρ = 0.53, p < 0.01).ConclusionA similar course in plasma glucose was observed in the copeptin-stimulating test, i.e., after glucagon and arginine, while macimorelin had no effect on glucose and copeptin levels. We hypothesize that a drop in glucose levels observed upon glucagon and arginine might stimulate copeptin.

207.3: Predictive Value of C-peptide Measures for Clinical Outcomes of Islet Transplantation in Type 1 Diabetes: A Report From the Collaborative Islet Transplant Registry (CITR)

CITR Investigators Introduction: Long-standing type 1 diabetes (T1D) can lead to impaired awareness of hypoglycemia and high-risk for severe hypoglycemic episodes (SHE). Islet transplantation (ITx) can restore endogenous insulin production, ameliorate glucose control, and abolish SHE. In the DCCT, a stimulated C-peptide >0.2 nmol/L was associated with lower HbA1c, reduced insulin requirements, and decreased prevalence of SHE. We set forth to determine what measures of C-peptide and levels are associated with achievement of ITx positive outcomes in T1D. Methods: Collaborative Islet Transplant Registry (CITR) Islet-Alone recipients with pre-transplant C-peptide <0.1 nmol/L and mean follow up of 4.6±1.1 years were included in the analyses (n=677). Post-transplant metabolic measures obtained from arginine stimulation test, IVGTT, OGTT, glucagon stimulation test and mixed meal stimulation test (MMTT) were evaluated. Predictive value of these measures for 7 primary outcomes of clinical ITx (i.e., absence of SHEs (ASHE); HbA1c<7.0%; HbA1c <7.0% & ASHE; HbA1c≤6.5; HbA1c≤6.5% & ASHE; insulin independence; and ASHE, HbA1c≤6.5%, and insulin independence) was assessed by area under the curve of receiver-operator characteristics curves (ROC-AUC). Measures with the highest ROC-AUC were then selected for determination of optimal cut points by ITx outcome. Results: Fasting C-peptide, MMTT stimulated C-peptide, fasting C-peptide to Glucose (Cpep/Glu) ratio, and MMTT stimulated Cpep/Glu ratio showed the highest ROC-AUCs among all measures evaluated (Table 1). Fasting C-peptide was highly predictive for ASHE (ROC-AUC = 0.9228; optimal cut point = 0.07 nmol/L), and the composite outcome of ASHE, HbA1c≤6.5%, and insulin independence (ROC-AUC = 0.8456; optimal cut point = 0.33 nmol/L) (Table 2). However, MMTT stimulated Cpep/Glu ratio outperformed both fasting and stimulated C-peptide for all outcomes except ASHE alone. Optimal cut point for the ideal composite outcome of ASHE, HbA1c≤6.5%, and insulin independence was 0.12 nmol/mmol for the MMTT stimulated Cpep/Glu ratio, and 0.97 nmol/L for MMTT stimulated C-peptide (Table 2). Discussion/Conclusion: Fasting C-peptide reliably predicts rates of ITx primary endpoints and is similar to other C-peptide measures at predicting ASHE. Although marginal endogenous fasting C-peptide is sufficient to eliminate SHEs, higher levels are required to achieve optimal ITx outcomes. The MMTT stimulated Cpep/Glu ratio provides better predictiveness for composite ITX outcomes, including insulin independence. In the absence of a MMTT, a fasting C-peptide ≥0.33 nmol/L is a reassuring measure of optimal metabolic control in ITx T1D recipients.The CITR has been funded continuously by grants from the National Institute of Diabetes and Digestive and Kidney Diseases since 2001 (Grants 1UCHDK098086-01, 1UC4DK114839-01) to collect data on the efficacy and safety of clinical islet transplantation from US and collaborating international institutions. The Juvenile Diabetes Research Foundation provided supplemental funding for reimbursement of efforts to report data from the European and Australian sites from 2006–2015. No other sponsors have provided support to the CITR. MRR is supported in part by Public Health Service Research Grant R01 DK 091331-8. We thank all the study participants and staff.

Diagnosing Growth Hormone Deficiency: Can a Combined Arginine and Clonidine Stimulation Test Replace 2 Separate Tests?

ObjectiveGiven the large number of false-positive growth hormone deficiency (GHD) diagnoses from a single growth hormone (GH) stimulation test in children, 2 different pharmacologic tests, performed on separate days or sequentially, are required. This study aimed to assess the reliability and safety of a combined arginine-clonidine stimulation test (CACST). MethodsThis was a retrospective, single-center, observational study. During 2017-2019, 515 children aged >8 years underwent GH stimulation tests (CACST: n = 362 or clonidine stimulation test [CST]: n = 153). The main outcome measures used to compare the tests were GH response (sufficiency/deficiency) and amplitude and timing of peak GH and safety parameters. ResultsPopulation characteristics were as follows: median age of 12.2 years (interquartile range [IQR]: 10.7, 13.4), 331 boys (64%), and 282 prepubertal children (54.8%). The GHD rate was comparable with 12.7% for CACST and 14.4% for CST followed by a confirmatory test (glucagon or arginine) (P = .609). Peak GH was higher and occurred later in response to CACST compared with CST (14.6 ng/mL [IQR: 10.6, 19.4] vs 11.4 ng/mL [IQR: 7.0, 15.8], respectively, P < .001; 90 minutes [IQR: 60, 90] vs 60 minutes [IQR: 60, 90], respectively, P < .001). No serious adverse events occurred following CACST. ConclusionOur findings demonstrate the reliability and safety of CACST in detecting GHD in late childhood and adolescence, suggesting that it may replace separate or sequential GH stimulation tests. By diminishing the need for the second GH stimulation test, CACST saves time, is more cost-effective, and reduces discomfort for children, caregivers, and medical staff.

The Arginine Stimulation Test Allows Rapid Diagnosis of Central Diabetes Insipidus in Children

Introduction: Water deprivation testing (H2O-dep) is usually required to distinguish between diabetes insipidus (DI) and primary polydipsia (PP) in children with polydipsia-polyuria syndrome (PP-S). The H2O-dep is challenging for children and their families. The prolonged fasting may provoke hypoglycemia and dehydration, particularly in younger children. Serum concentrations of copeptin (COP) (a surrogate marker of AVP, which is easier to measure by a robust assay), are known to increase in adults and children undergoing IV arginine (ARG) stimulation testing (ASTT). Objective: To test the hypothesis that COP levels during ASTT would differentiate between DI and PP. Methods: Serum COP responses to ARG were measured in 13 healthy short children being tested for GH deficiency (controls); and in 4 patients with PP-S. Arginine-HCl (500 mg/Kg) was infused IV from 0 to 30 min, with blood sampling at 0, 15, 30, 45, 60 min; seven of 13 controls also received clonidine PO (150 mcg/m2) at 0 min. COP was measured with a 2-site immunometric assay (BRAHMS Platform, Quest Diagnostics). Results: A-Controls. As the COP values at each time point were similar in the ARG and ARG-Clonidine controls, the data from both groups were combined. COP peaked at 45-60 min post ARG in the 13 controls. COP (Mean+SD; pMol/l)) increased from 9.7+4.3, (range 3-17) to a peak of 12.4+5.0 (range 6-21) at 60 min; Δ% increase 47+50 % (range 0-133). The peak COP values on ASTT showed no correlation with subjects’ age or peak GH response. Results B: Subjects with PP-S: On the basis of H2O-dep, MRI findings, and long-term response to desmopressin therapy, 3 of 4 children were diagnosed with central DI, and 1 with PP. Abbreviations: S[Osm], U[Osm]= serum, urine osmolality (mOsm/Kg); values obtained at the end of the H2O Dep: Subject 1. 3 y-old male, diagnosed with PP. After H2O-dep S[Osm] / U[Osm] 286 / 615. On ASTT COP (base vs. peak) 15 vs.116 pMol/l. Subject 2. 8 y-old male, diagnosed with central DI with Langerhans cell histiocytosis (LCH). MRI: absent bright spot. After H2O-dep S[Osm] / U[Osm] 318/202; On ASTT COP (base vs. peak) 2 vs. 2 pMol/l. Subject 3. 2 y-old male. diagnosed with central DI, possible LCH; MRI: absent bright spot. No H2O-dep; On ASTT COP (base vs. peak) 3 vs 3 pMol/l. Subject 4. Male, 3 y-old. Diagnosed with partial DI with LCH. MRI: absent bright spot. After H2O-dep S[Osm] / U[Osm] 297/569. On ASTT COP (base vs. peak) 5 vs. 6 pMol/l. Comment: In all DI patients, COP concentrations remained flat in the ASTT, at 2-3 pmol/L in 2 subjects with complete DI, and 5-6 pmol/L in 1 subject with partial DI. The latter response overlapped with that of 1 of 13 control subjects. Conclusions: These preliminary data support the hypothesis that ASTT is an easy, minimally invasive test, valuable for differentiating the etiology of PP-S in children. However, patients with partial DI may have low-normal COP responses at ASTT that overlap with values in normal children.

A Case With Adult GH Deficiency Complicated With Osteogenesis Imperfecta: Effect of GH Replacement on Bone Mineral Density

Background: Osteogenesis imperfecta (OI) is an inherited connective tissue disorder with many phenotypic presentations. Bisphosphonates are the mainstay of pharmacologic fracture prevention therapy, although they aren’t officially approved for the treatment of OI. Clinical Case: The patient was born by breech delivery. After he had multiple fractures at the age of two years, he was diagnosed with osteogenesis imperfecta (OI) type I by genetic analysis (c.1299 + 1G> A mutation in the COL1A1 gene). On the growth curve, his height fell below -2SD at the age of six years. When he was 12 years old, he visited another hospital because of short stature (Hight 119 cm: -2.7SD). Pituitary MRI revealed pituitary stalk disruption and pituitary atrophy. Endocrinological examinations (ITT, TRH, LHRH, arginine stimulation tests) showed severe GH deficiency. Growth hormone replacement therapy was started. At the age of 16 years, he was diagnosed to have central hypothyroidism and central diabetes insipidus, and levothyroxine and DDAVP were started. His bone mineral density of the lumbar spine was 0.546 g/cm2, and alendronate was started. At the age of 17, central hypogonadism was diagnosed by LHRH stimulation test, and HCG injections were initiated. His bone mineral density continued to increase by GH replacement, HCG injections and bisphosphonate and reached 0.820 g/cm2 (Z-score: -0.27) by the age of 18 years. GH replacement was discontinued (final height 180 cm). At that age, his bone mineral density declined to 0.717 g/cm2 at the age of 25 years, although he stayed on an alendronate and HCG injections. At that time, total testosterone 890 ng/dL (142<n<923 ng/dL) was within normal range, but IGF-1 level was below the lower limit (44 ng/mL; -4.6SD, 225<n<337 ng/mL). He was referred to our hospital for transition to adult endocrine care. Endocrinologic evaluation revealed low serum cortisol level in the early morning (2.26 µg/dL, 7.07<n<19.6 μg/dL). GH-releasing peptide-2 stimulation test revealed severe GH deficiency (peak GH 0.18 ng/mL, n> 15 ng/mL (1)) and replacements with GH and hydrocortisone were initiated. After the GH replacement, the bone mineral density started to increase to 0.954 g/cm2 (Z-score: -0.5). Conclusion: So far as we know, this is the first case report of OI with panhypopituitarism treated with GH and bisphosphonate. This case suggests that bisphosphonate alone is not sufficient to maintain bone mineral density complicated with both OI and severe GHD. GH replacement therapy was inevitable to increase bone mineral density in this patient. Reference: (1) Kazuo Chihara et al. A simple diagnostic test using GH-releasing peptide-2 in adult GH deficiency. Eur J Endocrinol.2007;157;19-27.

Diagnosis of Childhood and Adolescent Growth Hormone Deficiency Using Transcriptomic Data

Background: We have shown that gene expression (GE) data have promise as a novel tool to aid in the diagnosis of childhood growth hormone deficiency (GHD)1. Our previous study compared GE data in children with GHD to healthy control children of normal stature. The aim of this study was to assess the utility of GE data in the diagnosis of GHD in childhood and adolescence using non-GHD short stature children as a control group. Methods: GE data were obtained from patients undergoing growth hormone stimulation testing via a sample of blood taken at the start of the test. Arginine and glucagon stimulation tests with a cut-off for peak GH of <7mcg/L (IDS iSYS assay) were used for the diagnosis of GHD. GE was assessed in peripheral blood mononuclear cells via RNA-seq using the Illumina HiSeq 4000 platform. Data were taken for the 271 genes whose expression was utilised in our previous study. The synthetic minority oversampling technique was used to balance the dataset and a random forest algorithm applied to predict GHD status. Boruta was used to assess which of the genes were contributing to the predictive capacity. Results: Twenty-four patients were recruited to the study, with eight subsequently diagnosed with GHD. Of the eight patients diagnosed with GHD, three had two stimulation tests and five had one stimulation test with anterior pituitary hypoplasia (in addition one patient had an arachnoid cyst and another a thin stalk). Median (range) peak GH was 2.5 (0.1 - 5) mcg/L in the GHD group and 11.0 (7.4 - 31) mcg/L in the non-GHD group.There were no significant differences in gender, age, auxology (height SDS, weight SDS, BMI SDS) or biochemistry (IGF-I or IGFBP-3 SDS) between the GHD and non-GHD subjects. 82 of the 271 genes used in our previous study were above the threshold of detection for RNA-seq in this study. A random forest algorithm using these 82 genes gave an AUC of 0.97 (95% CI 0.93 - 1.0) for the diagnosis of GHD. Boruta was able to identify 65/82 genes with predictive capacity greater than permuted data within the dataset. Using a gene ontology approach the top fifty biological processes generated 16 clusters by affinity propagation which included regulation of TORC1 signalling and inositol phosphate metabolism. Conclusion: This study demonstrates highly accurate diagnosis of childhood GHD using a combination of GE data and random forest analysis and validates the findings of our original study. 1Murray etal (2018) JCI Insight 3(7): e93247

2295-PUB: Impaired First-Phase Insulin Secretion Predicts the Development of Hyperglycemia in a Human Model of Acute Beta-Cell Mass Reduction

β-cell functional defects temporally anticipate (and eventually cause) the subsequent development of hyperglycemia, whereas a significant reduction (∼50%) of beta-cell mass is observed at diagnosis of T2D. To further investigate the relative role of beta-cell mass reduction/dysfunction in the development of T2D, we performed, pre- and post-surgery, oral glucose tolerance tests (OGTT) and hyperglycemic clamps (HC), followed by arginine stimulation and mixed meal test (MMT), in 39 patients undergoing pancreatoduodenectomy (PD), as model of acute mass reduction. Based on post-surgery OGTT, subjects were divided into 3 groups depending on glucose tolerance: normal (NGT, n=11), impaired (IGT, n=10) or diabetic (DM, n=18) (23 F/16 M, 63±13.7 yrs, BMI 23.9±4.5 kg/m2). To evaluate β-cell function, β-cell glucose sensitivity (GS) was calculated during HC, MMT e OGTT as the ratio of insulin secretion (IS) and glucose increments. Comparison among the 3 groups revealed that PD had a significantly different effect on time-dependent change of glucose and insulin levels during all tests (P&amp;lt;0.01 for the interaction between PD, time and glucose tolerance). Before surgery, Arginine-stimulated Insulin Secretion rates (AIS) and GS were similar across groups, whereas incremental 1st phase IS were significantly lower in IGT and DM as compared with NGT subjects (p=0.01). Following PD, the reduction of GS during HC e OGTT was greater in IGT and DM compared to NGT (p=0.01 per HC and OGTT). A similarly reduction was observed in ΔAIS and 2nd phase of IS (p&amp;lt;0.01), but not in ΔIS1 (p=0.33). In this study the acute beta-cell mass reduction had a different impact on insulin secretory capacity, despite comparable functional mass at baseline, according to pre-surgery IS characteristics. This suggests that underlying impairment in β-cell dysfunction anticipates the decline of beta-cell responses, being the pivotal mechanism for the development of hyperglycemia. Disclosure T. Mezza: None. P. Ferraro: None. G. Di Giuseppe: None. C. Cefalo: None. S. Moffa: None. G. Quero: None. F. Cinti: None. F. Impronta: None. U. Capece: None. S. Alfieri: None. A. Mari: Consultant; Self; Lilly Diabetes. Research Support; Self; Boehringer Ingelheim International GmbH. A. Giaccari: Speaker’s Bureau; Self; Amgen, AstraZeneca, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Mundipharma, Novo Nordisk A/S, Sanofi-Aventis.

MON-093 Pleuropulmonary Blastoma and Multinodular Goiter in a 22 Yr Old Male with DICER1 Syndrome

Background DICER1 syndrome is an autosomal dominant condition due to mutations in the DICER1 gene, located on chromosome 14q32.13. Patients are at increased risk for malignant and benign tumors, including pleuropulmonary blastoma (PPB), cystic nephroma, ovarian Sertoli-Leydig cell tumors, multinodular goiter (MNG) and differentiated thyroid cancer (DTC). MNG is very common in patients with DICER1 Syndrome but data on incidence is lacking. MNG is more common in females than males.Case presentation:22 year old man who originally presented with pleuropulmonary blastoma, Type 3 at 3 years of age. His treatment included pulmonectomy, radiation of 46.6 Gy to thorax, and alkylating agents including Cisplatin, Ifosphamide and Cytoxan. He developed frontal lobe metastasis over the course of 3 years and was treated with focal cranial radiation. His father and maternal uncle had history of lung cancer.He was evaluated at the Endocrine clinic at 12 years 10 months for short stature. His height was 132.5 cm (SDS -2.96), weight 29.7 kg (SDS -2.40), and BMI 16.99kg/m² (SDS -0.61). On examination he had normal thyroid exam and Tanner 2 bilateral 4 cc testicles. He was treated with Levothyroxine for subclinical hypothyroidism (TSH: 5.96 uIU/ml (0.35–5.5) and Free T 4: 0.99 ng/dl (0.8–1.80) and growth hormone (GH) for growth hormone deficiency (peak GH was 7.7 ng/ml after Arginine and Clonidine GH stimulation test).At 14 years 10 month he developed respiratory distress. CT scan of chest showed right lower pole nodule 1.6 x 1.5 x 1.4 cm. Ultrasound of thyroid showed right thyroid solid mid pole isoechoic nodule 1.4 x 1.7 x 1.3 cm with multiple enlarged bilateral cervical nodes, largest left supraclavicular region > 1 cm. Biopsy of the right nodule was negative for malignancy. Over the course of 2 years he developed new right thyroid isoechoic nodule in the lower pole 2.1 x 2.5 x 1.9 cm and new left thyroid isoechoic nodule in the upper pole 1.0 x 0.5 x 0.5 cm. Biopsy was negative for malignancy.Due to his PPB, MNG and family history of lung cancer he was evaluated at our genetic cancer clinic and tested positive for germline DICER1 pathogenic variant c.4605_4606del (p.Cys1535Trpfs*3)Conclusion:Our 22 year old male presented with pleuropulmonary blastoma and over the course of few years developed MNG. Genetic testing was positive for germline DICER1 pathogenic variant c.4605_4606del (p.Cys1535Trpfs*3). Our case illustrates the importance of consideration of: 1) Testing children with PPB for DICER1 Syndrome as there are screening recommendations including regular thyroid ultrasound and examinations to look for MNG or other features concerning for thyroid gland neoplasia. 2) MNG is uncommon in children and detection of this should raise suspicion for consideration of testing for DICER1 Syndrome.

Analysis on clinical features of 106 type 2 diabetic patients complicated with insulin autoimmune syndrome

Objective To analyze the clinical features of type 2 diabetic patients with insulin autoimmune syndrome after treatment with exogenous insulin. Methods A total of 106 patients with type 2 diabetes diagnosed with exogenous insulin-related insulin autoimmune syndrome (EIAS) were included from September 2017 to March 2019 in the Department of Endocrinology, Zhongshan Hospital, Fudan University. The clinical data, physical examination, and laboratory examination results of patients were collected. Results Of the 106 patients, 84 (79.24%) used premixed human insulin or premixed insulin analogs, and 18 patients (16.98%) presented recurrent hypoglycemia. The arginine stimulation test showed that the median value of the baseline insulin was 73.40 (23.07-146.75) μU/ml, and the median ratio of 4 minute insulin to 0 minute insulin was 1.27 (1.03-1.85), with the mean of the ratio 1.72±1.47. The ratio of baseline insulin (μU/ml) to C-peptide (ng/ml) was 44.60 (14.92-87.93), with an average of 81.92±130.93. Taking the two-fold upper limit of fasting insulin reference value (49.8 μU/ml) as the cut-off point, the subjects were divided into insulin accumulation group (baseline insulin≥49.8 μU/ml) and insulin non-accumulation group (baseline insulin <49.8 μU/ml). Among the 66 patients in the insulin accumulation group, 14 patients had hypoglycemia (21.21%) and 4 patients in the insulin non-accumulation group presented hypoglycemia (10%). The ratio of 4 minute insulin to baseline insulin, ratio of baseline insulin to C-peptide, blood glucose level standard deviation (SDBG) and maximum blood glucose fluctuation amplitude (LAGE) in the insulin accumulation group were significantly higher than those in the insulin non-accumulation group (all P<0.05). Among 66 patients in the insulin accumulation group, 36 patients changed the type of insulin preparafion (insulin treatment group), 30 patients were changed from insulin to oral hypoglycemic agents (oral medication group). After treatment, both SDBG and LAGE in the two groups were significantly lower than before treatment (P<0.05). Conclusions With the aggravation of exogenous insulin accumulation, the fluctuation of blood glucose and the proportion of hypoglycemia were significantly increased. There was a characteristic change in islet function in patients with insulin autoimmune syndrome. After arginine stimulation, there was no significant peak of insulin secretion, showing a high-level curve. The baseline insulin/C-peptide ratio was significantly increased. The prognosis of EIAS patients is good after timely diagnosis and adjustment of treatment. Key words: Diabetes mellitus, type 2; Insulin autoantibody; Exogenous insulin-related insulin autoimmune syndrome

Long-term Metabolic and Socioeducational Outcomes of Transient Neonatal Diabetes: A Longitudinal and Cross-sectional Study.

Transient neonatal diabetes mellitus (TNDM) occurs during the 1st year of life and remits during childhood. We investigated glucose metabolism and socioeducational outcomes in adults. We included 27 participants with a history of TNDM currently with (n = 24) or without (n = 3) relapse of diabetes and 16 non-TNDM relatives known to be carriers of causal genetic defects and currently with (n = 9) or without (n = 7) diabetes. Insulin sensitivity and secretion were assessed by hyperinsulinemic-euglycemic clamp and arginine-stimulation testing in a subset of 8 TNDM participants and 7 relatives carrying genetic abnormalities, with and without diabetes, compared with 17 unrelated control subjects without diabetes. In TNDM participants, age at relapse correlated positively with age at puberty (P = 0.019). The mean insulin secretion rate and acute insulin response to arginine were significantly lower in TNDM participants and relatives of participants with diabetes than in control subjects (median 4.7 [interquartile range 3.7-5.7] vs. 13.4 [11.8-16.1] pmol/kg/min, P < 0.0001; and 84.4 [33.0-178.8] vs. 399.6 [222.9-514.9] µIU/mL, P = 0.0011), but were not different between participants without diabetes (12.7 [10.4-14.3] pmol/kg/min and 396.3 [303.3-559.3] µIU/mL, respectively) and control subjects. Socioeducational attainment was lower in TNDM participants than in the general population, regardless of diabetes duration. Relapse of diabetes occurred earlier in TNDM participants compared with relatives and was associated with puberty. Both groups had decreased educational attainment, and those with diabetes had lower insulin secretion capacity; however, there was no difference in insulin resistance in adulthood. These forms of diabetes should be included in maturity-onset diabetes of the young testing panels, and relatives of TNDM patients should be screened for underlying defects, as they may be treated with drugs other than insulin.

Impact of acute-phase insulin secretion on glycemic variability in insulin-treated patients with type 2 diabetes.

The association between β-cell function and glycemic variability remains to be clarified in insulin-treated patients with type 2 diabetes. Therefore, the study sought to examine the association of various indices of β-cell function with glycemic variability in Chinese insulin-treated patients with type 2 diabetes. Glycemic variability was assessed by the coefficient of variation (CV) of glucose levels with the use of continuous glucose monitoring (CGM). Basal β-cell function was evaluated by fasting C-peptide (FCP) and the homeostasis model assessment 2 for β-cell function (HOMA2-%β). Postload β-cell function was measured by 2-hour C-peptide (2hCP) and the acute C-peptide response (ACPR) to arginine. When a cutoff value of CV ≥ 36% was used to define unstable glucose, the multivariable-adjusted odds ratios for labile glycemic control were 0.34 (95% CI 0.18-0.64) for each 1 ng/mL increase in ACPR, 0.47 (95% CI 0.27-0.81) for each 1 ng/mL increase in FCP, 0.77 (95% CI 0.61-0.97) for each 1 ng/mL increase in 2hCP, and 1.00 (95% CI 0.98-1.01) for each 1% increase in HOMA2-%β. When we further adjusted for 2hCP and HOMA2-%β in the ACPR and FCP analyses, and adjusted for ACPR or FCP in the 2hCP analyses, only ACPR but not FCP or 2hPC remained to be a significant and inverse predictor for labile glycemic control. ACPR evaluated by the arginine stimulation test may be superior to other commonly used β-cell function parameters to reflect glycemic fluctuation in insulin-treated patients with type 2 diabetes.

Current aspects of diagnosis and treatment of adult GH-deficiency

Adult growth hormone (GH) deficiency (AGHD) is a condition characterized by alterations in body composition, lipid and carbohydrate metabolism, bone mineral density and poor quality of life; however, clinical presentations of AGHD are mostly non-specific. Untreated AGHD is associated with increased cardiovascular morbidity and mortality. Stimulation tests are used for the diagnosis: insulin tolerance test, glucagon stimulation test, growth-hormone releasing hormone and arginine stimulation test. Moreover, in 2017 FDA approved the use of macimorelin (oral GH secretagogue) for the diagnosis of AGHD. In childhood GH-deficiency, apolipoprotein A-IV, CFHR4 (complement factor H-related protein 4) and PBP (platelet basic protein) were identified as potential biomarkers of the disease, however, this was not investigated in AGHD. GH treatment starts from the minimal dose, which allows minimizing the adverse effects. According to published meta-analyses, AGHD treatment generally does not lead to increased risk of malignancy and recurrence of sellar neoplasms in adult patients. Published data on GH receptor polymorphism associations with treatment efficacy remains controversial. Development of long-acting GH formulations is a currect perspective for the increase of treatment compliance.

Management of growth failure and growth hormone deficiency after pediatric allogeneic HSCT: Endocrinologists are of importance for further guidelines and studies

Growth failure (GF) is a frequent problem after pediatric allogeneic hematopoietic stem cell transplantation (HSCT). Growth hormone deficiency (GHD) occurs in 20 to 85%, but published data on the efficacy of growth hormone treatment (GHT) are conflicting. Currently, there are no recommendations on screening for and treatment of GHD after HSCT. We aimed to describe the management of endocrine follow-up (FU)and details of GHT within European Society for Blood and Marrow Transplantation (EBMT) centers.In a retrospective questionnaire study, all EBMT centers performing pediatric HSCT were invited. Results were evaluated in correlation with the structure of endocrine aftercare (HSCT-clinicians and endocrinologists).The majority of centers (80%) reported endocrine FU by an endocrinologist – either within the HSCT-center or in a separate endocrine clinic. Fifty-four percent reported FU outside of the HSCT-center. As diagnostic tests the insulin-like growth factor IGF-I and insulin-like growth factor binding protein IGFBP3, insulin tolerance test and arginine stimulation test were most frequently used. Sixty-four percent of centers performed GHT and endocrinologists were more likely to prescribe GH (74%) compared to HSCT-clinicians (33%). The most frequent indication for GHT was GHD in 60%, with a distinct different approach of endocrinologists in comparison with HSCT-clinicians.Our study reveals substantial variation in practice and emphasizes the need for endocrine aftercare performed by dedicated endocrinologists in close collaboration with the HSCT-center. Our results indicate that the management of GHT depends on the structure of endocrine aftercare, which is important for the future development and distribution of studies and guidelines.