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Glycogen storage disease type Ia (GSD-Ia), deficient in glucose-6-phosphatase-α (G6PC), is characterized by impaired glucose homeostasis and a hallmark of fasting hypoglycemia. We have developed a recombinant adeno-associated virus (rAAV) vector-mediated gene therapy for GSD-Ia that is currently in a phase I/II clinical trial. While therapeutic expression of the episomal rAAV-G6PC clinical vector is stable in mice, the long-term durability of expression in humans is currently being established. Here we evaluated CRISPR/Cas9-based in vivo genome editing technology to correct a prevalent pathogenic human variant, G6PC-p.R83C. We have generated a homozygous G6pc-R83C mouse strain and shown that the G6pc-R83C mice manifest impaired glucose homeostasis and frequent hypoglycemic seizures, mimicking the pathophysiology of GSD-Ia patients. We then used a CRISPR/Cas9-based gene editing system to treat newborn G6pc-R83C mice and showed that the treated mice grew normally to age 16 weeks without hypoglycemia seizures. The treated G6pc-R83C mice, expressing ≥ 3% of normal hepatic G6Pase-α activity, maintained glucose homeostasis, displayed normalized blood metabolites, and could sustain 24 h of fasting. Taken together, we have developed a second-generation therapy in which in vivo correction of a pathogenic G6PC-p.R83C variant in its native genetic locus could lead to potentially permanent, durable, long-term correction of the GSD-Ia phenotype.

We aimed to estimate the prevalence of glucose and lipid metabolism disorders in children and adolescents with spinal muscular atrophy (SMA) types 2 and 3. A cross-sectional study was conducted. Medical history, anthropometric measurements, pubertal status, blood chemistry (glucose and insulin levels, lipid profile, aminotransferases, and hemoglobin A1c [HbA1c]), and liver ultrasound were obtained in all patients. Oral glucose tolerance test was performed in those with body mass index (BMI) >25th percentile or glucose or HbA1c levels in the prediabetic range. A total of 37 patients with SMA (22 type 2, 15 type 3) with a median age of 8.5 years (range 2–18.9 years) were included. Eleven patients (29.7%) met the criteria for prediabetes, but none had overt type 2 diabetes. Dyslipidemia was detected in 11 patients (29.7%), and 4 (10.8%) had hepatic steatosis on ultrasound. Sixteen patients (43.2%) had at least one abnormal finding (prediabetes, dyslipidemia, or hepatic steatosis); all but one were non-ambulatory and 12 (75%) had BMI ≥85th percentile. One young child developed fasting hypoglycemia. Our results suggest that non-ambulatory overweight/obese SMA patients are particularly prone to abnormalities in glucose and lipid metabolism. Young underweight patients might develop fasting hypoglycemia.

Hypoglycemic encephalopathy is a critical condition associated with a poor prognosis. Tumor-induced hypoglycemia is a rare clinical condition of hypoglycemia that occurs when a pancreatic islet beta-cell tumor insulinoma produces excessive insulin. We present the case of a non-diabetic 62-year-old woman with a 15-year history of recurrent fasting hypoglycemia, whose symptoms of weakness and giddiness would develop in the early mornings, prompting her to request sweetened tea and glucose cookies, after which her symptoms would improve. Investigations showed raised levels of insulin, C-peptide, pro-insulin, as well as a decreased value of beta-hydroxybutyrate and a negative screen for urine sulfonylureas. Computed tomography abdomen revealed a focal lesion in the body of the pancreas suggestive of insulinoma. Based on these investigations, a diagnosis of endogenous hyperinsulinism was made. This case emphasizes the importance of thorough history taking, attention, and observation in making a new diagnosis that has the potential to alter a patient’s health care and alleviate clinical outcomes, where the patient ignored the symptoms for nearly 15 years, leading to the development of hypoglycemic encephalopathy.

Aim:: To present an insulinoma case with post-prandial hypoglycemic symptoms associated with glucose inducible endogenous hyperinsulinemia. Case:: A 52-year-old female patient was evaluated for hypoglycemic symptoms especially those occuring within 3 hours after consuming sugary foods. These symptoms were persistent for a year and a half. She was diagnosed with reactive (post-prandial) syndrome and followed a recommended diet and was given acarbose but there was no improvement. The results suggested post-prandial endogenous hyperinsulinemia related hypoglycemia. Multiphasic computerized tomography revealed an 11x15x12 mm size mass lesion, anteriorly in the head and uncinate process of the pancreas and then the patients were treated surgically with pancreatic enucleation and cured. Conclusion:: Distinguishing post-prandial syndrome by careful history and clinical evaluation in patients with postprandial symptoms is of great importance in terms of cost-effectivity. However, it should not be forgotten that although organic pathologies are mostly presented with fasting hypoglycemia, they may also cause post-prandial symptoms. Severity and progression of the symptoms that point to neuroglycopenia is important, and in this condition the most convenient clinical approach to the patient should be performed with careful and appropriate assessment steps.

RESUMEN Objetivo: describir la experiencia de los pacientes con insulinoma, diagnosticados y tratados entre los años 2002 y 2017 en tres hospitales de la ciudad de Medellín, Colombia. Métodos: estudio descriptivo y retrospectivo de pacientes con criterios bioquímicos para hipoglucemia hiperinsulínica y confirmación histopatológica de insulinoma. Resultados: se estudiaron 19 casos, 10 eran mujeres (52,6 %), la edad media al diagnóstico fue 43 años (D.E 15,5). Hubo cuatro casos de insulinoma multifocal (21,1 %), tres asociados con NEM-1 (15,8 %) y dos malignos (10,6 %). Todos presentaron hipoglucemia en ayunas y 63,2 % posprandial. En la prueba de ayuno, el nadir de glucemia sucedió antes de 48 horas en todos los casos, en promedio 9 horas (D.E 8,0). El diagnóstico bioquímico fue realizado con hipoglucemia e insulina elevada en todos los casos, aunque el péptido C fue reportado en nueve pacientes (47,3 %) y las sulfonilureas en dos (11,1 %). La localización preoperatoria se hizo por imágenes en 12 individuos (68,5 %) y las pruebas invasivas fueron necesarias en seis (31,5 %). Las pruebas diagnósticas fueron positivas en un 83 % para resonancia, 50 % para ecografía endoscópica y prueba de estímulo intraarterial con calcio y 100 % para ecografía intraoperatoria. La cirugía se realizó en 18 casos (94,7 %). La mortalidad (15,8 %) fue derivada de complicaciones en el posoperatorio temprano; la curación se logró en todos los casos. Conclusiones: el insulinoma en nuestro medio tiene características demográficas y clínicas similares a otras series. Existen limitaciones locales para el acceso a los estudios bioquímicos y en el rendimiento diagnóstico de las pruebas de localización. SUMMARY Objective: The objective of the study was to describe the characteristics of patients with insulinoma in three hospitals in Medellín, Colombia, between 2002 and 2017. Methods: A retrospective analysis of patients with hyperinsulinemic hypoglycemia and histologic confirmation of insulinoma was conducted. Results: A total of 19 cases were identified. Ten women (52.6 %) and 9 males (47.4 %). The mean age at diagnosis was 43 years (S.D: 15.5). Four cases had multifocal insulinoma (21.1%), 3 cases were secondary to multiple endocrine neoplasia type 1 (15.8 %), and 2 of them were malignant (10.6 %). All patients presented fasting hypo-glycemia, and 63.2% presented post-prandial hypoglycemia. Glucose nadir in the fasting test occurred in the first 48 hours in all cases, with a mean time to hypoglycemia of 9 hours (S.D 8.0). The biochemical diagnosis was done with increased insulin in the presence of hypoglycemia. C-peptide was done in 9 patients (47.3 %), and sulfonylureas in 2 cases (11.1 %). Preoperative localization was done by imaging in 12 cases (68.5 %), and invasive tests were required in 6 cases (31.5 %). Localization tests were positive as follows: magnetic resonance imaging in 83%, endoscopic ultrasound in 50%, selective intra-arterial calcium injection in 50 %, and intraoperative ultrasound in 100%. Eighteen patients (94. 7%) underwent surgery. Mortality (15.8 %) was secondary to early post-operative complications. Conclusions: The characteristics of patients with insulinoma in Medellín are similar to other series. However, there are important local limitations for proper biochemical testing and imaging localization. This is the largest study in our country.

Several endocrine disorders have been defined in patients with Costello syndrome (CS). In this report, we describe a patient with CS accompanied by a clinical picture of hyperinsulinemic hypoglycemia responsive to diazoxide treatment. A 41-day-old female patient with a birth weight of 3,600 g was referred for atypical facial features and swallowing dysfunction. She had a weight of 4,000 g (−0.8 SDS), a length of 50 cm (−2.4 SDS), and a head circumference of 38 cm (0.2 SDS). The clinical findings were suggestive of a genetic syndrome, mainly a RASopathy or Beckwith-Wiedemann syndrome. Whole exome sequencing revealed a de novo heterozygous missense variant in the HRAS (NM_001130442) gene in exon 2: c.35G>C; p.(Gly12Ala), establishing the molecular diagnosis of CS. The patient developed symptomatic hypoglycemia (jitteriness and sweating) at the age of 13 months. The patient’s serum glucose was 38 mg/dL with simultaneous serum insulin and C-peptide levels, 2.8 μIU/mL and 1.8 ng/mL, respectively. Hyperinsulinism was suspected, and an exaggerated glucose response was detected in a glucagon test. Blood glucose monitoring indicated episodes of fasting hypoglycemia and postprandial hyperglycemia. Diazoxide of 10 mg/kg/day was initiated in 3 doses for hyperinsulinemic hypoglycemia, which resolved without new episodes of postprandial hyperglycemia. The patient deceased at the age of 17 months due to cardiorespiratory failure in the course of severe pneumonia complicated with pulmonary hypertension and hypertrophic cardiomyopathy. Several genetic syndromes including CS are associated with endocrinologic manifestations including abnormal glucose homeostasis. Although the frequency and underlying mechanisms leading to hyperinsulinemic hypoglycemia are yet unknown, hypoglycemia in CS responds well to diazoxide.

Non-islet cell tumor hypoglycemia (NICTH) is a relatively rare paraneoplastic syndrome associated with tumors of mesenchymal and epithelial cell origin. Hypoglycemia can be the presenting symptom of NICTH or can appear later in the disease course. The cause of NICTH is stated to be due to secretion of poorly processed insulin-like growth factor (IGF)-2 and in most previous reported cases, the diagnosis of NICTH is made based on the identification of this fraction of IGF-2 or an increased ratio between total IGF-2 and IGF-1. However, in clinical setting, especially in developing countries, such tests cannot be readily available and a diagnosis of NICTH should not be delayed in a patient with a combination of solid tumor, recurrent fasting hypoglycemia, and a low serum insulin and C-peptide level. We describe in our report an 87-year-old man with a history of a pleural tumor presenting with recurrent episode of hypoglycemia. Although surgical removal of the tumor is the ideal management, it is often not feasible as exemplified in our report. In such cases, treatment with glucocorticoid is effective in alleviating the symptoms of hypoglycemia.

A 3-year-old boy developed hypoglycemia with convulsions, rectal bleeding and hyperammonemia. Three-dimensional computed tomography scanning revealed the missing main branch of the portal vein, which confirmed the diagnosis of congenital absence of the portal vein (CAPV). Oral glucose tolerance test showed hyperglycemia with hyperinsulinemia at 30 min, whereas hypoglycemia was observed during fasting and at 120 min. Postprandial hyperglycemia was observed repeatedly. Repetitive hypoglycemia and rectal bleeding were uncontrollable. Living-donor liver transplantation, which was successfully performed, was apparently effective in preventing fasting hypoglycemia and improving hyperammonemia; rectal bleeding ceased after the surgery. Considerably, CAPV could result in hyperinsulinemia with partial failure of hepatic insulin degradation and hypoglycemia due to the lack of glycogen accumulation. Postprandial hyperglycemia could result from the fact that glucose-abundant splanchnic blood directly flows into the systemic circulation through the portosystemic shunt. Therefore, it is important to be aware of CAPV as a cause of glucose metabolism abnormalities including fasting hypoglycemia and postprandial hyperglycemia with hyperinsulinemia.

Giriş: Bu çalışma aile hekimliği yönelimli diyabet merkezi (AHYDM) ile hastane yönelimli diyabet merkezi (HYDM)’den takipli tip 2 diabetes mellitus (DM) hastalarında hipoglisemi sıklığı ve ilişkili faktörlerin karşılaştırılmasını amaçlamaktadır. Yöntem: Bu çalışmaya 1 Aralık 2017– 31 Aralık 2019 tarihleri arasında aynı hastaneye bağlı olan iki diyabet merkezine başvuran Tip 2DM hastaları dahil edilmiştir. Çalışmada hastane içerisinde yer alan ve İç Hastalıkları Kliniği tarafından yürütülen DM merkezi HYDM olarak kabul edilirken, hastane kampüsü dışında bulunan, Aile Hekimliği Kliniği tarafından yürütülen DM merkezi ise AHYDM olarak kabul edilmiştir. Her iki merkezdeki açlık plazma glukozu düzeyi en az iki defa 70 mg/dL’nin altında saptanan hastalar vaka grubuna dahil edilmiştir. Ardından, her bir merkezde vaka grubundaki hastalara yaş ve cinsiyet açısından eşleştirilmiş, hipoglisemi atağı bulunmayan Tip 2 DM hastaları kontrol grubu olarak kabul edilmiştir. Ayrıca, Hipoglisemi Korku Ölçeği (HKÖ) iki merkezdeki vaka grubuna da uygulanmıştır. Bulgular: Çalışmaya dahil edilen 240 hastanın 150 (%62,5)’si kadın idi. HYDM’deki tüm hastaların 53(%1,2)’ünde hipoglisemi saptanmışken, AHYDM’den katılan tüm hastaların 27(%0,31)’sinde hipoglisemi tespit edilmiştir. Her iki merkezdeki vaka grubunda DM süresi, insülin kullanım sıklığı ve toplam insülin dozu kontrol grubundan yüksekti (sırasıyla, HYDM için p=0,049, p0,05). Sonuç: DM hastalarında, özellikle insülin kullanan ve T2DM süresi uzun olan hastalarda hipoglisemi açısından dikkatli değerlendirilmesi gereklidir. Ayrıca hastaların aile hekimleri tarafından hipoglisemi ile ilgili eğitilmesi hipoglisemi görülme sıklığını azaltabilir., Introduction: This study aimed to compare the frequency of hypoglycemia and related factors in type 2 diabetes mellitus DM) patients followed up by a family practice-oriented diabetes center (FPODC) and hospital-oriented diabetes center (HODC). Method: Type 2 DM patients who applied to two diabetes centers affiliated with the same hospital between 1 December 2017-31 December 2019 were included in the study. The DM center located in the hospital and managed by the Internal Medicine Clinic was accepted as HODC, while the DM center located outside the hospital campus and manage by the Family Practice Clinic was accepted as FOPDC. Patients with fasting plasma glucose levels determined to be below 70 mg/dL at least twice in both centers were included in the case group. Subsequently, patients in the case group in each center were matched in terms of age and gender, and T2DM patients without hypoglycemia were accepted as the control group. Besides, the Hypoglycemia Fear Scale (HFS) was applied to the case group patients in both centres. Results: Of the 240 patients included in the study, 150 (62.5%) were female. While hypoglycemia was detected in 53 (1.2%) of patients in HODM, hypoglycemia was detected in 27 (0.31%) patients participating in FOPDC. The duration of DM, frequency of insulin use and insulin dose were higher in both centers cases than in the control group (p=0,049, p0,05). Conclusion: Evaluation of hypoglycemia is necessary for type2 2DM patients who use insulin and have a long duration of DM. In addition, educating patients about hypoglycemia by their family physicians may reduce the frequency of hypoglycemia.

BACKGROUND: Fasting hypoglycemia is a recognized occurrence among pediatric patients with acute lymphoblastic leukemia (ALL) during maintenance therapy. Existing publications describing this finding are limited to small studies and case reports. Our objective was to determine the incidence of hypoglycemia during maintenance chemotherapy and to investigate the association of age, as well as other potential risk factors, with this outcome in pediatric patients with ALL. PROCEDURE: This retrospective cohort study included individuals 1 to 21 years of age with ALL treated with antimetabolite-containing maintenance chemotherapy at a large children’s hospital between January 2011 and December 2014. The primary endpoint was time to first documented episode of hypoglycemia during maintenance therapy, defined as single measurement of plasma glucose

aintenance therapy containing methotrexate and 6-mercapto-purine is essential to cure acute lymphoblastic leukemia (ALL). Cytotoxicity is elicited by incorporation of thioguanine nucleotides into DNA (DNA-TG), and higher leukocyte DNA-TG is associated with increased relapse-free survival. As 6-thioguanine provides 6-fold higher cytosolic levels of thioguanine nucleotides than does 6-mercaptopurine, we added low-dose 6-thioguanine to methotrexate/6mercaptopurine maintenance therapy to explore if this combination results in significantly higher DNA-TG. The target population of the “Thiopurine Enhanced ALL Maintenance therapy” (TEAM) study was 30 patients with non-high-risk ALL, aged 1-45 years on methotrexate/6-mercaptopurine maintenance therapy receiving no other systemic chemotherapy. Incremental doses of 6-thioguanine were added to methotrexate/6-mercaptopurine maintenance therapy (starting 6-thioguanine dose: 2.5 mg/m2/day, maximum: 12.5 mg/m2/day). The primary endpoint was DNA-TG increments. Thirty-four patients were included, and 30 patients completed maintenance therapy according to the TEAM strategy. Of these 30 patients, 26 (87%) tolerated 10.0-12.5 mg/m2/day as the maximum 6-thioguanine dose. TEAM resulted in significantly higher DNA-TG levels compared to those in both TEAM patients before their inclusion in TEAM (on average 251 fmol/mg DNA higher [95% confidence interval: 160-341; P

In a nondiabetic patient, fasting hypoglycemia is uncommon and warrants careful assessment. Although rare, NICTH should be considered in patients with recurrent hypoglycemia especially in those with risk factors for HCC.

Highlights • Spontaneous fasting and/or postprandial hypoglycemia is common in people with CF. • The clinical significance of OGTT related hypoglycemia in CF is not clear. • Dietary modification is the first line treatment for postprandial hypoglycemia. • Patients with CFRD are at risk of hypoglycemia related to insulin therapy. • CGMs and closed loop insulin pump systems may reduce hypoglycemia risk in CFRD., Spontaneous episodes of hypoglycemia can occur in people with cystic fibrosis (CF) without diabetes, who are not on glucose lowering medications. Spontaneous hypoglycemia in CF could occur both in the fasting or postprandial state (reactive hypoglycemia). The pathophysiology of fasting hypoglycemia is thought to be related to malnutrition and increased energy expenditure in the setting of inflammation and acute infections. Reactive hypoglycemia is thought to be due to impaired first phase insulin release in response to a glucose load, followed by a delayed and extended second phase insulin secretion; ineffective counterregulatory response to dropping glucose levels may also play a role. The overall prevalence of spontaneous hypoglycemia varies from 7 to 69% as examined with oral glucose tolerance test (OGTT) or with continuous glucose monitoring (CGM) under free living conditions. Spontaneous hypoglycemia in CF is associated with worse lung function, higher hospitalization rates, and worse clinical status. In addition, patients with CF related diabetes on glucose-lowering therapies are at risk for iatrogenic hypoglycemia. In this article, we will review the pathophysiology, prevalence, risk factors, clinical implications, and management of spontaneous and iatrogenic hypoglycemia in patients with CF.

Non‐islet cell tumor hypoglycemia should be considered in unexplained recurrent non‐insulin‐dependent hypoglycemia. Where surgery is not possible steroids may be effective, even at low dose, at managing hypoglycaemia.

Background Glycogen storage disease type 1a (GSD Ia) is characterized by severe fasting hypoglycemia. The clinical management includes the administration of uncooked cornstarch (UCCS). Although such a diet approach is effective in achieving euglycemia, its impact on the quality of life of patients should be considered. In vitro analyses suggest a longer release of glucose when using sweet manioc starch (SMS). Methods We compared the efficacy and safety of the administration of SMS and UCCS during a short-fasting challenge in patients with GSD Ia in a randomized, triple-blind, phase I/II, cross-over study. GSD Ia patients aged ≥ 16 years and treated with UCCS were enrolled. Participants were hospitalized for two consecutive nights, receiving UCCS or SMS in each night. After the administration of the starches, glucose, lactate and insulin levels were measured in 1-h interval throughout the hospitalization period. The procedures were interrupted after 10 h of fasting or in a hypoglycemic episode ( Results Eleven individuals (mean age: 21.6 ± 4.3 years; all presenting body mass index > 25 kg/m2) participated in the study. The average fasting period was 8.2 ± 2.0 h for SMS and 7.7 ± 2.3 h for UCCS (p = 0.04). SMS maintained euglycemia for a greater period over UCCS. Increased lactate concentrations were detected even in absence of hypoglycemia, not being influenced by the different starches investigated (p = 0.17). No significant difference was found in total cholesterol, HDL, triglycerides and uric acid levels in both arms. None of the patients showed severe adverse events. Conclusions SMS appears to be non-inferior to UCCS in the maintenance of euglycemia, thus emerging as a promising alternative to the treatment of GSD Ia.

Insulinoma is a rare but common functional neuroendocrine tumor that secretes an excess amount of insulin resulting in mostly fasting hypoglycemia but can also cause postprandial hypoglycemia. It usually presents with neuroglycopenic and autonomic sympathetic symptoms that resolve following the administration of dextrose. The patients may remain symptomatic from 1 week to as long as several decades before diagnosis. Insulinoma presenting with psychiatric symptoms has been documented in case/case series reports. Laboratory findings of elevated insulin and C-peptide level in the presence of hypoglycemia and absence of plasma sulfonylurea are suggestive of the diagnosis. Localization of the tumor is essential preoperatively. Surgery usually cures most of the patients, but a minority will have a recurrence especially with malignant insulinoma. The manuscript presents a case of insulinoma presenting with psychiatric symptoms without sympathetic symptoms that led to the delay of the diagnosis for 3 months as initially thought to be related to psychiatric problems. Pancreatic insulinoma was localized by computed tomography (CT) scan and confirmed with endoscopic ultrasound (EUS). The patient underwent successful resection of the tumor, and her symptoms were completely resolved. J Med Cases. 2020;11(5):142-144 doi: https://doi.org/10.14740/jmc3477

Chronic glucocorticoid therapy has serious side effects, including diabetes and fatty liver. However, the molecular mechanisms responsible for steroid-induced diabetes remain largely enigmatic. Here, we show that hepatic Kruppel-like factor 9 (Klf9) gene expression is induced by dexamethasone and fasting. The overexpression of Klf9 in primary hepatocytes strongly stimulated Pgc1a gene expression through direct binding to its promoter, thereby activating the gluconeogenic program. However, Klf9 mutation abolished the stimulatory effect of dexamethasone on cellular glucose output. Adenovirus-mediated overexpression of KLF9 in the mouse liver markedly increased blood glucose levels and impaired glucose tolerance. Conversely, both global Klf9-mutant mice and liver-specific Klf9-deleted mice displayed fasting hypoglycemia. Moreover, the knockdown of Klf9 in the liver in diabetic mouse models, including ob/ob and db/db mice, markedly lowered fasting blood glucose levels. Notably, hepatic Klf9 deficiency in mice alleviated hyperglycemia induced by chronic dexamethasone treatment. These results suggest a critical role for KLF9 in the regulation of hepatic glucose metabolism and identify hepatic induction of KLF9 as a mechanism underlying glucocorticoid therapy-induced diabetes.

Background Glycogen storage disease (GSD) type Ia is a glycogenesis disorder with long-term complications such as hepatomegaly and renal dysfunction and is caused by congenital loss of glucose-6-phosphatase (G6Pase) expression. G6Pase is essential for the final step of gluconeogenesis and glycogenolysis, and its deficiency causes clinical hypoglycemia in the fasting state during infancy. Contrastingly, patients also show blood glucose trends and glucose intolerance similar to those in type II diabetes. Owing to the contrasting presentation of hypoglycemia with glucose intolerance, glucose control in patients remains a challenge, requiring management of both fasting hypoglycemia and post-prandial hyperglycemia. Case presentation The patient was a 45-year old Asian (Japanese) woman who showed disease onset at 3 years of age, when hypoglycemia and hepatomegaly were observed, and GDS type Ia was diagnosed by the lack of G6Pase activity. Over the past 45 years, she presented hyperglycemia and dumping syndrome like symptoms (a feeling of fullness, even after eating just a small amount, abdominal cramping, nausea, sweating, flushing, or light-headedness and rapid heartbeat) at 2 hours after food intake. Her liver and kidney dysfunction also worsened over time. Treatment with exercise combined with a sodium-glucose co-transporter 2 inhibitor and an alpha glucosidase inhibitor alleviated her glucose intolerance and dumping syndrome-like symptoms, without increasing hypoglycemic events. Conclusion This case suggests SGLT2 inhibitor as a promising candidate for treating glucose intolerance in GSD type Ia without worsening of hypoglycemia.

A 54-year-old male with liver cirrhosis (Child-Pugh score 5) presented with severe hepatogenous diabetes (HbA1c 12.6%). Contrast-enhanced CT showed a large portosystemic shunt from the inferior mesenteric vein to the left internal iliac vein. Glucose monitoring showed postprandial hyperglycemia and reactive hypoglycemia. After balloon-occluded retrograde transvenous obliteration (BRTO) and partial splenic transarterial embolization, postprandial hyperglycemia was diminished. Seven months later, HbA1c had improved from 12.6% to 6.7%. In this case, postprandial hyperglycemia occurred by direct delivery of glucose into the systemic circulation via the shunt, and fasting hypoglycemia occurred during treatment with oral antidiabetic agents and insufficient gluconeogenesis. BRTO of the portosystemic shunt resulted in improvement in hepatogenous diabetes.

Background: Patients with an insulinoma, a type of pancreatic neuroendocrine tumor, typically present with fasting hypoglycemia (1). Occurrence of exclusively postprandial hypoglycemia as a result of a predominantly proinsulin-secreting metastatic neuroendocrine tumor is rare (2). Clinical Case: A 69-year-old man presented with episodes of postprandial blurry vision, sweating and confusion for the last two years that were becoming more frequent over the last several weeks. Self-monitoring of blood glucose at home revealed postprandial hypoglycemia (45-70mg/dl) and symptoms were consistent with Whipple’s triad. Continuous glucose monitoring over 14-days via Dexcom G6 showed no nocturnal or fasting hypoglycemia and revealed only postprandial hypoglycemia within one-two hours after meals. Laboratory measurements were performed at 8am in fasting state which revealed a blood glucose of 97mg/dl, insulin level 7.8 µIU/ml (2-21 µIU/ml), c-peptide 1.67 ng/ml (1.1-4.4 ng/ml) and elevated proinsulin level of 39 pmol/l ( Conclusion: Pancreatic neuroendocrine tumor should be considered in post-prandial hypoglycemia, even in the absence of fasting hypoglycemia. Measuring proinsulin is essential in the diagnostic workup of insulinoma causing hypoglycemia References: 1. Placzkowski KA, Vella A, Thompson GB, Grant CS, Reading CC, Charboneau JW, et al. Secular trends in the presentation and management of functioning insulinoma at the Mayo Clinic, 1987-2007. J Clin Endocrinol Metab. 2009;94(4):1069-73.2. Murtha TD, Lupsa BC, Majumdar S, Jain D, Salem RR. A Systematic Review of Proinsulin-Secreting Pancreatic Neuroendocrine Tumors. J Gastrointest Surg. 2017;21(8):1335-41.

Background: Mutations of the insulin receptor (INSR) gene lead to a wide spectrum of inherited insulin resistance (IR) syndromes. Among these, type A-IR, usually caused by dominant negative INSR mutations, generally presents peri-pubertally in girls. Case: A 2.8-year-old girl was referred due to recurrent postprandial and fasting hypoglycemia. She had been born at full-term with birth weight 1.89 kg, and had developed transient neonatal diabetes. Examination showed satisfactory growth, reduced adipose tissue, acanthosis nigricans, and isolated thelarche. After 12 h of fasting, she developed hypoglycemia (glucose 2.8 mmol/L), with inappropriately raised plasma insulin concentration of 5.4 mU/L and suppressed fatty acids and ketone bodies. Oral glucose tolerance testing showed severely increased plasma insulin concentration (>300 mU/L) with hypoglycemia (glucose 1.6 mmol/L) at 2.5 h. She was initially managed on dietary modifications, cornstarch, and then trialed on acarbose for postprandial hyperinsulinemic hypoglycemia (PPHH) with some response. However, she was noted to have increased frequency of hyperglycemia after a couple of years of treatment. She was then switched to metformin and continued to have dietary carbohydrate modification including cornstarch that improved fasting tolerance, hyperglycemia, and postprandial hypoglycemia. Genetic testing identified heterozygous deletion of the last exon of the INSR gene, exon 22. Conclusion: We present a case of type A-IR, caused by a novel INSR deletion, presenting unusually early with transient neonatal diabetes, followed by episodes of hypoglycemia and hyperglycemia during later childhood. Early life presentations, including neonatal diabetes and PPHH, should lead to consideration of type A-IR.

A low fasting blood glucose level is a common symptom in diabetes patients and can be induced by high-fat diet (HFD) feeding at an early stage, which may play important roles in the development of diabetes, but has received little attention. In this study, five polysaccharides were prepared from Sargassumfusiforme and their effects on HFD-induced fasting hypoglycemia and gut microbiota dysbiosis were investigated. The results indicated that C57BL/6J male mice fed an HFD for 4 weeks developed severe hypoglycemia and four Sargassumfusiforme polysaccharides (SFPs), consisting of Sf-2, Sf-3, Sf-3-1, and Sf-A, significantly prevented early fasting hypoglycemia without inducing hyperglycemia. Sf-1 and Sf-A could also significantly prevent HFD-induced weight gain. Sf-2, Sf-3, Sf-3-1, and Sf-A mainly attenuated the HFD-induced decrease in Bacteroidetes, and all five SFPs had a considerable influence on the relative abundance of Oscillospira, Mucispirillum, and Clostridiales. Correlation analysis revealed that the fasting blood glucose level was associated with the relative abundance of Mucispinllum and Oscillospira. Receiver operating characteristic analysis indicated that Mucispinllum and Oscillospira exhibited good discriminatory power (AUC = 0.745&ndash, 0.833) in the prediction of fasting hypoglycemia. Our findings highlight the novel application of SFPs (especially Sf-A) in glucose homeostasis and the potential roles of Mucispinllum and Oscillospira in the biological activity of SFPs.

International audience; Hypoglycemia is defined by a low blood glucose level associated to clinical symptoms. Hypoglycemia may be related to treatment of diabetes, but also to drugs, alcohol, critical illness, cortisol insufficiency including hypopituitarism, insulinoma, bariatric or gastric surgery, pancreas transplantation or glucagon deficiency, or may be surreptitious. Some hypoglycemic episodes remain unexplained, and genetic, paraneoplastic and immune causes should be considered. Genetic causes may be related to endogenous hyperinsulinism and to inborn errors of metabolism (IEM). Endogenous hyperinsulinism is related to monogenic congenital hyperinsulinism, and especially to mutations of the glucokinase-activating gene or of insulin receptors, both characterised by postprandial hypoglycemia with major hyperinsulinism. In adulthood, IEM-related hypoglycemia can persist in a previously diagnosed childhood disease or may be a presenting sign. It is suggested by systemic involvement (rhabdomyolysis after fasting or exercising, heart disease, hepatomegaly), sometimes associated to a family history of hypoglycemia. The timing of hypoglycemic episodes with respect to the last meal also helps to orientate diagnosis. Fasting hypoglycemia may be related to type 0, I or III glycogen synthesis disorder, fatty acid oxidation or gluconeogenesis disorder. Postprandial hypoglycemia may be related to inherited fructose intolerance. Exercise-induced hyperinsulinism is mainly related to activating mutation of the SLC16A1 gene. Besides exceptional ectopic insulin secretion, paraneoplastic causes involve NICTH (Non-Islet-Cell Tumour Hypoglycemia), caused by Big-IGF2 secretion by a large tumour, with low blood levels of insulin, C-peptide and IGF1. Autoimmune causes involve antibodies against insulin (HIRATA syndrome), especially in case of Graves' disease, or against the insulin receptor. Medical history, timing, and insulin level orientate the diagnosis.

Epidemiological studies have consistently shown an association between exposure to environmental pollutants and diabetes risk in humans. We have previously shown that direct exposure of mouse and human islets (endocrine pancreas) to the highly persistent pollutant TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) causes reduced insulin secretion ex vivo. Furthermore, a single high-dose of TCDD (200 µg/kg) suppressed both fasting and glucose-induced plasma insulin levels and promoted beta-cell apoptosis after 7 days in male mice. The current study investigated the longer-term effects of a single high-dose TCDD injection (20 µg/kg) on glucose metabolism and beta cell function in male and female C57Bl/6 mice. TCDD-exposed males displayed modest fasting hypoglycemia for ~4 weeks post-injection, reduced fasting insulin levels for up to 6 weeks, increased insulin sensitivity, decreased beta cell area, and increased delta cell area. TCDD-exposed females also had long-term suppressed basal plasma insulin levels, and abnormal insulin secretion for up to 6 weeks. Unlike males, TCDD did not impact insulin sensitivity or islet composition in females, but did cause transient glucose intolerance 4 weeks post-exposure. Our results show that a single exposure to dioxin can suppress basal insulin levels long-term in both sexes, but effects on glucose homeostasis are sex-dependent.

Background Numerous patients develop diabetes in response to glucocorticoid therapy. This study explored the efficacy, safety, and preventive potential of the dipeptidyl peptidase-4 inhibitor, linagliptin (TRADJENTA®), in the development of glucocorticoid-induced diabetes mellitus. Methods From December 2014 to November 2015, we recruited non-diabetic Japanese patients scheduled for treatment with daily prednisolone ≥20 mg. Enrolled patients had at least one of following risk factors for glucocorticoid-induced diabetes mellitus: estimated glomerular filtration rate ≤ 60 mL/minute/1.73 m2; age ≥ 65 years; hemoglobin A1c > 6.0%. A daily dose of 5 mg of linagliptin was administered simultaneously with glucocorticoid therapy. The primary outcome was the development of glucocorticoid-induced diabetes mellitus. Additional orally administered hypoglycemic medications and/or insulin injection therapy was initiated according to the blood glucose level. Results Four of five patients developed glucocorticoid-induced diabetes mellitus within 1 week of glucocorticoid treatment. For 12 weeks, two of the four patients with glucocorticoid-induced diabetes mellitus required orally administered medications, but no patients required insulin. Blood glucose levels before breakfast and lunch tended to decrease with time; the median glucose levels before breakfast were 93 and 79.5 mg/dL at 1 and 3 weeks, respectively. Two patients experienced mild hypoglycemia around 2 weeks. Glucose levels after lunch remained high throughout all 4 weeks despite decreasing the glucocorticoid dosage. Conclusions Linagliptin may be insufficient to prevent the development of glucocorticoid-induced diabetes mellitus but has the potential to reduce the requirement for insulin injection therapy. Treatment of glucocorticoid-induced diabetes mellitus was continued for at least 1 month and fasting hypoglycemia in early morning should be monitored after 2 weeks. Trial registration This trial was registered 02 November 2014 with UMIN Clinical Trials Registry (no. 000015588).

Objective In children with presymptomatic type 1 diabetes, intermittent hyperglycemia and rising hemoglobin A1c levels are a known signal of progression toward insulin-dependency. Episodes of hypoglycemia, however, have also been reported in one published case. We investigated the prevalence of hypoglycemia and its association with disease progression in children with presymptomatic type 1 diabetes.Methods We compared the frequency of hypoglycemic fasting blood glucose levels (

The delayed diagnosis of insulinoma remains a clinical issue. One of the main causes of such a delay is hypoglycemia unawareness. A 53-year-old woman fell unconscious during postprandial exercises. Flash glucose monitoring (FGM) systems revealed glucose profiles with fasting hypoglycemia, which facilitated the clinical diagnosis of insulinoma even though she was unaware of her hypoglycemia. The preoperative comparison of the blood glucose values provided by FGM with those obtained from capillary blood were consistent. Thus, FGM may have potential utility in revealing the presence of insulinoma-induced hypoglycemia.

Objective CD36 deficiency is characterized by limited cellular long chain fatty acid uptake in the skeletal and cardiac muscles and often causes energy crisis in these muscles. However, suitable treatment for CD36 deficiency remains to be established. The aim of this study was to evaluate the clinical and metabolic effects of medium chain triacylglycerols (MCTs) in two CD36-deficient preschool children who often developed fasting hypoglycemia and exercise-induced myalgia. Methods Fasting blood glucose, total ketone bodies, and free fatty acids were examined and compared for usual supper diets and for diets with replacement of one component with 2 g/kg of 9% MCT–containing milk (MCT milk). Changes in serum creatine kinase and alanine aminotransferase levels, resulting from replacement of glucose water intake with 1 g/kg of MCT milk and determined by using bicycle pedaling tasks, were examined and compared. Hypoglycemic and/or myalgia episodes in daily life were also investigated. Results Biochemically, participants' blood glucose and total ketone bodies levels after overnight fasting substantially increased after dietary suppers containing MCT milk. Increases in serum creatine kinase and alanine aminotransferase levels resulting from the bicycle pedaling task were suppressed by MCT milk. Hypoglycemia leading to unconsciousness and tachycardia before breakfast decreased after introduction of dietary suppers containing MCT milk. Occurrence of myalgia in the lower limbs also decreased after intakes of MCT milk before long and/or strenuous exercising. Conclusion Our results suggest that MCTs can prevent fasting hypoglycemia and exercise-induced myalgia in CD36-deficient young children.

Background: Glycogen storage diseases (GSDs) are a collection of disorders related to glycogen synthesis or degradation that classically present in infancy with hypoglycemia, failure to thrive and hepatomegaly; however, their phenotype can vary significantly. Case presentation: We present the cases of two children, 5 years old and 3.5 years old, who were referred to endocrinology for short stature. They were ultimately found to have hepatomegaly, fasting hypoglycemia, mild elevation of transaminases and ketosis. Laboratory and genetic studies were consistent with double heterozygosity for GSDs Ia and III, with one novel mutation discovered in each patient. Nightly, both children were treated with cornstarch, which resulted in resolution of laboratory abnormalities and improvement in their growth velocity. These cases are unusual in that GSD was diagnosed relatively late in life in patients with no previous history of severe hypoglycemia. Conclusions: They highlight the importance of considering glycogen storage disease in a child presenting with short stature, as it is a treatable disease that can be diagnosed non-invasively with genetic testing.

The phenotype of individuals with glycogen storage disease (GSD) IX appears to be highly variable, even within subtypes. Features include short stature, fasting hypoglycemia with ketosis, hepatomegaly, and transaminitis. GSD IXɑ2 is caused by hemizygous pathogenic variants in PHKA2, and results in deficiency of the phosphorylase kinase enzyme, particularly in the liver. Like other GSDs, GSD IXɑ2 can present with hypoglycemia and post-prandial lactic acidosis, but has never been reported in a newborn, nor with lactic acidosis as the presenting feature. Here we describe the clinical presentation and course of a newborn boy with profound neonatal lactic and metabolic acidosis, renal tubulopathy, and sensorineural hearing loss (SNHL) diagnosed with GSD IXɑ2 through exome sequencing. Review of the literature suggests this case represents an atypical and severe presentation of GSD IXɑ2 and proposes expansion of the phenotype to include neonatal lactic acidosis and renal tubulopathy.

Insulin autoimmune syndrome (IAS) is a rare cause of hypoglycemia characterized by the presence of insulin autoantibodies (IAA) in patients without prior exposure to exogenous insulin. Differential diagnosis with other causes of hypoglycemia may be complex. We report three IAS cases with severe fasting hypoglycemia, referred to our Unit for the diagnostic workup of insulinoma. All three patients (two women and a man, age 66, 44, and 50 years) had history of severe fasting hypoglycemia leading to loss of consciousness along with weight gain. Both insulin and C-peptide were high, but their levels varied greatly among patients, ranging from 24 to 1500 μU/ml (n.v.

Fanconi-Bickel syndrome is a rare inherited disease characterized by the combination of hepatorenal glycogen accumulation, proximal renal tubular dysfunction and impaired utilization of glucose and galactose. The first symptoms of the disorder are recognized in late infancy as clinical characteristics appear. Therapeutic approach is mainly conservative with supplements of calcium, phosphate and vitamin D and small frequent feedings to avoid hypoglycemia. We report 1 clinical case of very early diagnosis, a 19 days old baby girl, in which the first clinical sign of the disease was the detection of glycosuria and vomits. Serum alkaline phosphatase levels were very high without rickets. The patient presented postprandial hyperglycemia and fasting hypoglycemia. A complete 24-hour glucose profile was obtained using a continuous glucose monitoring system in real time, which was fundamental not only for the diagnosis but also for the prevention of hypoglycemia. She received frequent small meals, galactose-free milk diet, and oral intakes of calcium, phosphorum, bicarbonate and vitamin D supplements with good evolution and normal height and weight gain.

Rationale: Glycogen storage diseases (GSD, glycogenosis) are a group of hereditary disorders of carbohydrate metabolism that is characterized by excess glycogen accumulation in various organs and tissues due to deficiency or absence of glycogen-splitting enzymes. GSD diagnostics requires an assessment of the patient's health status, severity and frequency of hypoglycemias, as well as the choice of a strategy for nutritional support to prevent hypoglycemia.Aim: To assess efficacy of continuous glucose monitoring (CGM) as a new method to diagnose hypoglycemia in children with hepatic types of GSD and the role of this assessment method in personalization of nutritional regimen in these disorders.Materials and methods: The study included 51 child with confirmed diagnosis of GSD at the age of 6.9 ± 0.7 years, of them 36 boys and 15 girls. Thirty three percent of patients had GSD type I, 22% – type III, 45% – types VI and IX. All patients had their glycemic levels measured as glycemic profiles and oral glucose tolerance test (OGTT), as well as by means of real-time CGM. The results were analyzed both in the whole group of patients and in the groups with various GSD types.Results: Measurement of glycemic profiles in children with GSD at daytime did not detect any significant abnormalities. During OGTT, more rapid decline of glucose levels was seen in younger kids and in patients with GSD type I; however, the differences were not statistically significant (11 patients (65% of cases) had the lowest glucose levels at 180 minutes of the test: 3.1 ± 0.3 mmol/L, p > 0.05). Fasting hypoglycemia in the OGTT was found in 4 (24%) children with GSD type I and in 3 (13%) children with GSD types VI and IX. Hypoglycemia at the end of the test was seen in 13 (76%) patients with GSD type I, in 3 (27%) with type III, and in 12 (55%) with types VI and IX. CGM showed hyperglycemia (10.2 ± 0.3 mmol/L) for 1 to 1.5 hours after a meal. Hypoglycemic episodes were registered at night time in 48 (94.1%) of children indicating the need for additional night feeding. Maximal total duration of low glucose levels was found in type I of the disease (10.2 ± 2.4 hours). Analysis of CGM results depending on GSD type showed that despite comparable glucose levels, more significant abnormalities are found in GSD type I (the proportion of hyperglycemic periods was 10.2 ± 2.3%, their duration 6.9 ± 1.8 hours; the proportion of hypoglycemic periods was 13.5 ± 2.6%, their duration 10.2 ± 2.4 hours, p < 0.05).Conclusion: The results obtained indicate the necessity to use CGM in all GSD patients to diagnose and prevent hypoglycemia that would be the basis to elaborate individual nutritional recommendations.

Insulinoma is a rare, usually benign, pancreatic neuroendocrine tumor. The clinical features of an insulinoma are fasting hypoglycemia with neuroglycopenic symptoms including confusion and unusual behavior, while hypertension is usually not associated with the disease. We herein report a patient with insulinoma who manifested paroxysmal hypertension and neuroglycopenic symptoms. The possible etiology of hypertension induced by an insulinoma is catecholamine release in response to hypoglycemia, which may cause acute hypertension through activation of the sympatho-adrenal system. This case implies that sustained hyperinsulinemia due to insulinoma can be functionally linked to the induction of paroxysmal hypertension.

Insulin autoimmune syndrome (IAS) involves not only fasting hypoglycemia, but also postprandial hyperglycemia. In the present study, we hypothesized that glycated albumin (GA) levels and the GA/HbA1c ratio, which reflect fluctuations in plasma glucose levels, are elevated in IAS patients. Four IAS patients were enrolled in the present study. Thirty-two non-diabetic subjects matched for gender, age, and BMI were used as the control group. The fasting plasma glucose levels in the IAS patients were significantly lower than in the control group. However, the oral glucose tolerance test (OGTT) revealed impaired glucose tolerance or diabetes mellitus in all the IAS patients, and thus the OGTT 2-h plasma glucose levels were significantly higher than in the control group. The GA levels and the GA/HbA1c ratio in the IAS patients were significantly higher than in the control group, despite no significant difference in the HbA1c levels between the two groups. In one case in which IAS spontaneously went into remission, there was a significant correlation between anti-insulin antibodies and GA, but not HbA1c. Improvement in glucose fluctuations was observed by continuous glucose monitoring in another patient along with improvement in the clinical symptoms. Furthermore, anti-insulin antibodies, GA, and the GA/HbA1c ratio decreased, but HbA1c did not change significantly in three IAS patients along with the improvement in clinical symptoms. These results suggest that GA and the GA/HbA1c ratio are useful indicators for determining the level of disease activity in IAS patients.

Inactivating mutations of β-cell KATP channels cause the most common and severe form of congenital hyperinsulinism (HI), a β-cell disorder that causes dysregulated insulin secretion and persistent hypoglycemia. Children with KATPHI are typically unresponsive to diazoxide, the only FDA-approved drug for HI. Octreotide, a sst2 peptide agonist that inhibits insulin secretion, is used as second line therapy, but poor efficacy and sst2-mediated side effects, such as glucagon suppression and necrotizing enterocolitis, limit its use in infants. Thus, most infants with KATPHI require pancreatectomy for intractable hypoglycemia. To address the unmet need for effective and safe therapies, we examined the ability of a selective sst5 nonpeptide agonist CRN02481 (Crinetics Pharmaceuticals) to suppress insulin secretion and prevent fasting hypoglycemia in the SUR1-/- mouse model of KATPHI. SUR1-/- mouse islets were treated with CRN02481 (100 nM) or vehicle and then stimulated with a physiologic amino acid mixture (4 mM). CRN02481 significantly decreased baseline (1.5 ± 0.2 vs. 2.4 ± 0.5 ng/uL, p≤0.01) and amino acid-stimulated (2.8 ± 1.5 vs. 4.4 ± 1.1 ng/uL, p≤0.05) insulin secretion. SUR1-/- mice were gavaged with CRN02481 (10 mg/kg/day) or PBS for 7 days (n=7/group) and fasting glucose, glucose tolerance and insulin tolerance tests were assessed. CRN02481 significantly increased fasting glucose and prevented fasting hypoglycemia (98 ± 18 vs. 44 ± 6 mg/dL, p Disclosure C. Juliana: Research Support; Self; Crinetics. J. Chai: None. E.F. Rico-Bautista: Employee; Self; Crinetics Pharmaceuticals. Stock/Shareholder; Self; Crinetics Pharmaceuticals. S.F. Betz: Employee; Self; Crinetics Pharmaceuticals. Stock/Shareholder; Self; Crinetics Pharmaceuticals. D.D. De Leon: Consultant; Self; Crinetics, Novartis Pharmaceuticals Corporation, ProSciento, Soleno Therapeutics, Zealand Pharma A/S. Employee; Spouse/Partner; Merck & Co., Inc. Research Support; Self; Crinetics, Dexcom, Inc., Zealand Pharma A/S. Stock/Shareholder; Self; Merck & Co., Inc. Funding Crinetics Pharmaceuticals (to D.D.D.)

The diagnostic evaluation of neonates and infants with persistent hypoglycemia requires a systematic approach to evaluate the integrity of the fuel and hormone responses during the development of fasting hypoglycemia. This is best accomplished by performing a closely monitored fasting test. The diagnosis of hyperinsulinism relies heavily on demonstrating inappropriate effects of insulin on fasting adaptation, i.e., inappropriate suppression of lipolysis and ketogenesis and inappropriate preservation of liver glycogen reserves as hypoglycemia develops. Once the diagnosis of hyperinsulinism has been established, evidence from the timing and the pattern of the hypoglycemia, the presence or absence of hyperammonemia, the response to substrate challenge tests (i.e., glucose and protein), and the results of genetic testing can specify the type of hyperinsulinism. This knowledge will allow one to implement the correct therapy and determine if the patient is a candidate for curative surgical approach such as is possible in focal KATP-HI and insulinomas.

Diazoxide responsiveness is typically the starting point for distinguishing congenital hyperinsulinism phenotypes since those who do not respond will often require surgery. Operationally, diazoxide responsiveness is defined as being able to appropriately develop a hyperketonemic response to fasting (beta-hydroxybutyrate >2 mmol/L) prior to developing hypoglycemia (