Hypoinsulinemic Hypoglycemia Research Articles

6712 Intractable Hypoglycemia: A Clue to Tumor Diagnosis

Abstract Disclosure: N. Kharkongor Chengappa: None. E.I. Krug: None. Background: Non-Islet Cell Tumor Hypoglycemia (NICTH) known as Doege-Potter syndrome, is a rare paraneoplastic syndrome of hypo-insulinemic hypoglycemia caused by excessive production of partially processed IGF-II from a solitary fibrous tumor (SFT).We present a case of a patient admitted with intractable hypoglycemia leading to the diagnosis and treatment of a large pelvic SFT. Clinical Case: A 59-year-old male with type 2 Diabetes Mellitus on metformin mono therapy, was admitted after he collapsed at work and was found to have blood glucose (BG) of 22 mg/dl. He was previously in his usual state of health except for an increase in his shoe size over the past year. Physical examination revealed coarse thick skin, large coarse bullous nose, enlarged fingers and a non-tender, firm abdomen with no obvious organomegaly. Laboratory results including CBC, CMP and thyroid function were normal. ACTH stimulation test revealed normal adrenal function. Hypoglycemic drug screen and insulin antibodies were negative. During a hypoglycemic event (BG of 45mg/dl) he had C-peptide level < 0.1ng/ml, beta-hydroxybutyrate levels of <0.05 and insulin level <0.4uIU/ml, indicating non-insulin mediated hypoglycemia. IGF-I and IGF-II levels were ordered. Due to a concern for paraneoplastic etiology of hypoglycemia. CT scan revealed a 20 cm solid mass, filling most of the pelvis and extending into the lower abdomen. Further investigations revealed normal PSA, CEA, CA19-9 and undetectable hCG and AFP levels. MRI confirmed a presence of 23 cm pelvic mass with few areas of central necrosis, extending into the lower abdomen. CT-guided biopsy revealed spindle cell neoplasm consistent with SFT. The patient underwent pelvic mass resection. Postoperatively, hypoglycemia resolved with BG readings of 138mg/dl to 178mg/dl. Surgical pathology results confirmed malignant SFT with positive STAT 6 and CD34 markers. IGF-II level obtained prior to surgery was markedly elevated at 2029 ng/ml (38-267 ng/mL). Conclusion: NICTH was described in 1930 by KW Doege and RP Potter. Less than 5% of patients with SFTs develop NICTH. Diagnosis requires manifestation of Whipple's triad, low insulin, pro-insulin and C-peptide levels, elevated IGF-II levels, or an IGF-I/IGF-II ratio>2, and the identification of the tumor. Positive immunohistochemical stain of the tumor for STAT6 confirms the diagnosis. Management involves resection of the tumor when feasible or debulking. For higher-risk tumors, radiation therapy may be considered. In inoperable cases, glucocorticoids, recombinant hGH and glucagon are recommended for palliation of hypoglycemia. Octreotide and Diazoxide are ineffective in NICTH.

7023 Hypoinsulinemic Hypoglycemia in a Severely Malnourished Patient with an Acute Liver Injury: A Marker of Poor Outcome!

7023 Hypoinsulinemic Hypoglycemia in a Severely Malnourished Patient with an Acute Liver Injury: A Marker of Poor Outcome!

Postprandial hypoinsulinemic hypoglycemia as a clue to hidden purging behavior in an adolescent boy with disordered eating

Postprandial hypoglycemia, hypoglycemia occurring within four hours of intake of meals, is an extremely uncommon condition in children. We report the case of an adolescent boy who presented with excessive hunger, poor weight gain, anasarca, hypoalbuminemia, and electrolyte imbalance. Investigating the history of post-meal drowsiness showed postprandial hypoglycemia, which on subsequent evaluation revealed elevated fasting insulin and suppressed postprandial insulin levels. This eventually led to the uncovering of a deliberately and cleverly concealed purging behavior. A meticulous interview of the family and the child confirmed the diagnosis of anorexia nervosa, binge-purging type, and averted unnecessary further investigations into the cause of failure to thrive.

Schmidt's Syndrome: An Uncommon Cause of Spontaneous Hypoglycemia

AbstractSchmidt's syndrome, or autoimmune polyendocrine syndrome type 2 (APS-2), is an uncommon disorder characterized by the co-occurrence of autoimmune thyroiditis and adrenalitis. APS-2 is defined as a combination of Addison's disease, autoimmune thyroid disease, and/or type 1 diabetes mellitus. It is an autosomal dominantly inherited polygenic disorder with incomplete penetrance; the candidate genes include but are not limited to HLA-DR3, HLA-DR4, CTLA-4, PTPN22, and CD25-IL-2. Autoimmune thyroiditis, often Hashimoto's disease, results in hypothyroidism. Primary adrenal failure results in enhanced secretion of adrenocorticotrophic hormone melanocyte and co-secretion of melanocyte-stimulating hormone, contributing to hyperpigmentation. Mineralocorticoid deficiency results in salt wasting, fatigue and cramps, postural hypotension, and hyperkalemia. Cortisol, an insulin counter-regulatory hormone, plays a pivotal role in maintaining euglycemia; deficiency predisposes to the development of hypoglycemia. We here report a rare presentation of Schmidt's syndrome as hypoinsulinemic hypoglycemia in a middle-aged male patient. Management includes treatment of acute hypoglycemic episodes with glucose or glucagon, long-term glucocorticoids and mineralocorticoids for adrenal insufficiency, and thyroid hormone supplements for hypothyroidism. This case report and brief overview aim to contribute to the scientific understanding of Schmidt's syndrome/APS-2. Additionally, here we briefly outline the diagnostic challenges in hypoglycemia evaluation, including the utilization of Whipple's triad and the gold standard supervised 72-hour fast and evaluation for primary adrenal and thyroid insufficiencies.

An expanded clinical spectrum of hypoinsulinaemic hypoketotic hypoglycaemia

BackgroundHypoketotic hypoglycaemia with suppressed plasma fatty acids and detectable insulin suggests congenital hyperinsulinism (CHI). Severe hypoketotic hypoglycaemia mimicking hyperinsulinism but without detectable insulin has recently been described in syndromic individuals with mosaic genetic activation of post-receptor insulin signalling. We set out to expand understanding of this entity focusing on metabolic phenotypes.MethodsMetabolic profiling, candidate gene and exome sequencing were performed in six infants with hypoketotic, hypoinsulinaemic hypoglycaemia, with or without syndromic features. Additional signalling studies were carried out in dermal fibroblasts from two individuals.ResultsTwo infants had no syndromic features. One was mistakenly diagnosed with CHI. One had mild features of megalencephaly-capillary malformation-polymicrogyria (MCAP) syndrome, one had non-specific macrosomia, and two had complex syndromes. All required intensive treatment to maintain euglycaemia, with CHI-directed therapies being ineffective. Pathogenic PIK3CA variants were found in two individuals – de novo germline c.323G>A (p.Arg108His) in one non-syndromic infant and postzygotic mosaic c.2740G>A (p.Gly914Arg) in the infant with MCAP. No causal variants were proven in the other individuals despite extensive investigation, although rare variants in mTORC components were identified in one. No increased PI3K signalling in fibroblasts of two individuals was seen.ConclusionsWe expand the spectrum of PI3K-related hypoinsulinaemic hypoketotic hypoglycaemia. We demonstrate that pathogenic germline variants activating post-insulin-receptor signalling may cause non-syndromic hypoinsulinaemic hypoketotic hypoglycaemia closely resembling CHI. This distinct biochemical footprint should be sought and differentiated from CHI in infantile hypoglycaemia. To facilitate adoption of this differential diagnosis, we propose the term “pseudohyperinsulinism”.

ODP267 Doege-Potter Syndrome in a Patient With Mediastinal Solitary Fibrous Tumor

Abstract N on-islet cell tumor hypoglycemia (NICTH) is a rare paraneoplastic syndromethat presents mostly with hypoinsulinemic hypoglycemia and is associated with benign and malignant neoplasms other than insulinoma. Doege-Potter Syndrome (DPS) is characterized when NICTH is secondary to a solitary fibrous tumor (SFT). The following is a case of DPS in which the patient presented with refractory hypoglycemia. An 81-year-old Caucasian male presented to emergency department with a 10-day history of worseningneuroglycopenic symptoms in fasting state. He experienced worsening night sweats, unsteadiness while walking, dizziness, and irritation, which resolved after breakfast each morning. Five years prior to this admission, he was diagnosed with a malignant mediastinal SFT (atypical spindle cell neoplasm). He was treated with radiation followed by mass resection (9.5×6.5×7.9 cm). Despite treatment with 3 lines of therapy of phase 1 clinical trial, his disease continued to progress with a right paraspinal mass and bilateral lung metastases being subsequently found. In ED, his initial blood glucose was 53 mg/dL. Despite receiving IV dextrose pushes and a continual dextrose infusion, he continued to be hypoglycemic. Upon admission, blood work revealed blood glucose of 41 mg/dL, low insulin level of 0.4 uIU/mL (2.6-24.9 uIU/mL) and low C-peptide level of 0.9 ng/mL (1.1-4.4ng/mL). Proinsulin (4.4pmol/L), Cortisol (17.2mcg/dL) and A1c (5.2%) were all within normal limits. Serum and urine ketones as well as a blood sulfonylurea panel were negative. He was started on hydrocortisone 50 mg 8 hourly for insulin-independent hypoglycemia. His IGF1 level was 46 ng/mL (55-166ng/mL), and IGF2 level was 564 ng/mL (333-967ng/mL) with a high IGF2: IGF1 ratio of 12. He was discharged home with same hydrocortisone regimen. On follow-up, hydrocortisone dose was reduced to 30-30-20 mg. He passed away 4 months later after being hospitalized for hypoxic respiratory failure secondary to a pleural effusion. Interestingly, he was maintained on the same regimen of hydrocortisone up until his death and did not have recurrence of severe hypoglycemic episodes. The main mechanism of NICTH is tumoral overexpression of the IGF2 gene and aberrant post-translational processing, resulting in partially processed high-molecular-weight IGF2 (big-IGF2). Big- IGF2 has a lower affinity for IGF-binding proteins, which favors its own availability to IGF1 and insulin related receptors resulting in profound hypoglycemia and occasionally acromegaloid features. Diagnosis of NICTH is typically made byan IGF2: IGF1 ratio of greater than 10 (normal 3: 1)due to unavailability of commercial assays for big-IGF2. Radical tumor resection is the definitive treatment of NICTH. In unresectable neoplasms, tumor debulking, or medical therapies such as glucocorticoids, recombinant GH, and glucagon are used to alleviate hypoglycemic symptoms. Exploring more about effectiveness of chemotherapy regimens in controlling NICTH will be helpful in inoperable tumors. Presentation: No date and time listed

ODP187 Doedge-Potter syndrome and papillary thyroid carcinoma: An unusual association

Abstract Hypoglycemia can occur in non-diabetic individuals. Doege-Potter is a rare paraneoplastic syndrome presented as a hypoinsulinemic hypoglycemia caused by ectopic secretion of insulin-like growth factor-2 (IGF-2) from a solitary fibrous tumor. There is recent evidence of the involvement of the IGF system in different malignancies as papillary thyroid carcinoma, being exceptional. A 69-year-old female was brought to Emergency after a routine analysis uncovered severe hypoglycemia. She mentioned a history of morning sickness, dizziness, and confusion for the last week that reverted after breakfast, and dry cough for three months. She had a 25-pack-year history of smoking, no history of alcohol use, no other antecedent of interest, no history ofdiabetes mellitus or weight loss surgery, nor chronic treatments. Physical examinations revealed diminished breath sounds in the left middle lung. A thorax radiography showed a submassive left pleural effusion and toracocentesis revealed a hemorrhagic exudate. Laboratory data showed normal GH, and cortisol levels. Despite marked hypoglycemia, insulin level was 0.4 μIU/mL (2,6-24,9), C-peptide 0.11ng/ml (1,1-4,4) and hydroxy butyrate <0.1 mg/dl. The serum IGF-2 level was 428μg/dL (350-1000), and the IGF-1 level was 55.4 μg/L(161-384). Anti-insulin antibodies and sulfonylureas concentration were negative. CT showed a solid mass concerning parietal pleura with areas of necrosis and calcifications, measuring 14.6×15.4×20cm. Low blood glucose with suppressed insulin, C-peptide and IGF-1 levels, elevated IGF-2/IGF-1 ratio (7,7, normal<3) and CT findings suggested the possibility of non-islet cell tumor hypoglycemia (NICTH). Corticoid treatment was initiated to manage the hypoglycemia. Biopsy of the mass showed a malignant solitary fibrous tumor, positive for CD34 and BCL2. After surgery, glucose and IGF-2 levels returned to normal, the patient didn't experience further episodes of hypoglycemia, and corticoid treatment was gradually suspended. A FDG-PET scan, part of extension study, found a PET-positive thyroid nodule. A thyroid ultrasound confirmed a solid, taller than wide thyroid nodule, measuring 6.7×6.4×9,5mm and fine-needle aspiration biopsy was suggestive of papillary thyroid carcinoma. Hemithyroidectomy was performed. The patient is with no evidence of disease. Doege-Potter syndrome is a rare cause of hypoglycemia, resulting from a tumor producing elevated levels of IGF-2. Diagnosis is suggested by low insulin, C-peptide and IGF-1 levels, normal or elevated IGF-2, and elevated IGF2/IGF1 ratio. High levels of ''big-IGF-2'' are associated with high risk papillary thyroid carcinoma, suggesting the relation between the IGF-system and tumor growth, nevertheless there are few cases reported describing this association. Surgical resection of the tumor is the treatment of choice. Presentation: No date and time listed

Interleukin-1b and Interferon-g are Associated with Malaria-Induced Hypoinsulinemic Hypoglycemia in Plasmodium berghei Anka-Infected Mice

Malaria-induced hypoglycemia is recognized as a serious complication of malaria and has one of the strongest associations with mortality in children. It has been speculated that oxidative stress and pro-inflammatory response during parasite infection were involved in its pathophysiology. Hence, this study aimed to investigate the development of malaria-induced hypoglycemia during Plasmodium berghei ANKA (PbANKA) infection with particular attention to the involvement of c-peptide, interleukin-1b (IL-1b), and interferon-g (IFN-g). ICR mice were infected with 1×107 parasitized erythrocytes of PbANKA, and parasitemia was monitored, and the development of hypoglycemia was assessed by measuring plasma glucose levels. The change of c-peptide level was evaluated. The pro-inflammatory response of IL-1b and IFN-g were also quantified in plasma. It was found that PbANKA infection resulted in hypoglycemia as indicated by a significantly (P < 0.05) decrease in plasma glucose levels on day 4 post-infection and associated with parasitemia. The c-peptide was slightly increased at day 2 post-infection, and then significantly (P < 0.05) decreased since day 4. Furthermore, we observed a significantly (P < 0.05) increased IL-1b, firstly responded, at day 2 post-infection followed by increasing the IFN-g level at day 4 in PbANKA-induced hypoglycemia. Our findings support the idea that hypoinsulinemic hypoglycemia in the PbANKA infected mice may be involved in the high IL-1b and IFN-g against the parasite infection.

PTEN Deletion in Adult Mice Induces Hypoinsulinemia With Concomitant Low Glucose Levels.

The PI3K/AKT pathway, negatively regulated by PTEN, plays a paramount role in glucose metabolism regulation due to its activation by the insulin receptor signaling pathway. We generated a PTEN-KO mouse to evaluate the systemic effect of the overactivation of the PI3K/AKT pathway in insulin signaling and glucose homeostasis. Our results demonstrate that PTEN-KO mice show very low glucose levels in the fasted state, which poorly respond to glucose and pyruvate administration. Insulinemia decreased without alterations in pancreatic islets. Among the possible reasons, we uncover the deregulation of the expression of proximal tubule glucose transporter and consequent glycosuria. Moreover, we evidence an altered activation of hepatic gluconeogenesis-related genes. In addition, the expression of several genes related to β-oxidation showed a delayed or even absent response to fasting, suggesting that the lack of PTEN not only impairs glucose metabolism but also slows down the use of lipids as a metabolic fuel. We conclude that the inducible full PTEN-KO mice could be a good model to study the metabolic interactions between glycidic and lipidic metabolism in hypoinsulinemic hypoglycemia and that PTEN could be an important mediator in the disease and/or a potential drug target.

Insulin Receptor Autoantibody–mediated Hypoglycemia in a Woman With Mixed Connective Tissue Disease

Autoantibodies to the insulin receptor are rare and typically cause severe insulin resistance and hyperglycemia, a condition termed type B insulin resistance. Uncommonly, antibodies to the insulin receptor can cause hypoglycemia. We present the case of a woman who developed recurrent severe hypoglycemia and myopathy, was found to have insulin receptor autoantibodies and mixed connective tissue disease, and had resolution of hypoglycemia with immunosuppression. A 55-year-old woman with a history of obesity, hypertension, and prior hemorrhagic stroke presented with recurrent severe hypoglycemia. A diagnostic fast resulted in hypoinsulinemic hypoketotic hypoglycemia. Adrenal function was intact. Progressive myopathy had developed simultaneously with her hypoglycemia, and rheumatologic evaluation revealed mixed connective tissue disease. The plasma acylcarnitine profile was normal, extensive oncologic evaluation including insulin-like growth factor 2 measurement was unrevealing, and anti-insulin antibody testing was negative. Ultimately, anti-insulin receptor antibodies were found to be present. The patient was treated with glucocorticoids and rituximab. Eight weeks after initiation of immunosuppression, the insulin receptor antibody titer had decreased and hypoglycemia had resolved. Eight months after diagnosis, the patient remained free of severe hypoglycemia despite tapering of glucocorticoids to a near-physiologic dose. Though antibodies to the insulin receptor typically cause severe insulin resistance, this patient had no evidence of insulin resistance and instead presented with recurrent severe hypoglycemia, which responded to glucocorticoids and rituximab. The diagnosis of insulin receptor antibody–mediated hypoglycemia is rare but should be considered in patients with systemic autoimmune disease, including mixed connective tissue disease, in the appropriate clinical context.

Efficacy and safety of sirolimus therapy in familial hypoinsulinemic hypoglycemia caused by AKT2 mutation inherited from the mosaic father

Activating mutation in the insulin signal-transducing kinase AKT2 results in severe hypoinsulinemic hypoketotic hypoglycemia and a characteristic phenotype of possible overgrowth and, sometimes, acanthosis nigricans. Herein, we describe a metabolic and hormonal profile before and during treatment with sirolimus in two brothers with AKT2 mutation inherited from the mosaic father, who showed low-level mosaicism in sperm. The boys, aged 1 and 14, who had severe non-insulin-dependent hypoketotic hypoglycemia and a typical dysmorphism, were admitted to endocrinology department for the analysis of their metabolic parameters: lipids, lactate, ammonia, glucose, insulin, c-peptide, and hormones (GH, IGF1, IGFBP3, TSH, fT4, cortisol, ACTH) before and during treatment with sirolimus. Previously, they had been treated with high-carbohydrate diet. The brothers were started on sirolimus with subsequent normalization of glycemia and reduced carbohydrate feedings overnight. The lowest fasting glucose levels improved from 20 mg/dl to 45 mg/dl in both sibs. The BMI of both brothers significantly dropped. After 6 months of sirolimus therapy we did not observe any laboratory or clinical side effects of the treatment.

Doege-Potter syndrome: a case report

Doege-Potter syndrome is a rare paraneoplastic syndrome presenting as hypoinsulinemic hypoglycemia due to ectopic secretion of prohormone: insulin-like growth factor-2 (IGF-2) from a solitary fibrous tumor (SFT). It is essentially a non-islet cell tumor hypoglycemia (NICTH) or in more recent terms, an ‘IGF-2oma’. In case of delay in diagnosis, tumor-induced hypoglycemia could cause hypoxic cerebral injury or death. We hereby present a case of 45 years old male who presented with hypoglycemia due to pleural SFT, which is a very rare and unique presentation. Upon biochemical and radiological investigations, Doege-Potter syndrome was diagnosed and the patient was planned for surgical resection of the tumor. This case stresses upon thorough evaluation of patients presenting with non-diabetic hypoglycemia to rule out underlying malignancy.

SUN-129 Hipoinsulinemic Hipoglycemia Caused by Solitary Fibrous Tumor IGF-2 Producer: Case Report

BACKGROUND: Solitary Fibrous Tumor is a mesenchymal neoplasm composed of CD34+ fibroblastic cells that can produce spontaneous hypoglycemia by the overproduction of IGF-2. It closely resembles the hypoglycemia characteristic of functioning islet cell tumors. CLINICAL CASE A 77-year-old male was found unconscious and taken to an emergency department with evidence of hypoglycemia and clinical improvement following intravenous glucose administration. He did not have a history of diabetes mellitus and was not taking any glucose lowering medications. He was discharged with nutritional orientation and for control of capillary glycaemia to prevent hypoglycemia. He had 3 episodes of capillary hypoglycemia (50, 45 and 38) at home, that was predominant in the fasting morning and during its occurrence he presented mild sweating, speech difficulty, staring and diplopia, with complete improvement of symptoms after oral glucose replacement. Months earlier, he sought an otolaryngologist for intermittent mild dyspnea; denied cough, hemoptysis, chest pain and unintentional weight loss. He performed chest X-ray with evidence of large right hemithorax mass. Physical examination revealed diminished breath sounds in the right middle and lower lung fields and dullness to percussion. Despite marked hypoglycemia (31 mg/dl), the serum insulin level was less than 0.6 μIU/mL (less than 3 μIU/mL), the C-peptide level was 0.24 nmol/L (less than 0,6 nmol/L), had negative ketonemia and a positive response after glucagon administration (glycaemia increased in 50 mg/dl). Anti-insulin antibodies were negative. Serum cortisol secretion and adrenocorticotropic hormone were normal. The serum level of growth hormone (GH) was 0,03 (less than 0,97ng/ml). The serum IGF-2 level was 227 ng/ml (267 - 616 ng/ml), the IGF-I level was 72 ng/ml (37,1 - 172 ng/ml) and the IGF2/ IGF1 was 3,15 (equal or greater than 3). Computed tomographic (CT) scan revealed a large heterogeneous mass with dimensions of 17,4 × 15× 12.2 cm. It determines almost total atelectasis of the lower lobe on this side and maintains broad medial contact with the mediastinum, compressing the right atrium and the inferior pulmonary vein on this side. Preoperatively, was administered 40 mg oral prednisone with capillary glucose normalization. The tumor was completely resected and was a grayish-white solid, with dimensions of 17 x 16 x 12 cm. Immunohistochemical stains demonstrated positivity for CD34 and IGF2 expression. Postoperatively, serum glucose and insulin levels returned to normal, and episodes of hypoglycemia are resolved. CONCLUSION This case reinforce the importance of investigate IGF-2 tumor production as a cause of hypoinsulinemic hypoglycemia and reports the complete resolution of hypoglycemia after corticoid administration and/or tumor resection.

Non-islet cell tumor hypoglycemia in a patient with pleural tumor and hypoinsulinemic hypoglycemia: A case report

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.

Paraneoplastična hipoglikemija kod pacijenta sa recidivom fibroznog tumora pleure

BACKGROUND: Solitary fibrous tumor of pleura represents a prototypical mesenchymal neoplasm that induces non-islet cell tumor hypoglycemia due to overproduction of insulin-like growth factor 2, named Doege Potter syndrome. CASE PRESENTATION: An 86-year-old man, non-diabetic, was admitted to hospital with a few months history of repetitive hypoglycemic symptoms and documented low blood glucose of 1.9 and 1.2 mmol/L on two occasions when he lost consciousness. His medical history was notable for primary pleural fibroma which was resected twenty years previously and for tumorous mass of right pulmonal lobe 103mm described on CT chest scan for respiratory infection six months prior to hospitalization. During hospitalization hypocorticism and hypoptuitarism were ruled out. He spontaneously developed mild neuroglycopenic episodes, when we confirmed hypoinsulinemic hypoglycemia accompanied with suppressed levels of growth hormone and IGF1, and IGF2 : IGF1 ratio of 7, which was all suggestive of paraneoplastic etiology. The response of glucose in Glucagon test was adequate. Beta-hydroxybutyrate was not done due to technical limitations. Abdominal MRI showed a few well-circumscribed cysts in the liver and hemangioma. Octreoscan revealed zone of diffuse increased uptake in right hemithorax. Subsequently, he was started on prednisolon for COPD exacerbation with which his hypoglycemic episodes subsided. Patient declined surgery and he was released with corticosteroid therapy. CONCLUSIONS: We report a case of hypoinsulinemic hypoglycemia in a patient with suppressed levels of hGH and IGF1 and higher-than-normal IGF2 : IGF1 ratio, along with recurrent pleural tumor which is somatostatine-receptor positive.

Non-islet-cell tumour hypoglycaemia (NICTH): About a series of 6 cases

The purpose of this study was to analyse the characteristics of 6 patients managed in a university hospital between 1996 and 2016 for non-islet cell tumor hypoglycemia (NICTH), a form of hypoglycaemia due to the paraneoplastic secretion of IGF-2 or its related substances. ResultsThree of these 6 patients (50%), aged over 69 years, including 2 with acromegaloid phenotype, presented with a pleural solitary fibrous tumor (SFT), with median diameter 20 cm (interquartile range, 12.5–20.5) with a low median SUV (3.3 g/mL (QR, 2–7.5)) on 18F-FDG PET. The other 3 patients presented respectively neuroendocrine carcinoma (NEC) of the palate (70-year-old woman), retroperitoneal myxofibrosarcoma (66-year-old man) and meningeal hemangiopericytoma (36-year-old woman). All 3 were inoperable and did not respond to any therapy other than glucose solution. Corticosteroid therapy was effective in the 3 SFTs and the NEC. One of the SFTs recurred 10 years later with asymptomatic hypoglycemia, which resolved after reintervention. Median (IQR) blood glucose levels of the 6 patients was 0.4g/L (QR, 0.31–0.41), with hypoinsulinemia at 0.7mIU/L (QR 0.7–2.0), undetectable GH, low IGF-1, normal IGF-2 level in 5/6 cases, a high IGF-2:IGF-1 ratio at 26.9 (QR, 20.8–37.8), hypokalemia and hypomagnesemia. ConclusionNICTH is a rare syndrome, which should be considered in the presence of hypoinsulinemic hypoglycemia with low GH and IGF-1, and a IGF-2:IGF-1 ratio>10. Corticosteroid therapy was effective in elderly subjects, particularly with solitary fibrous tumor, which was generally operable. Hemangiopericytoma and myxofibrosarcoma had poor prognosis in younger patients.

Hypoinsulinemic hypoglycemia triggered by liver injury in elderly subjects with low body weight: case reports.

SummaryHypoglycemia is induced by many causes, especially over-dose of insulin or oral hypoglycemic agents in diabetic subjects. In such a case, hyperinsulinemic hypoglycemia is usually observed. On the other hand, it is important to classify secondary hypoglycemia and hypoinsulinemic hypoglycemia. Liver injury-induced hypoglycemia is one of the causes of hypoinsulinemic hypoglycemia but rarely observed in clinical practice. Herein, we experienced similar 2 cases of non-diabetic hypoinsulinemic hypoglycemia. Both of them were elderly subjects with low body weight. Furthermore, it is likely that hypoinsulinemic hypoglycemia in both subjects was triggered by severe liver injury, at least in part, due to possible limited liver glycogen store. In elderly subjects with low body weight and/or malnutrition, metabolism in the liver is reduced and glycogen accumulation is decreased. Such alteration brings out acute and marked liver injury, which finally leads to the onset of severe hypoglycemia. It is known that not only liver injury but also multiple organ failure could be induced due to extreme emaciation in subjects. It is likely that in elderly subjects with low body weight and/or malnutrition, multiple organ failure including liver failure could be induced due to the similar reason. Therefore, we should be very careful of such subjects in order to avoid the development of multiple organ failure which leads to life-threatening situations. In conclusion, we should keep in mind the possibility of hypoinsulinemic hypoglycemia when we examine severe liver injury, especially in elderly or starving subjects with low body weight and limited liver glycogen stores.Learning points:It is important to classify secondary hypoglycemia and hypoinsulinemic hypoglycemia.Liver injury-induced hypoglycemia is one of the causes of hypoinsulinemic hypoglycemia but rarely observed in everyday clinical practice.Herein, we reported similar 2 cases of hypoinsulinemic hypoglycemia without diabetes presumably triggered by severe liver injury.In both cases, hypoglycemia was improved by glucose infusion, although their liver injury was not improved.We should keep in mind the possibility of hypoinsulinemic hypoglycemia when we examine severe liver injury, especially in elderly subjects with low body weight.

Constitutive Activation of AKT2 in Humans Leads to Hypoglycemia Without Fatty Liver or Metabolic Dyslipidemia.

Context:The activating p.Glu17Lys mutation in AKT2, a kinase mediating many of insulin’s metabolic actions, causes hypoinsulinemic hypoglycemia and left-sided hemihypertrophy. The wider metabolic profile and longer-term natural history of the condition has not yet been reported.Objective:To characterize the metabolic and cellular consequences of the AKT2 p.Glu17Lys mutation in two previously reported males at the age of 17 years.Design and Intervention:Body composition analysis using dual-energy X-ray absorptiometry, overnight profiling of plasma glucose, insulin, and fatty acids, oral glucose tolerance testing, and magnetic resonance spectroscopy to determine hepatic triglyceride content was undertaken. Hepatic de novo lipogenesis was quantified using deuterium incorporation into palmitate. Signaling in dermal fibroblasts was studied ex vivo.Results:Both patients had 37% adiposity. One developed hypoglycemia after 2 hours of overnight fasting with concomitant suppression of plasma fatty acids and ketones, whereas the other maintained euglycemia with an increase in free fatty acids. Blood glucose excursions after oral glucose were normal in both patients, albeit with low plasma insulin concentrations. In both patients, plasma triglyceride concentration, hepatic triglyceride content, and fasting hepatic de novo lipogenesis were normal. Dermal fibroblasts of one proband showed low-level constitutive phosphorylation of AKT and some downstream substrates, but no increased cell proliferation rate.Conclusions:The p.Glu17Lys mutation of AKT2 confers low-level constitutive activity upon the kinase and produces hypoglycemia with suppressed fatty acid release from adipose tissue, but not fatty liver, hypertriglyceridemia, or elevated hepatic de novo lipogenesis. Hypoglycemia may spontaneously remit.

Abstract #313: Effect of Imatinib in a Patient with Hypoinsulinemic Hypoglycemia Secondary To Unresectable and Recurrent Solitary Fibrous Tumor

Abstract #313: Effect of Imatinib in a Patient with Hypoinsulinemic Hypoglycemia Secondary To Unresectable and Recurrent Solitary Fibrous Tumor

Refractory hypoglycemia in a patient with functional adrenal cortical carcinoma.

SummaryAdrenacarcinomas are rare, and hypoglycemic syndrome resulting from the secretion of insulin-like growth factor II (IGF-II) by these tumors have been described infrequently. This study describes the case of a young woman with severe persistent hypoglycemia and a large adrenal tumor and discusses the physiopathological mechanisms involved in hypoglycemia. The case is described as a 21-year-old woman who presented with 8 months of general symptoms and, in the preceding 3 months, with episodes of mental confusion and visual blurring secondary to hypoglycemia. A functional assessment of the adrenal cortex revealed ACTH-independent hypercortisolism and hyperandrogenism. Hypoglycemia, hypoinsulinemia, low C-peptide and no ketones were also detected. An evaluation of the GH–IGF axis revealed GH blockade (0.03; reference: up to 4.4 ng/mL), greatly reduced IGF-I levels (9.0 ng/mL; reference: 180–780 ng/mL), slightly reduced IGF-II levels (197 ng/mL; reference: 267–616 ng/mL) and an elevated IGF-II/IGF-I ratio (21.9; reference: ~3). CT scan revealed a large expansive mass in the right adrenal gland and pulmonary and liver metastases. During hospitalization, the patient experienced frequent difficult-to-control hypoglycemia and hypokalemia episodes. Octreotide was ineffective in controlling hypoglycemia. Due to unresectability, chemotherapy was tried, but after 3 months, the patient’s condition worsened and progressed to death. In conclusion, our patient presented with a functional adrenal cortical carcinoma, with hyperandrogenism associated with hypoinsulinemic hypoglycemia and blockage of the GH–IGF-I axis. Patient’s data suggested a diagnosis of hypoglycemia induced by an IGF-II or a large IGF-II-producing tumor (low levels of GH, greatly decreased IGF-I, slightly decreased IGF-II and an elevated IGF-II/IGF-I ratio).Learning points:Hypoglycemyndrome resulting from the secretion of insulin-like growth factor II (IGF-II) by adrenal tumors is a rare condition.Hypoinsulinemic hypoglycemia associated with hyperandrogenism and blockage of the GH–IGF-I axis suggests hypoglycemia induced by an IGF-II or a large IGF-II-producing tumor.Hypoglycemia in cases of NICTH should be treated with glucocorticoids, glucagon, somatostatin analogs and hGH.