High Molecular Weight Insulin-like Growth Research Articles

Surgical resection of a retroperitoneal liposarcoma producing insulin-like growth factor II: a case report

BackgroundTumor-produced high molecular weight insulin-like growth factor-II (big insulin-like growth factor-II) is considered to cause non-islet cell tumor hypoglycemia. This paper presents a case of surgically resected retroperitoneal liposarcoma that produced big insulin-like growth factor-II.Case presentationHere, we report the case of a 62-year-old woman who presented with an abdominal mass and hypoglycemia. Non-islet cell tumor hypoglycemia due to retroperitoneal liposarcoma was suspected. After complete resection of the tumor, the patient’s hypoglycemia improved and big insulin-like growth factor-II disappeared in the molecular weight analysis of serum insulin-like growth factor-II by western blotting. The patient had no tumor recurrence or reappearance of hypoglycemia 16 months after the operation without any adjuvant therapy.ConclusionsAlthough insulin-like growth factor-II-producing tumors are generally large and difficult to operate on, surgical resection is currently the most effective and only treatment; thus, it is essential to attempt resection aggressively.

Think Outside the Thorax: Doege-Potter Syndrome Presenting as a Retroperitoneal Mass

Introduction: Non-islet cell tumor hypoglycemia (NICTH) is a rare paraneoplastic syndrome, occurring less commonly than insulinoma. These tumors produce high molecular weight insulin-like growth factor-2 or “big IGF-2”, resulting in hypoglycemia: big IGF-2 decreases glycogenolysis, gluconeogenesis, and glucagon release as well as increases glucose uptake by adipocytes and skeletal muscle. NICTH specifically associated with a solitary fibrous tumor (SFT) is known as Doege-Potter syndrome. Doege-Potter syndrome is seen most with thoracic SFT’s. This case study details the diagnosis and management of Doege-Potter syndrome due to retroperitoneal SFT.Case Description: Our patient is a 68-year-old, white female who initially presented to an outside facility with a 3-week history of episodic neuroglycopenic symptoms temporarily relieved with eating. She reported night sweats but no weight change or fever. Medical history was notable only for hypertension and GERD. She had no personal or family history of diabetes. She was transferred to our facility for further evaluation of an 18.6 cm multilobular mass seen just inferior to the liver on abdominal CT. Whipple’s triad was confirmed with venous glucose sampling while inpatient. C-peptide, free/total insulin, and pro-insulin were collected during permissive hypoglycemia and were low. Morning cortisol and TSH were unremarkable. Additionally, sulfonylurea screen and insulin antibodies were negative. Ultrasound-guided biopsy of the lesion was positive for CD34 and STAT6, consistent with SFT. Refractory hypoglycemia was treated with D5W infusion until surgical resection of the retroperitoneal mass, after which, she had complete resolution of her hypoglycemia.Discussion: This patient’s serum IGF-2 was within normal limits, consistent with reports of feedback inhibition exerted by increased levels of big-IGF-2. Therefore, the IGF-2:IGF-1 ratio is used to determine increased serum levels of big IGF-2, but this test is not widely available. SFT’s can recur within months to years of resection, necessitating surveillance. Recurrence is also more common with extrathoracic tumors. Surgical pathology noted tumor dimensions of 22 cm and 2270 g; mitotic rate was 1 per 10 hpf. Features typical of malignancy include large size (>15 cm) and mitotic rate >4 mitoses per hpf. This patient’s follow-up CT abdomen at 6 weeks did not show any findings to suggest recurrent or metastatic disease.

SAT-117 Refractory Paraneoplastic Non Islet Cell Tumor Hypoglycemia (NICTH) from Hepatocellular Carcinoma Managed with Somatostatin Analogue and Glucocorticoids

Non islet cell tumor hypoglycemia (NICTH) is a rare paraneoplastic syndrome generally seen in tumors of mesenchymal and hepatic origin. This syndrome is characterized by life threatening hypoglycemia caused by over expression of high molecular weight insulin-like growth factor 2 (IGF 2). The main stay of treatment is surgical resection of the tumor with no clear medical management being reported as standard of care.We present the case of a 72 year old Cambodian man with no history of diabetes mellitus who presented to our institution with severe hypoglycemia complicated by a seizure and was found to have hepatocellular carcinoma (HCC). Hypoglycemia occurred during times of fasting. Laboratory evaluation revealed a serum glucose of 30mg/dl with insulin level of 2.2 mcIU/mL [2.6 - 24.9 mcIU/ml], C-Peptide of 0.17 ng/mL [0.80 - 3.85 ng/ml], BHB <0.1 mmol/L [0.0 - 0.3 mmol/L] and Proinsulin of <0.4 pmol/L [< or = 18.8 pmol/L]. Hypoglycemic agents screening was negative. Insulin Antibody was negative <0.4 U/mL [<0.4 U/mL] and adrenal insufficiency and hypothyroidism was ruled out. Patient was found to have an elevated IGF 2: IGF 1 ratio of 78 confirming the diagnosis of NICTH. IGF 2 level was 780 ng/ml [333 - 967 ng/ml] while IGF-1 was < 10 ng/ml [32-200 ng/ml] He was not a candidate for surgery due to portal vein involvement and tumor radioembolization was unsuccessful. Despite Prednisone dose of 10 mg twice daily and frequent complex carbohydrate meals, he still continued to have hypoglycemia ultimately requiring hospitalization. During hospitalization, he was treated with 50% dextrose infusion, 37.5 grams of dextrose gel every three hours and frequent small meals. Hypoglycemia remained refractory and a trial of diazoxide was ineffective. He was then started on octreotide with titration to 100mg every 8 hours with significant reduction in hypoglycemic episodes. He continues to remain on octreotide, Prednisolone 20mg twice a day, dextrose gel and dextrose infusion. Goal is to wean dextrose infusion and transition him to Pasireotide 40mg monthly.Hepatocellular carcinoma has been associated with NICTH in the literature. NICTH is characterized by an IGF2:IGF1 ratio >10 as there is no commercially available assay for big IGF II. Definitive treatment involves surgical resection or tumor debulking. Octreotide has antiangiogenic and antineoplastic properties and unfortunately, few studies have shown improved survival and quality of life in patients with advanced HCC. In the case of our patient, tumor was unresectable and NICTH improved with octreotide and prednisolone.

Intraoperative glycemic control using an artificial endocrine pancreas in a patient with a recurrent pleural solitary fibrous tumor producing insulin-like growth factor 2: a case report

BackgroundNon-islet cell tumor producing insulin-like growth factor 2 involves hypoglycemia. During tumor resection, intense fluctuation of blood glucose level may occur. An artificial endocrine pancreas has been reported as beneficial for patients with insulinoma as it maintains stable glycemic levels, although scarcely described with insulin-like growth factor 2-releasing tumor.Case presentationAn 84-year-old man had a recurrent left pleural solitary fibrous tumor releasing high molecular weight insulin-like growth factor 2 and experienced a frequent syncope accompanied by hypoglycemia. After anesthesia induction, an artificial endocrine pancreas, STG-55, was connected to the patient. Blood glucose level was stable at around 150 mg/dl during the resection surgery. The patient followed an uneventful course and was discharged without any complications.ConclusionsAn artificial endocrine pancreas may have the potential to stabilize the intraoperative blood glucose change in insulin-like growth factor 2-releasing tumor resection.

Late recurrence of a malignant hypoglycemia-inducing pelvic solitary fibrous tumor secreting high-molecular-weight insulin-like growth factor-II: A case report with protein analysis.

The present study reports a case of recurrent malignant pelvic solitary fibrous tumor (SFT) that induced non-islet cell tumor hypoglycemia via high-molecular-weight insulin-like growth factor-II in a 72-year-old male patient. The tumor recurred ~12 years after the complete resection of the original mass. The recurrent tumor, which had directly invaded the left ureter and perirectal fat tissue, could not be completely excised due to its fragility and adhesiveness. At 13 days post-surgery, the patient presented with rectal perforation, and an urgent rectal resection and colostomy was performed. Neither recurrence of the tumor nor hypoglycemic symptoms were observed 9 months after the surgery. High molecular weight insulin-like growth factor-II was detected in the serum and tumor specimens by western blot analysis and immunohistochemistry. The present case report suggests that certain SFTs can relapse even ≥10 years after a presumed complete resection of the primary tumor, and that performing a safe and complete resection of these tumors can be challenging, due to their adhesiveness or physical presentation; therefore, the indications for surgery should be considered with caution.

Hypoglycemia Caused by Recurrent Renal Cell Carcinoma As Result of Production of High Molecular Weight Insulin-Like Growth Factor 2

Hypoglycemia Caused by Recurrent Renal Cell Carcinoma As Result of Production of High Molecular Weight Insulin-Like Growth Factor 2

Non–Islet Cell Tumor-Induced Hypoglycemia Associated with Macronodular Pulmonary Metastases from Poorly Differentiated Thyroid Carcinoma

Non-islet cell tumor-induced hypoglycemia (NICTH), a major cause of fasting hypoglycemia, is caused by the overproduction of incompletely processed, high molecular-weight insulin-like growth factor-II (IGF-II), termed "big" IGF-II. To the best of our knowledge, only two cases of thyroid carcinoma associated with NICTH have been documented. We report the case of a 72-year-old woman who was brought to the emergency department with impaired consciousness. The patient had a history of pulmonary metastases from poorly differentiated thyroid carcinoma (PDTC), spanning 12 years since initial treatment. Laboratory tests showed decreased plasma glucose levels even though immunoreactive insulin, IGF-I, and growth hormone (GH) were undetectable. Computed tomography (CT) scan revealed macronodular pulmonary metastases the estimated volume of which was 456 mL. Both the biochemical data and imaging results suggested NICTH. The results of Western blot analysis performed on a fractionated serum sample showed an increased expression of big IGF-II, an important indicator in the diagnosis of NICTH. Because the massive pulmonary metastases were considered inoperable, immunohistochemical analysis of stored formalin-fixed, paraffin-embedded tissues was performed. The analysis revealed that the tumor cells were positive for both IGF-II and thyroglobulin. A whole-body CT excluded extrapulmonary metastatic lesions. A retrospective review revealed a gradual decrease in glycohemoglobin levels accompanied by an increase in the estimated volume of pulmonary metastases. These findings suggested that NICTH had been caused by pulmonary metastases from PDTC. We describe here the third reported case of NICTH associated with thyroid carcinoma. This is also the first case reporting big IGF-II in the serum of a patient with thyroid carcinoma.

高分子insulin-like growth factor-II産生性孤立性線維性腫瘍の1例

低血糖発作を契機に孤立性線維性腫瘍（solitary fibrous tumor：SFT）が発見され，手術で軽快した1例を経験したので報告する．症例は54歳の女性．朝起床時に意識消失発作と言語障害があり，精査で低血糖と左胸腔内に最大径23×14×9 cmの腫瘤を認め，CTガイド下針生検でSFTと診断された．血中インスリン，C-ペプチドは低下し，下垂体と副腎機能は基準値内であり，低血糖は腫瘍随伴症状と考えられ，腫瘍摘出術を行った．術後，血糖値は安定した．また術前の採血検体から高分子のインスリン様成長因子-II（insulin-like growth factor - II：IGF-II）が検出され，免疫染色でIGF-II陽性であったことから，低血糖はSFTが産生した高分子IGF-IIによるものと考えられた．術後1年経過時点で低血糖症状や再発徴候は認めていない．

Retroperitoneal Solitary Fibrous Tumor-Induced Hypoglycemia Associated with High Molecular Weight Insulin-Like Growth Factor II

A man, aged 65 years, presented with frequent episodes of hypoglycemia and unconsciousness. Hypoglycemia was accompanied by undetectable serum insulin and C-peptide levels and a high serum insulin-like growth factor (IGF)-II level. He was found to have a retroperitoneal solitary fibrous tumor. He underwent successful resection of the tumor and had no hypoglycemic episodes after the operation. Immunohistochemical analysis revealed positive immunostaining for IGF-II in tumor cells. The presence of the high-molecular-weight form of IGF-II in the patient's serum was confirmed by immunoblotting, which suggests that his hypoglycemia was due to an increase in the plasma level of IGF-II secreted by the tumor.

Measurement of the acid-labile subunit of the insulin-like growth factor binding protein complex in human serum: a comparison of four immunoassays

The acid-labile subunit (ALS) of the high molecular weight insulin-like growth factor binding protein complex is a liver-derived glycoprotein which is regulated by growth hormone and serves as a serum marker of growth hormone action. We have compared the measurement of ALS by four immunoassay methods (two RIAs, two ELISAs) utilizing various polyclonal and monoclonal antibodies raised against natural or recombinant human ALS, or synthetic ALS peptides. Despite the variety of methodologies and reagents, results obtained by the four methods were highly correlated for 125 sera from various patient groups, and when compared for individual groups of sera from healthy children and adults, growth hormone-deficient children and adults, and subjects with acromegaly. Some weaker correlations among methods were seen when measuring ALS levels in groups of sera from pregnant subjects and subjects with chronic renal failure. An assay using antibodies raised against recombinant ALS yielded lower apparent values than the other methods in patient sera, the discrepancy probably being attributable to a difference in standardization. We conclude that a variety of assay formats and reagents can yield serum ALS values of potential clinical utility.

The High Molecular Weight Insulin-Like Growth Factor-Binding Protein Complex: Epitope Mapping, Immunoassay, and Preliminary Clinical Evaluation

The High Molecular Weight Insulin-Like Growth Factor-Binding Protein Complex: Epitope Mapping, Immunoassay, and Preliminary Clinical Evaluation

The High Molecular Weight Insulin-Like Growth Factor-Binding Protein Complex: Epitope Mapping, Immunoassay, and Preliminary Clinical Evaluation

Measurements of insulin-like growth factor I(IGF-I), IGF-binding protein-3 (IGFBP-3), and the acid-labile subunit (ALS) are important in assessing the GH-IGF axis. As nearly all IGF-I, IGFBP-3, and ALS circulate in a GH-dependent ternary protein complex, direct determination of the complex may be of significant analytical and clinical importance. We evaluated a panel of monoclonal antibodies (mAb) to human IGFBP-3 and classified them into four groups (G-1 to G-4). G-1 antibodies recognized epitopes that mapped at or near IGFBP-3 ligand (IGF)-binding site. This region overlapped with the G-2 defined region, which, in turn, overlapped with G-3 epitopes defined by one antibody (mAb 3). Only G-1 and G-3 antibodies paired without interference. mAb 9 recognized a conformational epitope (G-4), and mAb 10 was nonreactive. In pairwise mixed antibody evaluation, mAbs in G-2 and G-3 showed simultaneous binding to serum IGFBP-3 complexes in combination with an anti-IGF-I or an anti-ALS antibody. On this basis, two novel enzyme-linked immunosorbent assays (ELISAs) involving IGFBP-3/IGF-I (ELISA-1) and IGFBP-3/ALS (ELISA-2) recognition partners were developed, both demonstrating acceptable analytical performance characteristics. IGFBP-3 complexes measured by ELISA-1 and -2 in samples from normal individuals and subjects with GH deficiency, acromegaly, and GH receptor deficiency more tightly correlated with IGF-I, IGFBP-3, and ALS than IGF-II. ELISA-1 determinations were comparatively more age dependent and, in comparison to ELISA-2, showed better discriminations among the various sample groups, particularly among GH receptor deficiency, normal, and GH deficiency subjects. The development of IGFBP-3 complex ELISAs may simplify diagnostic applications and facilitate investigations of the physiological relevance of the ternary complex formation.

Identification of novel high molecular weight insulin-like growth factor-binding protein-3 association proteins in human serum.

The insulin-like growth factor (IGF)-binding proteins (IGFBPs) carry IGFs in serum and regulate their activity and bioavailability. The main IGFBP in serum, IGFBP-3, is known to form a 150-kDa complex with IGFs and the acid-labile subunit (ALS). We investigated the binding of IGFBP-3 to additional association proteins in human serum (IGFBP-3 APs). Ligand blots, column chromatography, and affinity cross-linking experiments revealed the specific binding of IGFBP-3 to at least three novel serum proteins. These techniques demonstrated the presence of proteins with molecular masses of 70, 100, and 150 kDa that bind IGFBP-3 with high affinity. Serum ALS migrated separately (at 88 kDa) from the novel IGFBP-3 APs (as evident by Western immunoblot), and bound IGFBP-3 weakly (by reverse ligand blots). We also demonstrated that large amounts of one of the IGFBP-3 APs and small amounts of ALS were coimmunoprecipitated with IGFBP-3 from human serum. Similar to ALS, these IGFBP-3 APs are acid labile and lose their IGFBP-3 binding capacity after exposure to low pH. We conclude that there are several serum proteins in addition to ALS and IGFs that bind IGFBP-3 with high affinity. These IGFBP-3 APs may serve as an additional reservoir of IGFBP-3 or modulate its functions.

Identification of Novel High Molecular Weight Insulin-Like Growth Factor-Binding Protein-3 Association Proteins in Human Serum

Identification of Novel High Molecular Weight Insulin-Like Growth Factor-Binding Protein-3 Association Proteins in Human Serum

Biophysical and Biological Properties of Naturally Occurring High Molecular Weight Insulin-like Growth Factor II Variants

A soluble form of the insulin-like growth factor II/mannose 6-phosphate receptor (sIGF-II/MPR) is present in fetal bovine serum and carries mature 7.5-kDa insulin-like growth factor II (IGF-II) and at least 12 different high molecular weight (Mr) IGF-II isoforms (Valenzano, K. J., Remmler, J., and Lobel, P. (1995) J. Biol. Chem. 270, 16441-16448). In this study, we used gel filtration and anion exchange chromatographies to resolve the isoforms into eight fractions that were characterized with respect to their biochemical, biophysical, and biological properties. Each fraction contained one to three major protein species with apparent sizes ranging from 11 to 17 kDa by SDS-polyacrylamide gel electrophoresis. The 11-kDa species contains no post-translational modifications and consists of an extended IGF-II backbone terminating at Gly-87. The remaining high Mr IGF-II isoforms are also composed of an 87-amino acid IGF-II peptide backbone but contain increasing amounts of sialated, O-linked sugars. Plasmon resonance spectroscopy experiments revealed that all the high Mr isoforms and mature 7.5-kDa IGF-II bound to immobilized recombinant soluble human IGF-I receptor, recombinant human IGF-binding protein 1, and sIGF-II/MPR with similar kinetics. In addition, radiolabeled tracer experiments demonstrated that both mature and high Mr IGF-II isoforms have similar binding profiles in fetal bovine serum and have similar affinities for IGF-II-binding proteins secreted from human fibroblasts. Finally, the biological activity of high Mr IGF-II was shown to be similar to or slightly better than mature IGF-II in stimulating amino acid uptake in fibroblasts and in inducing myoblast differentiation.

Increased amounts of a high molecular weight insulin-like growth factor II (IGF-II) peptide and IGF-II messenger ribonucleic acid in pancreatic islets of diabetic Goto-Kakizaki rats.

Insulin-like growth factor II (IGF-II), a member of the insulin family, regulates cell growth and differentiation. The IGF-II gene is localized close to the insulin gene in man and rat. IGF-II peptide binds weakly to the insulin receptor and exerts insulin-like effects on the blood glucose level. We studied IGF-II in endocrine pancreas in an animal model of noninsulin-dependent diabetes mellitus, the Goto-Kakizaki (GK) rat. At the age of 2 months, these rats have structural islet changes, with fibrosis and irregular configuration, so-called starfish-shaped islets. Immunohistochemical investigation revealed IGF-II immunoreactivity in the beta-cells in both GK and control rats. Pancreatic extraction, followed by size separation using gel chromatography, disclosed a high mol wt form of IGF-II in all animals, and RIA measurements revealed a considerably larger amount of the IGF-II peptide in the 2-and 6-month-old GK rats than in the 1-month GK and control rats. In situ hybridization of 3-month-old GK rats showed increased IGF-II messenger RNA expression in the starfish-shaped islets of GK rats than in the islets with normal structure in both diabetic and control animals. The reason for the increased amount of IGF-II is unclear. As the animals are diabetic before the islet changes occur, it might be a compensatory effect in response to hyperglycemia, but could also be a cause of the islet fibrosis.

Increased amounts of a high molecular weight insulin-like growth factor II (IGF-II) peptide and IGF-II messenger ribonucleic acid in pancreatic islets of diabetic Goto-Kakizaki rats

Increased amounts of a high molecular weight insulin-like growth factor II (IGF-II) peptide and IGF-II messenger ribonucleic acid in pancreatic islets of diabetic Goto-Kakizaki rats

Localized Pleural Mesothelioma With Elevation of High Molecular Weight Insulin-like Growth Factor II and Hypoglycemia

Recurrent hypoglycemia occurred in a 48-year-old woman with a localized pleural mesothelioma. During hypoglycemia, serum high molecular weight insulin-like growth factor II (IGF-II) was elevated. The tumor also contained a high level of high molecular weight IGF-II. We propose that the primary cause of the hypoglycemia in this patient was the high molecular weight IGF-II produced by the tumor.

Characterization of the high molecular weight insulin-like growth factor complex in term pregnancy serum.

Insulin-like growth factors (IGFs) circulate in human adult serum predominantly as a high mol wt complex of 150 kilodaltons (kDa), which is made up of three subunits: alpha, the acid-labile subunit, a glycoprotein of around 85-100 kDa; beta, the acid-stable IGF-binding protein subunit, which is the 40-kDa GH-dependent glycoprotein IGF-binding protein-3 (IGFBP-3); and gamma, the 7.5 IGF-I or -II peptide subunit. During human pregnancy, all three subunits are elevated when measured by RIA. However, recent ligand blotting studies have shown that IGFBP-3 is markedly reduced during pregnancy. When pregnancy serum is acidified and neutralized to inactivate endogenous alpha-subunit, ternary complex formation is normal with exogenous radiolabeled alpha-subunit, indicating functional IGFBP-3. We have attempted to clarify the status of IGFBP-3 and the high mol wt (alpha beta gamma) complex in human term pregnancy serum by further analyses. Term pregnancy (TP) or nonpregnancy (NP) pooled sera were fractionated on a S-300 neutral column. The high mol wt (125-150 kDa) and the low mol wt (30-40 kDa) IGF-IGFBP complexes were identified by both RIA for IGFBP-3 and ligand blotting; each was pooled separately. Half of each pool was lyophilized and rechromatographed in acid to separate the IGF-I peptides from their IGFBPs. The IGFBP fractions were recovered for further studies. When the IGFBPs from the high mol wt complex were cross-linked to [125I]IGF-I or -II, bands of 48, 34, 26, and 21 kDa, which were more intense with [125I]IGF-II, were observed, and all were immunoprecipitable by anti-IGFBP-3 antibody. The smaller forms were elevated in TP serum. Affinity cross-linking analysis with [125I]alpha-subunit showed that the IGFBPs from the high mol wt, but not the low mol wt, complex can reform the ternary 150-kDa complex when cold IGF-I or IGF-II is added exogenously. A smaller 130-kDa complex was also present, and it was the predominant form in TP serum. Both bands were immunoprecipitable by anti-IGFBP-3 antibody. When purified alpha-subunit or fractions from neutral Sephacryl S-300 chromatography were cross-linked to covalent [125I]IGF-II:IGFBP-3, a specific band at 150 kDa was observed with pure alpha-subunit as well as with S-300 150- to 100-kDa serum fractions. These results suggest that 1) functional alpha-subunit is present in TP serum; 2) intact as well as smaller fragments of IGFBP-3 are present in the big complex of TP serum and are able to bind IGF and complex with alpha-subunit; and 3) IGFBP-3 in TP serum has reduced binding to [125I]IGF-I, but not to [125I]IGF-II.

Characterization of the high molecular weight insulin-like growth factor complex in term pregnancy serum

Characterization of the high molecular weight insulin-like growth factor complex in term pregnancy serum