Introduction: Non-islet cell tumor hypoglycemia (NICTH) is a rare paraneoplastic syndrome caused by tumor secretion of insulin-like growth factor-2 (IGF-2), leading to recurrent hypoinsulinemic hypoglycemia. It is most commonly associated with large mesenchymal tumors, such as solitary fibrous tumor, particularly those arising from the pleura or lungs. This phenomenon, also known as Doege–Potter syndrome, may precede tumor detection or signal tumor recurrence. We report a striking case of late malignant recurrence presenting solely with hypoglycemia after a decade of remission. Case: A 68-year-old female was initially presented in 2016 with respiratory symptoms and recurrent symptomatic fasting and post-prandial hypoglycemia, and was found to have a large left upper lobe mass. Tumor resection in 2017 resulted in complete resolution of hypoglycemia. She remained asymptomatic for several years. In 2023, she developed recurrent hypoglycemia without respiratory or constitutional symptoms. Biochemical evaluation demonstrated hypoinsulinemic hypoglycemia with suppressed insulin and C-peptide, low IGF-1, and markedly elevated IGF-2, resulting in an IGF-2:IGF-1 ratio of 25, consistent with IGF-2-mediated NICTH. Computed tomography imaging revealed a large left thoracic mass with invasion into the intercostal muscles and diaphragm with extension toward the stomach, associated with contralateral lung nodules and possible liver metastases, suggesting recurrent malignant disease. Hypoglycemia improved with glucocorticoid therapy, and the patient was referred for oncological assessment. Despite initiation of systemic chemotherapy, her disease progressed and she succumbed during treatment. Conclusion This case highlights several important lessons: Firstly, recurrent hypoinsulinemic hypoglycemia warrants evaluation for NICTH even in the absence of tumor-related symptoms. Secondly, solitary fibrous tumors may recur or undergo malignant transformation after prolonged disease-free intervals; and glucocorticoids provide effective metabolic control but do not alter oncologic prognosis. Long-term surveillance should be considered in patients with prior solitary fibrous tumors due to the risk of delayed recurrence and paraneoplastic complications.
Insulin-Like Growth Factor II ; Hypoglycemia ; Neoplasms

The mandibular condyle is a critical growth center in craniofacial bone development, especially during postnatal stages. Postnatal condyle osteogenesis requires precise spatiotemporal coordination of growth factor signaling cascades and hierarchical gene regulatory networks. Plagl1, which encodes a zinc finger transcription factor, is a paternally expressed gene. We demonstrate that PLAGL1 is highly expressed in cranial neural crest cell (CNCC)-derived lineage cells in mouse condyles. Using the CNCC-derived lineage-specific Plagl1 knockout mouse model, we evaluate the function of PLAGL1 during postnatal mouse condyle development. Our findings show that PLAGL1 contributes significantly to osteoblast differentiation, and its deficiency impairs osteogenic lineage differentiation, which consequently disrupts mandibular condyle development. Mechanistically, insulin-like growth factor 2 (IGF2) in complex with IGF-binding proteins (IGFBPs) has been identified as the principal PLAGL1 effector responsible for osteogenic regulation during postnatal condyle morphogenesis. Plagl1 deficiency significantly downregulates the IGF2/IGFBP pathway, leading to disordered glucose metabolism, defective extracellular matrix organization, and impaired ossification. Exogenous IGF2 treatment rescues impaired osteoblast differentiation caused by Plagl1 deficiency. In conclusion, the PLAGL1-IGF2 axis is a critical regulator of osteogenesis during mandibular condyle development.
Animals ; Osteogenesis/genetics* ; Insulin-Like Growth Factor II/metabolism* ; Mice ; Transcription Factors/metabolism* ; Mice, Knockout ; Cell Differentiation ; DNA-Binding Proteins/genetics* ; Mandibular Condyle/growth & development* ; Osteoblasts/cytology* ; Signal Transduction ; Neural Crest/cytology*

Insulin-like growth factor 2 (IGF2) is a critical endocrine mediator implicated in male reproductive physiology. To investigate the correlation between IGF2 protein levels and various aspects of male infertility, specifically focusing on sperm quality, inflammation, and DNA damage, a cohort of 320 male participants was recruited from the Women's Hospital, Zhejiang University School of Medicine (Hangzhou, China) between 1 st January 2024 and 1 st March 2024. The relationship between IGF2 protein concentrations and sperm parameters was assessed, and Spearman correlation and linear regression analysis were employed to evaluate the independent associations between IGF2 protein levels and risk factors for infertility. Enzyme-linked immunosorbent assay (ELISA) was used to measure IGF2 protein levels in seminal plasma, alongside markers of inflammation (tumor necrosis factor-alpha [TNF-α] and interleukin-1β [IL-1β]). The relationship between seminal plasma IGF2 protein levels and DNA damage marker phosphorylated histone H2AX (γ-H2AX) was also explored. Our findings reveal that IGF2 protein expression decreased notably in patients with asthenospermia and teratospermia. Correlation analysis revealed nuanced associations between IGF2 protein levels and specific sperm parameters, and low IGF2 protein concentrations correlated with increased inflammation and DNA damage in sperm. The observed correlations between IGF2 protein levels and specific sperm parameters, along with its connection to inflammation and DNA damage, underscore the importance of IGF2 in the broader context of male reproductive health. These findings lay the groundwork for future research and potential therapeutic interventions targeting IGF2-related pathways to enhance male fertility.
Humans ; Male ; Insulin-Like Growth Factor II/metabolism* ; Infertility, Male/genetics* ; DNA Damage ; Adult ; Inflammation/metabolism* ; Spermatozoa/metabolism* ; Semen Analysis ; Semen/metabolism* ; Tumor Necrosis Factor-alpha/metabolism* ; Histones/metabolism* ; Interleukin-1beta/metabolism*

BACKGROUND: Prenatal stress can cause neurobiological and behavioral defects in offspring; environmental factors play a crucial role in regulating the development of brain and behavioral; this study was designed to test and verify whether an enriched environment can repair learning and memory impairment in offspring rats induced by prenatal stress and to explore its mechanism involving the expression of insulin-like growth factor-2 (IGF-2) and activity-regulated cytoskeletal-associated protein (Arc) in the hippocampus of the offspring. METHODS: Rats were selected to establish a chronic unpredictable mild stress (CUMS) model during pregnancy. Offspring were weaned on 21st day and housed under either standard or an enriched environment. The learning and memory ability were tested using Morris water maze and Y-maze. The expression of IGF-2 and Arc mRNA and protein were respectively measured by using RT-PCR and Western blotting. RESULTS: There was an elevation in the plasma corticosterone level of rat model of maternal chronic stress during pregnancy. Maternal stress's offspring exposed to an enriched environment could decrease their plasma corticosterone level and improve their weight. The offspring of maternal stress during pregnancy exhibited abnormalities in Morris water maze and Y-maze, which were improved in an enriched environment. The expression of IGF-2, Arc mRNA, and protein in offspring of maternal stress during pregnancy was boosted and some relationships existed between these parameters after being exposed enriched environment. CONCLUSIONS The learning and memory impairment in offspring of prenatal stress can be rectified by the enriched environment, the mechanism of which is related to the decreasing plasma corticosterone and increasing hippocampal IGF-2 and Arc of offspring rats following maternal chronic stress during pregnancy.
Animals ; Cytoskeletal Proteins/metabolism* ; Female ; Gene Expression Regulation ; Hippocampus/metabolism* ; Insulin-Like Growth Factor II/metabolism* ; Learning ; Learning Disabilities/psychology* ; Male ; Memory Disorders/psychology* ; Nerve Tissue Proteins/metabolism* ; Pregnancy ; Prenatal Exposure Delayed Effects/psychology* ; Random Allocation ; Rats ; Rats, Wistar ; Social Environment ; Stress, Psychological/genetics*

Non-islet cell tumor-induced hypoglycemia (NICTH) secondary to phyllodes tumor is extremely rare but potentially life threatening if not treated promptly. We report a case of a 46-year-old Indian female without underlying diabetes mellitus who presented with a large breast tumor and recurrent severe symptomatic hypoglycemia. Investigations supported the diagnosis of NICTH. The hypoglycemia only resolved after corticosteroids and mastectomy. This case highlights the importance of considering NICTH in the evaluation of patients with voluminous tumor and hypoglycemia.
Hypoglycemia ; Insulin-Like Growth Factor II ; Phyllodes Tumor ; Mastectomy ; Adrenal Cortex Hormones

Objective: To investigate the influence of high fat diet-induced obesity (HFDIO) on the differentially methylated region (DMR) of the imprinted gene and global genome methylation of sperm DNA. METHODS: We performed bisulfite sequencing on the DMR of the imprinted gene and global genome methylation of sperm DNA in the mouse model of HFDIO. RESULTS: No statistically significant differences were found between the HFDIO model and normal control mice in MEG3-IG (93.73 vs 97.26%, P = 0.252), H19 (98.00 vs 97.83%, P = 0.920), IGF2 (97.34 vs 96.25%, P =0.166), IGF2R (1.43 vs 1.11%, P = 0.695), PEG3 (0.19 vs 0.38%, P = 0.537), MEST (0.23 vs 0.68%, P = 0.315), NNAT (0.31 vs 0.00%, P = 0.134), or SNRPN (1.88 vs 3.13%, P = 0.628). A total of 8 942 DMRs were detected across the sperm genome (P <0.05). Gene functional enrichment analysis indicated that the enriched terms with the largest numbers of genes were the metabolic process (n = 1 482), RNA synthesis (n = 779), and transcription (n = 767). CONCLUSIONS The methylation level underwent no significant change in the DMRs of the imprinted genes from the mice with HFDIO, but the CG methylation of the genes involved in the metabolic process, RNA synthesis and transcription were significantly altered.
Animals ; DNA Methylation ; Diet, High-Fat ; Genome ; Genomic Imprinting ; Insulin-Like Growth Factor II ; Male ; Mice ; Obesity ; genetics ; metabolism ; RNA ; biosynthesis ; Spermatozoa ; metabolism

Angiotensin II (Ang II), a key mediator of hypertensive, causes structural changes in the arteries (vascular remodeling), which involve alterations in cell growth, vascular smooth muscle cell (VSMC) hypertrophy. Ang II promotes fibrotic factor like IGFBP5, which mediates the profibrotic effects of Ang II in the heart and kidneys, lung and so on. The purpose of this study was to identify the signaling pathway of IGFBP5 on cell proliferation and migration of Ang II-stimulated VSMC. We have been interested in Ang II-induced IGFBP5 and were curious to determine whether a Pitavastatin would ameliorate the effects. Herein, we investigated the question of whether Ang II induced the levels of IGFBP5 protein followed by proliferation and migration in VSMC. Pretreatment with the specific Angiotensin receptor type 1 (AT1) inhibitor (Losartan), Angiotensin receptor type 2 (AT2) inhibitor (PD123319), MAPK inhibitor (U0126), ERK1/2 inhibitor (PD98059), P38 inhibitor (SB600125) and PI3K inhibitor (LY294002) resulted in significantly inhibited IGFBP5 production, proliferation, and migration in Ang II-stimulated VSMC. In addition, IGFBP5 knockdown resulted in modulation of Ang II induced proliferation and migration via IGFBP5 induction. In addition, Pitavastatin modulated Ang II induced proliferation and migration in VSMC. Taken together, our results indicated that Ang II induces IGFBP5 through AT1, ERK1/2, P38, and PI3K signaling pathways, which were inhibited by Pitavastatin. These findings may suggest that Pitavastatin has an effect on vascular disease including hypertension.
Angiotensin II ; Angiotensins ; Arteries ; Cell Proliferation ; Heart ; Hypertension ; Hypertrophy ; Insulin-Like Growth Factor Binding Protein 5* ; Kidney ; Lung ; Muscle, Smooth, Vascular ; Vascular Diseases

BACKGROUNDThe insulin-like growth factor signaling pathway plays an important role in the modulation of cell growth and proliferation. The aim of this study was to investigate the role of polymorphisms of the insulin-like growth factor 2 (IGF2) and IGF-binding protein 3 (IGFBP3) genes, which encode key proteins of this pathway, as risk factors for gastric carcinoma (GC).

METHODSA case-control study including 404 histologically confirmed GC patients and 424 healthy controls of the same ethnicity was conducted to retrospectively investigate the genetic polymorphisms of two genes, IGF2+820A>G (rs680) and IGFBP3 A-202C (rs2854744). Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using Logistic regression.

RESULTSThe IGF2 genetic variants examined contributed to GC risk individually (OR, 1.26; 95% CI, 1.08-1.46). The genotype frequencies of IGFBP3 A-202C were not significantly different between the cancer cases and controls (P > 0.05). Compared to the IGF2 AA genotype, carriers of one variant combined genotype were more pronounced among young subjects (<60 years), male subjects, never smokers, and those with a family history of cancer (OR = 1.36, 95% CI = 1.09-1.72, P < 0.05; OR = 1.61, 95% CI = 1.28-2.08, P < 0.05; OR = 1.46, 95% CI = 1.11-1.98, P < 0.05; OR = 1.53, 95% CI = 0.91-2.6, P < 0.05; respectively). Moreover, when the combined effects of the risk genotypes were investigated, significant associations were detected between highrisk genotypes in IGF2 and IGFBP3 (OR, 2.47; 95% CI, 1.75-3.49).

CONCLUSIONSOur results suggest that polymorphic variants of the IGF2 genes modulate gastric carcinogenesis. Moreover, when the IGF2 and IGFBP3 variants are evaluated together, a greater effect on GC risk is observed.

Adult ; Aged ; Case-Control Studies ; China ; Female ; Genetic Predisposition to Disease ; genetics ; Genotype ; Humans ; Insulin-Like Growth Factor Binding Protein 3 ; genetics ; Insulin-Like Growth Factor II ; genetics ; Logistic Models ; Male ; Middle Aged ; Polymorphism, Genetic ; genetics ; Stomach Neoplasms ; genetics

Since its discovery in 1921, insulin has been considered to be the most important hormone in the regulation of glucose and fat metabolism. In recent years, studies have revealed that besides metabolism regulation, insulin can also act as a growth factor like hormone in regulating multiple processes and various cellular activities in the process of wound healing. This review summarizes the role of insulin in wound healing and its underlying mechanism.
Glucose ; metabolism ; Growth Hormone ; metabolism ; physiology ; Humans ; Insulin ; physiology ; Insulin-Like Growth Factor I ; physiology ; Insulin-Like Growth Factor II ; physiology ; Wound Healing ; physiology

BACKGROUND: Insulin-like growth factor II mRNA-binding protein 3 (IMP3) has been reported as a prognostic biomarker in various cancers. To validate IMP3 as a prognostic biomarker in renal cell carcinoma (RCC), we investigated the expression of IMP3, p53, and Ki-67, and their associations with clinicopathologic outcomes. METHODS: We studied 148 clear cell RCCs (CCRCCs) from patients who underwent radical nephrectomy. The expression levels of IMP3, p53, and Ki-67 were assessed by immunohistochemical staining and the clinical and pathologic parameters were retrospectively reviewed. RESULTS: Twenty-nine percent of CCRCCs expressed IMP3. Forty-one percent of IMP3-immunopositive tumors developed metastases, while only 11.4% of IMP3-negative tumors developed metastases (p<.001). A Kaplan-Meier curve showed that patients with IMP3-immunopositive tumors had lower metastasis-free survival and cancer-specific survival than did those with IMP3-immunonegative tumors (p<.001 and p<.001, respectively). Expression of high Ki-67 proliferation index was also associated with a higher metastatic rate. In the multivariate Cox regression analysis, pT stage and IMP3-positivity were independently associated with disease-specific survival. CONCLUSIONS: IMP3 is an independent prognostic biomarker for patients with CCRCC to predict metastasis and poor outcome.
Carcinoma, Renal Cell* ; Humans ; Insulin-Like Growth Factor II ; Neoplasm Metastasis ; Nephrectomy ; Retrospective Studies ; Tumor Suppressor Protein p53