Insulin Insulin-like Growth Factors Research Articles

FRI489 The Interplay Between Thyroid Nodular Disease And Insulin Resistance Indices In Pregnant Women

Abstract Disclosure: A.J. Nowak: None. M. Trofimiuk-Muldner: None. J. Podlewski: None. A. Hubalewska-Dydejczyk: None. Thyroid cells proliferation and function is regulated by TSH. Other factor, such as insulin/insulin-like growth factors (IGF), through their mitogenic effects, may affect thyroid growth and nodules formation [1].This study evaluated the interplay between insulin resistance indices and thyroid structure in pregnant women. The study group was recruited from the Polish National Program for Elimination of Iodine Deficiency, conducted between 2007-2017. We assessed the fasting glucose, insulin levels, TSH in 1069 pregnant women (median age 29 years, IQR 6 years). Thyroid ultrasound was performed in each study participant. Based on calculated HOMA-IR, pregnant women were stratified into three subgroups HOMA1 (324 women with HOMA-IR < 1), HOMA 2 (570 women with HOMA-IR ≥1& <2.5) and HOMA3 (175 women with HOMA-IR ≥ 2.5). Results: Median (IQR) TSH concentrations were 1.42 (1.33) mIU/L, 1.65 (1.31) mIU/L, and 1.77 (1.29) mIU/L in HOMA1, HOMA2, and HOMA3 subgroups, respectively. The mean (±SD) thyroid volume was 12.36 (4.27) mL, 12.71 (5.37) mL, and 13.70 (4.92) mL in HOMA1, HOMA2, HOMA3 subgroups respectively.33 (10.2%) of women in HOMA1, 53 (9.3%) in HOMA2 and 11 (6.3%) in HOMA3 subgroup had at least one thyroid nodule - there was no significant difference between the subgroups (P = 0.4724)Fasting insulin >10 mIU/mL was found in 27.53% of pregnant women (286 out of 1039) with thyroid volume <25 mL, and in 36.67% women (11 out of 30) with thyroid volume ≥25mL (P=0.27). Conclusions: We have not found any significant relationship between the thyroid volume or structure and insulin or insulin resistance indices in pregnant women. 1. Kimura T., Van Keymeulen A., Golstein J., Fusco A., Dumont J.E., Roger P.P. Regulation of thyroid cell proliferation by TSH and other factors: A critical evaluation of in vitro models. Endocr. Rev. 2001;22:631–656. doi: 10.1210/edrv.22.5.0444. Presentation: Friday, June 16, 2023

Modifying Effects of Glucose and Insulin/Insulin-Like Growth Factors on Colon Cancer Cells.

There are only a few experimental studies which have investigated effects of glucose alone, and glucose in combination with insulin/insulin-like growth factors (IGF) on the growth of colon cancer. In the present study, we studied in vitro in human colorectal cancer cells originating from four Dukes’ stages of colorectal cancer the effects of glucose, insulin and IGFs on proliferation, migration, cell cycle progression and gene expression of the IGF system. Growth of colon cancer cells originating from a Dukes’ stage A was glucose-dependent, whereas growth of cancer cells from Dukes’ stage B, C and D was glucose-independent. Stimulatory effects of insulin and IGFs on cell growth were observed only in colon cancer cells originating from Dukes’ stage C and D. IGF-II stimulated migration in Dukes’ stage B cells only. The growth stimulatory effects in Dukes’ stage C and D colorectal cancer cells were accompanied by G2/M arrest and associated with an increased IGF-IR/IGF-II receptor ratio. In conclusion, our in vitro data suggest that the stimulating effects of glucose, IGFs and insulin on proliferation differ between colorectal cancer cells from early and late Dukes’ stages. Stimulatory effects of glucose on proliferation appear predominantly present in stage Dukes’ stage A colorectal cancer cells, while in contrast growth factor-mediated stimulation of cell proliferation is more pronounced in Dukes’ late stage (metastasized) colorectal cancer cells. Moreover, our study suggests that a stringent glucose control may be important to control tumor growth in early stages of colorectal cancer, while inhibition of the endocrine actions of the IGFs and insulin become more important in the late (metastasized) stages of colorectal cancer to restrain growth of colon cancer cells.

Insulin Growth Factor Binding Protein 7 (IGFBP7)-Related Cancer and IGFBP3 and IGFBP7 Crosstalk.

The insulin/insulin-like growth factors (IGFs) have crucial tasks in the growth, differentiation, and proliferation of healthy and pernicious cells. They are involved in coordinated complexes, including receptors, ligands, binding proteins, and proteases. However, the systems can become dysregulated in tumorigenesis. Insulin-like growth factor-binding protein 7 (IGFBP7) is a protein belonging to the IGFBP superfamily (also termed GFBP-related proteins). Numerous studies have provided evidence that IGFBP3 and IGFBP7 are involved in a variety of cancers, including hepatocellular carcinoma (HCC), breast cancer, gastroesophageal cancer, colon cancer, prostate cancer, among many others. Still, very few suggest an interaction between these two molecules. In studying several cancer types in our laboratories, we found that both proteins share some crucial signaling pathways. The objective of this review is to present a comprehensive overview of the relationship between IGFBP7 and cancer, as well as highlighting IGFBP3 crosstalk with IGFBP7 reported in recent studies.

The Insulin-Like Proteins dILPs-2/5 Determine Diapause Inducibility in Drosophila.

Diapause is an actively induced dormancy that has evolved in Metazoa to resist environmental stresses. In temperate regions, many diapausing insects overwinter at low temperatures by blocking embryonic, larval or adult development. Despite its Afro-tropical origin, Drosophila melanogaster migrated to temperate regions of Asia and Europe where females overwinter as adults by arresting gonadal development (reproductive diapause) at temperatures <13°C. Recent work in D. melanogaster has implicated the developmental hormones dILPs-2 and/or dILP3, and dILP5, homologues of vertebrate insulin/insulin-like growth factors (IGFs), in reproductive arrest. However, polymorphisms in timeless (tim) and couch potato (cpo) dramatically affect diapause inducibility and these dILP experiments could not exclude this common genetic variation contributing to the diapause phenotype. Here, we apply an extensive genetic dissection of the insulin signaling pathway which allows us to see both enhancements and reductions in egg development that are independent of tim and cpo variations. We show that a number of manipulations dramatically enhance diapause to ~100%. These include ablating, or reducing the excitability of the insulin-producing cells (IPCs) that express dILPs-2,3,5 employing the dilp2,3,5-/- triple mutant, desensitizing insulin signaling using a chico mutation, or inhibiting dILP2 and 5 in the hemolymph by over-expressing Imaginal Morphogenesis Protein-Late 2 (Imp-L2). In addition, triple mutant dilp2,3,5-/- females maintain high levels of diapause even when temperatures are raised in adulthood to 19°C. However at 22°C, these females all show egg development revealing that the effects are conditional on temperature and not a general female sterility. In contrast, over-expression of dilps-2/5 or enhancing IPC excitability, led to levels of ovarian arrest that approached zero, underscoring dILPs-2 and 5 as key antagonists of diapause.

Insulin–Insulin-like Growth Factors Hybrids as Molecular Probes of Hormone:Receptor Binding Specificity

Insulin, insulin-like growth factors 1 and 2 (IGF-1 and -2, respectively), and their receptors (IR and IGF-1R) are the key elements of a complex hormonal system that is essential for the development and functioning of humans. The C and D domains of IGFs (absent in insulin) likely play important roles in the differential binding of IGF-1 and -2 to IGF-1R and to the isoforms of IR (IR-A and IR-B) and specific activation of these receptors. Here, we attempted to probe the impact of IGF-1 and IGF-2 D domains (DI and DII, respectively) and the IGF-2 C domain (CII) on the receptor specificity of these hormones. For this, we made two types of insulin hybrid analogues: (i) with the C-terminus of the insulin A chain extended by the amino acids from the DI and DII domains and (ii) with the C-terminus of the insulin B chain extended by some amino acids derived from the CII domain. The receptor binding affinities of these analogues and their receptor autophosphorylation potentials were characterized. Our results indicate that the DI domain has a more negative impact than the DII domain does on binding to IR, and that the DI domain Pro-Leu-Lys residues are important factors for a different IR-A versus IR-B binding affinity of IGF-1. We also showed that the additions of amino acids that partially "mimic" the CII domain, to the C-terminus of the insulin B chain, change the binding and autophosphorylation specificity of insulin in favor of the "metabolic" IR-B isoform. This opens new venues for rational enhancement of insulin IR-B specificity by modifications beyond the C-terminus of its B chain.

Diabetes-associated changes in the fetal insulin/insulin-like growth factor system are organ specific in rats.

Diabetes in pregnancy affects fetal growth and development. The insulin/insulin-like growth factors (IGF) system comprising insulin, IGF, their receptors, and binding proteins, has been implicated in fetal growth regulation. This study tested the hypothesis that maternal diabetes alters the fetal insulin/IGF system in a tissue-specific manner. Wistar rats were rendered diabetic by neonatal administration of streptozotocin and mated with control rats. At day 21 of gestation, the weights of fetuses, placentas, and fetal organs (heart, lung, liver, stomach, intestine, and pancreas) were determined. Maternal and fetal plasma concentrations of insulin, IGF1, and IGF2 were measured by ELISA, and expression of IGF1, IGF2, IGF1R, IGF2R, IR, IGFBP1, BP2, and BP3 in placenta and fetal organs by qPCR. The well-known increase in fetal growth in this model of mild diabetes is accompanied by elevated insulin and IGF1 levels and alterations of the insulin/IGF system in the fetus and the placenta. These alterations were organ and gene specific. The insulin/IGF system was generally upregulated, especially in the fetal heart, while it was downregulated in fetal lung. In our model of mild diabetes, the effect of maternal diabetes on fetal weight and fetal insulin/IGF system expression is organ specific with highly sensitive organs such as lung and heart, and organs that were less affected, such as stomach.

Regulation of the Cell Cycle by Somatomedins

Publisher Summary This chapter discusses the regulation of the cell cycle by somatomedins. The chapter analyzes a group of growth factors that resemble insulin—insulin-like growth factors (ILGFs). The group consists of somatomedins A, nonsuppressible insulinlike activity (that is made up of insulin growth factors one and two, IGF I, IGF II), and multiplication stimulating activity (MSA). The ILGFs may constitute one of the first groups of growth regulators. A range of different culture lines has been evaluated for responses to insulin-like growth factors. In some cases, the cells are stimulated to increase DNA synthesis by a single purified factor whereas, in others, varying combinations are required. The ones responsive to somatomedin C are chondrocytes, frog and rabbit lens epithelium, Sertoli and granulosa cells, fetal liver and limb bud, some blood cell lines, and pituitary tumor cells. In the lens, the migration of epithelial cells and the fashioning of fibers from these cells are stopped in the absence of somatomedin-like molecules.

Permeability of heated skin

This chapter discusses the regulation of the cell cycle by somatomedins. The chapter analyzes a group of growth factors that resemble insulin—insulin-like growth factors (ILGFs). The group consists of somatomedins A, nonsuppressible insulinlike activity (that is made up of insulin growth factors one and two, IGF I, IGF II), and multiplication stimulating activity (MSA). The ILGFs may constitute one of the first groups of growth regulators. A range of different culture lines has been evaluated for responses to insulin-like growth factors. In some cases, the cells are stimulated to increase DNA synthesis by a single purified factor whereas, in others, varying combinations are required. The ones responsive to somatomedin C are chondrocytes, frog and rabbit lens epithelium, Sertoli and granulosa cells, fetal liver and limb bud, some blood cell lines, and pituitary tumor cells. In the lens, the migration of epithelial cells and the fashioning of fibers from these cells are stopped in the absence of somatomedin-like molecules.