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Journal of Diabetes Research 2022Several epidemiological studies have identified diabetes as a risk factor for colorectal cancer (CRC). The potential pathophysiological mechanisms of this association... (Review)
Review
Several epidemiological studies have identified diabetes as a risk factor for colorectal cancer (CRC). The potential pathophysiological mechanisms of this association include hyperinsulinemia, insulin-like growth factor (IGF) axis, hyperglycemia, inflammation induced by adipose tissue dysfunction, gastrointestinal motility disorder, and impaired immunological surveillance. Several studies have shown that underlying diabetes adversely affects the prognosis of patients with CRC. This review explores the novel anticancer agents targeting IGF-1R and receptor for advanced glycation end products (RAGE), both of which play a vital role in diabetes-induced colorectal tumorigenesis. Inhibitors of IGF-1R and RAGE are expected to become promising therapeutic choices, particularly for CRC patients with diabetes. Furthermore, hypoglycemic therapy is associated with the incidence of CRC. Selection of appropriate hypoglycemic agents, which can reduce the risk of CRC in diabetic patients, is an unmet issue. Therefore, this review mainly summarizes the current studies concerning the connections among diabetes, hypoglycemic therapy, and CRC as well as provides a synthesis of the underlying pathophysiological mechanisms. Our synthesis provides a theoretical basis for rational use of hypoglycemic therapies and early diagnosis and treatment of diabetes-related CRC.
Topics: China; Colorectal Neoplasms; Diabetes Mellitus, Type 2; Humans; Incidence; Receptor for Advanced Glycation End Products; Risk Factors; Somatomedins
PubMed: 35296101
DOI: 10.1155/2022/1747326 -
International Journal of Molecular... Apr 2024The insulin-like growth factor (IGF) system has paracrine and endocrine roles in the central nervous system. There is evidence that IGF signalling pathways have roles in... (Review)
Review
The insulin-like growth factor (IGF) system has paracrine and endocrine roles in the central nervous system. There is evidence that IGF signalling pathways have roles in the pathophysiology of neurodegenerative disease. This review focusses on Alzheimer's disease and Parkinson's disease, the two most common neurodegenerative disorders that are increasing in prevalence globally in relation to the aging population and the increasing prevalence of obesity and type 2 diabetes. Rodent models used in the study of the molecular pathways involved in neurodegeneration are described. However, currently, no animal model fully replicates these diseases. Mice with triple mutations in , and show promise as models for the testing of novel Alzheimer's therapies. While a causal relationship is not proven, the fact that age, obesity and T2D are risk factors in both strengthens the case for the involvement of the IGF system in these disorders. The IGF system is an attractive target for new approaches to management; however, there are gaps in our understanding that first need to be addressed. These include a focus beyond IGF-I on other members of the IGF system, including IGF-II, IGF-binding proteins and the type 2 IGF receptor.
Topics: Humans; Animals; Neurodegenerative Diseases; Alzheimer Disease; Signal Transduction; Insulin-Like Growth Factor I; Somatomedins; Disease Models, Animal; Parkinson Disease; Insulin-Like Growth Factor Binding Proteins; Insulin-Like Peptides
PubMed: 38674097
DOI: 10.3390/ijms25084512 -
Brain and Behavior Jan 2023We aimed to investigate if there is a significant difference in peripheral insulin-like growth factor 1 (IGF-1) levels between schizophrenia patients and healthy... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
We aimed to investigate if there is a significant difference in peripheral insulin-like growth factor 1 (IGF-1) levels between schizophrenia patients and healthy controls and to determine whether a difference exists before and after initiation of antipsychotics.
METHODS
PubMed/MEDLINE, Scopus, and Web of Science were searched up to March 27, 2022. Original clinical studies of any type that reported peripheral blood, serum or plasma IGF-1 levels measured after fasting in schizophrenia patients and/or healthy control group were selected based on inclusion and exclusion criteria. Data were analyzed using Meta-Essentials: Workbooks for meta-analysis and pooled through random-effects meta-analyses.
RESULTS
Twelve publications met eligibility criteria. Schizophrenia patients under antipsychotic treatment had significantly lower peripheral IGF-1 levels compared to healthy controls (n = 632, Hedges' g -0.42, 95% CI from -0.79 to -0.04, p = .006, I = 70.38%), while no significant difference was found between schizophrenia patients regardless of the antipsychotic treatment status and healthy controls, as well as between antipsychotic naïve or free schizophrenia patients and healthy controls, and before and after initiation of antipsychotic treatment. However, high heterogeneity was observed and its potential sources in some of the subgroup analyses included sample type and region.
CONCLUSIONS
Schizophrenia patients under antipsychotic treatment seem to have lower peripheral IGF-1 levels compared to healthy controls. Additional studies with larger and more homogenous samples are needed to confirm these findings.
Topics: Humans; Schizophrenia; Antipsychotic Agents; Insulin-Like Growth Factor I; Fasting
PubMed: 36448977
DOI: 10.1002/brb3.2819 -
Journal of Molecular Endocrinology Jul 2018The IGF-binding protein family contains six members that share significant structural homology. Their principal function is to regulate the actions of IGF1 and IGF2.... (Review)
Review
The IGF-binding protein family contains six members that share significant structural homology. Their principal function is to regulate the actions of IGF1 and IGF2. These proteins are present in plasma and extracellular fluids and regulate access of both IGF1 and II to the type I IGF receptor. Additionally, they have functions that are independent of their ability to bind IGFs. Each protein is regulated independently of IGF1 and IGF2, and this provides an important mechanism by which other hormones and physiologic variables can regulate IGF actions indirectly. Several members of the family are sensitive to changes in intermediary metabolism. Specifically the presence of obesity/insulin resistance can significantly alter the expression of these proteins. Similarly changes in nutrition or catabolism can alter their synthesis and degradation. Multiple hormones such as glucocorticoids, androgens, estrogen and insulin regulate IGFBP synthesis and bioavailability. In addition to their ability to regulate IGF access to receptors these proteins can bind to distinct cell surface proteins or proteins in extracellular matrix and several cellular functions are influenced by these interactions. IGFBPs can be transported intracellularly and interact with nuclear proteins to alter cellular physiology. In pathophysiologic states, there is significant dysregulation between the changes in IGFBP synthesis and bioavailability and changes in IGF1 and IGF2. These discordant changes can lead to marked alterations in IGF action. Although binding protein physiology and pathophysiology are complex, experimental results have provided an important avenue for understanding how IGF actions are regulated in a variety of physiologic and pathophysiologic conditions.
Topics: Animals; Humans; Insulin-Like Growth Factor Binding Proteins; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Receptors, Growth Factor
PubMed: 29563157
DOI: 10.1530/JME-18-0016 -
Molecular Metabolism Oct 2021The insulin-like growth factor family of ligands (IGF-I, IGF-II, and insulin), receptors (IGF-IR, M6P/IGF-IIR, and insulin receptor [IR]), and IGF-binding proteins... (Review)
Review
BACKGROUND
The insulin-like growth factor family of ligands (IGF-I, IGF-II, and insulin), receptors (IGF-IR, M6P/IGF-IIR, and insulin receptor [IR]), and IGF-binding proteins (IGFBP-1-6) play critical roles in normal human physiology and disease states.
SCOPE OF REVIEW
Insulin and insulin receptors are the focus of other chapters in this series and will therefore not be discussed further. Here we review the basic components of the IGF system, their role in normal physiology and in critical pathology's. While this review concentrates on the role of IGFs in human physiology, animal models have been essential in providing understanding of the IGF system, and its regulation, and are briefly described.
MAJOR CONCLUSIONS
IGF-I has effects via the circulation and locally within tissues to regulate cellular growth, differentiation, and survival, thereby controlling overall body growth. IGF-II levels are highest prenatally when it has important effects on growth. In adults, IGF-II plays important tissue-specific roles, including the maintenance of stem cell populations. Although the IGF-IR is closely related to the IR it has distinct physiological roles both on the cell surface and in the nucleus. The M6P/IGF-IIR, in contrast, is distinct and acts as a scavenger by mediating internalization and degradation of IGF-II. The IGFBPs bind IGF-I and IGF-II in the circulation to prolong their half-lives and modulate tissue access, thereby controlling IGF function. IGFBPs also have IGF ligand-independent cell effects.
Topics: Animals; Cell Communication; Humans; Insulin-Like Growth Factor Binding Proteins; Ligands; Receptor, Insulin; Somatomedins
PubMed: 33962049
DOI: 10.1016/j.molmet.2021.101245 -
International Journal of Molecular... Nov 2023The insulin-like growth factor axis is a multifaceted, complex system that comprises two ligands, IGF-I and IGF-II, receptors (IGF-1R, IGF-IIR, insulin receptor isoforms...
The insulin-like growth factor axis is a multifaceted, complex system that comprises two ligands, IGF-I and IGF-II, receptors (IGF-1R, IGF-IIR, insulin receptor isoforms IR-A and B, and hybrid receptors) six high affinity IGF-binding proteins (IGFBPs 1-6), and IGFBP proteases [...].
Topics: Insulin-Like Growth Factor II; Insulin-Like Growth Factor I; Insulin-Like Growth Factor Binding Proteins; Protein Binding; Insulin-Like Growth Factor Binding Protein 6
PubMed: 38069291
DOI: 10.3390/ijms242316969 -
Best Practice & Research. Clinical... Oct 2015Insulin-like growth factor binding proteins (IGFBPs) 4-6 have important roles as modulators of IGF actions. IGFBP-4 and IGFBP-6 predominantly inhibit IGF actions,... (Review)
Review
Insulin-like growth factor binding proteins (IGFBPs) 4-6 have important roles as modulators of IGF actions. IGFBP-4 and IGFBP-6 predominantly inhibit IGF actions, whereas IGFBP-5 may enhance these actions under some circumstances. IGFBP-6 is unique among the IGFBPs for its marked IGF-II binding preference. IGFBPs 4-6 are found in the circulation as binary complexes with IGFs that can enter tissues. Additionally, about half of the circulating IGFBP-5 is found in ternary complexes with IGFs and an acid labile subunit; this high molecular complex cannot leave the circulation and acts as an IGF reservoir. IGFBPs 4-6 also have IGF-independent actions. These IGFBPs are regulated in a cell-specific manner and their dysregulation may play a role in a range of diseases including cancer. However, there is no clear clinical indication for measuring serum levels of these IGFBPs at present.
Topics: Humans; Insulin-Like Growth Factor Binding Proteins; Signal Transduction; Somatomedins
PubMed: 26522456
DOI: 10.1016/j.beem.2015.06.002 -
Journal of Peptide Science : An... May 2016The synthesis of insulin has inspired fundamental advances in the art of peptide science while simultaneously revealing the structure-function relationship of this... (Review)
Review
The synthesis of insulin has inspired fundamental advances in the art of peptide science while simultaneously revealing the structure-function relationship of this centrally important metabolic hormone. This review highlights milestones in the chemical synthesis of insulin that can be divided into two separate approaches: (i) disulfide bond formation driven by protein folding and (ii) chemical reactivity-directed sequential disulfide bond formation. Common to the two approaches are the persistent challenges presented by the hydrophobic nature of the individual A-chain and B-chain and the need for selective disulfide formation under mildly oxidative conditions. The extension and elaboration of these synthetic approaches have been ongoing within the broader insulin superfamily. These structurally similar peptides include the insulin-like growth factors and also the related peptides such as relaxin that signal through G-protein-coupled receptors. After a half-century of advances in insulin chemistry, we have reached a point where synthesis is no longer limiting structural and biological investigation within this family of peptide hormones. The future will increasingly focus on the refinement of structure to meet medicinal purposes that have long been pursued, such as the development of a glucose-sensitive insulin. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.
Topics: Animals; Disulfides; Humans; Hydrogen Bonding; Insulin; Molecular Structure; Peptides; Protein Folding; Relaxin; Somatomedins
PubMed: 26910514
DOI: 10.1002/psc.2863 -
International Journal of Molecular... Jan 2021The insulin and insulin-like growth factor (IGF) system plays an important role in regulating normal cell proliferation and survival. However, the IGF system is also... (Review)
Review
The insulin and insulin-like growth factor (IGF) system plays an important role in regulating normal cell proliferation and survival. However, the IGF system is also implicated in many malignancies, including breast cancer. Preclinical studies indicate several IGF blocking approaches, such as monoclonal antibodies and tyrosine kinase inhibitors, have promising therapeutic potential for treating diseases. Uniformly, phase III clinical trials have not shown the benefit of blocking IGF signaling compared to standard of care arms. Clinical and laboratory data argue that targeting Type I IGF receptor (IGF1R) alone may be insufficient to disrupt this pathway as the insulin receptor (IR) may also be a relevant cancer target. Here, we review the well-studied role of the IGF system in regulating malignancies, the limitations on the current strategies of blocking the IGF system in cancer, and the potential future directions for targeting the IGF system.
Topics: Breast Neoplasms; Cell Proliferation; Cell Survival; Female; Humans; Insulin; Molecular Targeted Therapy; Receptor, IGF Type 1; Somatomedins
PubMed: 33429867
DOI: 10.3390/ijms22020555 -
Trends in Endocrinology and Metabolism:... Jun 2016Insulin-like growth factors (IGFs) circulate in extracellular fluids bound to a family of binding proteins. Although they function in a classical manner to limit the... (Review)
Review
Insulin-like growth factors (IGFs) circulate in extracellular fluids bound to a family of binding proteins. Although they function in a classical manner to limit the access of the IGFs to their receptors they also have a multiplicity of actions that are independent of this property; they bind to their own receptors or are transported to intracellular and intranuclear sites to influence cellular functions that may directly or indirectly modify IGF actions. The availability of genetically modified animals has helped to determine their functions in a physiological context. These results show that many of their actions are cell type- and context-specific, and have led to a broader understanding of how these proteins function coordinately with IGF-I and -II to regulate growth and metabolism.
Topics: Animals; Atherosclerosis; Humans; Insulin Resistance; Obesity; Somatomedins
PubMed: 27117513
DOI: 10.1016/j.tem.2016.03.019