The insulin‐like growth factor system and diabetes—an overview

Heald, Adrian; Stephens, Richard; Gibson, J. M.

doi:10.1111/j.1464-5491.2006.01833f.x

Cited by 17 publications

(10 citation statements)

References 44 publications

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“…IGF2BP2 binds to the 5 UTR of the insulinlike growth factor 2 (IGF2) mRNA and plays a role in regulating IGF2 translation. IGF2 is known to exert a number of effects, some of which are involved in obesity and T2DM [40,41] . Functional studies are needed to elucidate whether the IGF2BP2 rs4402960 SNP alters IGF2 translation.…”

Section: Discussionmentioning

confidence: 99%

Evidence of Interaction between Type 2 Diabetes Susceptibility Genes and Dietary Fat Intake for Adiposity and Glucose Homeostasis-Related Phenotypes

Ruchat¹,

Elks²,

Loos³

et al. 2009

Lifestyle Genomics

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Background/Aims: Genome-wide association studies have led to the identification of several susceptibility genes for type 2 diabetes mellitus (T2DM). The objective of this study was to test the hypothesis that the associations between single nucleotide polymorphisms (SNPs) in these genes and adiposity and glucose homeostasis-related phenotypes are influenced by dietary fat intake. Methods: Thirty-three SNPs in 9 T2DM genes (CDKAL1, CDKN2A/B, HHEX, HNF1B, IGF2BP2, KCNJ11, SLC30A8, TCF7L2 and WFS1) were tested in a maximum of 669 subjects from the Quebec Family Study. Subjects were measured for several adiposity indices and underwent a 75-gram oral glucose tolerance test. Total fat intake was estimated from a 3-day dietary record. Results: We observed 13 significant (p ≤ 0.01) SNP-dietary fat interactions. Among them, IGF2BP2 rs4402960, alone or in interaction with dietary fat intake, influenced abdominal total fat (ATF: SNP effect, p = 0.006, interaction effect, p = 0.009) and abdominal visceral fat (AVF: SNP effect, p = 0.007, interaction effect, p = 0.01). Similarly, TCF7L2 rs12573128 alone or in interaction with dietary fat intake, influenced insulin sensitivity (SNP effect and interaction effect, p ≤ 0.008) and glucose tolerance (SNP effect p ≤ 0.009 and interaction effect, p ≤ 0.01). Conclusion: These results suggest that gene-dietary fat interactions may influence glucose homeostasis-related phenotypes and play an important role in determining the increased risk of diabetes associated with the T2DM susceptibility genes.

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Section: Discussionmentioning

confidence: 99%

Evidence of Interaction between Type 2 Diabetes Susceptibility Genes and Dietary Fat Intake for Adiposity and Glucose Homeostasis-Related Phenotypes

Ruchat¹,

Elks²,

Loos³

et al. 2009

Lifestyle Genomics

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“…Insulin predominantly induces metabolic effects, whereas IGFs are far more potent as growth factors and anabolic agents (13). The IR and IGF-IR have high affinity for their cognate ligand, whereas the binding affinities of insulin to IGF-IR and IGF-I to IR are ϳ100-fold lower (14,15).…”

Section: Most Mammalian Cells Express Both Insulin Receptor (Ir)mentioning

confidence: 99%

Hybrid Receptors Formed by Insulin Receptor (IR) and Insulin-like Growth Factor I Receptor (IGF-IR) Have Low Insulin and High IGF-1 Affinity Irrespective of the IR Splice Variant

Slaaby

Schäffer

Lautrup-Larsen

et al. 2006

Journal of Biological Chemistry

175

128

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Insulin receptor (IR) and insulin-like growth factor I receptor (IGF-IR) are both from the same subgroup of receptor tyrosine kinases that exist as covalently bound receptor dimers at the cell surface. For both IR and IGF-IR, the most described forms are homodimer receptors. However, hybrid receptors consisting of one-half IR and one-half IGF-IR are also present at the cell surface. Two splice variants of IR are expressed that enable formation of two isoforms of the IGF-IR/IR hybrid receptor. In this study, these two splice variants of hybrid receptors were studied with respect to binding affinities of insulin, insulin-like growth factor I (IGF-I), and insulin-like growth factor II (IGF-II). Unlike previously published data, in which semipurified receptors have been studied, we found that the two hybrid receptor splice variants had similar binding characteristics with respect to insulin, IGF-I, and IGF-II binding. We studied both semipurified and purified hybrid receptors. In all cases we found that IGF-I had at least 50-fold higher affinity than insulin, irrespective of the splice variant. The binding characteristics of insulin and IGF-I to both splice variants of the hybrid receptors were similar to classical homodimer IGF-IR.

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“…Although underlying molecular mechanisms are incompletely understood, two models have been proposed (5,12). The first posits cross-binding of insulin to IGFR in colonic epithelia and neoplastic clones, driving proliferation and tumorigenesis; the second proposes indirect IGFR activation through perturbation of the IGF-I axis (including expression of the IGF-binding proteins) (13,14). Whereas consistent changes in bioactive IGF-I have been difficult to document (4), evidence favoring the direct model is provided by studies of epithelial proliferation in rats (15).…”

mentioning

confidence: 99%

Design of an Insulin Analog with Enhanced Receptor Binding Selectivity

Zhao

Wan

Whittaker

et al. 2009

Journal of Biological Chemistry

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Insulin binds with high affinity to the insulin receptor (IR) and with low affinity to the type 1 insulin-like growth factor (IGF) receptor (IGFR). Such cross-binding, which reflects homologies within the insulin-IGF signaling system, is of clinical interest in relation to the association between hyperinsulinemia and colorectal cancer. Here, we employ nonstandard mutagenesis to design an insulin analog with enhanced affinity for the IR but reduced affinity for the IGFR. Unnatural amino acids were introduced by chemical synthesis at the N-and C-capping positions of a recognition ␣-helix (residues A1 and A8). These sites adjoin the hormone-receptor interface as indicated by photocross-linking studies. Specificity is enhanced more than 3-fold on the following: Epidemiological studies have demonstrated an association between the metabolic syndrome and type 2 diabetes mellitus (DM) 4 with enhanced risk of colorectal cancer (CRC) (1-3). Animal models suggest that this risk is due to hyperinsulinemia (4, 5). An increased risk of CRC is conferred by treated-derived hyperinsulinemia, either as a direct consequence of insulin replacement therapy or as an indirect response to sulfonylurea secretagogues (6 -9). A reduced CRC risk is by contrast associated with metformin treatment, which results in lower circulating insulin concentrations (7). Because of the global epidemic of type 2 DM (10, 11), it would be of interest to develop a form of insulin therapy that does not elevate CRC risk in this clinical setting.A variety of evidence suggests that the association between hyperinsulinemia and CRC is due to aberrant activation of the type 1 IGF receptor (IGFR) (for review see Refs. 5,12). Although underlying molecular mechanisms are incompletely understood, two models have been proposed (5, 12). The first posits cross-binding of insulin to IGFR in colonic epithelia and neoplastic clones, driving proliferation and tumorigenesis; the second proposes indirect IGFR activation through perturbation of the IGF-I axis (including expression of the IGF-binding proteins) (13,14). Whereas consistent changes in bioactive IGF-I have been difficult to document (4), evidence favoring the direct model is provided by studies of epithelial proliferation in rats (15). Exogenous administration of insulin with a euglycemic clamp causes an acute dose-dependent increase in the proliferation rate of colonic epithelia despite decreased IGF-I expression. Such increased proliferation was not observed as a consequence of hyperglycemia or following infusion of a triglyceride emulsion (15).Insulin binds with high affinity (K d ϳ0.05 nM) to the insulin receptor (IR) and with low but significant affinity (K d Ј ϳ9.0 nM) to IGFR (16). Such cross-binding reflects the structural homology between insulin and IGF-I (17) and between IR and IGFR (18). The structural basis for receptor discrimination by insulin and IGF-I has been described recently (19). As a first step toward dissecting the molecular mechanism of insulin-dependent proliferation of colonic epithelia c...

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The insulin‐like growth factor system and diabetes—an overview

Cited by 17 publications

References 44 publications

Evidence of Interaction between Type 2 Diabetes Susceptibility Genes and Dietary Fat Intake for Adiposity and Glucose Homeostasis-Related Phenotypes

Evidence of Interaction between Type 2 Diabetes Susceptibility Genes and Dietary Fat Intake for Adiposity and Glucose Homeostasis-Related Phenotypes

Hybrid Receptors Formed by Insulin Receptor (IR) and Insulin-like Growth Factor I Receptor (IGF-IR) Have Low Insulin and High IGF-1 Affinity Irrespective of the IR Splice Variant

Design of an Insulin Analog with Enhanced Receptor Binding Selectivity

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