Disruption Of Insulin-like Growth Factor Research Articles

Interrelationships between Habitual Beverage Consumption, Plasma Biomarkers and Risk of Type 2 Diabetes: Results From a Prospective Case-Control Study

ObjectivesTo elucidate potential pathways of dietary risk of type 2 diabetes (T2D) by defining a model that describes how identified patterns of habitual beverage consumption associate with identified networks of circulating cardiometabolic plasma biomarkers. MethodsThis study included 1,231 cases and 1,560 controls from a nested case-control study of T2D within the Nurses’ Health Study I. Participants completed validated food frequency questionnaires assessing their habitual beverage intake and provided plasma samples to assess 27 different plasma biomarkers of cardiometabolic risk. Common exploratory factor analysis (EFA) was used to identify common factors that separately described beverage consumption patterns and biomarker networks. False discovery rate corrected multivariable-adjusted regression elucidated the relationships between beverage and biomarker factors, and their associations with T2D risk. ResultsEFA revealed five factors describing beverage consumption patterns and seven factors explaining underlying biomarker networks. Preferential consumption of alcoholic beverages was associated with reduced risk of T2D (P < 0.0001) and lower concentrations of detrimental biomarkers of endothelial dysfunction (P = 0.014). Also, a preferential consumption of low-calorie sweetened beverages (LCSBs) was associated with increased risk of T2D (P < 0.0001), and lower concentrations of insulin-like growth factor binding protein 1 and 2, and soluble leptin receptor (P = 0.010). ConclusionsThese analyses provide new mechanistic insight into how different patterns of beverage consumption may relate to T2D risk, and indicate that preferential consumption of LCSB may exert diabetogenic effects through mechanisms involving the disruption of insulin-like growth factor and leptin signalling. Funding SourcesNational Institutes of Health.

Astrocyte Resilience to Oxidative Stress Induced by Insulin-like Growth Factor I (IGF-I) Involves Preserved AKT (Protein Kinase B) Activity

Disruption of insulin-like growth factor I (IGF-I) signaling is a key step in the development of cancer or neurodegeneration. For example, interference of the prosurvival IGF-I/AKT/FOXO3 pathway by redox activation of the stress kinases p38 and JNK is instrumental in neuronal death by oxidative stress. However, in astrocytes, IGF-I retains its protective action against oxidative stress. The molecular mechanisms underlying this cell-specific protection remain obscure but may be relevant to unveil new ways to combat IGF-I/insulin resistance. Here, we describe that, in astrocytes exposed to oxidative stress by hydrogen peroxide (H2O2), p38 activation did not inhibit AKT (protein kinase B) activation by IGF-I, which is in contrast to our previous observations in neurons. Rather, stimulation of AKT by IGF-I was significantly higher and more sustained in astrocytes than in neurons either under normal or oxidative conditions. This may be explained by phosphorylation of the phosphatase PTEN at the plasma membrane in response to IGF-I, inducing its cytosolic translocation and preserving in this way AKT activity. Stimulation of AKT by IGF-I, mimicked also by a constitutively active AKT mutant, reduced oxidative stress levels and cell death in H2O2-exposed astrocytes, boosting their neuroprotective action in co-cultured neurons. These results indicate that armoring of AKT activation by IGF-I is crucial to preserve its cytoprotective effect in astrocytes and may form part of the brain defense mechanism against oxidative stress injury.

Pharmacological disruption of insulin-like growth factor 1 binding to IGF-binding proteins restores anabolic responses in human osteoarthritic chondrocytes

Insulin-like growth factor 1 (IGF-1) has poor anabolic efficacy in cartilage in osteoarthritis (OA), partly because of its sequestration by abnormally high levels of extracellular IGF-binding proteins (IGFBPs). We studied the effect of NBI-31772, a small molecule that inhibits the binding of IGF-1 to IGFBPs, on the restoration of proteoglycan synthesis by human OA chondrocytes. IGFBPs secreted by human OA cartilage or cultured chondrocytes were analyzed by western ligand blot. The ability of NBI-31772 to displace IGF-1 from IGFBPs was measured by radiobinding assay. Anabolic responses in primary cultured chondrocytes were assessed by measuring the synthesis of proteoglycans in cetylpyridinium-chloride-precipitable fractions of cell-associated and secreted 35S-labeled macromolecules. The penetration of NBI-31772 into cartilage was measured by its ability to displace 125I-labeled IGF-1 from cartilage IGFBPs. We found that IGFBP-3 was the major IGFBP secreted by OA cartilage explants and cultured chondrocytes. NBI-31772 inhibited the binding of 125I-labeled IGF-1 to IGFBP-3 at nanomolar concentrations. It antagonized the inhibitory effect of IGFBP-3 on IGF-1-dependent proteoglycan synthesis by rabbit chondrocytes. The addition of NBI-31772 to human OA chondrocytes resulted in the restoration or potentiation of IGF-1-dependent proteoglycan synthesis, depending on the IGF-1 concentrations. However, NBI-31772 did not penetrate into cartilage explants. This study shows that a new pharmacological approach that uses a small molecule inhibiting IGF-1/IGFBP interaction could restore or potentiate proteoglycan synthesis in OA chondrocytes, thereby opening exciting possibilities for the treatment of OA and, potentially, of other joint-related diseases.

American College of Medical Genetics Statement on Diagnostic Testing for Uniparental Disomy

American College of Medical Genetics Statement on Diagnostic Testing for Uniparental Disomy