Cross-talk between Insulin and Wnt Signaling in Preadipocytes

Palsgaard, Jane; Emanuelli, Brice; Winnay, Jonathon N.; Sumara, Grzegorz; Karsenty, G.; Kahn, C. Ronald

doi:10.1074/jbc.m111.337048

Cited by 91 publications

(52 citation statements)

References 58 publications

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“…LRP6 transcriptional regulation of IR is important for adipogenic transformation of 3T3L1 cells [34] and for preferential glucose uptake in a drosophila model of insulin resistance [35]. Reduced IR expression can be rescued by either TCF7L2 overexpression or high doses of Wnt3a [Figure 1].…”

Section: Monogenic Causes Of Metabolic Syndromementioning

confidence: 99%

Metabolic syndrome

Ziki

Mani

2016

Current Opinion in Lipidology

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Purpose of review Metabolic syndrome (MetS) is a cluster of inter-related and heritable metabolic traits, which collectively impart unsurpassed risk for atherosclerotic cardiovascular disease and type 2 diabetes. Considerable work has been done to understand the underlying disease mechanisms by elucidating its genetic etiology. Recent findings Genome-wide association studies (GWAS) have been widely utilized albeit with modest success in identifying variants that are associated with more than two metabolic traits. Another limitation of this approach is the inherent small effect of the common variants, a major barrier for dissecting their cognate pathways. Modest advances in this venue have been also made by genetic studies of kindreds at the extreme ends of quantitative distributions. These efforts have led to the discovery of a number of disease genes with large effects that underlie the association of diverse traits of this syndrome. Summary Substantial progress has been made over the last decade in identification of genetic risk factors associated with the various traits of MetS. The heterogeneity and multifactorial heritability of MetS, however, has been a challenge towards understanding the factors underlying the association of these traits. Genetic investigations of outlier kindreds or homogenous populations with high prevalence for the disease can potentially improve our knowledge of the disease pathophysiology.

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Section: Monogenic Causes Of Metabolic Syndromementioning

confidence: 99%

Metabolic syndrome

Ziki

Mani

2016

Current Opinion in Lipidology

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“…Indeed, our study demonstrated that IR-overexpressing β-cells have higher therapeutic potential and function than pure β-cells without gene manipulation for DM and activated Wnt signaling pathway, e.g., the increase in cyclin D1 and GK or the stimulation of β-catenin nuclear translocation. These results were associated with the evidence that insulin or IR-activated insulin signaling could interplay with Wnt signaling through GSK3β phosphorylation or inducible interaction with LRP 5/6 co-receptors [9]. LRP5/6 co-receptor leads to an inactivation of GSK3β.…”

Section: Discussionmentioning

confidence: 77%

“…This interaction between insulin and Wnt signaling pathways has been recently demonstrated in a variety of organs or cells, such as kidney, bone, preadipocyte, intestinal endocrine cells, and skeletal muscle cells [8], [9], [24]–[26]. However, there is not yet known the cross-talk between insulin and Wnt signaling pathways in β-cells, and more previous studies focused on insulin repceptor substrate or IR regulation by Wnt signaling [9], [24], [27].…”

Section: Discussionmentioning

confidence: 98%

“…However, there is not yet known the cross-talk between insulin and Wnt signaling pathways in β-cells, and more previous studies focused on insulin repceptor substrate or IR regulation by Wnt signaling [9], [24], [27]. Furthermore, the impairment of β-cell growth and overt glucose intolerance shownin a β-cell-specific IR knockout (βIRKO) mouse [28] or an IRS-2 null mouse [29] are relevant to AKT-mediated anti-apoptotic and proliferative mechanisms [30], [31] regardless the involvement of Wnt signaling.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, cross-talk between insulin and Wnt signaling pathways has been revealed to exist in a variety of cells, including preadipocytes, skeletal muscle cells, and intestinal cells [9]–[11], but not yet in β-cells. Generally, early intensive insulin therapy controls hyperglycemia and delays β-cell damage and restores β-cell function in type 2 diabetic patients.…”

Section: Introductionmentioning

confidence: 99%

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Insulin Receptor-Overexpressing β-Cells Ameliorate Hyperglycemia in Diabetic Rats through Wnt Signaling Activation

2013

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To investigate the therapeutic efficacy and mechanism of β-cells with insulin receptor (IR) overexpression on diabetes mellitus (DM), rat insulinoma (INS-1) cells were engineered to stably express human insulin receptor (INS-IR cells), and subsequently transplanted into streptozotocin- induced diabetic rats. Compared with INS-1 cells, INS-IR cells showed improved β-cell function, including the increase in glucose utilization, calcium mobilization, and insulin secretion, and exhibited a higher rate of cell proliferation, and maintained lower levels of blood glucose in diabetic rats. These results were attributed to the increase of β-catenin/PPARγ complex bindings to peroxisome proliferator response elements in rat glucokinase (GK) promoter and the prolongation of S-phase of cell cycle by cyclin D1. These events resulted from more rapid and higher phosphorylation levels of insulin-signaling intermediates, including insulin receptor substrate (IRS)-1/IRS-2/phosphotylinositol 3 kinase/v-akt murine thymoma viral oncogene homolog (AKT) 1, and the consequent enhancement of β-catenin nuclear translocation and Wnt responsive genes including GK and cyclin D1. Indeed, the higher functionality and proliferation shown in INS-IR cells were offset by β-catenin, cyclin D1, GK, AKT1, and IRS-2 gene depletion. In addition, the promotion of cell proliferation and insulin secretion by Wnt signaling activation was shown by 100 nM insulin treatment, and to a similar degree, was shown in INS-IR cells. In this regard, this study suggests that transferring INS-IR cells into diabetic animals is an effective and feasible DM treatment. Accordingly, the method might be a promising alternative strategy for treatment of DM given the adverse effects of insulin among patients, including the increased risk of modest weight gain and hypoglycemia. Additionally, this study demonstrates that the novel mechanism of cross-talk between insulin and Wnt signaling plays a primary role in the higher therapeutic efficacy of IR-overexpressing β-cells.

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Dietary glycemic and insulin scores and colorectal cancer survival by tumor molecular biomarkers

Keum

Yuan

Nishihara

et al. 2017

Intl Journal of Cancer

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Accumulating evidence suggests that post-diagnostic insulin levels may influence colorectal cancer (CRC) survival. Yet, no previous study has examined CRC survival in relation to a post-diagnostic diet rich in foods that increase post-prandial insulin levels. We hypothesized that glycemic and insulin scores (index or load; derived from food frequency questionnaire data) may be associated with survival from specific CRC subtypes sensitive to the insulin signaling pathway. We prospectively followed 1,160 CRC patients from the Nurses’ Health Study (1980–2012) and Health Professionals Follow-Up Study (1986–2012), resulting in 266 CRC deaths in 10,235 person-years. CRC subtypes were defined by seven tumor biomarkers (KRAS, BRAF, PIK3CA mutations, and IRS1, IRS2, FASN, and CTNNB1 expression) implicated in the insulin signaling pathway. For overall CRC and each subtype, hazard ratio (HR) and 95% confidence interval (95% CI) for an increase of one standard deviation in each of glycemic and insulin scores were estimated using time-dependent Cox proportional hazards model. We found that insulin scores, but not glycemic scores, were positively associated with CRC mortality (HR=1.19, 95% CI=1.02 to 1.38 for index; HR=1.23, 95% CI=1.04 to 1.47 for load). The significant positive associations appeared more pronounced among PIK3CA wild-type cases and FASN-negative cases, with HR ranging from 1.36 to 1.60 across insulin scores. However, we did not observe statistically significant interactions of insulin scores with PIK3CA, FASN, or any other tumor marker (P interaction > .12). While additional studies are needed for definitive evidence, a high-insulinogenic diet after CRC diagnosis may contribute to worse CRC survival.

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Cross-talk between Insulin and Wnt Signaling in Preadipocytes

Cited by 91 publications

References 58 publications

Metabolic syndrome

Metabolic syndrome

Insulin Receptor-Overexpressing β-Cells Ameliorate Hyperglycemia in Diabetic Rats through Wnt Signaling Activation

Dietary glycemic and insulin scores and colorectal cancer survival by tumor molecular biomarkers

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