Variants of Insulin-Signaling Inhibitor Genes in Type 2 Diabetes and Related Metabolic Abnormalities

Lorenzo, Carlo De; Greco, Annalisa; Fiorentino, Teresa Vanessa; Mannino, Gaia Chiara; Hribal, Marta Letizia

doi:10.1155/2013/376454

Cited by 12 publications

(8 citation statements)

References 112 publications

(188 reference statements)

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“…Increased bone expression of osteotesticular protein tyrosine phosphatase (ESP or OST-PTP) also occurred with HYP mice consistent with the observed hyperglycemia and abnormal insulin/leptin levels ( Figure 4A and Table 4 ). Specifically, both ESP and ENPP1 mutations and over expression are associated with abnormalities in glucose metabolism, insulin sensitivity, obesity and diabetes [85] – [89] .…”

Section: Resultsmentioning

confidence: 99%

PHEX Mimetic (SPR4-Peptide) Corrects and Improves HYP and Wild Type Mice Energy-Metabolism

2014

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ContextPHEX or DMP1 mutations cause hypophosphatemic-rickets and altered energy metabolism. PHEX binds to DMP1-ASARM-motif to form a complex with α5β3 integrin that suppresses FGF23 expression. ASARM-peptides increase FGF23 by disrupting the PHEX-DMP1-Integrin complex. We used a 4.2 kDa peptide (SPR4) that binds to ASARM-peptide/motif to study the DMP1-PHEX interaction and to assess SPR4 for the treatment of energy metabolism defects in HYP and potentially other bone-mineral disorders.DesignSubcutaneously transplanted osmotic pumps were used to infuse SPR4-peptide or vehicle (VE) into wild-type mice (WT) and HYP-mice (PHEX mutation) for 4 weeks.ResultsSPR4 partially corrected HYP mice hypophosphatemia and increased serum 1.25(OH)2D3. Serum FGF23 remained high and PTH was unaffected. WT-SPR4 mice developed hypophosphatemia and hypercalcemia with increased PTH, FGF23 and 1.25(OH)2D3. SPR4 increased GAPDH HYP-bone expression 60× and corrected HYP-mice hyperglycemia and hypoinsulinemia. HYP-VE serum uric-acid (UA) levels were reduced and SPR4 infusion suppressed UA levels in WT-mice but not HYP-mice. SPR4 altered leptin, adiponectin, and sympathetic-tone and increased the fat mass/weight ratio for HYP and WT mice. Expression of perlipin-2 a gene involved in obesity was reduced in HYP-VE and WT-SPR4 mice but increased in HYP-SPR4 mice. Also, increased expression of two genes that inhibit insulin-signaling, ENPP1 and ESP, occurred with HYP-VE mice. In contrast, SPR4 reduced expression of both ENPP1 and ESP in WT mice and suppressed ENPP1 in HYP mice. Increased expression of FAM20C and sclerostin occurred with HYP-VE mice. SPR4 suppressed expression of FAM20C and sclerostin in HYP and WT mice.ConclusionsASARM peptides and motifs are physiological substrates for PHEX and modulate osteocyte PHEX-DMP1-α5β3-integrin interactions and thereby FGF23 expression. These interactions also provide a nexus that regulates bone and energy metabolism. SPR4 suppression of sclerostin and/or sequestration of ASARM-peptides improves energy metabolism and may have utility for treating familial rickets, osteoporosis, obesity and diabetes.

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Section: Resultsmentioning

confidence: 99%

PHEX Mimetic (SPR4-Peptide) Corrects and Improves HYP and Wild Type Mice Energy-Metabolism

2014

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“…One reason for this could be the upregulation of other phosphatases during adipocyte differentiation that substitute for the reduced PTEN function. Possible candidates for this role could be PH domain leucine-rich repeat protein phosphatases (PHLPP) 1 and 2 [39], protein-tyrosine phosphatase 1B [40] or protein-tyrosine phosphatase receptor type F (PTP-RF) [41] as they target the insulin signalling pathway and were shown to be implicated in the development of insulin resistance. We found a higher expression of PTP-RF in LipPD1 compared to SGBS cells during adipocyte differentiation.…”

Section: Discussionmentioning

confidence: 99%

A new human adipocyte model with PTEN haploinsufficiency

et al. 2020

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Few human cell strains are suitable and readily available as in vitro adipocyte models. We used resected lipoma tissue from a patient with germline phosphatase and tensin homolog (PTEN) haploinsufficiency to establish a preadipocyte cell strain termed LipPD1 and aimed to characterize cellular functions and signalling pathway alterations in comparison to the established adipocyte model Simpson-Golabi-Behmel-Syndrome (SGBS) and to primary stromal-vascular fraction cells. We found that both cellular life span and the capacity for adipocyte differentiation as well as adipocytespecific functions were preserved in LipPD1 and comparable to SGBS adipocytes. Basal and growth factor-stimulated activation of the PI3 K/AKT signalling pathway was increased in LipPD1 preadipocytes, corresponding to reduced PTEN levels in comparison to SGBS cells. Altogether, LipPD1 cells are a novel primary cell model with a defined genetic lesion suitable for the study of adipocyte biology.

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“…We will focus on the most multifunctional of these Tribbles proteins, i.e. TRIB3, and present findings that demonstrate its role in regulating disease progression in both metabolic syndrome and cancer [63][64][65][66][67][68].…”

Section: Inflammation: a Common Etiology In Chronic Diseases Obesitymentioning

confidence: 99%

Tripping on TRIB3 at the junction of health, metabolic dysfunction and cancer

2016

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Metabolic diseases like obesity, atherosclerosis and diabetes are frequently associated with increased risk of aggressive cancers. Although metabolic dysfunctions in normal cells are manifested due to defective signaling networks that control cellular homeostasis, malignant cells utilize these signaling networks for their increased survival, growth and metastasis. Despite decades of research, a common mechanistic link between these chronic pathologies is still not well delineated. Evidences show that the unfolded protein response (UPR) and the endoplasmic reticulum stress (ERS) pathways are often dysregulated in both metabolic diseases and cancer. The UPR also triggers coordinated signaling with both PI3K/AKT/mTOR and Autophagy pathways in order to promote stress-adaptive mechanisms. Whereas, uncontrolled UPR and the resultant ERS escalates cells towards metabolic dysfunctions and ultimately cell death. In this review, we will discuss findings that implicate a crucial role for the multifunctional ERS-induced protein, TRIB3. The 'pseudokinase' function of TRIB3 facilitates the inactivation of multiple transcription factors and signaling proteins. The MEK1 binding domain of TRIB3 enables it to deactivate multiple MAP-kinases. In addition, the COP1 motif of TRIB3 assists ubiquitination and proteasomal degradation of numerous TRIB3 associated proteins. The most well studied action of TRIB3 has been on the PI3K/AKT/mTOR pathway, where TRIB3-mediated inhibition of AKT phosphorylation decreases insulin signaling and cell survival. Conversely, cancer cells can either upregulate the AKT survival pathway by suppressing TRIB3 expression or alter TRIB3 localization to degrade differentiation inducing nuclear transcription factors such as C/EBPα and PPARγ. The gain-of-function Q84R polymorphism in TRIB3 is associated with increased risk of diabetes and atherosclerosis. TRIB3 acts as a crucial 'stress adjusting switch' that links homeostasis, metabolic disease and cancer; and is being actively investigated as a disease biomarker and therapeutic target.

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Variants of Insulin-Signaling Inhibitor Genes in Type 2 Diabetes and Related Metabolic Abnormalities

Cited by 12 publications

References 112 publications

PHEX Mimetic (SPR4-Peptide) Corrects and Improves HYP and Wild Type Mice Energy-Metabolism

PHEX Mimetic (SPR4-Peptide) Corrects and Improves HYP and Wild Type Mice Energy-Metabolism

A new human adipocyte model with PTEN haploinsufficiency

Tripping on TRIB3 at the junction of health, metabolic dysfunction and cancer

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