Dataset Information

Signaling cross talk between growth hormone (GH) and insulin-like growth factor-I (IGF-I) in pancreatic islet ?-cells.

ABSTRACT: Dysfunction and destruction of pancreatic islet ?-cells is a hallmark of diabetes. Better understanding of cell signals regulating ?-cell growth and antiapoptosis will allow development of therapeutic strategies for diabetes by preservation and expansion of ?-cell mass. GH and IGF-I share a complicated physiological relationship and have both been implicated in ?-cell function. GH and IGF-I exert their biological effects through binding to respective receptors (GHR and IGF-IR) and subsequently engaging downstream signaling pathways. However, their collaborative roles in modulation of ?-cell mass and the underlying molecular mechanisms remain poorly understood. In this study, we demonstrate that cultured ?-cells are appealing systems for investigating potential GH-IGF-I signaling cross talk. We uncover that GH specifically promotes formation of a protein complex containing GHR, Janus kinase 2 (a nonreceptor kinase coupled to GH/GHR signaling), and IGF-IR. More importantly, GH and IGF-I synergistically activate both signal transducer and activator of transcription 5 and Akt pathways. Concomitantly, ?-cells proliferate more robustly and are better protected from serum deprivation-induced apoptosis when exposed to GH and IGF-I in combination vs. GH or IGF-I alone. The augmented proliferative effects by GH and IGF-I are confirmed in isolated islets. Taken together, our findings strongly suggest that there exists a novel signaling relationship between GH/GHR and IGF-I/IGF-IR systems in ?-cells, i.e. IGF-IR may serve as a proximal component of GH/GHR signaling, contributing to enhancement of ?-cell mass and function. In support of this, IGF-IR knockdown in ?-cells resulted in the desensitization of acute GH-induced signal transducer and activator of transcription 5 activation.

SUBMITTER: Ma F

PROVIDER: S-EPMC3231823 | biostudies-other | 2011 Dec

REPOSITORIES: biostudies-other

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Signaling cross talk between growth hormone (GH) and insulin-like growth factor-I (IGF-I) in pancreatic islet β-cells.

Ma Fanxin F Wei Zhe Z Shi Chunwei C Gan Yan Y Lu Jia J Frank Stuart J SJ Balducci James J Huang Yao Y

Molecular endocrinology (Baltimore, Md.) 20111027 12

Dysfunction and destruction of pancreatic islet β-cells is a hallmark of diabetes. Better understanding of cell signals regulating β-cell growth and antiapoptosis will allow development of therapeutic strategies for diabetes by preservation and expansion of β-cell mass. GH and IGF-I share a complicated physiological relationship and have both been implicated in β-cell function. GH and IGF-I exert their biological effects through binding to respective receptors (GHR and IGF-IR) and subsequently e ...[more]

PMID: 22034225

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Project description:It has been reported that growth hormone (GH) and insulin-like growth factor 1 (IGF-1) exert protective and regenerative actions in response to neural damage. It is also known that these peptides are expressed locally in nervous tissues. When the central nervous system (CNS) is exposed to hypoxia-ischemia (HI), both GH and IGF-1 are upregulated in several brain areas. In this study, we explored the neuroprotective effects of GH and IGF-1 administration as well as the involvement of these endogenously expressed hormones in embryonic chicken cerebellar cell cultures exposed to an acute HI injury. To induce neural damage, primary cultures were first incubated under hypoxic-ischemic (<5% O2, 1g/L glucose) conditions for 12 h (HI), and then incubated under normal oxygenation and glucose conditions (HI + Ox) for another 24 h. GH and IGF-1 were added either during or after HI, and their effect upon cell viability, apoptosis, or necrosis was evaluated. In comparison with normal controls (Nx, 100%), a significant decrease of cell viability (54.1 ± 2.1%) and substantial increases in caspase-3 activity (178.6 ± 8.7%) and LDH release (538.7 ± 87.8%) were observed in the HI + Ox group. On the other hand, both GH and IGF-1 treatments after injury (HI + Ox) significantly increased cell viability (77.2 ± 4.3% and 72.3 ± 3.9%, respectively) and decreased both caspase-3 activity (118.2 ± 3.8% and 127.5 ± 6.6%, respectively) and LDH release (180.3 ± 21.8% and 261.6 ± 33.9%, respectively). Incubation under HI + Ox conditions provoked an important increase in the local expression of GH (3.2-fold) and IGF-1 (2.5-fold) mRNAs. However, GH gene silencing with a specific small-interfering RNAs (siRNAs) decreased both GH and IGF-1 mRNA expression (1.7-fold and 0.9-fold, respectively) in the HI + Ox group, indicating that GH regulates IGF-1 expression under these incubation conditions. In addition, GH knockdown significantly reduced cell viability (35.9 ± 2.1%) and substantially increased necrosis, as determined by LDH release (1011 ± 276.6%). In contrast, treatments with GH and IGF-1 stimulated a partial recovery of cell viability (45.2 ± 3.7% and 53.7 ± 3.2%) and significantly diminished the release of LDH (320.1 ± 25.4% and 421.7 ± 62.2%), respectively. Our results show that GH, either exogenously administered and/or locally expressed, can act as a neuroprotective factor in response to hypoxic-ischemic injury, and that this effect may be mediated, at least partially, through IGF-1 expression.

Project description:Here we explore association with human longevity of common genetic variation in three major candidate pathways: GH/IGF-1/insulin signaling, DNA damage signaling and repair and pro/antioxidants by investigating 1273 tagging SNPs in 148 genes composing these pathways. In a case-control study of 1089 oldest-old (age 92-93) and 736 middle-aged Danes we found 1 pro/antioxidant SNP (rs1002149 (GSR)), 5 GH/IGF-1/INS SNPs (rs1207362 (KL), rs2267723 (GHRHR), rs3842755 (INS), rs572169 (GHSR), rs9456497 (IGF2R)) and 5 DNA repair SNPs (rs11571461 (RAD52), rs13251813 (WRN), rs1805329 (RAD23B), rs2953983 (POLB), rs3211994 (NTLH1)) to be associated with longevity after correction for multiple testing. In a longitudinal study with 11 years of follow-up on survival in the oldest-old Danes we found 2 pro/antioxidant SNPs (rs10047589 (TNXRD1), rs207444 (XDH)), 1 GH/IGF-1/INS SNP (rs26802 (GHRL)) and 3 DNA repair SNPs (rs13320360 (MLH1), rs2509049 (H2AFX) and rs705649 (XRCC5)) to be associated with mortality in late life after correction for multiple testing. When examining the 11 SNPs from the case-control study in the longitudinal data, rs3842755 (INS), rs13251813 (WRN) and rs3211994 (NTHL1) demonstrated the same directions of effect (p<0.05), while rs9456497 (IGF2R) and rs1157146 (RAD52) showed non-significant tendencies, indicative of effects also in late life survival. In addition, rs207444 (XDH) presented the same direction of effect when inspecting the 6 SNPs from the longitudinal study in the case-control data, hence, suggesting an effect also in survival from middle age to old age. No formal replications were observed when investigating the 11 SNPs from the case-control study in 1613 oldest-old (age 95-110) and 1104 middle-aged Germans, although rs11571461 (RAD52) did show a supportive non-significant tendency (OR=1.162, 95% CI=0.927-1.457). The same was true for rs10047589 (TNXRD1) (HR=0.758, 95%CI=0.543-1.058) when examining the 6 SNPs from the longitudinal study in a Dutch longitudinal cohort of oldest-old (age 85+, N=563). In conclusion, the present candidate gene based association study, the largest to date applying a pathway approach, not only points to potential new longevity loci, but also underlines the difficulties of replicating association findings in independent study populations and thus the difficulties in identifying universal longevity polymorphisms.

Dataset Information

Signaling cross talk between growth hormone (GH) and insulin-like growth factor-I (IGF-I) in pancreatic islet ?-cells.

Publications

Signaling cross talk between growth hormone (GH) and insulin-like growth factor-I (IGF-I) in pancreatic islet β-cells.

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