Plasma Insulin-like Growth Factor Research Articles

Progressive substitution of fish oil with Schizochytrium-derived algal oil in the diet of Atlantic salmon (Salmo salar) parr subjected to winter signal period

The aim of this study was to investigate the impact of progressive replacement of fish oil with Schizochytrium-derived oil from Veramaris® (VMO) in the diets of Atlantic salmon, focusing on its effect during the pre-adaptation to smoltification phase of parr, with an emphasis on the winter signal period. Substitution of fish oil with VMO during this critical developmental phase of salmon (pre-adaptation to smoltification phase) can contribute to the goal of reducing dependence on wild fisheries as a primary source of essential fatty acids in aquafeeds. Three isoproteic, isolipidic and isoenergetic diets were formulated; a control diet containing 5% fish oil and 12% plant oil (0VMO) and two other diets, in which 50% and 100% of the EPA+DHA from fish oil were replaced with VMO, henceforth referred to as 50VMO and 100VMO, respectively. The fish were exposed to a 12 L:12D photoperiod over a 49-day window with samples collected at five time points, including a 48-h salt water challenge to evaluate the effects on common smoltification-related biomarkers including the expression of two genes coding for the two protein isoforms of the NKA alpha catalytic subunit (nkaa1a, nkaa1b), the gene coding for NA+/K+Cl⁻ co-transporter (nkcc1) in the gills as well as osmolality, Cl-, Mg2+, Ca2+, cortisol, growth hormone, and insulin-like growth factor-1 in plasma. The results showed non-significant differences in growth performance and only minor differences in smoltification-related parameters between the dietary treatment groups. Overall, the unconventional source of EPA+DHA was not detrimental to growth, hypoosmoregulatory ability or general welfare, suggesting that the progressive substitution of fish oil with Schizochytrium-derived oil in diets for Atlantic salmon parr is a viable option for adoption by the aquaculture industry.

Extravascular administration of IGF1R antagonists protects against aortic aneurysm in rodent and porcine models.

An abdominal aortic aneurysm (AAA) is a life-threatening cardiovascular disease. We identified plasma insulin-like growth factor 1 (IGF1) as an independent risk factor in patients with AAA by correlating plasma IGF1 with risk. Smooth muscle cell- or fibroblast-specific knockout of Igf1r, the gene encoding the IGF1 receptor (IGF1R), attenuated AAA formation in two mouse models of AAA induced by angiotensin II infusion or CaCl2 treatment. IGF1R was activated in aortic aneurysm samples from human patients and mice with AAA. Systemic administration of IGF1C, a peptide fragment of IGF1, 2 weeks after disease development inhibited AAA progression in mice. Decreased AAA formation was linked to competitive inhibition of IGF1 binding to its receptor by IGF1C and modulation of downstream alpha serine/threonine protein kinase (AKT)/mammalian target of rapamycin signaling. Localized application of an IGF1C-loaded hydrogel was developed to reduce the side effects observed after systemic administration of IGF1C or IGF1R antagonists in the CaCl2-induced AAA mouse model. The inhibitory effect of the IGF1C-loaded hydrogel administered at disease onset on AAA formation was further evaluated in a guinea pig-to-rat xenograft model and in a sheep-to-minipig xenograft model of AAA formation. The therapeutic efficacy of IGF1C for treating AAA was tested through extravascular delivery in the sheep-to-minipig model with AAA established for 2 weeks. Percutaneous injection of the IGF1C-loaded hydrogel around the AAA resulted in improved vessel flow dynamics in the minipig aorta. These findings suggest that extravascular administration of IGF1R antagonists may have translational potential for treating AAA.

Identification of potential mediators of the relationship between body mass index and colorectal cancer: a Mendelian randomization analysis.

Colorectal cancer (CRC) is the third-most-common cancer worldwide and its rates are increasing. Elevated body mass index (BMI) is an established risk factor for CRC, although the molecular mechanisms behind this association remain unclear. Using the Mendelian randomization (MR) framework, we aimed to investigate the mediating effects of putative biomarkers and other CRC risk factors in the association between BMI and CRC. We selected as mediators biomarkers of established cancer-related mechanisms and other CRC risk factors for which a plausible association with obesity exists, such as inflammatory biomarkers, glucose homeostasis traits, lipids, adipokines, insulin-like growth factor 1 (IGF1), sex hormones, 25-hydroxy-vitamin D, smoking, physical activity (PA) and alcohol consumption. We used inverse-variance weighted MR in the main univariable analyses and performed sensitivity analyses (weighted-median, MR-Egger, Contamination Mixture). We used multivariable MR for the mediation analyses. Genetically predicted BMI was positively associated with CRC risk [odds ratio per SD (5 kg/m2) = 1.17, 95% CI: 1.08-1.24, P-value = 1.4 × 10-5] and robustly associated with nearly all potential mediators. Genetically predicted IGF1, fasting insulin, low-density lipoprotein cholesterol, smoking, PA and alcohol were associated with CRC risk. Evidence for attenuation was found for IGF1 [explained 7% (95% CI: 2-13%) of the association], smoking (31%, 4-57%) and PA (7%, 2-11%). There was little evidence for pleiotropy, although smoking was bidirectionally associated with BMI and instruments were weak for PA. The effect of BMI on CRC risk is possibly partly mediated through plasma IGF1, whereas the attenuation of the BMI-CRC association by smoking and PA may reflect confounding and shared underlying mechanisms rather than mediation.

Effects of dietary pectin on the growth performance, intestinal barrier, and antioxidant status of juvenile rainbow trout (Oncorhynchus mykiss)

To evaluate the effects of dietary pectin on growth performance, intestinal barrier, and antioxidant status of juvenile rainbow trout (Oncorhynchus mykiss), 10-week feeding trial was conducted. Five isoproteic and isoenergetic diets were formulated to contain 0% (P0), 4% (P4), 8% (P8), and 16% (P16) pectin as well as 0.02% pectinase (PE) at the expense of wheat starch, respectively. Dietary inclusion of 416% pectin linearly promoted the feed intake and growth performance but depressed the feed efficiency, but significant differences were only observed between the P16 and P0 groups. Similarly, dietary inclusion of 816% pectin significantly increased the foregut trypsin and amylase activities but decreased the foregut and midgut sucrase activity. The midgut muc2 gene expression level was significantly down-regulated by the inclusion of 16% pectin. Dietary inclusion of 2% pectin increased the abundance of Proteobacteria and Stenotrophomonas but reduced the abundance of Actinobacteria, Bacteroides and Helicobacter; while the lowest values of observed species, Chao1 and ACE indices of intestinal flora were found in the P8 group. Fish fed with the P8 diet exhibited the lowest plasma catalase and midgut glutathione S-transferase activities as well as malondialdehyde content, but the highest midgut malondialdehyde content. Dietary inclusion of 816% pectin significantly depressed the plasma growth hormone (GH), insulin-like growth factor-1 (IGF-1) and mechanistic target of rapamycin contents as well as alanine aminotransferase activity, the hepatic adenosine monophosphate deaminase and glutamate dehydrogenase (GDH) activities. Dietary treatment with 0.02% pectinase did not affect the growth performance, but depressed the foregut sucrase activity, the midgut amylase and sucrase activities, increased the plasma GH and IGF-1 contents as well as hepatic GDH and aspartate aminotransferase activities. In conclusion, high-dose of dietary pectin (816%) may promote the feed intake and intestinal digestive enzyme activities and thereby improve the growth performance of rainbow trout.

Growth Hormone Mediators and Glycemic Control in Youths With Type 2 Diabetes

Youth-onset type 2 diabetes (T2D) has a more aggressive phenotype than adult-onset T2D, including rapid loss of glycemic control and increased complication risk. To identify associations of growth hormone mediators with glycemic failure, beta cell function, and insulin sensitivity in youth-onset T2D. This post hoc secondary analysis of the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) randomized clinical trial, which enrolled participants from July 2004 to February 2009, included 398 participants from 15 university-affiliated medical centers with available plasma samples from baseline and 36 months. Participants were youths aged 10 to 17 years with a duration of T2D of less than 2 years who were randomized to metformin, metformin plus lifestyle intervention, or metformin plus rosiglitazone. Participants were followed up for a mean (SD) of 3.9 (1.5) years during the trial, ending in 2011. Statistical analysis was performed from August 2022 to November 2023. Plasma insulin-like growth factor-1 (IGF-1), growth hormone receptor (GHR), and insulin-like growth factor binding protein 1 (IGFBP-1). Main outcomes were (1) loss of glycemic control during the TODAY study, defined as hemoglobin A1c (HbA1c) level of 8% or more for 6 months or inability to wean from insulin therapy, and (2) baseline and 36-month measures of glycemia (fasting glucose, HbA1c), insulin sensitivity (1/fasting C-peptide), high-molecular-weight adiponectin, and beta cell function (C-peptide index, C-peptide oral disposition index). This analysis included 398 participants (mean [SD] age, 13.9 [2.0] years; 248 girls [62%]; 166 Hispanic participants [42%]; 134 non-Hispanic Black participants [34%], and 84 non-Hispanic White participants [21%]). A greater increase in IGF-1 level between baseline and 36 months was associated with lower odds of glycemic failure (odds ratio [OR], 0.995 [95% CI, 0.991-0.997]; P < .001) and higher C-peptide index per 100-ng/mL increase in IGF-1 (β [SE], 0.015 [0.003]; P < .001). A greater increase in log2 GHR level between baseline and 36 months was associated with higher odds of glycemic failure (OR, 1.75 [95% CI, 1.05-2.99]; P = .04) and lower C-peptide index (β [SE], -0.02 [0.006]; P < .001). A greater increase in log2 IGFBP-1 level between baseline and 36 months was associated with higher odds of glycemic failure (OR, 1.37 [95% CI, 1.09-1.74]; P = .007) and higher high-molecular-weight adiponectin (β [SE], 431 [156]; P = .007). This study suggests that changes in plasma growth hormone mediators are associated with loss of glycemic control in youth-onset T2D, with IGF-1 associated with lower risk and GHR and IGFBP-1 associated with increased risk. ClinicalTrials.gov Identifier: NCT00081328.

Association between Expression of Insulin-like Growth Factor-1 (IGF-1), IGF-1 Receptor (IGF-1R), and Hypertension-Mediated Organ Damage (HMOD) Parameters in Leukocytes and Plasma of Children/Adolescents with Primary Hypertension.

A decrease in IGF-1 is often linked to inflammation. Low systemic and local IGF-1 production and downregulation of IGF-1R expression may precede and predict PH development in children/adolescents. Leukocyte mRNA expression of IGF-1 and its receptor (IGF-1R) and plasma IGF-1 were measured in a group of 39 PH children/adolescents (29 boys and 10 girls) and 35 age-matched normotensive children (19 boys and 16 girls) using the RT-PCR and ELISA tests. The expression of the IGF-1R protein was assessed by flow cytometry. Plasma IGF-1 concentration was evaluated with ELISA. The expression of IGF-1 and IGF-1R and plasma concentrations of IGF-1 did not differ between groups. However, the PH children had a decreased percentage in IGF-1R-bearing lymphocytes (p = 0.02) and monocytes (p = 0.0003), as well as a low density of IGF-R in monocytes (p = 0.02). The IGF-1 expression was negatively correlated with pulse-wave velocity (PWV) (r = -0.49), systolic blood pressure (SBP) (-0.44), and carotid intima-media thickness (cIMT) (-0.43). The IGF-1R expression was negatively correlated with PWV (r = -0.42) and SBP (r = -0.41). Our results suggest that early subclinical hypertensive arterial injury is associated with lower activity of IGF-1-IGF-1R expression and loss of protective actions.

Mating Season Influences Placental Characteristics, Plasma IGF Concentration, and mRNA Expression without Affecting Lamb Birth Weight in Akkaraman Ewes

Seasonal variations significantly impact lambs’ birth weight and post-natal growth of lambs, yet the underlying physiological mechanisms remain insufficiently explored. Therefore, this study examined the effects of mating season on lamb birth weight, placental characteristics, maternal concentrations of insulin-like growth factors (IGFs) in plasma, and placental mRNA expression levels of IGFs in Akkaraman ewes reared under extensive conditions. Ewes were mated in the breeding season (September; n = 35) and out-of-breeding season (April; n = 27). Blood samples were taken from the jugular vein of all ewes using a vacutainer in sterile heparin tubes every month from mating to parturition. Post-lambing, both dam and lamb weights were recorded, and placental characteristics were documented within 12 hours of parturition in both seasons. The number and weight of cotyledons were higher (P&lt;0.05) in ewes mated during the breeding season than those mated during the out-of-breeding season. Also, ewes mated during the breeding season demonstrated thicker large cotyledons (P&lt;0.05). Although placental and cotyledonal efficiencies were similar in both mating seasons, volumetric cotyledon efficiency was higher (P&lt;0.05) in ewes mated during the out-of-breeding season than in those bred during the breeding season. Additionally, ewes mated in the breeding season exhibited higher plasma concentration of IGF-I at three months of gestation than ewes mated in the out-of-breeding season (123.8 ± 9.8 vs. 99.3 ± 11.4 ng/ml, respectively; P&lt;0.05). Although the mating season did not affect the IGF-I gene’s placental mRNA expression levels, the IGF-II gene’s expression level was notably higher (P&lt;0.05; fold change: 2.84) in ewes mated during the breeding season. The results suggest that mating season influences placental characteristics, maternal plasma IGF-I concentrations, and IGF-II gene expression levels of cotyledons due to alterations in cotyledon numbers and size on the surface of the placenta.

Insulin-like growth factor 1 and its prognostic value in the course of acute ischemic cerebrovascular events.

The aim of the study was to evaluate insulin-like growth factor 1 (IGF-1) as a predictor of the course of an acute cerebral ischemic event (AICE). This polypeptide, by activating receptors that are present in most tissues, including the brain, mediates the anabolic activity of growth hormone (GH) and its impact on growth and maturation processes, as well as organisms' survival time. AICE can occur in the form of a transient ischemic attack (TIA) or an ischemic stroke (IS). The study included 86 participants. The correlation between serum IGF-1 concentration and the clinical status of 56 patients on days 1 and 9 of AICE, as well as risk factors and the course of the disease, were prospectively analyzed. The control group consisted of 30 healthy volunteers. Patients with a minor baseline neurological syndrome had higher serum IGF-1 concentrations than patients with severe baseline neurological dysfunctions. Multidimensional analyses showed that high IGF-1 values independently determined the worse course of the disease, especially in patients with a severe neurological deficit present on the first day of AICE. Our results indicate that the high level of circulating IGF-1 on the first day of AICE is an independent factor determining the unfavorable course of the stroke, and this relationship is proportional to the severity of the baseline neurological deficit. The study also revealed a positive correlation between the decreased plasma IGF-1 concentration on the first day of AICE and the severity of neurological symptoms.

Plasma Glial Cell-Derived Neurotrophic Factor and Insulin-like Growth Factor-1 Levels Were Not Correlated with the Severity of Age-Related Hearing Impairment in Humans.

The relationship between plasma glial cell-derived neurotrophic factor (GDNF) or insulin-like growth factor-1 (IGF-1) levels and age-related hearing impairment (ARHI) has not been reported in humans. By cross-sectional design, 268 subjects older than 33, with normal cognitive function and normal or symmetric sensorineural hearing loss, were selected randomly. Multivariate linear regression analysis was performed to test the impact of the plasma GDNF or IGF-1 level on the pure tone threshold of low frequencies (PTA-low) and high frequencies (PTA-high), respectively. Results showed that plasma GDNF and IGF-1 levels decreased with age without statistical significance. Multivariate linear regression analysis showed that GDNF or IGF-1 levels were not significantly correlated with PTA-low or PTA-high after adjusting age, gender, body mass index, systemic diseases, habits, and noise exposure. In conclusion, plasma GDNF or IGF-1 levels were not associated with the severity of ARHI in humans. However, these findings did not support the roles of GDNF or IGF-1 genotypes on hearing.

Blockade of angiotensin II modulates insulin-like growth factor 1-mediated skeletal muscle homeostasis in experimental steatohepatitis

Sarcopenia is associated with mortality in patients with nonalcoholic steatohepatitis (NASH). Angiotensin II receptor blocker (ARB) has been suggested to prevent sarcopenia, but reports on its effect on NASH-derived skeletal muscle atrophy in conjunction with insulin-like growth factor 1 (IGF-1)-mediated muscle homeostasis are few. Our aim was to examine the combined effect of the ARB losartan and IGF-1 replacement on skeletal muscle atrophy in a methionine–choline deficient (MCD) diet-fed murine steatohepatitis model. The MCD-fed mice developed steatohepatitis and skeletal muscle atrophy, as indicated by the reduction of psoas muscle mass and attenuation of forelimb and hindlimb grip strength. Significantly suppressed steatohepatitis and skeletal muscle atrophy was observed after single treatment with ARB or IGF-1, and these effects were augmented after combination treatment. Treatment with ARB and IGF-1 effectively inhibited ubiquitin proteasome-mediated protein degradation by reducing forkhead box protein O1 (FOXO1) and FOXO3a transcriptional activity in the skeletal muscle. Combined ARB and IGF-1 decreased the intramuscular expression of proinflammatory cytokines (i.e., TNFα, IL6, and IL1β) and increased the Trolox equivalent antioxidant capacity and antioxidant enzymes (CAT, GPX1, SOD2, and CYTB). This antioxidant effect was based on downregulation of NADPH oxidase (NOX) 2, normalization of mitochondrial biogenesis and dynamics. Moreover, ARB increased the hepatic and plasma IGF-1 levels and improved steatohepatitis, leading to enhanced skeletal muscle protein synthesis mediated by IGF-1/ AKT/ mechanistic target of rapamycin signaling. Collectively, combined ARB and IGF-1 replacement could be a promising new therapeutic target for NASH-derived skeletal muscle wasting.

Advanced maternal age leads to changes within the insulin/IGF system and lipid metabolism in the reproductive tract and preimplantation embryo: insights from the rabbit model.

Reproductive potential in women declines with age. The impact of ageing on embryo-maternal interactions is still unclear. Rabbits were used as a reproductive model to investigate maternal age-related alterations in reproductive organs and embryos on Day 6 of pregnancy. Blood, ovaries, endometrium, and blastocysts from young (16-20 weeks) and advanced maternal age phase (>108 weeks, old) rabbits were analysed at the mRNA and protein levels to investigate the insulin-like growth factor (IGF) system, lipid metabolism, and stress defence system. Older rabbits had lower numbers of embryos at Day 6 of pregnancy. Plasma insulin and IGF levels were reduced, which was accompanied by paracrine regulation of IGFs and their receptors in ovaries and endometrium. Embryos adapted to hormonal changes as indicated by reduced embryonic IGF1 and 2 levels. Aged reproductive organs increased energy generation from the degradation of fatty acids, leading to higher oxidative stress. Stress markers, including catalase, superoxide dismutase 2, and receptor for advanced glycation end products were elevated in ovaries and endometrium from aged rabbits. Embryonic fatty acid uptake and β-oxidation were increased in both embryonic compartments (embryoblast and trophoblast) in old rabbits, associated with minor changes in the oxidative and glycative stress defence systems. In summary, the insulin/IGF system, lipid metabolism, and stress defence were dysregulated in reproductive tissues of older rabbits, which is consistent with changes in embryonic metabolism and stress defence. These data highlight the crucial influence of maternal age on uterine adaptability and embryo development.

Short- and long-term effects of nutritional state on IGF-1 levels in nestlings of a wild passerine

Growth trajectories of young animals are intimately connected to their fitness prospects, but we have little knowledge of growth regulation mechanisms, particularly in the wild. Insulin-like growth factor 1 (IGF-1) is a central hormone in regulating resource allocation, with higher IGF-1 levels resulting in more growth. IGF-1 levels generally increase in conjunction with nutritional state, but whether IGF-1 levels are adjusted in response to current nutrient availability or to the nutrient availability integrated over a longer term is not well known. We tested for such effects by supplementary feeding the jackdaw (Corvus monedula) nestlings in experimentally reduced or enlarged broods with either water (control) or a food solution; these manipulations have long- and short-term effects on the nutritional state, respectively. Baseline plasma IGF-1 levels were higher in reduced broods. Food supplementation induced an increase in plasma IGF-1 levels measured one hour later, and this effect was significantly more substantial in nestlings in reduced broods. Changes in plasma IGF-1 levels increased with increased retention of the supplementary food, which was higher in reduced broods, explaining the stronger IGF-1 response. Thus, IGF-1 levels respond to short-term variations in the nutritional state, but this effect is amplified by longer-term variations in the nutritional state. We discuss our findings using a graphical model that integrates the results of the two treatments.

Insulin-like growth factor 1 associated with altered immune responses in preterm infants and pigs

BackgroundPreterm infants show low blood levels of insulin-like growth factor 1 (IGF-1), known to be negatively correlated with Interleukin-6 (IL-6). We hypothesized that circulating IGF-1 is associated with systemic immune-markers following preterm birth and that exogenous IGF-1 supplementation modulates immune development in preterm pigs, used as model for preterm infants.MethodsPlasma levels of IGF-1 and 29 inflammatory markers were measured in very preterm infants (n = 221). In preterm pigs, systemic immune development, assessed by in vitro challenge, was compared between IGF-1 treated (2.25 mg/kg/day) and control animals.ResultsPreterm infants with lowest gestational age and birth weight showed the lowest IGF-1 levels, which were correlated not only with IL-6, but a range of immune-markers. IGF-1 supplementation to preterm pigs reduced plasma IL-10 and Interferon-γ (IFN-γ), IL-2 responses to challenge and reduced expression of genes related to Th1 polarization. In vitro addition of IGF-1 (100 ng/mL) further reduced the IL-2 and IFN-γ responses but increased IL-10 response.ConclusionsIn preterm infants, plasma IGF-1 correlated with several immune markers, while supplementing IGF-1 to preterm pigs tended to reduce Th1 immune responses. Future studies should document whether IGF-1 supplementation to preterm infants affects immune development and sensitivity to infection.ImpactSupplementation of insulin-like growth factor 1 (IGF-1) to preterm infants has been proposed to promote postnatal growth, but its impact on the developing immune system is largely unknown.In a cohort of very preterm infants, low gestational age and birth weight were the primary predictors of low plasma levels of IGF-1, which in turn were associated with plasma immune markers. Meanwhile, in immature preterm pigs, experimental supplementation of IGF-1 reduced Th1-related immune responses in early life.Supplementation of IGF-1 to preterm infants may affect the developing immune system, which needs consideration when evaluating overall impact on neonatal health.

Effects of post-spawning ration restriction on reproductive development and the growth hormone/insulin-like growth factor-1 axis in female rainbow trout (Oncorhynchus mykiss)

In iteroparous female salmonids, the growth and reproductive endocrine axes interact during the period after spawning. Energy depletion due to pre-spawn fasting, migration, and ovarian development must be restored, and the next reproductive cycle is initiated in consecutively maturing fish. In the natural environment, food availability is often limited during the post-spawn period. To investigate the growth and reproductive endocrinology of the post-spawn period, we sampled female rainbow trout over the 30 weeks following their first spawning. Fish were fasted for 2 months prior to spawning, then fed a standard or a restricted ration. Analysis was confined to reproductive fish. Plasma estradiol-17β decreased during the 8 weeks following spawning and then began increasing in both ration groups and was lower in feed-restricted versus standard ration fish from 8 weeks onward. Plasma insulin-like growth factor-1 increased over the same period and then remained constant in both ration groups and was lower in feed-restricted versus standard ration fish from week 8 to week 30. Plasma growth hormone decreased following spawning in standard ration fish and became elevated in feed-restricted versus standard ration fish at 20- and 30-weeks post-spawn. Growth rates, condition factor, and muscle lipid levels were higher in standard ration versus feed-restricted fish within 2–4 weeks after spawning. These results suggest that two phases occurred during the post-spawn period: recovery from spawning and restoration of energy reserves over weeks 0 to 8, followed by adjustment of the growth and reproductive endocrine axes to ration level over weeks 8 to 30.

134-OR: Associations of Growth Hormone (GH) Mediators with Loss of Glycemic Control in Youth with Type 2 Diabetes (T2D)

T2D in youth has a more severe phenotype than in adults, with puberty as a potential contributor to this difference. Pubertal changes in GH mediators (e.g., insulin-like growth factor 1 (IGF-1), growth hormone receptor (GHR), insulin-like growth factor binding protein 1 (IGFBP-1)) may impact insulin sensitivity and beta cell function. We examined associations of GH mediators with loss of glycemic control in youth with T2D using the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) cohort (N= 310). We performed paired comparison of plasma concentrations of IGF-1, GHR, and IGFBP-1 (ELISA), between 0mo and 36mo based on TODAY primary outcome of loss of glycemic control vs. maintained glycemic control (LGC vs MGC), with LGC defined as HbA1c ≥ 8% for 6 months and/or insulin dependence. We studied associations of GH mediators with HbA1c, insulinogenic index, oral disposition index, and 1/fasting insulin. Models were adjusted for age, sex, race, treatment arm, and baseline HbA1c (linear regression). Mean plasma IGF-1 (ng/mL) was lower in LGC group at 0mo (LGC: 451 ± 141, MGC: 485 ± 155, p = 0.04), and at 36mo (LGC: 340 ± 117, MGC: 400 ± 136, p&amp;lt; 0.0001). Increase in IGF-1 between 0-36mo predicted lower HbA1c at 36mo (B = -3.2E-3, SE = 9.0E-4, p &amp;lt; 0.001). Higher GHR was associated with higher HbA1c (B = 1.2E-2, SE = 3.0E-3, p &amp;lt; 0.001) and lower 1/fasting insulin (B = -6.6E-4, SE = 2.1E-4, P &amp;lt; 0.01) at 0mo. Increase in GHR between 0-36mo predicted higher 36mo HbA1c (B = 3.0E-2, SE = 9.4E-3, p &amp;lt; 0.01). IGFBP-1 was positively associated with 1/fasting insulin at 0m (B = 1.1E-3, SE = 4.9E-4, p = 0.03). In exploratory analyses stratified by Tanner stage (TS) at study entry, GH mediators changed differentially between TS 1-3 (n = 31) vs TS 4-5 (n = 274). In conclusion, GH mediators differed based on primary outcome in TODAY, and were associated with HbA1c and insulin sensitivity. Whether changes in GH mediators contribute to, or are the result of, changes in glucose metabolism is a key area for future studies. Disclosure C.Lu: None. D.Wolfs: None. L.El ghormli: None. L.M.Laffel: Advisory Panel; Medtronic, Lilly Diabetes, Novo Nordisk, Vertex Pharmaceuticals Incorporated, Roche Diagnostics, Provention Bio, Inc., Consultant; Dexcom, Inc., Janssen Pharmaceuticals, Inc., Medscape. M.Patti: Consultant; MBX Biosciences, AstraZeneca, Hanmi Pharm. Co., Ltd., Other Relationship; Fractyl Health, Inc. E.M.Isganaitis: None. Funding National Institutes of Health (2T32DK007260-46); National Institute of Diabetes and Digestive and Kidney Diseases (5U01DK061230-16)

Effect of Ca-octanoate supplementation on concentrations of ghrelin and ghrelin-related hormones in plasma and milk of beef cattle

We aimed to evaluate the effect of dietary calcium (Ca)-octanoate supplementation on concentrations of ghrelin, growth hormone (GH), insulin-like growth factor-1 (IGF-1), and insulin in plasma and milk of beef cattle during late gestation and early postpartum. Twelve Japanese Black cattle were offered concentrate without (CON, n = 6) or with Ca-octanoate supplementation at 1.5% of dietary dry matter (OCT, n = 6). Blood samples were collected at −60, −30, and −7 d relative to the expected parturition date and daily from d 0 to 3 after parturition. Milk samples were collected daily postpartum. Compared to the CON group, concentrations of acylated ghrelin increased in plasma as parturition approached in the OCT group (P = 0.02). However, concentrations of GH, IGF-1, and insulin in plasma and milk were not affected by treatment groups throughout the study. Additionally, we showed for the first time that bovine colostrum and transition milk contain acylated ghrelin at a significantly higher concentration than plasma (P = 0.01). Interestingly, concentrations of acylated ghrelin in milk were negatively correlated with those in plasma postpartum (r = −0.50, P < 0.01). Feeding Ca-octanoate increased concentrations of total cholesterol (T-cho) in plasma and milk (P < 0.05), tended to increase those of glucose in plasma at postpartum and milk (P < 0.1). We conclude that feeding Ca-octanoate in late gestation and early postpartum may contribute to increased concentrations of glucose and T-cho in plasma and milk without affecting concentrations of ghrelin, GH, IGF-1, and insulin in plasma and milk.

Circulating IGF-1 and IGFBP-2 may be biomarkers for risk stratification in patients with acute coronary syndrome: A prospective cohort study

Background and aimThe involvement of insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-2 (IGFBP-2) following acute coronary syndrome (ACS) is rarely studied in clinical practice. Therefore, we sought to evaluate the relationship between IGF-1 and IGFBP-2 concentrations at admission and risk stratification based on the Thrombolysis in Myocardial Infarction (TIMI) risk score in patients with ACS. Methods and resultsIn all, 304 patients diagnosed with ACS were included in this study. Plasma IGF-1 and IGFBP-2 were measured using commercially available ELISA kits. The TIMI risk score was calculated and the study population was stratified into high (n = 65), medium (n = 138), and low (n = 101) risk groups. Levels of IGF-1 and IGFBP-2 were analyzed for their predictive ability of risk stratification based on the TIMI risk scores. Correlation analysis showed that IGF-1 levels were negatively correlated with TIMI risk levels (r = −0.144, p = 0.012), while IGFBP-2 levels were significantly and positively correlated with TIMI risk levels (r = 0.309, p < 0.001). In multivariate logistic regression analysis, IGF-1 (odds ratio [OR]: 0.995; 95% confidence interval [CI]: 0.990–1.000; p = 0.043) and IGFBP-2 (OR: 1.002; 95%CI: 1.001–1.003; p < 0.001) were independent predictors of high TIMI risk levels. In receiver operating characteristic curves, the area under the curve values for IGF-1 and IGFBP-2 in the prediction of high TIMI risk levels were 0.605 and 0.723, respectively. ConclusionsIGF-1 and IGFBP-2 levels are excellent biomarkers for risk stratification in patients with ACS, which provides further guidance for clinicians to identify patients at high risk and to lower their risk.

Down-regulating insulin-like growth factor-1 receptor reduces amyloid-β deposition in mice cortex induced by chronic sleep restriction

ObjectiveInsufficient sleep affects cognitive function, but the underlying mechanism and potential protective ways are yet to be fully understood. This study aimed to explore the influence of chronic sleep restriction (CSR) on the insulin-like growth factor-1 (IGF-1) signaling pathway, and whether down-regulating IGF-1 signaling pathway would modulate amyloid-β (Aβ) peptides metabolism and its cortical deposition after CSR. Methods 8-week IGF-1R+/- mice and wild-type (WT) C57BL/6 (C57) mice were divided into four groups: IGF-1R+/- CSR (MUSR), IGF-1R+/- control (MUCO), C57 CSR (C57SR) and C57 control (C57CO). CSR model was established by application of slowly rotating drum for 2 months. Body weight and Lee's index were measured. The level of IGF-1 in plasma was measured by enzyme linked immunosorbent assay (ELISA). Aβ accumulation was detected by immunofluorescence. The expressions of amyloid precursor protein (APP), β-site amyloid precursor protein-cleaving enzyme-1 (BACE-1) and C99 were detected using western-blot (WB). Results Two-way ANOVA showed genotypic effect was significant on body weight and Lee’s index. Neither treatment effect nor interaction reached significant difference on body weight and Lee’s index. The level of IGF-1 in plasma was significantly decreased in C57SR compared with C57CO. Besides, compared with C57CO, Aβ was markedly accumulated in frontal cortex, in parallel with increased expressions of BACE-1 and C99, and with no difference of APP in C57SR group. Further, no significant changes of Aβ, BACE-1, C99 and APP were detected in MUSR compared with MUCO. Conclusions This study showed that CSR could induce the decrease of circulating IGF-1 in mice. By using the IGF-1R+/- mice, we found that down-regulating IGF-1R could reduce Aβ deposition in mice frontal cortex after CSR via inhibiting BACE-1 protein expression and activity, which were independent of the changes of body weight and Lee’s index. These findings indicate that the blockage of IGF-1 signaling pathway might be a protection mechanism for alleviating the impact of CSR.

Stimbiotics Supplementation Promotes Growth Performance by Improving Plasma Immunoglobulin and IGF-1 Levels and Regulating Gut Microbiota Composition in Weaned Piglets.

This study was conducted to investigate the effects of dietary supplementation with stimbiotics (STB) on growth performance, diarrhoea incidence, plasma antioxidant capacity, immunoglobulin concentration and hormone levels, and faecal microorganisms in weaned piglets. Compared with the control (CT) group, the addition of STB improved the body weight (BW) of piglets on days 28 and 42 (p < 0.05) and increased daily weight gain and daily feed intake from days 14-28 and throughout the trial period (p < 0.05). Correspondingly, the plasma insulin-like growth factor 1 (IGF-1) level on day 42 was significantly improved by STB (p < 0.05). VistaPros (VP) group levels of immunoglobulin (Ig) A and G were significantly higher on days 14 and 42 (p < 0.05) than the CT group levels. In addition, the activity of plasma catalase tended to be increased on day 14 (p = 0.053) in the VP group, as for superoxide dismutase, glutathione peroxidase, and malondialdehyde, STB did not significantly affect their levels (p > 0.05). Moreover, dietary STB increased the relative abundance of beneficial bacteria, including norank_f_Muribaculaceae, Rikenellaceae_RC9_gut_group, Parabacteroides, and unclassified_f__Oscillospiraceae. In summary, STB improved the immunity and IGF-1 levels in the plasma of weaned piglets and consequently promoted the growth performance of weaned piglets.

Insulin-like Growth Factor-1 Prevents Hypoxia/Reoxygenation-Induced White Matter Injury in Sickle Cell Mice

Occlusion of cerebral blood vessels causes acute cerebral hypoxia-an important trigger of ischemic white matter injury and stroke in sickle cell disease (SCD). While chronic hypoxia triggers compensatory neuroprotection via insulin-like growth factor-1 (IGF-1) and hypoxia inducible factor-1α (HIF-1α), severe bouts of acute hypoxia and subsequent restoration of blood flow (hypoxia/reoxygenation, H/R) overwhelm compensatory mechanisms and cause neuroaxonal damage-identified as white matter lesions-in the brain. The neuroprotective role of IGF-1 in the pathogenesis of white matter injury in SCD has not been investigated; however, it is known that systemic IGF-1 is reduced in individuals with SCD. We hypothesized that IGF-1 supplementation may prevent H/R-induced white matter injury in SCD. Transgenic sickle mice homozygous for human hemoglobin S and exposed to H/R developed white matter injury identified by elevated expression of non-phosphorylated neurofilament H (SMI32) with a concomitant decrease in myelin basic protein (MBP) resulting in an increased SMI32/MBP ratio. H/R-challenge also lowered plasma and brain IGF-1 expression. Human recombinant IGF-1 prophylaxis significantly induced HIF-1α and averted H/R-induced white matter injury in the sickle mice compared to vehicle-treated mice. The expression of the IGF-1 binding proteins IGFBP-1 and IGFBP-3 was elevated in the IGF-1-treated brain tissue indicating their potential role in mediating neuroprotective HIF-1α signaling. This study provides proof-of-concept for IGF-1-mediated neuroprotection in SCD.