Decreased Serum Insulin-like Growth Factor Research Articles

Egg White Extract Supplementation Improves Albumin and IGF-1 Levels in Malnourished Elderly Patients: A Randomized Controlled Trial

Background: Malnutrition is a prevalent issue among the elderly, often leading to hypoalbuminemia (low albumin levels) and decreased serum Insulin-like growth factor 1 (IGF-1) levels. These conditions are associated with increased morbidity and mortality. Egg white extract (EWE) supplementation has shown promise in improving hypoalbuminemia. This study investigated the effects of EWE supplementation on serum albumin and IGF-1 levels in malnourished elderly patients. Methods: A double-blind randomized controlled trial was conducted, involving 46 malnourished elderly inpatients with hypoalbuminemia. Participants were randomly assigned to receive either EWE (30 grams daily) or a placebo for two weeks. Serum albumin and IGF-1 levels were measured before and after the intervention. Results: After two weeks, the EWE group showed a significant increase in both serum albumin and IGF-1 levels compared to the placebo group. The mean serum albumin level in the EWE group increased from 2.80 g/dL to 3.7 g/dL, while the placebo group remained unchanged. The mean serum IGF-1 level in the EWE group increased from 1.74 ng/mL to 24.74 ng/mL, while the placebo group experienced a smaller increase. There was a moderate positive correlation between changes in albumin and IGF-1 levels. Conclusion: EWE supplementation effectively improves serum albumin and IGF-1 levels in malnourished elderly patients with hypoalbuminemia. This intervention may help reduce malnutrition-related complications and improve overall health outcomes in this vulnerable population.

Association between serum insulin-like growth factor 1 and osteoporosis risk in Parkinson's disease: a cross-sectional study.

To examine the correlation between serum insulin-like growth factor 1 (IGF-1) and osteoporosis (OP) in Parkinson's disease (PD). We retrospectively analyzed clinical data from 105 PD patients (PD group) and 78 individuals in the health examination group (HC group). We compared general clinical data and serum IGF-1 levels between the two groups. PD patients were further categorized into PD with OP (50 cases) and PD without OP (55 cases) based on dual-energy X-ray absorptiometry (DXA) results for bone density. We compared general clinical data and serum IGF-1 levels between these two subgroups. Pearson correlation coefficient analysis was conducted to assess the relationship between serum IGF-1 levels and bone density at the lumbar spine and left femoral neck. Multifactorial logistic regression analysis was performed to identify risk factors for PD with OP. Serum IGF-1 levels were significantly lower in the PD group compared to the HC group (P < 0.05). Pearson correlation analysis revealed a positive association between serum IGF-1 levels and both lumbar spine and left femoral neck bone densities (r = 0.653, P < 0.001; r = 0.625, P < 0.001). Multivariate logistic regression analysis identified decreased serum IGF-1 levels, lower uric acid levels, and higher H-Y stage as risk factors for PD with OP (P < 0.05). Reduced levels of serum IGF-1, uric acid, and an increased H-Y stage are closely linked to osteoporosis in PD. Elevating serum levels of IGF-1 and uric acid may potentially offer therapeutic avenues for PD with osteoporosis.

Alterations in the fecal microbiota and serum metabolome in unstable angina pectoris patients.

Unstable angina pectoris (UAP) is a type of Coronary artery disease (CAD) characterized by a series of angina symptoms. Insulin-like growth factor 1 (IGF-1) system may be related to CAD. However, the correlation between the IGF-1 system, metabolism, and gut microbiota has not been studied. In the present study, we investigated the alterations of serum IGF-1 system, metabolomics, and gut microbiota in patients with UAP. Serum and stool samples from healthy volunteers and UAP patients were collected. Serum metabolomics, PAPP-A, IGF-1, IGFBP-4, STC2, hs-CRP, TNF-α, and IL-6 were detected in serum samples by LC-MS, and commercial ELISA kits, respectively. Fecal short-chain fatty acids (SCFAs) were measured by gas chromatography. 16S rDNA was used to measure the changes of the gut microbiota. The correlation of the above indicators was analyzed. There were 24 upregulated and 31 downregulated metabolites in the serum of UAP patients compared to those in the controls. Pathway analysis showed that these metabolites were enriched in pathways including linoleic acid metabolism, amino acid metabolism, starch metabolism, sucrose metabolism, and citrate cycle (TCA cycle), etc. Additionally, the UAP patients had lower fecal levels of 2-hydroxyisobutyric acid and succinic acid. 16S rDNA sequencing results showed that the relative abundances of Bacteroidetes, Synergistetes, Lactobacillaceae, Burkholderiaceae, Synergistaceae, and Subdoligranulum were significantly higher in the UAP patients than the healthy subjects. Moreover, the UAP patients had lower serum IGF-1, IGFBP-4, and STC2 and higher serum inflammatory cytokines (hs-CRP, TNF-α, and IL-6) levels than the healthy controls. Furthermore, there was a strong correlation between serum amino acids and IL-6, which played an important role in the development of UAP. These results indicated that the UAP patients had decreased serum IGF-1 level and imbalanced amino acids metabolism, which may be caused by the altered gut microbiota. It may provide a new therapeutic strategy for unstable angina pectoris.

One Bout of Resistance Training Does Not Enhance Metformin Actions in Prediabetic and Diabetic Individuals.

This study aimed to determine the separated and combined effects of metformin and resistance exercise on glycemic control, insulin sensitivity, and insulin-like growth factor 1 (IGF-1) in overweight/obese individuals with prediabetes and type 2 diabetes mellitus. Fourteen adults with a body mass index of 32.1 ± 4.1 kg·m-2, insulin resistance (HOMA-2 1.6 ± 0.6), and poor glycemic control (glycated hemoglobin, 6.9% ± 0.9%; 51.9 ± 10.7 mmol·mol-1) while taking metformin (1561 ± 470 g·d-1) were recruited. Participants underwent four 72-h long experimental trials in a randomized counterbalanced order, either 1) taking metformin (MET), 2) replacing metformin by placebo pills (PLAC), 3) taking placebo and undergoing a resistance training bout (RT + PLAC), and 4) taking metformin and undergoing the same RT bout (RT + MET). Interstitial fluid glucose concentration was frequently sampled to obtain 72-h glucose area under the curve (GAUC) and the percentage hyperglycemic glucose readings (>180 mg·dL-1; GPEAKS). Insulin sensitivity (i.e., HOMA-2) and IGF-1 were also assessed. HOMA-2 was not affected by treatments. GAUC and GPEAKS were similarly reduced below PLAC during RT + MET and MET (all P < 0.05). In contrast, RT + PLAC did not affect glucose concentration. Metformin decreased serum IGF-1 concentrations (P = 0.006), and RT did not reverse this reduction. A bout of full-body RT does not interfere or aid on metformin's blood glucose-lowering actions in individuals with prediabetes and type 2 diabetes mellitus.

Possible Biochemical Processes Underlying the Positive Health Effects of Plant-Based Diets-A Narrative Review.

Plant-based diets are becoming more popular for many reasons, and epidemiological as well as clinical data also suggest that a well-balanced vegan diet can be adopted for the prevention, and in some cases, in the treatment of many diseases. In this narrative review, we provide an overview of the relationships between these diets and various conditions and their potential biochemical background. As whole plant foods are very rich in food-derived antioxidants and other phytochemicals, they have many positive physiological effects on different aspects of health. In the background of the beneficial health effects, several biochemical processes could stand, including the reduced formation of trimethylamine oxide (TMAO) or decreased serum insulin-like growth factor 1 (IGF-1) levels and altered signaling pathways such as mechanistic target of rapamycin (mTOR). In addition, the composition of plant-based diets may play a role in preventing lipotoxicity, avoiding N-glycolylneuraminic acid (Neu5Gc), and reducing foodborne endotoxin intake. In this article, we attempt to draw attention to the growing knowledge about these diets and provide starting points for further research.

Protective effects of growth hormone-releasing hormone analogs in DSS-induced colitis in mice

Besides its metabolic and endocrine effects, growth hormone (GH)-releasing hormone (GHRH) is involved in the modulation of inflammation. Recently synthetized GHRH antagonist MIA-690 and MR-409, GHRH agonist, developed by us have shown potent pharmacological effects in various experimental paradigms. However, whether their administration modify resistance to chronic inflammatory stimuli in colon is still unknown. Ex vivo results demonstrated that MIA-690 and MR-409 inhibited production of pro-inflammatory and oxidative markers induced by lipopolysaccharide on isolated mouse colon specimens. In vivo, both MIA-690 and MR-409 have also been able to decrease the responsiveness to nociceptive stimulus, in hot plate test. Additionally, both peptides also induced a decreased sensitivity to acute and persistent inflammatory stimuli in male mice, in formalin test and dextran sodium sulfate (DSS)-induced colitis model, respectively. MIA-690 and MR-409 attenuate DSS-induced colitis with particular regard to clinical manifestations, histopathological damage and release of pro-inflammatory and oxidative markers in colon specimens. Respect to MR-409, MIA-690 showed higher efficacy in inhibiting prostaglandin (PG)E2, 8-iso-PGF2α and serotonin (5-HT) levels, as well as tumor necrosis factor (TNF)-α, interleukin (IL)-6 and nitric oxide synthase gene expression in colon specimens of DSS-induced colitis. Furthermore, MIA-690 decreased serum insulin-like growth factor (IGF)-1 levels in mice DSS-treated, respect to MR-409. Thus, our findings highlight the protective effects of MIA-690 and MR-409 on inflammation stimuli. The higher antinflammatory and antioxidant activities observed with MIA-690 could be related to decreased serum IGF-1 levels.

Beneficial alterations in body composition, physical performance, oxidative stress, inflammatory markers, and adipocytokines induced by long-term high-intensity interval training in an aged rat model

Sarcopenia is associated with loss of muscle mass and function as well as oxidative stress, chronic low-grade inflammatory status, and adipocytokine dysfunction. It has been reported that sarcopenia can be attenuated by exercise training. The purpose of this study was to evaluate whether long-term high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) protocols could differentially modulate changes in body composition, physical performance, inflammatory parameters, and adipocytokines in fat tissues and serum, as well as oxidative parameters and insulin-like growth factor 1 (IGF-1) levels in skeletal muscle tissue of aged rats. Middle-aged (18-month-old) female Sprague Dawley rats (n = 36) were subjected to 8 months of MICT (26-m MICT) or HIIT (26-m HIIT) treadmill training (45 min, 5 times per week), and the results were compared with those of age-matched sedentary controls (26-m SED); 8-month-old (8-m SED) and 18-month-old (18-m SED) rats served as aging sedentary controls. Body composition parameters; physical performance; serum and skeletal muscle oxidative stress parameters; levels of IGF-1, a serum and fat tissue inflammatory marker; adipocytokine (leptin, adiponectin) levels; and plasma glucose and lipid metabolism-related parameters were analyzed among the five groups. The percent fat and body fat to lean mass ratio increased as a main effect with age, whereas 26-m HIIT but not 26-m MICT attenuated these alterations. The 26-m HIIT group showed a larger improvement in grip strength compared to that of 26-m MICT, with a similar increase in inclined plane performance, maximum running speed, and exhaustion over time as compared with the 26-m SED group. Notably, the 26-m HIIT group showed lower high-sensitivity C-reactive protein levels and higher IL-10 in serum compared with those of the 26-m SED and 26-m MICT groups. Both exercise protocols promoted increased skeletal muscle IGF-1 and decreased serum IGF-1 and adiponectin relative to those in the 26-m SED group, whereas only 26-m HIIT dampened the age-related decrease in plasma free fatty acids and increased serum leptin, along with providing lower fat tissue leptin as compared with that in the 26-m SED group. Moreover, the 26-m HIIT group showed lower serum and skeletal muscle malonylaldehyde and skeletal muscle 8-hydroxydeoxyguanosine (8-OHdG) levels than those in the 26-m MICT group, albeit similar decreases in serum and skeletal muscle 4-hydroxynonenal and serum 8-OHdG and increases in skeletal muscle superoxide dismutase 2 activity. In conclusion, HIIT initiated late in life exhibited greater beneficial effects in ameliorating aged-related elevations in oxidative stress and inflammation, as well as dysfunction of circulating adipocytokine levels, than a volume-matched MICT program. HIIT may therefore contribute to improvements in body composition and physical performance changes associated with aging.

Expression and significance of serum insulin-like growth factor-1 in patients with obstructive sleep apnea hypopnea syndrome

Objective:To investigate the expression and significance of serum insulinlike growth factor-1(IGF-1) in adult patients with obstructive sleep apnea hypopnea syndrome(OSAHS).Method:One hundred and seven patients of OSAHS diagnosed with PSG were included in the observation group，which were divided into heavy, medium and light group according to AHI.Fifty case of healthy people without OSAHS were included in control group.Serum IGF-1 were measured by ELISA. Thirty patients of heavy OSAHS received surgery and CPAP treatment for three months,and were retested the levels of IGF-1 and PSG six months later.Result:①With the increase of OSAHS severity, the levels of serum IGF-1 were gradually decreased (F=37.732,P<0.01). There was no significant difference between mild group and healthy people (P>0.05), while there was significant differences between the remaining groups (P<0.01). ②Serum IGF-1 level has no correlation with BMI and age in OSAHS patients(P>0.05), and negatively correlated with LSaO₂,and positively correlated with AHI (P<0.01). ③Serum IGF-1 level［(46.56±3.74)μg/L］ increased slightly compared with those before treatment［(42.79±4.87）μg/L］ in 30 severe patients after treatment with 3 months CPAP and regimen (P<0.01). Serum IGF-1 level［(56.61±5.46)μg/L］ increased significantly after treatment for six months; AHI level (18.72±7.36) was significantly lower than that before treatment (48.77±10.51), and LSaO₂［(87.42±8.61)%］ increased significantly than that before treatment［(68.33±10.24)%］.Conclusion:OSAHS patients with decreased serum IGF-1 level may be associated with concurrent insulin resistance. Surgery combined with more than half a year of CPAP treatment can significantly reduce AHI, improve the level of LSaO₂ and serum IGF-1. Serum IGF-1 levels could be used as a monitor of efficacy evaluation.

Diet-Induced Nonalcoholic Fatty Liver Disease Is Associated with Sarcopenia and Decreased Serum Insulin-Like Growth Factor-1.

Decreased muscle mass or sarcopenia has been associated with nonalcoholic fatty liver disease (NAFLD). However, the functional consequences of this association and its pathogenesis remain ill-defined. To evaluate muscle mass and function in a diet-induced NAFLD mouse model and explore its association with changes in serum insulin-like growth factor-1 (IGF-1). Weight gain, visceral fat, serum biochemical parameters, liver histology, and hepatic triglyceride content (HTC) were assessed in C57/Bl6 mice fed a westernized diet during 16weeks. In addition, we determined muscle fiber size and strength of limb skeletal muscle, myosin heavy chain (MHC) protein levels, and IGF-1 serum levels. Westernized diet feeding was associated with weight gain, increased visceral fat mass (epididymal pad weight: 0.76g±0.13 vs. 0.33±0.27g; p=0.0023), hepatic steatosis (HTC: 118.2±6.88mg/g liver vs. 43.26±5.63mg/g<, p<0.05), and necroinflammation (histological scores: 1.29±0.42 vs. 4.00±0.53<, p<0.05). Also, mice fed the experimental diet had an increased proportion of low-diameter muscle fibers (0-30μm) and a decreased proportion of high-diameter muscle fibers (60-90μm), which correlated with decreased MHC protein levels, consistent with significant muscle atrophy. Functional studies showed that mice fed a westernized diet had reduced muscle strength and lower serum levels of IGF-1 (284.2±20.04pg/ml) compared with chow-fed mice (366.0±12.42pg/ml, p<0.05). Experimental NAFLD is associated with sarcopenia, decreased muscle strength, and reduced IGF-1 serum levels. IGF-1 reduction may be involved in pathogenesis of NAFLD-associated sarcopenia.

Impact of Decreased Serum Insulin-Like Growth Factor-1 Levels on Central Aortic Compliance in Small-for-Gestational-Age Infants

Background: Intrauterine growth restriction is associated with arterial hypertension in adulthood; however, the underlying mechanism is unclear. Objectives: We hypothesized that serum insulin-like growth factor-1 (IGF-1) levels affect central aortic elastic properties and structure in small-for-gestational-age (SGA) infants. Methods: Eighteen SGA infants and 22 appropriate-for-gestational-age (AGA) infants were enrolled in this study. The serum IGF-1 level within 1 h of birth and abdominal aortic echo parameters at 1 week of age were retrospectively compared. Results: In the SGA infants, IGF-1 levels (27.6 ± 17.7 vs. 42.6 ± 15 ng/ml, p = 0.006), aortic strain (10.2 ± 3.1 vs. 12.8 ± 3.1%, p = 0.01), and aortic distensibility (0.73 ± 0.19 vs. 0.92 ± 0.34 cm²/dyn × 10^-4, p = 0.05) were significantly lower compared with AGA infants. By contrast, blood pressure, aortic intima-media thickness (aIMT) in relation to body weight (383 ± 163 vs. 256 ± 43 μm/kg, p < 0.001), aortic stiffness index in relation to body weight (2.0 ± 1.7 vs. 1.1 ± 0.4, p = 0.005), and arterial pressure-strain elastic modulus (293 ± 72 vs. 242 ± 78 mm Hg, p = 0.04) were higher compared with AGA infants. In the SGA infants, IGF-1 levels were significantly correlated with aortic strain (r = 0.49, p = 0.04), aIMT in relation to body weight (r = -0.61, p = 0.007), and aortic stiffness index in relation to body weight (r = -0.63, p = 0.005). Conclusions: Decreased serum IGF-1 levels in SGA infants may affect the vascular compliance and structure of the central aorta.

Serum insulin-like growth factor-1 and insulin-like growth factor binding protein-3 levels in patients with chronic hepatitis B / Kronik hepatit B hastalarında serum insülin benzeri büyüme faktörü 1 (IGF-1) ve insülin benzeri büyüme faktörü bağlayıcı protein 3 (IGFBP-3) düzeyleri

Abstract Objective: Decreased serum insulin-like growth factor-1 (IGF-1) and insulin like growth factor binding protein-3 (IGFBP-3) levels have been found in patients with chronic liver disease of different etiologies, but these factors have not been studied extensively in patients with hepatitis B virus (HBV)-induced chronic liver disease. Methods: We have investigated serum IGF-1 and IGFBP-3 levels in 40 patients with chronic HBV and 40 patients with HBV-induced cirrhosis. According to Child-Pugh classification cirrhotic patients were divided into three groups. Forty age-and sex-matched healthy subjects served as controls. IGF-1 and IGFBP-3 levels were measured by immunochemiluminescence. The results were compared with those for serum albumin, total bilirubin, transaminase activity, and with prothrombin time. Results: IGF-1 and IGFBP-3 levels were significantly lower in patients with cirrhosis than in those with chronic HBV and in controls (p&lt;0.001). In chronic HBV patients, IGFBP-3 levels were significantly lower than in controls (p=0.013). IGF-1 and IGFBP-3 levels were significantly lower in cirrhotic patients with Child-Pugh stage B and Child-Pugh stage C compared with Child-Pugh stage A (for IGF-1 p=0.037 and p&lt;0.001, for IGFBP-3 p=0.036 and p&lt;0.001, respectively). In patients with Child-Pugh stage C significantly IGF-1 levels were lower than in patients with Child-Pugh stage B (p=0.003). IGF-1 and IGFBP-3 levels were positively correlated with serum albumin concentrations and negatively correlated with serum total bilirubin and prothrombin time concentrations in cirrhotic patients. IGF-1 and IGFBP-3 levels in chronic HBV patients were negatively correlated with serum transaminases. Conclusion: We conclude that serum levels of IGF-1 and IGFBP-3 may be useful markers for liver dysfunction in patients with HBV-induced chronic liver disease.

Characteristics of cognitive impairment and risk factors in type 2 diabetic mellitus patients

Objective To investigate the characteristics of cognitive impairment in patients with type 2 diabetes mellitus (T2DM), and to analyze the correlation of T2DM with its risk factors and serum insulin-like growth factor-1 (IGF-1) levels Methods A total of 78 hospitalized patients with T2DM at our hospital from November 2011 to March 2012 were divided into the cognitive impairment group (n=39) and the non-cognitive impairment group (n=39) according to Montreal Cognitive Assessment (MoCA) scores, and general clinical data were collected. Levels of blood lipids, glycosylated hemoglobin (HbAlc), fasting blood glucose (FBG), fasting blood insulin (FBI) and other biochemical indicators were detected, insulin resistance index (HOMA-IR) scores were calculated, and serum IGF-1 levels were determined by the enzyme-linked immunosorbent assay (ELISA). Results The education levle was (8.94±4.13) years for the cognitive impairment group and (12.65±2.50) years for the non-cognitive impairment group, and there was a statistically significant difference between the two groups (P=0.004). HbAlc levels were (9.69±1.25) and (7.96±1.31) for the cognitive impairment group and the non-cognitive impairment group, respectively, and were statistically difference between the two groups (P=0.001). Serum IGF-1 levels were (122.60±11.56) mmol/L and (139.32±9.57) mmol/L in the cognitive impairment group and the non-cognitive impairment group, respectively, and had a statistically significant difference between the two groups (P=0.037). Additionally, compared with the non-cognitive impairment group, scores on visuospatial ability, naming, language, abstraction, delayed recall and orientation were lower in the cognitive impairment group (P<0.05 or 0.01). Moreover, MoCA scores were negatively correlated with TC, LDL-C, TG, HbAlc, FBI levels and HOMA-IR (r=-0.498, -0.411, -0.414, -0.452, -0.449, -0.539, respectively, P<0.05 for all), and positively correlated with education level and IGF-1 level (r=0.579 and 0.491, respectively, P<0.05 for both). Conclusions Cognitive impairment caused by T2DM is prominent in visuospatial ability, language, memory and executive functions, and is closely related to poor education, poor glycemic control, dyslipidemia and insulin resistance. Furthermore, decreased serum IGF-1 levels might be a risk factor for diabetic cognitive impairment. Key words: Diabetes mellitus, type 2; Cognition disorders; Insulin-like growth factor-1

Calcium homeostasis and bone metabolic responses to high-protein diets during energy deficit in healthy young adults: a randomized controlled trial

Although consuming dietary protein above current recommendations during energy deficit (ED) preserves lean body mass, concerns have been raised regarding the effects of high-protein diets on bone health. The objective was to determine whether calcium homeostasis and bone turnover are affected by high-protein diets during weight maintenance (WM) and ED. In a randomized, parallel-design, controlled trial of 32 men and 7 women, volunteers were assigned diets providing protein at 0.8 [Recommended Dietary Allowance (RDA)], 1.6 (2 × RDA), or 2.4 (3 × RDA) g · kg(-1) · d(-1) for 31 d. Ten days of WM preceded 21 d of ED, during which total daily ED was 40%, achieved by reduced dietary energy intake (∼30%) and increased physical activity (∼10%). The macronutrient composition (protein g · kg(-1) · d(-1) and % fat) was held constant from WM to ED. Calcium absorption (ratio of (44)Ca to (42)Ca) and circulating indexes of bone turnover were determined at day 8 (WM) and day 29 (ED). Regardless of energy state, mean (±SEM) urinary pH was lower (P < 0.05) at 2 × RDA (6.28 ± 0.05) and 3 × RDA (6.23 ± 0.06) than at the RDA (6.54 ± 0.06). However, protein had no effect on either urinary calcium excretion (P > 0.05) or the amount of calcium retained (P > 0.05). ED decreased serum insulin-like growth factor I concentrations and increased serum tartrate-resistant acid phosphatase and 25-hydroxyvitamin D concentrations (P < 0.01). Remaining markers of bone turnover and whole-body bone mineral density and content were not affected by either the protein level or ED (P > 0.05). These data demonstrate that short-term consumption of high-protein diets does not disrupt calcium homeostasis and is not detrimental to skeletal integrity. This trial was registered at www.clinicaltrials.gov as NCT01292395.

Associations of serum insulin-like growth factor-I and insulin-like growth factor-binding protein 3 levels with biomarker-calibrated protein, dairy product and milk intake in the Women's Health Initiative

It is well established that protein-energy malnutrition decreases serum insulin-like growth factor (IGF)-I levels, and supplementation of 30 g of whey protein daily has been shown to increase serum IGF-I levels by 8 % after 2 years in a clinical trial. Cohort studies provide the opportunity to assess associations between dietary protein intake and IGF axis protein levels under more typical eating conditions. In the present study, we assessed the associations of circulating IGF axis protein levels (ELISA, Diagnostic Systems Laboratories) with total biomarker-calibrated protein intake, as well as with dairy product and milk intake, among postmenopausal women enrolled in the Women's Health Initiative (n 747). Analyses were carried out using multivariate linear regression models that adjusted for age, BMI, race/ethnicity, education, biomarker-calibrated energy intake, alcohol intake, smoking, physical activity and hormone therapy use. There was a positive association between milk intake and free IGF-I levels. A three-serving increase in milk intake per d (approximately 30 g of protein) was associated with an estimated average 18·6 % higher increase in free IGF-I levels (95 % CI 0·9, 39·3 %). However, total IGF-I and insulin-like growth factor-binding protein 3 (IGFBP-3) levels were not associated with milk consumption and nor were there associations between biomarker-calibrated protein intake, biomarker-calibrated energy intake, and free IGF-I, total IGF-I or IGFBP-3 levels. The findings of the present study carried out in postmenopausal women are consistent with clinical trial data suggesting a specific relationship between milk consumption and serum IGF-I levels, although in the present study this association was only statistically significant for free, but not total, IGF-I or IGFBP-3 levels.

Genetic ablation of carotene oxygenases and consumption of lycopene or tomato powder diets modulate carotenoid and lipid metabolism in mice

Carotene-15,15′-monooxygenase (CMO-I) cleaves β-carotene to form vitamin A, whereas carotene-9′,10′-monooxygenase (CMO-II) preferentially cleaves non–provitamin A carotenoids. Recent reports indicate that β-carotene metabolites regulate dietary lipid uptake, whereas lycopene regulates peroxisome proliferator-activated receptor expression. To determine the physiologic consequences of carotenoids and their interactions with CMO-I and CMO-II, we characterized mammalian carotenoid metabolism, metabolic perturbations, and lipid metabolism in female CMO-I−/− and CMO-II−/− mice fed lycopene or tomato-containing diets for 30 days. We hypothesized that there would be significant interactions between diet and genotype on carotenoid accumulation and lipid parameters. CMO-I−/− mice had higher levels of leptin, insulin, and hepatic lipidosis but lower levels of serum cholesterol. CMO-II−/− mice had increased tissue lycopene and phytofluene accumulation, reduced insulin-like growth factor 1 levels and cholesterol levels, but elevated liver lipids and cholesterol compared with wild-type mice. The diets did not modulate these genotypic perturbations, but lycopene and tomato powder significantly decreased serum insulin-like growth factor 1. Tomato powder also increased hepatic peroxisome proliferator-activated receptor expression, independent of genotype. These data point to the pleiotropic actions of CMO-I and CMO-II supporting a strong role of these proteins in regulating tissue carotenoid accumulation and the lipid metabolic phenotype as well as tomato carotenoid-independent regulation of lipid metabolism.

Increased serum sclerostin and decreased serum IGF-1 are associated with vertebral fractures among postmenopausal women with type-2 diabetes

Insulin-like growth factor 1 (IGF-1) is a determinant of bone mass and is inversely associated with vertebral fractures (VFs). Sclerostin regulates bone formation by inhibiting Wnt/β-catenin signaling. Currently, there is little information on circulating sclerostin levels among postmenopausal women with type-2 diabetes mellitus (T2DM) with VFs in relation to serum IGF-1 (s-IGF-1). We investigated the relationships between serum sclerostin, s-IGF-1, and VFs in postmenopausal women with T2DM. We assessed cross-sectionally 482 postmenopausal women with T2DM and 482 age-matched postmenopausal women without T2DM who were recruited at diabetic clinics and primary health care centers for inclusion in a bone health survey. The main outcome measures were serum sclerostin, s-IGF-1, bone mineral density (BMD), and bone turnover markers. Lateral X-rays of the thoracic and lumbar spine were taken to diagnose VFs. Serum sclerostin levels were increased, whereas s-IGF-1 levels were decreased when T2DM women were stratified by the number of VFs (P<0.0001). Multiple logistic regression analysis showed that serum sclerostin levels were positively associated with 1 VF (odds ratio [OR]=1.27, (95%CI:1.01–2.03), P=0.016), 2 VFs (OR=1.41, (95%CI:1.03–2.36), P=0.006), and ≥3 VFs (OR=1.54, (95%CI:1.12–2.44) P=0.005). s-IGF-1 levels were inversely associated with 1 VF (OR=0.58, (95%CI:0.39–0.88), P=0.041), 2 VFs (OR=0.42, (95%CI:0.21–0.90), P=0.012), and≥3 VFs (OR=0.19, (95%CI: 0.14–0.27), P<0.001). Increased serum sclerostin and decreased s-IGF-1 were associated with VFs among postmenopausal women with T2DM, suggesting that sclerostin and/or IGF-1 may be involved in increased bone fragility in T2DM and could be potential markers of VF severity.

Calorie restriction delays the progression of lesions to pancreatic cancer in the LSL-KrasG12D; Pdx-1/Cre mouse model of pancreatic cancer

Since pancreatic cancer is a lethal disease, developing prevention strategies is an important goal. We determined whether calorie restriction would prevent the development and delay progression of pancreatic intraepithelial neoplasms to pancreatic ductal adenocarcinoma (PDA) in LSL-KrasG12D/+; Pdx-1/Cre mice that develop all the precursor lesions that progress to PDA. Eight-week-old LSL-KrasG12D; Pdx-1/Cre mice were assigned to three groups: (1) ad libitum (AL) fed the AIN93M diet or (2) intermittently calorie restricted (ICR) a modified AIN93M at 50% of AL intake followed by one week intervals at 100% of AL intake, or (3) chronically calorie restricted (CCR) an AIN93M diet at 75% of AL intake. AL fed mice had a greater percentage of pancreatic ducts with PanIN-2 (13.6%) than did the ICR (1.0%) and CCR groups (1.6%), P < 0.0001. Calorie restriction (ICR [0%] and CCR [0.7%]) reduced the percentage of ducts with PanIN-3 lesions compared to the AL group (7.0%), P < 0.0001. The incidence of PanIN-2 or more lesions was significantly reduced in both ICR (27%; n = 16) and CCR (40%) mice (n = 15; P < 0.001) compared to AL (70%) fed mice (n = 11). The delayed progression of lesions in ICR and CCR mice was associated with reduced proliferation measured by proliferating cell nuclear antigen staining, reduced protein expression of Glut1, increased protein expression of Sirt1, increased serum adiponectin, and decreased serum leptin. CCR resulted in decreased phosphorylated mammalian target of rapamycin and decreased serum insulin-like growth factor-1. In summary, this is the first study to show in LSL-KrasG12D; Pdx-1/Cre mice that ICR and CCR delay the progression of lesions to PDA.

Pathogenesis of growth failure and partial reversal with gene therapy in murine and canine Glycogen Storage Disease type Ia

Glycogen Storage Disease type Ia (GSD-Ia) in humans frequently causes delayed bone maturation, decrease in final adult height, and decreased growth velocity. This study evaluates the pathogenesis of growth failure and the effect of gene therapy on growth in GSD-Ia affected dogs and mice. Here we found that homozygous G6pase (−/−) mice with GSD-Ia have normal growth hormone (GH) levels in response to hypoglycemia, decreased insulin-like growth factor (IGF) 1 levels, and attenuated weight gain following administration of GH. Expression of hepatic GH receptor and IGF 1 mRNAs and hepatic STAT5 (phospho Y694) protein levels are reduced prior to and after GH administration, indicating GH resistance. However, restoration of G6Pase expression in the liver by treatment with adeno-associated virus 8 pseudotyped vector expressing G6Pase (AAV2/8-G6Pase) corrected body weight, but failed to normalize plasma IGF 1 in G6pase (−/−) mice. Untreated G6pase (−/−) mice also demonstrated severe delay of growth plate ossification at 12days of age; those treated with AAV2/8-G6Pase at 14days of age demonstrated skeletal dysplasia and limb shortening when analyzed radiographically at 6months of age, in spite of apparent metabolic correction. Moreover, gene therapy with AAV2/9-G6Pase only partially corrected growth in GSD-Ia affected dogs as detected by weight and bone measurements and serum IGF 1 concentrations were persistently low in treated dogs. We also found that heterozygous GSD-Ia carrier dogs had decreased serum IGF 1, adult body weights and bone dimensions compared to wild-type littermates. In sum, these findings suggest that growth failure in GSD-Ia results, at least in part, from hepatic GH resistance. In addition, gene therapy improved growth in addition to promoting long-term survival in dogs and mice with GSD-Ia.

Serum Insulin-Like Growth Factor-1 Levels Predict Outcomes of Patients with Advanced Hepatocellular Carcinoma Receiving Antiangiogenic Therapy

Patients with liver cirrhosis or hepatocellular carcinoma (HCC) have decreased serum insulin-like growth factor (IGF)-1 levels. We evaluated whether IGF-1 levels were associated with the outcomes of patients with advanced HCC treated with systemic antiangiogenic therapy. The study was based on patients with advanced HCC who were enrolled in two clinical trials evaluating first-line combination antiangiogenic therapy. Serum samples were collected before treatment and four to six weeks after the start of treatment. The levels of IGF-1, IGF-2, and IGF-binding protein-3 (IGFBP3) were analyzed for their associations with treatment outcomes. A total of 83 patients were included in the study. Patients who had high (≥the median level) baseline IGF-1 levels had significantly higher disease control rate (DCR) than patients who had low (<the median level) levels (71% vs. 39%, P = 0.003). The levels of posttreatment IGF-1, and pre- or posttreatment IGF-2 and IGFBP3 were not associated with DCR. Patients with high baseline IGF-1 levels, compared with patients with low levels, had significantly longer progression-free survival (PFS; median, 4.3 vs. 1.9 months, P = 0.014) and overall survival (OS; median, 10.7 vs. 3.9 months, P = 0.009). The high baseline IGF-1 level remains an independent factor associated with favorable PFS and OS in multivariate analysis. High pretreatment IGF-1 levels were associated with better DCR, PFS, and OS of patients who received antiangiogenic therapy for advanced HCC. This finding warrants validation in large studies.

The Insulin-like Growth Factor-1 Binding Protein Acid-labile Subunit Alters Mesenchymal Stromal Cell Fate

Age-related osteoporosis is accompanied by an increase in marrow adiposity and a reduction in serum insulin-like growth factor-1 (IGF-1) and the binding proteins that stabilize IGF-1. To determine the relationship between these proteins and bone marrow adiposity, we evaluated the adipogenic potential of marrow-derived mesenchymal stromal cells (MSCs) from mice with decreased serum IGF-1 due to knockdown of IGF-1 production by the liver or knock-out of the binding proteins. We employed 10-16-week-old, liver-specific IGF-1-deficient, IGFBP-3 knock-out (BP3KO) and acid-labile subunit knock-out (ALSKO) mice. We found that expression of the late adipocyte differentiation marker peroxisome proliferator-activated receptor gamma was increased in marrow isolated from ALSKO mice. When induced with adipogenic media, MSC cultures from ALSKO mice revealed a significantly greater number of differentiated adipocytes compared with controls. MSCs from ALSKO mice also exhibited decreased alkaline-phosphatase positive colony size in cultures that were stimulated with osteoblast differentiation media. These osteoblast-like cells from ALSKO mice failed to induce osteoclastogenesis of control cells in co-culture assays, indicating that impairment of IGF-1 complex formation with ALS in bone marrow alters cell fate, leading to increased adipogenesis.