Elevated Insulin-like Growth Factor Research Articles

Characteristics and treatment outcomes of micromegaly - acromegaly with apparently normal basal GH: A retrospective study and literature review.

Objective. Micromegaly describes a subgroup of patients with clinically evident acromegaly and elevated insulin-like growth factor I (IGF-I) with apparently normal basal growth hormone (bGH) and often a glucose-suppressed growth hormone (GH) of <1 ng/mL at diagnosis. It is controversial whether this condition is a distinct clinical entity or a classic acromegaly in early stages. The aim of the present article was to characterize the prevalence, clinical and biochemical characteristics, and therapeutic outcomes of micromegaly. Methods. A retrospective study of patients with an acromegaly followed ≥1 year at a tertiary center from 1995 to 2019. Patients without IGF-I or GH measurements at diagnosis were excluded. At diagnosis, bGH was considered normal if <2 ng/mL. Results. From 74 patients with acromegaly, 6 (8.1%) had normal bGH levels. There was no difference in the gender distribution, median diagnostic delay, and follow-up time between patients with normal bGH and elevated bGH. Patients with normal bGH were significantly older at time of the first acromegalic manifestation and diagnosis they had significantly lower nadir post-glucose GH and IGF-I levels, and tended to have a higher prevalence of obesity than patients with the elevated bGH. The frequency of acromegalic symptoms, signs, and other comorbidities than obesity was similar between groups. Five patients (83.3%) with normal bGH presented microadenomas. Post-operative remission and outcomes at last visit were comparable between patients with or without normal bGH. Conclusions. Normal bGH acromegaly is relatively uncommon in our patients. These patients showed differentiating characteristics from the classical acromegaly with elevated bGH. Further studies are needed to extend the knowledge about its clinical behavior, therapeutic outcomes, morbidity, and mortality.

Dipeptidyl peptidase-4 inhibitors reduced long-term cardiovascular risk in diabetic patients after percutaneous coronary intervention via insulin-like growth factor-1 axis

Dipeptidyl-peptidase-4 inhibitors (DPP4i) have been the most used antidiabetic medications worldwide due to their good safety profiles and tolerability with a low risk of hypoglycemia, however, large cardiovascular outcome trials (CVOTs) have not shown any significant the prognostic superiority. On the contrary, since observational studies have suggested the effects of DPP4i are enhanced some populations, such as Asians and those who without overweight, their prognostic benefit is still under debate. The aim of this study was thus to assess the prognostic impact of DPP4i in patients with both diabetes and coronary artery disease (CAD) who underwent percutaneous coronary intervention (PCI) through the insulin-like growth factor-1 (IGF-1) axis, a substrate of DPP4. This single-center analysis involved consecutive Japanese diabetic patients who underwent PCI for the first time between 2008 and 2018 (n = 885). Primary and secondary endpoints were set as cardiovascular (CV) death and the composite of CV death, non-fatal myocardial infarction and ischemic stroke (3P-MACE). Serum levels of IGF-1 and its main binding protein (insulin-like growth factor binding protein-3: IGFBP-3) were measured. In consequences, unadjusted Kaplan–Meier analyses revealed reduced incidences of CV-death and 3P-MACE by DPP4i, which was particularly enhanced in patients who were not overweight (BMI ≤ 25). Multivariate Cox hazard analyses consistently indicated reduced risks of CV death by DPP4i at PCI (hazard ratio (HR) 0.39, 95% confidence interval (CI) 0.16–0.82, p = 0.01) and 3P-MACE (HR 0.47, 95% CI 0.25–0.84, p = 0.01), respectively. Moreover, elevated IGF-1 activity indicated by the IGF-1/IGFBP-3 ratio was associated with decreased risks of both endpoints and it was significantly higher in patients with DPP4i (p < 0.0001). In conclusion, the findings of the present study indicate beneficial effects of DPP4i to improve outcomes in Japanese diabetic patients following PCI, which might be mediated by DPP4–IGF-1 axis.

Pinusthunbergii bark extract rich in flavonoids promotes hair growth in dorsal skin by regulating inflammatory cytokines and increasing growth factors in mice.

Korean maritime pine bark (Pinus thunbergii) has been used as an alternative medicine due to its beneficial properties, including anti-inflammatory effects. To date, the anti-inflammatory and hair growth-promoting effects of Pinus densiflora bark extract have remained elusive. Therefore, in the present study, Pinus thunbergii bark was extracted with pure water (100°C) and the extract was examined to determine its polyphenol and flavonoid content. C57BL/6 mice were used to assess the effects of the extract to promote hair growth. The extract (1, 2 and 4%) was topically applied onto shaved dorsal skin and hair growth was observed for 17 days. A significant increase in hair growth was observed with 2 and 4% extract. Based on this finding, the optimal dose of the extract for effective hair growth promotion was determined to be 2%. The mechanisms of hair growth promotion were investigated via immunohistochemical analysis of changes in inflammatory cytokines and growth factors in the hair follicles following treatment with 2% extract. The treatment reduced the levels of TNF-α and IL-1β, which are pro-inflammatory cytokines, while it enhanced the levels of IL-4 and IL-13, which are anti-inflammatory cytokines, in the hair follicles. In addition, elevated insulin-like growth factor I and vascular epidermal growth factor were detected in hair follicles following treatment. Based on these findings, it was suggested that the extract of Pinus thunbergii bark may be utilized for hair loss prevention and/or hair growth promotion.

Insulin-like growth factor-1 directly affects cardiac cellular remodelling via distinct pathways

BackgroundStudies of insulin-like growth factor 1 (IGF-1) as a novel therapy for the treatment of cardiovascular diseases have proven promising. However, elevated IGF-1 levels have also been associated with poor patient outcomes in heart failure with reduced ejection fraction. IGF-1 therapy has additionally been shown to not be beneficial in the percutaneous coronary intervention setting. Although IGF-1 activation of the PI3K/Akt and ERK1/2 pathways have been demonstrated as cardioprotective, other cellular mechanisms have not been fully investigated.MethodsNeonatal rat cardiac myocytes (NCMs) and fibroblasts (NCFs) were isolated from 1 to 2-day old pups using enzymatic digestion. NCMs and NCFs were pre-treated with IGF binding protein 6, inhibitors for the PI3K/Akt Wortmannin, ERK1/2 U0126, Rho Associated Protein Kinase (ROCK) GSK576371, Apoptosis Signal-regulating Kinase-1 (ASK-1) G2261818A, and p38MAPK RWJ67657 pathways before stimulation with IGF-1 for 62 and 50 h, respectively. Cardiac myocyte hypertrophy and fibroblast collagen synthesis were determined by 3H-leucine and 3H-proline incorporation, respectively.ResultsIGF-1 dose-dependently stimulated NCM hypertrophy and NCF collagen synthesis.Treatment with IGFBP6 and the kinase inhibitors, Wortmannin, U0126, GSK576371, G2261818A and RWJ67657 significantly inhibited IGF-1 stimulated NCM hypertrophy and NCF collagen synthesis.ConclusionThis study is the first to demonstrate that IGF-1 treatment in NCMs and NCFs activates the ROCK, ASK-1 and p38MAPK pathways. Future research may be guided by consideration of the PI3K/Akt and ERK1/2 pathways potentially increasing collagen synthesis, and the utilisation of a biased agonist to reduce activation of the ROCK, ASK-1 and p38MAPK pathways to maximise cardioprotective benefit whilst mitigating risks.

A Rare Case of a Plurihormonal Pituitary Adenoma

Background: Pituitary adenomas are usually benign tumors that arise from adenophypophyseal cells and produce one or two types of hormones. Plurihormonal adenomas are a rare subtype that produce two or more hormones and represent less than 1% of all pituitary adenomas. Clinical Presentation: A 76-year-old female presented for evaluation of abnormal thyroid function test results. She was found to have an elevated free T4 of 1.92 ng/dL and total T4 of 14.4 ug/dL with an inappropriately normal TSH of 2.11 uIU/mL. Physical examination was significant for tachycardia, tremors, diaphoresis, coarse facial features, and enlarged hands. Further biochemical evaluation of her pituitary hormone levels demonstrated an elevated prolactin (PRL) of 237.2 ng/mL, elevated insulin-like growth factor 1 (IGF-1) of 787 ng/mL, normal morning ACTH of 47 pg/mL, normal morning cortisol of 17.0 ug/dL, an inappropriately suppressed FSH of <5.0 mIU/mL, an elevated alpha subunit of pituitary glycoprotein hormones (PGH) of 6.9 ng/mL, and an elevated free T4 of 3.5 ng/dL by equilibrium dialysis. She underwent an MRI of the pituitary and brain which demonstrated a pituitary adenoma measuring 1.2 x 1.3 x 1.8 cm with a portion herniating into the sella turcica with no mass effect of the optic chiasm. A formal visual field examination was normal. The patient underwent workup for Cushing’s Disease with a low dose overnight dexamethasone suppression test, resulting in an appropriate response with an 8 AM cortisol of <1.0 ug/dL. Glucose suppression test confirmed the diagnosis of acromegaly with growth hormone at 120 minutes of 19.90 ng/mL. Neurosurgery performed a trans-sphenoidal pituitary adenoma resection. Thyroid function tests on post-operative day 4 demonstrated a suppressed TSH of 0.01 uIU/mL and an elevated free T4 of 2.30 ng/dL. Histological evaluation revealed dual expression of transcription factors pituitary-specific positive transcription factor 1 (PIT1) and steroidogenic factor 1 (SF1) as well as PRL, GH, TSH and FSH expression. Immunostaining for LH and ACTH were negative. Post-operative IGF-1 and GH levels were 106 ng/mL and 0.51 ng/mL at 17 weeks, respectively. Post-operative TSH normalized to 0.82 uIU/mL, free T4 normalized to 1.04 ng/dL, and PRL normalized to 8.1 ng/mL at 12 weeks. The patient remained symptom free after successful surgical resection. Discussion: Our case demonstrates the clinical course of a unique patient with clinical and biochemical manifestations of thyroid dysfunction and acromegaly with a pituitary adenoma immunoreactive for GH, TSH, FSH, and PRL. The co-secretion of GH, TSH, PRL, and FSH as well as positivity for the alpha-subunit is extremely unusual. This case emphasizes the importance of considering pituitary abnormalities as a cause for abnormal thyroid function tests.

Reduced glucose-stimulated insulin secretion following a 1-wk IGF-1 infusion in late gestation fetal sheep is due to an intrinsic islet defect.

Insulin and insulin-like growth factor-1 (IGF-1) are fetal hormones critical to establishing normal fetal growth. Experimentally elevated IGF-1 concentrations during late gestation increase fetal weight but lower fetal plasma insulin concentrations. We therefore hypothesized that infusion of an IGF-1 analog for 1 wk into late gestation fetal sheep would attenuate fetal glucose-stimulated insulin secretion (GSIS) and insulin secretion in islets isolated from these fetuses. Late gestation fetal sheep received infusions with IGF-1 LR3 (IGF-1, n = 8), an analog of IGF-1 with low affinity for the IGF binding proteins and high affinity for the IGF-1 receptor, or vehicle control (CON, n = 9). Fetal GSIS was measured with a hyperglycemic clamp (IGF-1, n = 8; CON, n = 7). Fetal islets were isolated, and insulin secretion was assayed in static incubations (IGF-1, n = 8; CON, n = 7). Plasma insulin and glucose concentrations in IGF-1 fetuses were lower compared with CON (P = 0.0135 and P = 0.0012, respectively). During the GSIS study, IGF-1 fetuses had lower insulin secretion compared with CON (P = 0.0453). In vitro, glucose-stimulated insulin secretion remained lower in islets isolated from IGF-1 fetuses (P = 0.0447). In summary, IGF-1 LR3 infusion for 1 wk into fetal sheep lowers insulin concentrations and reduces fetal GSIS. Impaired insulin secretion persists in isolated fetal islets indicating an intrinsic islet defect in insulin release when exposed to IGF-1 LR3 infusion for 1 wk. We speculate this alteration in the insulin/IGF-1 axis contributes to the long-term reduction in β-cell function in neonates born with elevated IGF-1 concentrations following pregnancies complicated by diabetes or other conditions associated with fetal overgrowth.NEW & NOTEWORTHY After a 1-wk infusion of IGF-1 LR3, late gestation fetal sheep had lower plasma insulin and glucose concentrations, reduced fetal glucose-stimulated insulin secretion, and decreased fractional insulin secretion from isolated fetal islets without differences in pancreatic insulin content.

Status epilepticus and diabetes ketoacidosis: uncommon clinical presentations of acromegaly.

SummaryAcromegaly is a rare disease caused by hypersecretion of the growth hormone (GH). Most cases are caused by either pituitary microadenoma or macroadenoma. The GH producing tumors present with clinical manifestations of acromegaly due to excessive GH secretion or symptoms resulting from mass effects of the enlarging tumor. The physical changes are usually slow and, therefore, recognition of the disease is delayed. These adenomas are never malignant but can have significant morbidity and mortality. A subgroup of patients with acromegaly present with severe hyperglycemia resulting in diabetic ketoacidosis (DKA) which requires insulin. Rarely are pituitary tumors responsible for generalized convulsions except when they are too large. We hereby present two cases, the first is that of a 26-year-old female who presented with new onset status epilepticus, DKA with a 1-year history of diabetes mellitus (DM). On examination, she had clinical features of acromegaly. The second case is that of a 34-year-old female who presented with new onset status epilepticus, hyperglycemia with a history of recently diagnosed DM, and features of gigantism. In both cases, their diagnosis was confirmed by elevated serum GH and later by elevated insulin-like growth factor type 1 levels, and CT of the head demonstrating large pituitary macroadenoma. The importance of clinical history and examination, as well as investigations is vital in the recognition of acromegaly. The prognosis of acromegalic patients depends on early clinical recognition and tumor size reduction by either medical or surgical therapy.Learning pointsConditions such as status epilepticus and DKA may be clinical presentations in patients presenting with acromegaly.Seizures are rare in people with pituitary adenoma and typically occur when the tumor invades the suprasellar area due to mass effect on the brain.This article shows how best we were able to manage the acromegaly complications in a low resource setting.Hyperprolactinemia in acromegaly may be due to disruption of the normal dopaminergic inhibition of prolactin secretion due to mass effect of the macroadenoma, and around 25% of GH-secreting adenomas co-secrete prolactin.

Prkar1a haploinsufficiency ameliorates the growth hormone excess phenotype in Aip-deficient mice.

Mutations of the regulatory subunit (PRKAR1A) of the cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA), leading to activation of the PKA pathway, are the genetic cause of Carney complex which is frequently accompanied by somatotroph tumors. Aryl hydrocarbon receptor-interacting protein (AIP) mutations lead to somatotroph tumorigenesis in mice and humans. The mechanisms of AIP-dependent pituitary tumorigenesis are still under investigation and evidence points to a connection between the AIP and PKA pathways. In this study, we explore the combined effects of Aip and Prkar1a deficiency on mouse phenotype and, specifically, pituitary histopathology. Aip+/- mice were compared with double heterozygous Aip+/-, Prkar1a+/- mice. The phenotype (including histopathology and serological studies) was recorded at 3, 6, 9 and 12months of age. Detailed pituitary histological and immunohistochemical studies were performed at 12months. Twelve-month old Aip+/- mice demonstrated phenotypic and biochemical evidence of GH excess including significantly elevated insulin-like growth factor 1 levels, larger weight and body length, higher hemoglobin and cholesterol levels and a higher frequency of growth plate thickening in comparison to Aip+/, Prkar1a+/- mice. Pituitary histopathology did not uncover any pituitary adenomas or somatotroph hyperplasia in either group. These results demonstrate a slow progression from elevated GH release to the formation of overt somatotropinomas in Aip+/- mice; the acromegalic phenotype of these mice is surprisingly ameliorated in Aip+/-, Prkar1a+/- mice. This highlights the complexities of interaction between the AIP and PKA pathway. Specifically targeting GH secretion rather than somatotroph proliferation may be an advantage in the medical treatment of AIP-dependent human acromegaly.

Insulin-like growth factor-1 and site-specific cancers: A Mendelian randomization study.

Insulin‐like growth factor‐1 (IGF‐1) is involved in several processes relevant to carcinogenesis. We used 416 single‐nucleotide polymorphisms robustly associated with serum IGF‐1 levels to assess the potential causal associations between this hormone and site‐specific cancers through Mendelian randomization. Summary‐level genetic association estimates for prostate, breast, ovarian, and lung cancer were obtained from large‐scale consortia including individuals of European‐descent. Furthermore, we estimated genetic associations with 14 site‐specific cancers in European‐descent individuals in UK Biobank. Supplementary analyses were conducted for six site‐specific cancers using summary‐level data from the BioBank Japan Project. Genetically predicted serum IGF‐1 levels were associated with colorectal cancer. The odds ratio (OR) per standard deviation increase of IGF‐1 levels was 1.11 (95% confidence interval [CI] 1.01‐1.22; P = .03) in UK Biobank and 1.22 (95% CI 1.09‐1.36; P = 3.9 × 10−4) in the BioBank Japan Project. For prostate cancer, the corresponding OR was 1.10 (95% CI 1.01‐1.21; P = .04) in UK Biobank, 1.03 (95% CI 0.97‐1.09; P = .41) in the prostate cancer consortium, and 1.08 (95% CI 0.95‐1.22; P = .24) in the BioBank Japan Project. For breast cancer, the corresponding OR was 0.99 (95% CI 0.92‐1.07; P = .85) in UK Biobank and 1.08 (95% CI 1.02‐1.13; P = 4.4 × 10−3) in the Breast Cancer Association Consortium. There was no statistically significant association between genetically predicted IGF‐1 levels and 14 other cancers. This study found some support for a causal association between elevated serum IGF‐1 levels and increased risk of colorectal cancer. There was inconclusive or no evidence of a causal association of IGF‐1 levels with prostate, breast, and other cancers.

Acromegaly and a Giant Retroperitoneal Liposarcoma Producing IGF-1

Liposarcoma is the most common histotype of retroperitoneal sarcomas, representing up to 45% of all cases. We report a rare combination of acromegaly and liposarcoma in the same individual. Laboratory and imaging studies including an oral glucose tolerance test, measurements of growth hormone (GH) and insulin-like growth factor-1 (IGF-1), and a computed tomography scan were performed. The patient was a 60-year-old male with a history of acromegaly diagnosed on the basis of elevated IGF-1 at 1,373 ng/mL (age-appropriate reference range is 87 to 225 ng/mL) and macroadenoma treated with transsphenoidal surgery. He presented 8 years later with a history of abdominal distension and weight loss. Physical examination was notable for a right-sided abdominal mass that was tense and non-fluctuant. Two years earlier, he had a post oral glucose tolerance test GH level <0.25 ng/mL and IGF-1 level of 256 ng/mL (age-appropriate reference range is 55 to 206 ng/mL). Pituitary magnetic resonance imaging reported a 3.7 × 2.0-mm left-sided parasagittal lesion. Computed tomography scan showed a 25.0 × 22.0 × 32.3-cm heterogeneous giant mass in the right abdomen corresponding to a liposarcoma causing displacement of kidney, liver, and bowel loops. The patient was treated with a complete en bloc resection of the liposarcoma with the right kidney (45 × 33 × 17 cm) and tumor (9,400 g). Immunohistochemical examination revealed positive IGF-1 and GH staining. The patient suffered postoperative gastrointestinal bleeding that resulted in hemorrhagic shock and died on the 29th postoperative day after a cardiorespiratory arrest. Acromegalic patients are at increased risk of developing various types of neoplasms. This is the first documented coexistence of liposarcoma and history of acromegaly.

SAT-257 Coexisting Craniopharyngioma and Acromegaly

Background: Craniopharyngioma has a bimodal age distribution with adults having more pronounced hormone deficiencies.1 Studies indicate hormone deficiencies in >80% of cases, most commonly growth hormone (GH) deficiency.2 Comparatively, acromegaly is due to excess GH primarily from a pituitary adenoma.3 Coexistence of a craniopharyngioma and a secretory pituitary adenoma is extremely rare,4 and here we present a case with both. Clinical Case: A 59-year-old woman presented with a two-month history of acutely worsening headache and a week of vision change. A computerized tomography (CT) head scan revealed a 2.2 cm partially solid and cystic sellar mass compressing the optic chiasm. The patient underwent emergent resection. Pre-operational biochemical studies demonstrated normal hypothalamus-pituitary axes except a mildly elevated insulin-like growth factor 1 (IGF-1). Pathology revealed an adamantinomatous craniopharyngioma. Although decreased, IGF-1 remained elevated post-operatively and magnetic resonance imaging (MRI) showed a small non-enhancing area within the pituitary. The patient recalled a gradual increase in shoe and glove size, coarser facial features, weight gain, bilateral carpal tunnel, and mild fluid retention in ankles over the past few years. The GH remained unsuppressed in a glucose suppression test. Conclusion: We present a case of pathology proven craniopharyngioma and concurrent GH excess. The patient presented with a sellar mass with mass effect prompting emergent pituitary resection. Although findings of combined solid and cystic with calcification on MRI point to craniopharyngioma diagnosis,1 it is difficult to discern a concurrent GH-secreting tumor as it tends to be smaller and hypointense on T2-weighted MRI.5 While most craniopharyngioma patients demonstrate hormone deficiency, comprehensive hormonal evaluation and close follow-up are warranted, as in rare cases, patients can have co-existing secretory pituitary adenoma and craniopharyngioma. Early diagnosis and intervention can help prevent detrimental complications related to excess growth hormone.

Associations between circulating bone-derived hormones osteocalcin, lipocalin 2, and glucose metabolism in patients with acromegaly

Objective The aim of this study was to examine the change of serum bone-derived hormones osteocalcin and lipocalin 2 (LCN2) level in patients with active acromegaly, and to further investigate the potential role of osteocalcin and LCN2 in glucose metabolism. Methods Fifty consecutive patients diagnosed as acromegaly in Nanjing Drum Tower Hospital from December 2016 to August 2018 were recruited. Of those, 41 patients after operations with complete follow-up data were also included. 30 sex, age, and body mass index matched healthy persons as normal controls. Serum osteocalcin and LCN2 levels were compared between controls and patients with acromegaly, as well as at pre- and post- operation periods. Univariate and multivariate linear regression analyses were used to investigate the correlation between bone-derived hormones and glucose metabolism indexes and to determine the independent associations between variables. Results Compared with normal controls, serum osteocalcin increased [(55.45±34.02 vs 19.46±6.69)ng/ml, P 0.05). After operation, with the decrease of serum growth hormone (GH) and insulin-like growth factor 1 (IGF-1), serum osteocalcin level decreased [24.79(18.39, 32.59) vs 43.51(26.73, 65.66)ng/ml, P<0.01] and LCN2 level increased [(45.15±15.33 vs 37.03±9.73)ng/ml, P<0.05] significantly compare to pre-operation levels. In a multivariate linear stepwise regression analysis, lean mass was shown to be the only positive predictor for LCN2 (β=0.44, P=0.015) and elevated serum IGF-1 was a positive predictor for osteocalcin (β=0.512, P<0.01). In the multivariate models, low LCN2 (β=-0.398, P=0.017) and elevated serum osteocalcin (β=0.553, P=0.001) were predictors for AUCINS, osteocalcin was a positive predictor of HOMA- β (β=0.519, P=0.004). GH (β=0.294, P=0.029) and IGF-1(β = 0.428, P=0.002) were all identified as positive predictors of HOMA-IR during multivariate testing in acromegaly patients. Conclusions Acromegaly patients had increased osteocalcin and decreased LCN2 serum levels, and corresponding alteration was detected with the correction of biochemical abnormalities. Serum osteocalcin and LCN2 were predictors of β-cell function in acromegaly patients. This study adds new evidence for the role of bone in regulating glucose metabolism in acromegaly. Key words: Acromegaly; Osteocalcin; Lipocalin 2; Glucose metabolism

Role of insulin-like growth factor 1 in pathogenesis of acne vulgaris: relation to acne severity and body mass index

&lt;div class="Section1"&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Background:&lt;/strong&gt; Acne vulgaris is a multifactorial skin disease. A potential role for insulin-like growth factor-1 (IGF-1) has been suggested in the pathogenesis of acne. Several studies have shown that elevated levels of serum IGF-1 correlate with overproduction of sebum and acne. Objective: Measurement of the serum level of IGF-1 in acne patients in comparison to normal controls and evaluating the relationship of these levels to severity of acne and body mass index (BMI), in order to investigate the role of this factor in the pathogenesis of acne.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Methods:&lt;/strong&gt; Fifty-four patients with acne vulagaris and 42 healthy controls were included. History taking, dermatological examination, clinical assessments of acne severity, calculation of BMI were performed for patients. Blood samples were collected from all participants for estimation of serum IGF-1 level using enzyme linked immunosorbant assay.&lt;strong&gt;&lt;/strong&gt;&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Results:&lt;/strong&gt; There was a significantly higher serum IGF-1 level in acne patients (p&amp;lt;0.05) than controls. Authors didn’t find a relation of significance between elevated serum IGF-1 level and degree of acne severity and BMI (p&amp;gt;0.05). There was a significant positive correlation between serum IGF-1 level and age of the patients.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Conclusions:&lt;/strong&gt; There is a significantly higher serum IGF-1 in acne patients than controls not related to acne severity and BMI. That is adding to the scientific evidence of IGF-1 role in pathogenesis of acne vulgaris.&lt;/p&gt;&lt;/div&gt;

Platelet-Rich Plasma Therapy Enhances the Beneficial Effect of Bone Marrow Stem Cell Transplant on Endometrial Regeneration.

This study aimed to investigate the potential effect of platelet-rich plasma (PRP) therapy on treatment using bone marrow stem cell (BMSC) transplant for uterine horn damage, and to reveal the potential underlying molecular mechanism. Uterine horn damage was established in a rat model, which can be repaired by transplant using BMSCs receiving control or PRP treatment. Immunohistochemistry was conducted to evaluate thickness and expression of α-SMA and vWF in the regenerated endometrium tissues. mRNA and proteins of insulin-like growth factor-1 (IGF-1) and interleukin-10 (IL-10) were measured both in the regenerated endometrium tissues and in cultured BMSCs to evaluate the effect of PRP treatment on their expression. Enzyme-linked immunosorbent assay was employed to measure the secretory levels of IL-10 in cultured BMSCs. Multi-differentiation assays were performed to address the effect of PRP treatment on tri-lineage potential of cultured BMSCs. Chromatin immunoprecipitation and luciferase reporter assays were applied to analyze NF-κB subunit p50 binding on IL-10 promoter and the resulted regulatory effect. PRP treatment significantly improved the efficacy of BMSC transplant in repairing uterine horn damage of rats, and elevated IGF-1 and IL-10 expression in regenerated endometrium tissues and cultured BMSCs, as well as enhanced tri-lineage differentiation potential of BMSCs. On the other hand, p50 inhibition and silencing suppressed the PRP-induced expression and secretion of IL-10 without affecting IGF-1 in the BMSCs. Furthermore, p50 was able to directly bind to IL-10 promoter to promote its expression. Data in the current study propose a working model, where PRP therapy improves endometrial regeneration of uterine horn damage in rats after BMSC transplant therapy, likely mediated through the NF-κB signaling pathway subunit p50 to directly induce the expression and production of IL-10.

L-Glutamine Increases IGF-1 Liver Expression to Prevent Bone Loss in Sickle Mice

BACKGROUND: Chronic red blood cell (RBC) hemolysis that accompanies sickle cell disease (SCD) is associated with elevated iron storage in tissues, in particular the liver (Nguyen et al. 2014). Iron storage within the liver leads to oxidative stress and fibrosis, reducing circulating antioxidants (vitamin D &amp; hemopexin) and essential hormones, namely insulin-like growth factor-1 (IGF-1). We have previously shown that SCD mice progressively develop a pronounced osteopenia, although the particular drivers of this are unknown (Green et al. 2015). Outside studies suggest this is largely due to the significant decrease of IGF-1 expression, which is vital for bone growth and development (Xiao et al. 2016). FDA approval of L-glutamine (GLN) is said to reduce the acute complications of SCD by increasing antioxidant capacity of RBCs, however opposing research has led to uncertainty about the proposed therapeutic mechanism (Quinn 2018). GLN is utilized ubiquitously as a precursor for antioxidant synthesis to combat oxidative stress; therefore, the benefit experienced by sickle patients may be explained by means outside of RBC usage. Under normal conditions the liver is one of the primary sources of GLN for the body. However, the liver becomes a major site of GLN consumption during disease states to maintain homeostatic activity and reduce hepatic damage from oxidative stress (Cruzat et al. 2018). We hypothesize that GLN therapy prevents sickle bone loss by increasing liver expression of IGF-1. METHODS: Male Townes sickle mice (SS, Jackson) and littermate controls (AA) were evaluated at 4, 8, 12 and 16 wks old. (n=10/group, IACUC approved). Half the animals received GLN in drinking water (0.7% w/v) from weaning at 4 wks old until sacrifice. Changes in femoral cortical and trabecular bone were assessed by µCT. Livers were weighed, as hepatomegaly provides a clinical index for iron storage and cirrhosis in SCD. In addition, plasma concentrations of liver derived IGF-1, the antioxidant hemopexin (HPX), and gamma-glutamyl transferase (GGT) activity were measured to determine therapeutic efficacy. RESULTS: At 4wks there was no difference in bone, but SS livers were 20% larger than AA although liver plasma markers did not significantly differ. GLN therapy was effective at 8 wks, preventing cortical bone thinning in SS mice and reducing hepatomegaly by 12%; which remained consistent at all ages. IGF-1 plasma concentrations reflected this reduction in liver size with ~2 fold increase. HPX and GGT levels were similar to controls within treatment group, but were significantly reduced in untreated SS mice. At 12 wks, GLN effects split into two groups: (i) elevated IGF-1 (GLN+, like AA) or (ii) reduced IGF-1 (GLN-) consistent with loss of GLN effect in these mice. At 12 wks, cortical and trabecular bone in GLN+ mice group were similar to AA, while bone of GLN- mice were comparable to untreated SS mice. Protective effect of GLN on cortical bone remained by 16 wks, but was lost in trabecular bone, even in GLN+ mice. HPX concentrations followed a similar pattern, however GGT activity of GLN+ group reduced to GLN- rates. DISCUSSION: Our studies reveal that GLN therapy increases the expression of IGF-1 and prevents the osteopenia that develops in adolescence in SCD. However, the protective effects of GLN on trabecular bone in SS mice appears to be lost with skeletal maturity. GLN therapy increases the amount of HPX available to prevent iron absorption into the tissue; however sickle RBC hemolysis still occurs during GLN therapy, thereby delaying oxidative stress derived hepatic damage as suggested by GGT at 16 wks. Why cortical and trabecular bone respond differently to GLN in SCD at maturity is not yet clear. Previous studies have shown that systemic liver derived IGF-1 preferentially affects cortical bone growth in normal mice, while locally produced IGF-1 is responsible for trabecular. In a similar manner to the liver, we speculate that iron accumulate within sickle bone may alter local bone cell expression of IGF-1. Disclosures No relevant conflicts of interest to declare.

Mixed gangliocytoma-pituitary adenoma containing GH and GHRH co-secreting adenoma cells.

SummaryA 67-year-old woman with a past history of type 2 diabetes mellitus presented with worsening glycemic control. She had some acromegaly symptoms and magnetic resonance imaging demonstrated a pituitary tumor. Endocrinological examination found the resting growth hormone (GH) level within the normal range, but elevated insulin-like growth factor 1 level. A 75 g oral glucose tolerance test showed inadequate suppression of nadir GH levels. Acromegaly due to GH-secreting pituitary tumor was diagnosed. The patient underwent endoscopic transsphenoidal surgery resulting in gross total removal of the tumor and recovered well postoperatively. Histological examination of the tumor showed coexistence of relatively large gangliocytoma cells and pituitary adenoma cells, suggesting mixed gangliocytoma-pituitary adenoma. In addition, colocalization of GH and GH-releasing hormone (GHRH) in pituitary adenoma cells was revealed, so the adenomatous components were more likely to produce GHRH in our mixed gangliocytoma-pituitary adenoma case. Mixed gangliocytoma-pituitary adenoma is very rare, and the present unique case demonstrated only the adenomatous components associated with GHRH production.Learning points:Sellar gangliocytoma coexisting with pituitary adenoma is recognized as a mixed gangliocytoma-pituitary adenoma and is very rare.A proposed developmental mechanism of growth hormone (GH)-secreting mixed gangliocytoma-pituitary adenoma involves GH-releasing hormone (GHRH) produced by the gangliocytic components promoting the growth of tumor including GH-secreting adenomatous components.Since our present case indicated that the adenomatous components of mixed gangliocytoma-pituitary adenoma could secrete both GH and GHRH simultaneously, progression of GH-secreting mixed gangliocytoma and pituitary adenoma may involve exposure to spontaneously produced GHRH due to the adenomatous components.

Type 2 diabetes mellitus: a marker or a risk factor for pancreatic cancer?

Introduction. Pancreatic cancer (PC) is characterized by asymptomatic, aggressive course, high mortality and low patients survival. Patients with diabetes mellitus (DM) have an increased risk of PC, but there are two views of diabetes: as a risk factor or as a PC marker. The aim of the study was to investigate the role of pathogenetic factors of type 2 diabetes in the de­­velopment of PC. Materials and methods. The study included 42 participants that were divided into groups: I — healthy (control group) (n = 10), II — patients with type 2 diabetes mellitus (n = 13), III — non-diabetic patients with PC (n = 11), IV — patients with a combination of PC and type 2 diabetes (n = 8). DM compensation was determined by the level of glycosylated haemoglobin (HbA1c) and ion-exchange chromatography. The levels of insulin and insulin-like growth factor-1 (IGF-1) were determined by immune-enzymatic methods. Results and discussion. Significant hyperinsuline­mia was revealed only in patients of group II with type 2 diabetes compared with the control group (P = 0.0001), group III (P = 0.0002) and group IV (P = 0.04). Increased level of IGF-1 compared to the control group was detected in patients of group II with type 2 DM (P = 0.04) and in patients of group III with PC (P = 0.004). PC was diagnosed in non-obese patients of group IV with an average duration of diabetes up to 3 years. In patients of groups II and IV, the level of HbA1c was determined 7.68 % and 8.20 %, respectively and did not differ significantly between the groups (P > 0.05). Conclusions. In the examined patients with pan­creatic cancer that occurred on the background of type 2 diabetes mellitus, obesity, hyperinsulinemia and elevated IGF-1 levels were not revealed, which leads us to suggestion that they have secondary diabetes (T3cDM). Type 2 diabetes, first detected in patients without obesity and without hyperinsulinemia, should be differentiated from T3cDM. Patients with newly diagnosed type 2 diabetes are advised to screen for pancreatic cancer, since diabetes can be both a marker and a risk factor of cancer of this localization.

Non-islet Cell Hypoglycemia: Case Series and Review of the Literature

Non-islet cell hypoglycemia (NICH) is hypoglycemia due to the overproduction of insulin-like growth factor-2 (IGF-2) and its precursors which can activate the insulin receptor. Typically, large mesenchymal and epithelial tumors can cause NICH. Diagnosis is confirmed by finding an elevated IGF-2/IGF-1 ratio. The mainstay of treatment is surgical excision. Glucocorticoids may be used in cases where surgery is not possible. We present two cases of NICH with different outcomes. A 33-year-old male patient admitted with altered mental. He was found walking naked outside his house. Laboratory assessment revealed severe hypoglycemia. Further evaluation showed low levels of insulin, C-peptide, and beta-hydroxybutyrate along with an elevated IGF-2/IGF-1 ratio confirming the diagnosis of NICH. Computed tomography (CT) of the abdomen showed a massive tumor of the liver consistent with hepatocellular carcinoma. Since the patient refused surgery, he was started on prednisone however the hypoglycemia persisted. A 54-year-old female patient with a history of type 2 diabetes mellitus (DM) admitted with recent onset hypoglycemia. Despite stopping her insulin, she continued to have hypoglycemia necessitating the administration of high concentrations of intravenous dextrose. Further evaluation showed low levels of insulin, C-peptide, and beta-hydroxybutyrate along with an elevated IGF-2/IGF-1 ratio consistent with the diagnosis of NICH. CT abdomen showed a 24 cm tumor near the uterus. The pathology was consistent with a gastrointestinal stromal tumor (GIST). After surgical excision of the tumor, the hypoglycemia resolved.

Relationship between serum levels of osteoproteins, inflammatory cytokines and coronary heart disease and disease severity

To explore the relationship between serum levels of osteoprotein (OPG), soluble nuclear factor-κB receptor activator ligand (sRANKL), inflammatory factors and coronary heart disease (CHD) and its severity. The patients who underwent coronary angiography (CAG) due to chest pain admitted to department of cardiology of Tianjin Chest Hospital from April 2017 to December 2018 were enrolled, and they were divided into CHD group and non-CHD group according to the CAG results. The gender, age, history of hypertension, smoking history, diabetes, the levels of cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), apolipoprotein AI (apoAI), apolipoprotein B (apoB), lipoprotein (a) [Lp (a)], MB isoenzyme of creatine kinase (CK-MB) and other clinical data of patients were collected. The serum levels of OPG, sRANKL, matrix metalloproteinase-9 (MMP-9), monocyte chemotactic protein-1 (MCP-1), insulin-like growth factor-1 (IGF-1) and interleukin-6 (IL-6) were determined by enzyme-linked immunosorbent assay (ELISA). According to the results of CAG, the patients with CHD were divided into single-, double-, triple-branch coronary artery lesion groups, and the relationship between the levels of serum OPG, sRANKL, inflammatory factors and the degree of coronary artery lesions was observed. Multivariate Logistic regression was used to analyze the risk factors of CHD, and receiver operating characteristic (ROC) curve was plotted to analyze the predictive value of main risk factors for CHD. A total of 472 patients were enrolled in the final analysis during the study period, including 264 patients in the CHD group, 208 patients in the non-CHD group, 79 patients in the CHD group with single-branch disease, 75 patients with double-branch disease, and 110 patients with three-branch disease. (1) Compared with the non-CHD group, the CHD group had more older male patients, as well as higher proportion of hypertension and diabetes, the levels of serum Lp (a) and CK-MB were significantly increased, and the levels of serum HDL-C and apoAI were significantly lowered. There was no statistically significant difference in serum TC, LDL-C, or apoB between the two groups. The levels of serum OPG, MMP-9, MCP-1, IGF-1 and IL-6 in the CHD group were significantly higher than those in the non-CHD group [OPG (μg/L): 1.79±0.50 vs. 1.50±0.30, MMP-9 (μg/L): 57.91 (33.50, 130.46) vs. 38.33 (29.43, 109.78), MCP-1 (μg/L): 298.30 (207.96, 537.16) vs. 252.73 (165.22, 476.01), IGF-1 (μg/L): 734.03±486.11 vs. 217.75±126.45, IL-6 (ng/L): 64.76±40.25 vs. 48.60±15.80, all P < 0.05], and the levels of serum sRANKL was significantly lower than that in the non-CHD group (ng/L: 344.31±122.14 vs. 378.74±109.27, P < 0.05). (2) The serum OPG level showed a slight upward tendency with the increase in the number of coronary artery lesions, and the sRANKL level showed a slight downward tendency [OPG (μg/L) in the single-, double-, triple-branch coronary artery lesion groups was 1.74±0.49, 1.76±0.50, 1.85±0.52, and sRANKL (ng/L) was 354.96±116.64, 340.05±124.24, 339.57±125.03, respectively) without statistically significant differences (all P > 0.05). The levels of IGF-1 and IL-6 were increased with the number of coronary artery lesions [IGF-1 (μg/L) in the single-, double- and triple-branch coronary artery lesions groups was 372.13±258.42, 676.06±350.29, 1 033.47±468.06, and IL-6 (ng/L) was 48.87±16.72, 65.36±18.84, 75.76±22.72, respectively], and the differences among different lesion groups were statistically significant (all P < 0.01). Correlation analysis showed that IGF-1 level was significantly positively correlated with the number of coronary artery lesions (r = 0.612, P < 0.01), while IL-6 was not correlated with the number of coronary artery lesions (r = 0.185, P > 0.05). (3) Multivariate Logistic regression analysis showed that elevated serum OPG and IGF-1 levels were risk factors for CHD [OPG: odds ratio (OR) = 1.995, 95% confidence interval (95%CI) = 1.936-2.067, P = 0.012; IGF-1: OR = 1.009, 95%CI = 1.004-1.015, P = 0.001]. (4) ROC curve analysis showed that the area under ROC curve (AUC) of OPG and IGF-1 was 0.716 and 0.867, respectively. When the cut-off value of OPG was 1.13 μg/L, the sensitivity was 81.7%, the specificity was 58.1%; when the cut-off value of sRANKL was 401.20 μg/L, the sensitivity was 69.7%, the specificity was 95.7%. CHD was associated with increased in OPG, related inflammatory cytokines including MMP-9, MCP-1, IGF-1 and IL-6, and decreased in sRANKL. The level of IGF-1 was positively correlated with the severity of CHD. The serum levels of OPG and IGF-1 were risk factors for CHD, which had good predictive value for CHD.

MON-314 Insulin-like Growth Factor 2 Drives Hepatocellular Carcinoma In Hepatocyte Srsf3 Ko Mice

Background: Hepatocellular Carcinoma (HCC) is the most common liver cancer and is the second highest cause of cancer-related death worldwide. Previously we demonstrated that hepatocyte-specific deletion of serine/arginine rich splicing factor 3 (SRSF3-HKO) caused spontaneous hepatocellular carcinoma in aging with very high tumor expression of insulin-like growth factor 2 (IGF2). Elevated IGF2 has been reported in human HCC and we have also shown loss of SRSF3 occurs in human HCC, so the SRSF3HKO mouse represents a useful model for human HCC. Whether the elevated IGF2 is involved in HCC development or growth remains to be determined however. Here, we aimed to test whether IGF2 drives tumor development in the SRSF3HKO mouse by creating a double hepatocyte deletion of SRSF3 and IGF2. Methods: We generated hepatocyte specific SRSF3-IGF2-DKO mice to assess the role of IGF2 in tumor growth in the SRSF3-HKO mice over 12 months. Proliferation, apoptosis, steatosis, fibrosis and tumor phenotype were assessed by immunohistochemistry and immunoblot. We measured IGF1, Insulin, IGF2 and growth hormone levels in plasma. In addition we measured gene expression of lipid storage, oxidation, transportation, and inflammation. Results: None of the SRSF3-IGF2-DKO mice developed tumors over 12 months while all SRSF3-HKO mice developed HCC. Histology of livers showed (1) nuclear morphology in the SRSF3-IGF2-DKO mice resembling that of the SRSF3-HKO mice, (2) reduced fibrosis as indicated by decreased collagen staining in SRSF3-IGF2-DKO mice livers at 6 and 12 month of age, (3) SRSF3-IGF2-DKO mice livers have greater steatosis than SRSF3-HKO, and (4) SRSF3-IGF2-DKO mice livers have lower inflammation than SRSF3-HKO. Gene expression by qRT-PCR suggested (1) higher expression of lipid synthesis and accumulation in SRSF3-IGF2-DKO livers, (2) lower levels of inflammation in SRSF3-IGF2-DKO livers. Immunohistochemistry showed more Ki67-positive staining for proliferation and also for apoptosis (TUNEL and caspase3) in SRSF3-HKO mice compared to WT and SRSF3-IGF2-DKO mice. ELISA data showed the elevated levels of IGF1 and insulin in plasma of SRSF3-IGF2-DKO.We also confirmed over expression of IGF2 in human early liver diseases as has been shown in HCC. We furthermore showed that H19 expression was high in both SRSF3 HKO and SRSF3-IGF2-DKO mice livers suggesting altered epigenetic imprinting of the IGF2-H19 locus. Conclusion: IGF2 over expression is essential for HCC formation in SRSF3HKO mice.