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1.
The Role of Iron in Benign and Malignant Hematopoiesis.
Sinha, S, Pereira-Reis, J, Guerra, A, Rivella, S, Duarte, D
Antioxidants & redox signaling. 2021;(6):415-432
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Abstract
Significance: Iron is an essential element required for sustaining a normal healthy life. However, an excess amount of iron in the bloodstream and tissue generates toxic hydroxyl radicals through Fenton reactions. Henceforth, a balance in iron concentration is extremely important to maintain cellular homeostasis in both normal hematopoiesis and erythropoiesis. Iron deficiency or iron overload can impact hematopoiesis and is associated with many hematological diseases. Recent Advances: The mechanisms of action of key iron regulators such as erythroferrone and the discovery of new drugs, such as ACE-536/luspatercept, are of potential interest to treat hematological disorders, such as β-thalassemia. New therapies targeting inflammation-induced ineffective erythropoiesis are also in progress. Furthermore, emerging evidences support differential interactions between iron and its cellular antioxidant responses of hematopoietic and neighboring stromal cells. Both iron and its systemic regulator, such as hepcidin, play a significant role in regulating erythropoiesis. Critical Issues: Significant pre-clinical studies are on the way and new drugs targeting iron metabolism have been recently approved or are undergoing clinical trials to treat pathological conditions with impaired erythropoiesis such as myelodysplastic syndromes or β-thalassemia. Future Directions: Future studies should explore how iron regulates hematopoiesis in both benign and malignant conditions. Antioxid. Redox Signal. 35, 415-432.
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ANGPTL8 in metabolic homeostasis: more friend than foe?
Guo, C, Wang, C, Deng, X, He, J, Yang, L, Yuan, G
Open biology. 2021;(9):210106
Abstract
ANGPTL8 is an important cytokine, which is significantly increased in type 2 diabetes mellitus (T2DM), obesity and metabolic syndrome. Many studies have shown that ANGPTL8 can be used as a bio-marker of these metabolic disorders related diseases, and the baseline ANGPTL8 level has also been found to be positively correlated with retinopathy and all-cause mortality in patients with T2DM. This may be related to the inhibition of lipoprotein lipase activity and the reduction of circulating triglyceride (TG) clearance by ANGPTL8. Consistently, inhibition of ANGPTL8 seems to prevent or improve atherosclerosis. However, it is puzzling that ANGPTL8 seems to have a directing function for TG uptake in peripheral tissues; that is, ANGPTL8 specifically enhances the reserve and buffering function of white adipose tissue, which may alleviate the ectopic lipid accumulation to a certain extent. Furthermore, ANGPTL8 can improve insulin sensitivity and inhibit hepatic glucose production. These contradictory results lead to different opinions on the role of ANGPTL8 in metabolic disorders. In this paper, the correlation between ANGPTL8 and metabolic diseases, the regulation of ANGPTL8 and the physiological role of ANGPTL8 in the process of glucose and lipid metabolism were summarized, and the physiological/pathological significance of ANGPTL8 in the process of metabolic disorder was discussed.
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Assessment of circulating betatrophin concentrations in lean glucose-tolerant women with polycystic ovary syndrome.
Erol, O, Özel, MK, Ellidağ, HY, Toptaş, T, Derbent, AU, Yılmaz, N
Journal of obstetrics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology. 2017;(5):633-638
Abstract
The aims of the current study were to investigate the betatrophin levels in lean glucose-tolerant women with polycystic ovary syndrome (PCOS), and to explore the relationships between these levels and antropometric, hormonal and metabolic parameters. The study population consisted of 50 lean (body mass index [BMI] < 25 kg/m2) women diagnosed with PCOS using the Rotterdam criteria, and 60 age- and BMI-matched healthy controls without any features of clinical or biochemical hyperandrogenism. Before recruitment, glucose tolerance was evaluated in all of the subjects using the 2-h 75 g oral glucose-tolerance test, and only those exhibiting normal glucose tolerance were enrolled. Serum betatrophin levels were significantly higher in women with PCOS (median 322.3; range 44.7-1989.3 ng/L) compared to the controls (median 199.9; range 6.2-1912.9 ng/L; p = .005). In the control group, no significant correlation was evident between betatrophin levels and clinical or biochemical parameters. In the PCOS group, betatrophin levels were positively correlated with prolactin levels (r = .286, p = .046) and negatively correlated with BMI (r = -.283, p = .049), waist/hip ratio (r = -.324, p = .023), and low-density lipoprotein cholesterol levels (r = -.385, p = .006). Impact statement What is already known on this subject: Several studies have suggested that primary alteration in beta-cell function is a pathophysiological feature of PCOS, and insulin resistance is the most significant predictor of beta-cell dysfunction independent of obesity. Betatrophin is a circulating protein that is primarily expressed in the liver in humans. Early experimental investigations demonstrated that overexpression of betatrophin significantly promoted pancreatic beta-cell proliferation, insulin production and improved glucose tolerance. Few studies have investigated the association between PCOS and betatrophin. However, in contrast to our study, the authors included overweight/obese patients and glucose tolerance was not evaluated before recruitment. What the results of this study add: Our results showed that serum betatrophin levels were significantly higher in lean glucose-tolerant PCOS women than in age- and BMI-matched healthy controls. What are the implications of these findings for clinical practice and/or further research: Elevated betatrophin levels in PCOS women, in the absence of obesity and glucose intolerance, may reflect a compensatory mechanism in order to counteract metabolic syndrome-related risk factors.
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ANGPTL8 (betatrophin) role in diabetes and metabolic diseases.
Abu-Farha, M, Abubaker, J, Tuomilehto, J
Diabetes/metabolism research and reviews. 2017;(8)
Abstract
Diabetes is a major disease worldwide that is reaching epidemic levels. Its increased prevalence as well as its association with a high number of complications such as cardiovascular diseases, nephropathy, and retinopathy makes it an important disease for investigation. ANGPTL8 is a recently identified hormone that has been associated with two functionally important processes in the development of type 2 diabetes, insulin resistance as well as lipid metabolism. Initial work has shown that ANGPTL8 was expressed in liver, white adipose, and brown adipose tissues. ANGPTL8 regulates the activity of lipoprotein lipase, which is a key enzyme in lipoprotein lipolysis pathway through its direct interaction with ANGPTL3. It has been also reported that it regulates the replication of β-cells in response to insulin resistance. As a result, many recent studies have focused on the association of ANGPTL8 with diabetes and obesity as well as its association with various metabolic markers in order to better understand its physiological role in glucose homeostasis and lipid metabolism. In this review, we will highlight some of the key clinical findings, mainly from human studies, that investigated the role of ANGPTL8 in metabolic diseases such as diabetes, obesity, and the metabolic syndrome.
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Renal function is independently associated with circulating betatrophin.
Maurer, L, Schwarz, F, Fischer-Rosinsky, A, Schlueter, N, Brachs, S, Möhlig, M, Pfeiffer, A, Mai, K, Spranger, J, Bobbert, T
PloS one. 2017;(3):e0173197
Abstract
OBJECTIVE Betatrophin has been identified as a marker linking liver with beta cell function and lipid metabolism in murine models. Until now, the regulation of circulating betatrophin in humans is not entirely clear. We here analyzed the relation of betatrophin levels to phenotypes of the metabolic syndrome and speculated that renal function might influence circulating betatrophin levels and explain age-dependent changes of betatrophin. SUBJECTS We analyzed blood samples from 535 individuals participating in the Metabolic Syndrome Berlin Potsdam study. RESULTS In a crude analysis we found a positive correlation between betatrophin levels and HbA1c (r = 0.24; p < 0.001), fasting glucose (r = 0.20; p < 0.001) and triglycerides (r = 0.12; p = 0.007). Furthermore betatrophin was positively correlated with age (r = 0.47; p <0.001), systolic blood pressure (r = 0.17; p < 0.001), intima media thickness (r = 0.26; p < 0.001) and negatively correlated with CKD-EPI eGFR (r = -0.33; p < 0.001) as an estimate of renal function. Notably, eGFR remained highly associated with betatrophin after adjustment for age, waist circumference, gender, HbA1c and lipid parameters in a multivariate linear regression model (β = -0.197, p< 0.001). CONCLUSIONS Our data suggest that circulating levels of betatrophin depend on age, gender, waist circumference, total/HDL cholesterol ratio and renal function. Especially the association to eGFR highlights the importance for future studies to address renal function as possible influence on betatrophin regulation and consider eGFR as potential confounder when analyzing the role of betatrophin in humans.
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Plasma ghrelin levels after two high-carbohydrate meals producing different insulin responses in patients with metabolic syndrome.
Heinonen, MV, Karhunen, LJ, Chabot, ED, Toppinen, LK, Juntunen, KS, Laaksonen, DE, Siloaho, M, Liukkonen, KH, Herzig, KH, Niskanen, LK, et al
Regulatory peptides. 2007;(2-3):118-25
Abstract
Ghrelin is an orexigenic peptide produced in the stomach and its plasma levels are decreased acutely in response to ingested nutrients. To further clarify the role of insulin on ghrelin secretion, the present study was designed to investigate whether circulating ghrelin is affected differently by two mixtures of whole-grain breads known to produce low or high insulin responses in obese non-diabetic subjects with metabolic syndrome. After an overnight fast eight obese subjects with the metabolic syndrome (3 men and 5 women; BMI 33.7+/-0.7 kg/m(2); age 55.6+/-1.8 y) received two different meals consisting of whole-grain rye or wheat breads. The comparison group (3 men and 5 women; BMI 22.5+/-0.5 kg/m(2); age 26.0+/-0.9 y) received a wheat bread meal. Blood samples were collected postprandially at time intervals for 2 h. Feelings of hunger and satiety were analyzed using the visual analogue scales. Ghrelin concentrations decreased after bread meals in lean individuals, but not in obese individuals with the metabolic syndrome. Despite the difference in plasma insulin response, there was no difference in plasma ghrelin or feelings of hunger and satiety in patients with metabolic syndrome. After both rye and wheat bread meals, the decrease in ghrelin concentrations seen in normal-weight individuals after wheat bread meal was absent in subjects with metabolic syndrome. Despite the different plasma insulin response in obese patients, ghrelin levels did not change in response to either type of bread meals. In addition, ghrelin levels did not correlate with insulin, glucose, HOMA1-IR and satiety and hunger ratings in either study groups. This indicates that regulation of ghrelin might be altered in obese patients with metabolic syndrome independently of insulin.
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Mechanisms of disease: Cytokine and adipokine signaling in uremic cachexia.
Mak, RH, Cheung, W, Cone, RD, Marks, DL
Nature clinical practice. Nephrology. 2006;(9):527-34
Abstract
Clinical wasting is an important risk factor for mortality in uremic patients and is reported to have a prevalence of 30-60%. 'Malnutrition' is often inappropriately used to describe a group of nutritional abnormalities in uremic patients, which are characterized by anorexia, increased basal metabolic rate, loss of lean body mass, and declining levels of serum proteins. This syndrome--more accurately described as 'cachexia'--manifests as growth failure in children with uremia. Acidosis and inflammation are important causes of uremic cachexia but the underlying molecular mechanism is not well understood. Concentrations of circulating cytokines, such as leptin, tumor necrosis factor-alpha, interleukin-1, and interleukin-6, are elevated in patients with end-stage renal disease and correlate with the degree of cachexia in these individuals. Other energy-modulating hormones such as ghrelin, and adipokines such as adiponectin and resistin, are also perturbed in uremia and could contribute to nutritional abnormalities. We recently showed that elevated levels of circulating cytokines might be an important contributor to uremia-associated cachexia via signaling through the central melanocortin system. Small-molecule melanocortin antagonists, which are biologically active when administered orally or intraperitoneally, are now available and have been used successfully to ameliorate experimental cachexia. These findings could form the basis of a novel therapeutic strategy for uremic cachexia.
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Ghrelin improves endothelial function in patients with metabolic syndrome.
Tesauro, M, Schinzari, F, Iantorno, M, Rizza, S, Melina, D, Lauro, D, Cardillo, C
Circulation. 2005;(19):2986-92
Abstract
BACKGROUND Metabolic syndrome importantly accelerates the atherosclerotic process, the earliest event of which is endothelial dysfunction. Ghrelin, a gastric peptide with cardiovascular actions, has been shown to inhibit proatherogenic changes in experimental models. This study therefore investigated whether ghrelin administration might beneficially affect endothelial function in metabolic syndrome. METHODS AND RESULTS Endothelium-dependent and -independent vasodilator responses to intra-arterial infusion of increasing doses of acetylcholine and sodium nitroprusside (SNP), respectively, were assessed by strain-gauge plethysmography before and after local administration of human ghrelin (200 microg/min). During saline, the vasodilator response to acetylcholine was significantly blunted (P=0.008) in patients with metabolic syndrome (n=12, 5 female) compared with controls (n=12, 7 female), whereas the vasodilator response to SNP was not different between groups (P=0.68). In patients with metabolic syndrome, basal plasma ghrelin was significantly lower than in controls (P=0.02). In these patients, ghrelin infusion markedly increased intravascular concentrations of the peptide (P<0.001) and resulted in a potentiation of the vasodilator response to acetylcholine (P=0.001 versus saline) but not to SNP (P=0.22). This effect was likely related to enhanced nitric oxide bioavailability because, in a group of patients with metabolic syndrome (n=6, 2 female), ghrelin had no effect on the vasodilator response to acetylcholine (P=0.78 versus saline) after nitric oxide inhibition by NG-monomethyl-L-arginine. CONCLUSIONS These findings indicate that ghrelin reverses endothelial dysfunction in patients with metabolic syndrome by increasing nitric oxide bioactivity, thereby suggesting that decreased circulating levels of the peptide, such as those found in these patients, might play a role in the pathobiology of atherosclerosis.
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Correlation of serum ghrelin levels with body mass index and carbohydrate metabolism in patients treated with atypical antipsychotics.
Palik, E, Birkás, KD, Faludi, G, Karádi, I, Cseh, K
Diabetes research and clinical practice. 2005;:S60-4
Abstract
The prevalence of diabetes mellitus and metabolic syndrome is higher in patients with schizophrenia than in the normal population. Atypical antipsychotic drugs are used in psychiatry since the beginning of 1990. These drugs differ from the "typical" antipsychotics used previously, as they have less extrapyramidal side effects, and because of this they are tolerated better, but are associated with weight-gain and disturbances in carbohydrate metabolism. Ghrelin is an orexigen hormone partaking in body weight regulation. It is produced in the enteroendocrine P/D1 cells of the gastric mucosa and secreted to the circulation. The aim of our study was to determine ghrelin levels of atypical antipsychotic-treated patients in relationship with their body mass index (BMI) and carbohydrate metabolism. We measured the fasting serum ghrelin levels in 56 patients (male/female: 16/40, age mean+/-S.D.: 50.6+/-5.6 years) treated with atypical antipsychotics (clozapine, olanzapine, risperidon and quetiapine), and in 75 healthy control subjects, age and gender matched (RIA Linco, USA) in relationship with their BMI and their fasting and 75 g OGTT 120 min blood glucose values. The serum ghrelin levels of the patient group were notably higher (1333+/-659 pg/ml) than in the control group (368+/-103, p<0.0001; Mann-Whitney). We found no difference among the four antipsychotics in weight-gain, diabetes prevalence and the serum ghrelin levels. The BMI of the patient group was significantly higher (29.3+/-7.2 kg/m2 versus 24.3+/-3.7 kg/m2, p<0.0001; Mann-Whitney); 32% of them had blood glucose abnormality (18/56). There was no difference between the ghrelin levels in diabetic and non-diabetic patients. We found a significant negative linear correlation between the serum ghrelin and BMI (r=-0.35, p=0.0078; Spearman), the ghrelin and fasting blood glucose (r=-0.32, p=0.015) and OGTT 75 g 120 min blood glucose levels (r=-0.27, p=0.036). The orexigen effect of elevated serum ghrelin levels can contribute to the weight-gain and high diabetes prevalence associated with atypical antipsychotic treatment. The link between atypical antipsychotic treatment and elevated serum ghrelin levels is unknown so far, but a dysregulation of the central feedback mechanism can be hypothesised.
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Metabolic regulation of growth hormone by free fatty acids, somatostatin, and ghrelin in HIV-lipodystrophy.
Koutkia, P, Meininger, G, Canavan, B, Breu, J, Grinspoon, S
American journal of physiology. Endocrinology and metabolism. 2004;(2):E296-303
Abstract
Human immunodeficiency virus (HIV)-lipodystrophy is a syndrome characterized by changes in fat distribution and insulin resistance. Prior studies suggest markedly reduced growth hormone (GH) levels in association with excess visceral adiposity among patients with HIV-lipodystrophy. We investigated mechanisms of altered GH secretion in a population of 13 male HIV-infected patients with evidence of fat redistribution, compared with 10 HIV-nonlipodystrophic patients and 11 male healthy controls similar in age and body mass index (BMI). Although similar in BMI, the lipodystrophic group was characterized by increased visceral adiposity, free fatty acids (FFA), and insulin and reduced extremity fat. We investigated ghrelin and the effects of acute lowering of FFA by acipimox on GH responses to growth hormone-releasing hormone (GHRH). We also investigated somatostatin tone, comparing GH response to combined GHRH and arginine vs. GHRH alone with a subtraction algorithm. Our data demonstrate an equivalent number of GH pulses (4.1 +/- 0.6, 4.7 +/- 0.8, and 4.5 +/- 0.3 pulses/12 h in the HIV-lipodystrophic, HIV-nonlipodystrophic, and healthy control groups, respectively, P > 0.05) but markedly reduced GH secretion pulse area (1.14 +/- 0.27 vs. 4.67 +/- 1.24 ng.ml(-1).min, P < 0.05, HIV-lipodystrophic vs. HIV-nonlipodystrophic; 1.14 +/- 0.27 vs. 3.18 +/- 0.92 ng.ml(-1).min, P < 0.05 HIV-lipodystrophic vs. control), GH pulse area, and GH pulse width in the HIV-lipodystrophy patients compared with the control groups. Reduced ghrelin (418 +/- 46 vs. 514 +/- 37 pg/ml, P < 0.05, HIV-lipodystrophic vs. HIV-nonlipodystrophic; 418 +/- 46 vs. 546 +/- 45 pg/ml, P < 0.05, HIV-lipodystrophic vs. control), impaired GH response to GHRH by excess FFA, and increased somatostatin tone contribute to reduced GH secretion in patients with HIV-lipodystrophy. These data provide novel insight into the metabolic regulation of GH secretion in subjects with HIV-lipodystrophy.