Investigating the role of adipokines in chronic migraine

Cephalalgia ◽  
2016 ◽  
Vol 37 (11) ◽  
pp. 1067-1073 ◽  
Author(s):  
Elisa Rubino ◽  
Alessandro Vacca ◽  
Flora Govone ◽  
Annalisa Gai ◽  
Silvia Boschi ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Chronic Migraine ◽  
Plasma Concentrations ◽  
Hdl Cholesterol ◽  
Serum Levels ◽  
Episodic Migraine ◽  
Markers Of Inflammation ◽  
Total Adiponectin ◽  
Inflammatory Processes ◽  
Chronic Migraineurs

Background and aims Adiponectin, leptin, and resistin are adipocyte-derived secretory factors involved in endothelial function, weight, inflammation, and insulin resistance. Recent studies suggested a role for adipokines in episodic migraine as mediators of inflammatory processes. The aim of this study was to investigate plasma concentrations of adiponectin, leptin, and resistin in patients with chronic migraine. Materials and methods Twenty-seven chronic migraineurs (20 females, 7 males; mean age 49.0 ± 9.0 yrs) and 37 healthy controls (23 females, 14 males; mean age 49.8 ± 15.0 yrs) were selected for the study. Fasting plasmatic levels of total adiponectin, leptin, and resistin were measured using ELISA kits during a pain-free period. Fasting glucose, insulin, total and HDL-cholesterol, triglycerides, and ESR were also determined. Results Serum levels of adiponectin and resistin were significantly increased in chronic migraineurs in comparison with controls ( p = 0.001 and p = 0.032, respectively). After correction for BMI, sex and age, leptin levels were significantly increased in chronic migraineurs ( p = 0.007). A positive correlation between leptin concentrations and both indices of insulin resistance and markers of inflammation was found. Discussion Our data suggest that adiponectin and resistin are altered in non-obese chronic migraineurs. Further studies are needed to elucidate the neurobiological mechanisms underlying adipokine dysfunction in migraine.

scholarly journals Osteopontin Expression in Human and Murine Obesity: Extensive Local Up-Regulation in Adipose Tissue but Minimal Systemic Alterations

Endocrinology ◽  
2007 ◽  
Vol 149 (3) ◽  
pp. 1350-1357 ◽  
Author(s):  
Florian W. Kiefer ◽  
Maximilian Zeyda ◽  
Jelena Todoric ◽  
Joakim Huber ◽  
René Geyeregger ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Plasma Concentrations ◽  
Morbidly Obese ◽  
Low Grade ◽  
Obese Patients ◽  
Multifunctional Protein ◽  
Inflammatory Processes ◽  
Low Grade Inflammation

Obesity is associated with a chronic low-grade inflammation characterized by macrophage infiltration of adipose tissue (AT) that may underlie the development of insulin resistance and type 2 diabetes. Osteopontin (OPN) is a multifunctional protein involved in various inflammatory processes, cell migration, and tissue remodeling. Because these processes occur in the AT of obese patients, we studied in detail the regulation of OPN expression in human and murine obesity. The study included 20 morbidly obese patients and 20 age- and sex-matched control subjects, as well as two models (diet-induced and genetic) of murine obesity. In high-fat diet-induced and genetically obese mice, OPN expression was drastically up-regulated in AT (40 and 80-fold, respectively) but remained largely unaltered in liver (<2-fold). Moreover, OPN plasma concentrations remained unchanged in both murine models of obesity, suggesting a particular local but not systemic importance for OPN. OPN expression was strongly elevated also in the AT of obese patients compared with lean subjects in both omental and sc AT. In addition, we detected three OPN isoforms to be expressed in human AT and, strikingly, an obesity induced alteration of the OPN isoform expression pattern. Analysis of AT cellular fractions revealed that OPN is exceptionally highly expressed in AT macrophages in humans and mice. Moreover, OPN expression in AT macrophages was strongly up-regulated by obesity. In conclusion, our data point toward a specific local role of OPN in obese AT. Therefore, OPN could be a critical regulator in obesity induced AT inflammation and insulin resistance.

scholarly journals Metabolically-Unhealthy Obesity Is Associated With Increased Adipose Tissue Inflammatory Gene Expression and 24-Hour Plasma Concentrations of PAI-1, but Not Other Inflammatory Cytokines

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A21-A22
Author(s):  
Max C Petersen ◽  
Gordon I Smith ◽  
Mihoko Yoshino ◽  
Vincenza Cifarelli ◽  
Jun Yoshino ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Plasma Concentrations ◽  
Fat Free Mass ◽  
Whole Body ◽  
Glucose Disposal ◽  
Insulin Resistant ◽  
Markers Of Inflammation ◽  
Metabolically Healthy ◽  
Metabolically Unhealthy Obesity ◽  
Pai 1

Abstract Insulin resistant glucose metabolism is the most common metabolic complication associated with obesity; however, a subset of people with obesity have normal insulin sensitivity and are considered to be metabolically healthy. In rodent models of obesity, adipose tissue (AT) inflammation contributes to whole-body insulin resistance mediated, at least in part, by production of proinflammatory cytokines that are secreted into the systemic circulation. We therefore hypothesized that AT markers of inflammation and plasma concentrations of inflammatory cytokines would be greater in people with metabolically-unhealthy obesity (MUO) and insulin-resistant glucose metabolism than in insulin-sensitive people with metabolically-healthy obesity (MHO). We measured AT expression of genes that encode for proinflammatory proteins by using RNA sequencing and plasma cytokine concentrations assessed serially over 24 hours by using multiplex assays in: i) 28 people with MHO (defined as normal glucose tolerance and normal insulin-stimulated glucose disposal assessed using the hyperinsulinemic-euglycemic clamp procedure [48 ± 2 µmol/kg fat-free mass/min]); and ii) 28 people with MUO (defined as prediabetes and impaired insulin-stimulated glucose disposal [28 ± 1 µmol/kg fat-free mass/min]). AT markers of inflammation (expression of SERPINE1, CCL3, CCL5, CD68, CD74, MRC1, and CXCL16) were greater in the MUO than in the MHO group (all P < 0.05). However, the 24-hour plasma concentration areas-under-the curve (AUC) for TNFα, MCP-1, IL-6, RANTES, IL-1β, IL-17, and IFN-γ were not different between MHO and MUO groups. In contrast, 24-hour plasma plasminogen activator inhibitor 1 (PAI-1) AUC was greater in the MUO (1,759 ± 169 ng/mL x h) group than in the MHO (716 ± 85 ng/mL x h) group (P < 0.001) and plasma PAI-1 was inversely correlated with whole-body insulin sensitivity (r= -0.57; P < 0.001). We conclude that, with the exception of PAI-1, AT inflammation does not contribute to whole-body insulin resistance by increasing systemic circulating inflammatory cytokine levels. However, increased AT production of PAI-1 is associated with whole-body insulin resistance in people with MUO.

Prevalence of right-to-left shunts on transcranial Doppler in chronic migraine and medication-overuse headache

Cephalalgia ◽  
2013 ◽  
Vol 34 (1) ◽  
pp. 37-41 ◽  
Author(s):  
Song Guo ◽  
Sarvnaz Shalchian ◽  
Pascale Gérard ◽  
Michael Küper ◽  
Zaza Katsarava ◽  
...  
Keyword(s):  
Chronic Migraine ◽  
Transcranial Doppler ◽  
Medication Overuse ◽  
Medication Overuse Headache ◽  
Episodic Migraine ◽  
Severe Form ◽  
Cross Sectional ◽  
Headache Clinic ◽  
Chronic Headaches ◽  
Chronic Migraineurs

Background It was suggested that right-to-left shunt (RLS) may be highly prevalent in chronic migraine (CM) patients, indicating that patent foramen ovale (PFO) might be an aggravating and chronifying factor of migraine. Since a high proportion of chronic migraineurs also have medication-overuse headache (MOH), one may wonder if they have a more severe form of the disorder and more frequently a PFO. Objective The objective of this study is to determine the prevalence and grade of RLS in patients suffering from CM and MOH. Methods A cross-sectional multicenter study of air-contrast transcranial Doppler was conducted in 159 patients with CM ( n = 57) or MOH ( n = 102) attending a tertiary headache clinic. Results The prevalence of RLS in CM was 37% (11% large shunts) and in MOH patients 31% (13% large shunts). There was no difference between the two groups ( p = 0.49). Conclusion RLS prevalence in CM is within the upper range of those reported in episodic migraine without aura or in the general population, and not higher in MOH. PFO is thus unlikely to have a significant causal role in these chronic headaches.

Determinants of glucose metabolism and the role of NPY in the progression of insulin resistance in chronic migraine

Cephalalgia ◽  
2017 ◽  
Vol 38 (11) ◽  
pp. 1773-1781 ◽  
Author(s):  
Zeynep Oşar Siva ◽  
Derya Uluduz ◽  
Fatma Ela Keskin ◽  
Feyza Erenler ◽  
Huriye Balcı ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Neuropeptide Y ◽  
Chronic Migraine ◽  
Cell Function ◽  
Episodic Migraine ◽  
Oral Glucose ◽  
Β Cell ◽  
Β Cell Function ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Background Chronic migraine has a well-documented association with increased insulin resistance and metabolic syndrome. The hypothalamus may play a role in the progression of insulin resistance in chronic migraine through the regulation of orexigenic peptides such as neuropeptide Y. Insulin resistance may lead to increased risk of future type 2 diabetes mellitus in patients with chronic migraine, which is more likely to occur if other pathogenetic defects of type 2 diabetes mellitus, such as impaired pancreatic β-cell functions and defects in intestinal glucagon-like peptide-1 secretion after meals. We studied the relationship of fasting neuropeptide Y with insulin resistance, β-cell function, and glucagon-like peptide-1 secretion in non-obese female chronic migraine patients. We also aimed to investigate glucose-stimulated insulin and glucagon-like peptide-1 secretions as early pathogenetic mechanisms responsible for the development of carbohydrate intolerance. Methods In this cross-sectional controlled study, 83 non-obese female migraine patients of reproductive age categorized as having episodic migraine or chronic migraine were included. The control group consisted of 36 healthy females. We studied glucose-stimulated insulin and glucagon-like peptide-1 secretion during a 75 g oral glucose tolerance test. We investigated the relationship of neuropeptide Y levels with insulin resistance and β-cell insulin secretion functions. Results Fasting glucose levels were significantly higher in migraine patients. Plasma glucose and insulin levels during the oral glucose tolerance test were otherwise similar in chronic migraine, episodic migraine and controls. Patients with chronic migraine were more insulin resistant than episodic migraine or controls ( p = 0.048). Glucagon-like peptide-1 levels both at fasting and two hours after glucose intake were similar in chronic migraine, episodic migraine, and controls. Neuropeptide Y levels were higher in migraineurs. In chronic migraine, neuropeptide Y was positively correlated with fasting glucagon-like peptide-1 levels (r = 0.57, p = 0.04), but there was no correlation with insulin resistance (r = 0.49, p = 0.09) or β-cell function (r = 0.50, p = 0.07). Discussion Non-obese premenopausal female patients with chronic migraine have higher insulin resistance, but normal β-cell function is to compensate for the increased insulin demand during fasting and after glucose intake. Increased fasting neuropeptide Y levels in migraine may be a factor leading to increased insulin resistance by specific alterations in energy intake and activation of the sympathoadrenal system.

scholarly journals Assessment of peripheral biomarkers potentially involved in episodic and chronic migraine: a case-control study with a focus on NGF, BDNF, VEGF, and PGE2

2022 ◽  
Vol 23 (1) ◽  
Author(s):  
Mohammad Mozafarihashjin ◽  
Mansoureh Togha ◽  
Zeinab Ghorbani ◽  
Abolfazl Farbod ◽  
Pegah Rafiee ◽  
...  
Keyword(s):  
Growth Factor ◽  
Chronic Migraine ◽  
Case Control Study ◽  
Demographic Data ◽  
Serum Levels ◽  
Episodic Migraine ◽  
Case Control ◽  
Blood Levels ◽  
Headache Frequency ◽  
Control Study

Abstract Background Several inflammatory and vascular molecules, and neurotrophins have been suggested to have a possible role in the development of migraine. However, pathophysiological events leading to migraine onset and transformation of episodic migraine (EM) to chronic migraine (CM) are not fully understood. Thus, we aimed to assess peripheral levels of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), and prostaglandin E2 (PGE2) in EM and CM patients, and controls. Methods From September 2017 to June 2020, 89 subjects were enrolled in a case-control study; 23 and 36 EM and CM patients, respectively, and 30 age and sex-matched controls. Demographic data and medical history were obtained from all patients. Headache characteristics were recorded at baseline visit and ensuing 30 days for persons with migraine disease. Serum levels of NGF, BDNF, VEGF, and PGE2 were measured once for controls and EM and CM patients, and adjusted for age, sex, and body mass index. Results Serum levels of NGF were significantly lower in EM patients compared to controls and CM patients (P-value=0.003 and 0.042, respectively). Serum levels of BDNF were significantly lower in EM and CM patients as opposed to controls (P-value<0.001), but comparable between EM and CM patients (P-value=0.715). Peripheral blood levels of VEGF were significantly higher in EM and CM patients as opposed to controls (P-value<0.001), but not different between EM and CM patients (P-value=0.859). Serum levels of PGE2 were significantly lower in EM patients compared to controls (P-value=0.011), however similar between EM and CM patients (P-value=0.086). In migraine patients, serum levels of NGF and PGE2 positively correlated with headache frequency (NGF: ρ = 0.476 and P-value<0.001; PGE2: ρ = 0.286 and P-value=0.028), while corresponding levels of BDNF and VEGF did not correlate with headache frequency (BDNF: ρ = 0.037 and P-value=0.778; VEGF: ρ= -0.025 and P-value=0.850). Conclusions Our findings suggest that NGF, BDNF, PGE2, and VEGF may play a significant role in migraine pathogenesis and/or chronification, and therefore might bear potential value for novel targeted abortive and prophylactic migraine therapy. Further prospective cohort studies with larger sample sizes can more robustly evaluate the implications of these findings.

The effects of weight loss on adipokines and markers of inflammation in dogs

2011 ◽  
Vol 106 (S1) ◽  
pp. S11-S14 ◽  
Author(s):  
Joseph J. Wakshlag ◽  
Angela M. Struble ◽  
Corri B. Levine ◽  
Jennifer J. Bushey ◽  
Dorothy P. Laflamme ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Weight Loss ◽  
Chronic Inflammation ◽  
Interquartile Range ◽  
Serum Samples ◽  
Monocyte Chemoattractant Protein 1 ◽  
Markers Of Inflammation ◽  
Hmw Adiponectin ◽  
Total Adiponectin ◽  
Before And After

Evidence suggests that adipose tissue-derived adipokines induce mild inflammation and may play a role in insulin resistance associated with diabetes. The present study was designed to examine a series of adipokines and markers of inflammation in dogs before and after a successful weight loss. The study included fasting serum samples from twenty-five dogs before and after a weight-loss programme. Serum C-reactive protein (CRP) and monocyte chemoattractant protein-1 (MCP-1) were measured as indicators of chronic inflammation, while serum adipokines including total adiponectin, high-molecular-weight (HMW) adiponectin, resistin and leptin were also examined. Medians for CRP (before, 10·0 (interquartile range 5·4–15·0) μg/ml; after, 5·6 (interquartile range 3·8–7·0) μg/ml) and MCP-1 (before, 212 (interquartile range 157–288) ng/ml; after, 185 (interquartile range 143–215) ng/ml) decreased significantly after weight loss. Medians for resistin showed a mild, yet significant reduction (before, 67·1 (interquartile range 44·4–88·5) pg/ml; after, 60·5 (interquartile range 32·3–67·1) pg/ml), while leptin showed a dramatic decrease after weight loss (before, 18·9 (interquartile range 10·8–35·4) ng/ml; after, 6·6 (interquartile range 3·9–10·2) ng/ml). Serum total adiponectin and HMW adiponectin were unchanged on all analyses performed. These data suggest that weight loss can decrease chronic inflammation; however, the clinical implications of this decrease are not well elucidated in dogs. Surprisingly, there was no increase in total or HMW serum adiponectin after weight loss, as observed previously in human subjects. The lack of change in total and HMW adiponectin might explain why insulin resistance and type 2 diabetes are less prevalent in obese dogs when compared with humans and cats.

scholarly journals Markers of Triglyceride-rich Lipoprotein Remnant Metabolism in Visceral Obesity

2002 ◽  
Vol 48 (2) ◽  
pp. 278-283 ◽  
Author(s):  
Dick C Chan ◽  
Gerald F Watts ◽  
P Hugh Barrett ◽  
John CL Mamo ◽  
Trevor G Redgrave
Keyword(s):  
Insulin Resistance ◽  
Polyacrylamide Gel Electrophoresis ◽  
Plasma Concentrations ◽  
Sodium Dodecyl ◽  
Visceral Obesity ◽  
Hdl Cholesterol ◽  
Isotope Ratio Mass Spectrometry ◽  
Apo B ◽  
Catabolic Rate ◽  
Triglyceride Rich Lipoprotein

Abstract Background: Triglyceride-rich lipoprotein remnants are atherogenic, and this may be particularly important in visceral obesity. We investigated remnant metabolism in obese men by measuring remnant-like particle-cholesterol (RLP-C), apolipoprotein (apo) B-48, apoC-III, and the clearance of a labeled remnant-like emulsion. Methods: Fasting RLP-C, apoB-48, and apoC-III concentrations were measured in 48 viscerally obese men and 10 lean controls. RLP-C was determined by immunoseparation assay, apoB-48 by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and enhanced chemiluminescence, and apoC-III by immunoturbidimetric assay. The catabolism of chylomicron remnants was measured by intravenous injection of a remnant-like emulsion containing cholesteryl [13C]oleate, with isotopic enrichment of 13CO2 in breath determined by isotope-ratio mass spectrometry and a multicompartmental model to estimate fractional catabolic rate (FCR) of the emulsion. Results: Compared with controls, obese men had significantly increased plasma concentrations of RLP-C, apoB-48, and apoC-III (P &lt;0.001 for all). Plasma total apoB-100, non-HDL-cholesterol, LDL-cholesterol, triglycerides, and insulin resistance (HOMA score) were also significantly higher in the obese group (P &lt;0.001 for all). Obese men had a significantly lower FCR of the remnant-like emulsion compared with controls (P = 0.020). Conclusions: Viscerally obese individuals have insulin resistance and increased plasma concentrations of triglyceride-rich lipoprotein remnants, which may be attributable to decreased catabolism of these particles.

Iron deposition in periaqueductal gray matter as a potential biomarker for chronic migraine

Neurology ◽  
2019 ◽  
Vol 92 (10) ◽  
pp. e1076-e1085 ◽  
Author(s):  
Clara Domínguez ◽  
Ana López ◽  
Pedro Ramos-Cabrer ◽  
Alba Vieites-Prado ◽  
Maria Pérez-Mato ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Chronic Migraine ◽  
Gray Matter ◽  
Red Nucleus ◽  
Serum Levels ◽  
Periaqueductal Gray ◽  
Iron Deposition ◽  
Periaqueductal Gray Matter ◽  
Markers Of Inflammation ◽  
Potential Biomarker

ObjectiveTo study iron deposition in red nucleus (RN), globus pallidus (GP), and periaqueductal gray matter (PAG) as a potential biomarker of chronic migraine (CM) and its association with levels of biomarkers related to migraine pathophysiology.MethodsThis case-control study included 112 patients with migraine (55 CM, 57 episodic migraine [EM]) and 25 headache-free controls. We analyzed iron deposition using 3T MRI and the NIH software platform ImageJ; we analyzed serum levels of markers of inflammation, endothelial dysfunction, and blood-brain barrier (BBB) disruption by ELISA in peripheral blood during interictal periods.ResultsPatients with CM showed larger iron grounds volume in RN compared to patients with EM (70.2 ± 6.8 vs 25.5 ± 7.3 μL, p < 0.001) and controls (70.2 ± 6.8 vs 15.1 ± 10.8 μL, p < 0.001), as well as larger iron deposits in PAG compared to patients with EM (360.3 ± 6.5 vs 249.7 ± 6.9 μL, p < 0.001) and controls (360.3 ± 6.5 vs 168.6 ± 10.3 μL, p < 0.001). In PAG, differences were also significant between patients with EM and controls. No significant differences were obtained for GP. Receiver operating characteristic curves showed that the optimal threshold for iron volume was 15 μL in RN (80% sensitivity, 71% specificity) and 240 μL in PAG (93% sensitivity, 97% specificity). Iron grounds volume in PAG was correlated with higher plasma levels of soluble tumor necrosis factor–like WEAK (r = 0.395, p = 0.005) and cellular fibronectin (r = 0.294, p = 0.040).ConclusionsPatients with CM showed increased iron deposition in RN and PAG compared to patients with EM and controls. Iron grounds volume in PAG identified correctly patients with CM and was associated with elevated biomarkers of endothelial dysfunction and BBB disruption.

scholarly journals Mild systemic inflammation enhances response to OnabotulinumtoxinA in chronic migraineurs

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yago Leira ◽  
Clara Domínguez ◽  
Pablo Ameijeira ◽  
Esteban López-Arias ◽  
Paulo Ávila-Gómez ◽  
...  
Keyword(s):  
High Sensitivity ◽  
Serum Levels ◽  
Poor Responders ◽  
Reactive Protein ◽  
Inflammatory Parameters ◽  
Markers Of Inflammation ◽  
Calcitonin Gene ◽  
Inflammatory State ◽  
Hs Crp ◽  
Chronic Migraineurs

AbstractThe anti-inflammatory effect of OnabotulinumtoxinA (OnabotA) has been a matter of discussion for many years. In chronic migraine, however, increased pro-inflammatory state is associated with good response to OnabotA. We aimed to investigate whether a mild systemic inflammatory state elicited by a common oral infection (periodontitis) could enhance treatment response to OnabotA. In this study, we included 61 chronic migraineurs otherwise healthy treated with OnabotA of which 7 were poor responders and 54 good responders. Before receiving OnabotA therapy, all participants underwent a full-mouth periodontal examination and blood samples were collected to determine serum levels of calcitonin gene-related peptide (CGRP), interleukin 6 (IL-6), IL-10 and high sensitivity C-reactive protein (hs-CRP). Periodontitis was present in 70.4% of responders and 28.6% of non-responders (P = 0.042). Responders showed greater levels of inflammation than non-responders (IL-6: 15.3 ± 8.7 vs. 9.2 ± 4.7 ng/mL, P = 0.016; CGRP: 18.8 ± 7.6 vs. 13.0 ± 3.1 pg/mL, P = 0.002; and hs-CRP: 3.9 ± 6.6 vs. 0.9 ± 0.8 mg/L, P = 0.003). A linear positive correlation was found between the amount of periodontal tissue inflamed in the oral cavity and markers of inflammation (IL-6: r = 0.270, P = 0.035; CGRP: r = 0.325, P = 0.011; and hs-CRP: r = 0.370, P = 0.003). This report shows that in presence of elevated systemic inflammatory markers related to periodontitis, OnabotA seems to reduce migraine attacks. The changes of scheduled inflammatory parameters after treatment and subsequent assessment during an adequate period still need to be done.

Plasma obestatin is lower at fasting and not suppressed by insulin in insulin-resistant humans

2007 ◽  
Vol 293 (5) ◽  
pp. E1393-E1398 ◽  
Author(s):  
Marietta Anderwald-Stadler ◽  
Michael Krebs ◽  
Miriam Promintzer ◽  
Martina Mandl ◽  
Martin G. Bischof ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Infusion ◽  
Plasma Concentrations ◽  
Hdl Cholesterol ◽  
Whole Body ◽  
Glucose Disposal ◽  
Insulin Resistant ◽  
Amino Acid Peptide ◽  
Fasting Plasma ◽  
Precursor Peptide

Obestatin, a recently discovered 23-amino acid peptide, is involved in the regulation of appetite and body weight in antagonistic fashion to ghrelin, both deriving from a common precursor peptide. Ghrelin was shown to be associated with insulin resistance, which may also affect obestatin. We investigated the association between insulin resistance and plasma concentrations of obestatin and ghrelin in nondiabetic individuals with high (IS; n = 18, 13 females and 5 males, age 47 ± 2 yr, BMI = 25.5 ± 0.9 kg/m2) and low (IR; n = 18, 12 females and 6 males, age 45 ± 2 yr, P = 0.49, BMI = 27.5 ± 1.1 kg/m2, P = 0.17) insulin-stimulated glucose disposal (M), measured by 2-h hyperinsulinemic (40 mU·min−1·m−2) isoglycemic clamp tests. M100–120 min was higher in IS (10.7 ± 0.7) than in IR (4.4 ± 0.2 mg·min−1·kg−1, P < 10−9), whereas insulin-dependent suppression of free fatty acids (FFA) in plasma was reduced in IR (71 ± 6% vs. IS: 82 ± 5%, P < 0.02). In both groups, plasma ghrelin concentrations were comparable at fasting and similarly reduced by 24–28% during insulin infusion. IR had lower fasting plasma obestatin levels (383 ± 26 pg/ml vs. IS: 469 ± 23 pg/ml, P < 0.02). Clamp insulin infusion reduced plasma obestatin to ∼81% of basal values in IS ( P < 0.00002), but not in IR. Fasting plasma obestatin was correlated positively with M ( r = 0.34, P = 0.04), HDL cholesterol ( r = 0.45, P = 0.01), and plasma ghrelin concentrations ( r = 0.80, P < 0.000001) and negatively with measures of adiposity, plasma FFA during clamp ( r = −0.42, P < 0.01), and systolic blood pressure ( r = −0.33, P < 0.05). In conclusion, fasting plasma concentrations of obestatin, but not of ghrelin, are reduced in insulin resistance and are positively associated with whole body insulin sensitivity in nondiabetic humans. Furthermore, plasma obestatin is reduced by insulin in insulin-sensitive but not in insulin-resistant persons.

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