scholarly journals OR08-04 Differences in Advanced Lipoprotein Profile Between Rabson-Mendenhall Syndrome and Lipodystrophy

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Mohammad Al-Jundi ◽  
Marissa Lightbourne ◽  
Megan Startzell ◽  
Robert D Shamburek ◽  
Rebecca J Brown
Keyword(s):  
Insulin Resistance ◽  
Signaling Pathways ◽  
Insulin Signaling ◽  
Lipoprotein Profile ◽  
Cvd Risk ◽  
Lipoprotein Particles ◽  
Lipoprotein Particle ◽  
Ldl Particles ◽  
Low Hdl ◽  
Artery Disease

Abstract Insulin resistance (IR) is associated with metabolic dyslipidemia (high triglycerides [TG] and low HDL) and increased cardiovascular disease (CVD) risk. In obesity-associated IR, dyslipidemia is thought to be caused by increased insulin-mediated stimulation of hepatic lipogenesis, whereas IR in glucoregulatory pathways leads to hyperglycemia. This dichotomy in insulin signaling pathways is termed selective insulin resistance. Rare human conditions exist in which there is extreme, non-selective, IR impairing all insulin signaling pathways (e.g. mutations of the insulin receptor, INSR) or extreme IR affecting only selected intracellular insulin signaling pathways analogous to obesity (e.g. lipodystrophy). Lipodystrophy leads to very high TG, low HDL, and increased CVD, while INSR mutation leads to low TG and high HDL, with unknown CVD risk. We sought to further characterize the lipid phenotype and atherogenicity in these conditions in order to understand effects of different insulin signaling pathways on CVD risk. We studied 7 patients with INSR mutation (42% female; 5 homozygous; 2 heterozygous) and 21 with lipodystrophy (85% female; 5 generalized; 16 partial). Fasting lipoprotein profiles were assessed by NMR using the LP4 deconvolution algorithm. The major lipoprotein particle categories defined by this method are small, medium, and large HDL and LDL particles (HDLP and LDLP) and very small, small, medium, large, and very large TG rich lipoprotein particles (TRLP). Very small TRLP (median 189.6 [68.7, 315.0] vs 4.5 [0.00, 9.4], p=0.0001), small LDLP (mean 1425.0 ± 636.2 vs 612.8 ± 233.9, p=0.003), small HDLP (mean 14.0 ± 4.7 vs 9.0 ± 3.2, p=0.014) were more elevated in patients with lipodystrophy vs INSR mutation. This lipoprotein profile has been associated with increased atherosclerotic coronary artery disease. GlycA, a marker of inflammation was also more elevated in lipodystrophy vs INSR mutation (435.9 ± 107.2 vs 315.7 ± 74.4, p=0.01). Insulin resistance assessed by HOMA-IR was higher in patients with INSR mutation vs lipodystrophy (mean 93.5 ± 94.4 vs 15.6 ± 14.7, p=0. 00085).) Lipoprotein insulin resistance (LPIR), an index of IR based on lipoprotein particles, was lower in patients with INSR mutation (25.0 ± 19.0 vs 84.0 ± 9.0, p < 0.0001) despite their higher HOMA-IR. In conclusion, severe, selective insulin resistance in patients with lipodystrophy was associated with a more atherogenic lipoprotein particle profile and increased inflammation compared to severe, non-selective insulin resistance caused by INSR mutations. Patients with INSR mutations had a striking discrepancy between a glucose/insulin-based index of insulin resistance (HOMA-IR) and a lipid-based marker of insulin resistance (LPIR). These findings point toward a key role of selective insulin resistance in the development of an atherogenic lipid profile, which should lead to increased CVD risk.

scholarly journals Advanced Lipoprotein Analysis Shows Atherogenic Lipid Profile That Improves After Metreleptin in Patients with Lipodystrophy

2019 ◽  
Vol 3 (8) ◽  
pp. 1503-1517 ◽  
Author(s):  
Alexandra B Kinzer ◽  
Robert D Shamburek ◽  
Marissa Lightbourne ◽  
Ranganath Muniyappa ◽  
Rebecca J Brown
Keyword(s):  
Insulin Resistance ◽  
High Density Lipoprotein ◽  
Lipid Profile ◽  
Density Lipoprotein ◽  
High Density ◽  
Lipoprotein Profile ◽  
Cvd Risk ◽  
Lipoprotein Particles ◽  
Atherogenic Lipid Profile ◽  
Atherogenic Lipid

Abstract Context Patients with lipodystrophy have dyslipidemia and insulin resistance. Leptin treatment with metreleptin in lipodystrophy decreases insulin resistance and lowers triglycerides without changing high-density lipoprotein. Detailed measurement of lipoprotein particles with nuclear magnetic resonance (NMR) spectroscopy can offer insights into cardiovascular disease (CVD) risk and lipid metabolism beyond a standard lipid panel. We hypothesized that patients with lipodystrophy would have a more atherogenic lipid profile than controls at baseline, which would be ameliorated with metreleptin treatment. Objective To characterize the lipoprotein profile in patients with lipodystrophy compared with controls and to evaluate effects of metreleptin treatment. Design, Setting, Patients, and Intervention Patients with lipodystrophy (N = 17) were studied before and after metreleptin for 2 weeks and 6 months and compared with 51 insulin-sensitive sex-matched controls. Main Outcome Measures Lipoprotein profiles were measured by NMR with the LP4 deconvolution algorithm, which reports triglyceride-rich lipoprotein particles (TRLPs), high-density lipoprotein particles (HDLPs), and low-density lipoprotein particles (LDLPs). Results Patients with lipodystrophy had elevated large TRLPs and smaller HDLPs and LDLPs compared with controls. Five patients with lipodystrophy had chylomicrons, compared with zero controls. Metreleptin decreased the size and concentration of TRLPs, eliminated chylomicrons in all but one patient, decreased LDLPs, and increased LDLP size. Metreleptin treatment did not have major effects on HDLPs. Conclusions Patients with lipodystrophy had an atherogenic lipoprotein profile at baseline consistent with elevated CVD risk, which improved after metreleptin treatment. The presence of fasting chylomicrons in a subset of patients with lipodystrophy suggests saturation of chylomicron clearance by lipoprotein lipase.

scholarly journals Visfatin Induces Inflammation and Insulin Resistance via the NF-κB and STAT3 Signaling Pathways in Hepatocytes

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Yu Jung Heo ◽  
Sung-E Choi ◽  
Ja Young Jeon ◽  
Seung Jin Han ◽  
Dae Jung Kim ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Signaling Pathways ◽  
Western Blotting ◽  
Insulin Signaling ◽  
Proinflammatory Cytokine ◽  
Hepg2 Cells ◽  
Molecular Mechanisms ◽  
Immunocytochemical Staining ◽  
Mrna Levels ◽  
Rt Pcr

Background. It has been suggested that visfatin, which is an adipocytokine, exhibits proinflammatory properties and is associated with insulin resistance. Insulin resistance and inflammation are the principal pathogeneses of nonalcoholic fatty liver disease (NAFLD), but the relationship, if any, between visfatin and NAFLD remains unclear. Here, we evaluated the effects of visfatin on hepatic inflammation and insulin resistance in HepG2 cells and examined the molecular mechanisms involved. Methods. After treatment with visfatin, the inflammatory cytokines IL-6, TNF-α, and IL-1β were assessed by real-time polymerase chain reaction (RT-PCR) and immunocytochemical staining in HepG2 cells. To investigate the effects of visfatin on insulin resistance, we evaluated insulin-signaling pathways, such as IR, IRS-1, GSK, and AKT using immunoblotting. We assessed the intracellular signaling molecules including STAT3, NF-κB, IKK, p38, JNK, and ERK by western blotting. We treated HepG2 cells with both visfatin and either AG490 (a JAK2 inhibitor) or Bay 7082 (an NF-κB inhibitor); we examined proinflammatory cytokine mRNA levels using RT-PCR and insulin signaling using western blotting. Results. In HepG2 cells, visfatin significantly increased the levels of proinflammatory cytokines, reduced the levels of proteins (e.g., phospho-IR, phospho-IRS-1 (Tyr612), phospho-AKT, and phospho-GSK-3α/β) involved in insulin signaling, and increased IRS-1 S307 phosphorylation compared to controls. Interestingly, visfatin increased the activities of the JAK2/STAT3 and IKK/NF-κB signaling pathways but not those of the JNK, p38, and ERK pathways. Visfatin-induced inflammation and insulin resistance were regulated by JAK2/STAT3 and IKK/NF-κB signaling; together with AG490 or Bay 7082, visfatin significantly reduced mRNA levels of IL-6, TNF-α and IL-1β and rescued insulin signaling. Conclusion. Visfatin induced proinflammatory cytokine production and inhibited insulin signaling via the STAT3 and NF-κB pathways in HepG2 cells.

scholarly journals Role of Neu-p11/luzindole in the regulation of insulin signaling pathways and insulin resistance

2016 ◽  
Vol 48 (5) ◽  
pp. 485-486
Author(s):  
Xiuping Li ◽  
Shichang Cai ◽  
Weidong Yin ◽  
Xiaobo Hu ◽  
Sujun Zhang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Signaling Pathways ◽  
Insulin Signaling

scholarly journals Crosstalk between the AMP-activated kinase and insulin signaling pathways rescues murine blastocyst cells from insulin resistance

Reproduction ◽  
2008 ◽  
Vol 136 (3) ◽  
pp. 335-344 ◽  
Author(s):  
Erica Louden ◽  
Maggie M Chi ◽  
Kelle H Moley
Keyword(s):  
Insulin Resistance ◽  
Signaling Pathways ◽  
Insulin Signaling ◽  
Kinase Activity ◽  
Pi3 Kinase ◽  
Ampk Activation ◽  
Embryonic Cells ◽  
Insulin Resistant

Maternal insulin resistance results in poor pregnancy outcomes. In vivo and in vitro exposure of the murine blastocyst to high insulin or IGF1 results in the down-regulation of the IGF1 receptor (IGF1R). This in turn leads to decreased glucose uptake, increased apoptosis, as well as pregnancy resorption and growth restriction. Recent studies have shown that blastocyst activation of AMP-activated protein kinase (AMPK) reverses these detrimental effects; however, the mechanism was not clear. The objective of this study was to determine how AMPK activation rescues the insulin-resistant blastocyst. Using trophoblast stem (TS) cells derived from the blastocyst, insulin resistance was recreated by transfecting with siRNA to Igf1r and down-regulating expression of the protein. These cells were then exposed to AMPK activators 5-aminoimidazole-4-carboxamide riboside and phenformin, and evaluated for apoptosis, insulin-stimulated 2-deoxyglucose uptake, PI3-kinase activity, and levels of phospho-AKT, phospho-mTor, and phospho-70S6K. Surprisingly, disrupted insulin signaling led to decreased AMPK activity in TS cells. Activators reversed these effects by increasing the AMP/ATP ratio. Moreover, this treatment increased insulin-stimulated 2-deoxyglucose transport and cell survival, and led to an increase in PI3-kinase activity, as well as increased P-mTOR and p70S6K levels. This study is the first to demonstrate significant crosstalk between the AMPK and insulin signaling pathways in embryonic cells, specifically the enhanced response of PI3K/AKT/mTOR to AMPK activation. Decreased insulin signaling also resulted in decreased AMPK activation. These findings provide mechanistic targets in the AMPK signaling pathway that may be essential for improved pregnancy success in insulin-resistant states.

scholarly journals Growth Hormone Signaling in Vivo in Human Muscle and Adipose Tissue: Impact of Insulin, Substrate Background, and Growth Hormone Receptor Blockade

2008 ◽  
Vol 93 (7) ◽  
pp. 2842-2850 ◽  
Author(s):  
Charlotte Nielsen ◽  
Lars C. Gormsen ◽  
Niels Jessen ◽  
Steen Bønløkke Pedersen ◽  
Niels Møller ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Growth Hormone ◽  
Signaling Pathways ◽  
Cross Talk ◽  
Insulin Signaling ◽  
Human Muscle ◽  
Receptor Blockade ◽  
Gh Receptor ◽  
Igf I

Abstract Context: GH induces insulin resistance in muscle and fat, and in vitro data indicate that this may involve cross-talk between the signaling pathways of the two hormones. Objective: Our objective was to investigate GH and insulin signaling in vivo in human muscle and fat tissue in response to GH, GH receptor blockade, and insulin stimulation. Design: We conducted two randomized crossover studies. Participants: Sixteen healthy males participated. Intervention: GH was administered as a bolus (n = 8) and constant infusion (n = 8). The bolus study included three arms: 1) control (saline), 2) GH (0.5 mg iv), and 3) GH blockade (pegvisomant 30 mg sc), each combined with a hyperinsulinemic glucose clamp. The infusion study included two arms: 1) GH infusion (45 ng/·kg·min, 5.5 h) and 2) saline infusion (5.5 h) combined with a hyperinsulinemic glucose clamp during the final 2.5 h. Main Outcome Measures: Muscle and fat biopsies were subjected to Western blotting for expression of Stat5/p-Stat5, Akt/p-Akt, and ERK1/2/p-ERK1/2 and to real-time RT-PCR for expression of SOCS1–3 and IGF-I mRNA. Results: GH significantly reduced insulin sensitivity. The GH bolus as well as GH infusion induced phosphorylation of Stat5 in muscle and fat, and SOCS3 and IGF-I mRNA expression increased after GH infusion. Hyperinsulinemia induced Akt phosphorylation in both tissues, irrespective of GH status. In muscle, ERK1/2 phosphorylation was increased by insulin, but insulin per se did not induce phosphorylation of Stat5. Conclusions: GH exposure associated with insulin resistance acutely translates into GH receptor signaling in human muscle and fat without evidence of cross-talk with insulin signaling pathways. The molecular mechanisms subserving GH-induced insulin resistance in humans remain unclarified.

scholarly journals The Correlation of Dyslipidemia with the Extent of Coronary Artery Disease in the Multiethnic Study of Atherosclerosis

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Moshrik Abd alamir ◽  
Michael Goyfman ◽  
Adib Chaus ◽  
Firas Dabbous ◽  
Leslie Tamura ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cardiovascular Disease ◽  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Statistical Significance ◽  
Cvd Risk Factors ◽  
Cvd Risk ◽  
Low Hdl ◽  
Artery Disease ◽  
Prevalence Ratios

Background.The extent of coronary artery calcium (CAC) improves cardiovascular disease (CVD) risk prediction. The association between common dyslipidemias (combined hyperlipidemia, simple hypercholesterolemia, metabolic Syndrome (MetS), isolated low high-density lipoprotein cholesterol, and isolated hypertriglyceridemia) compared with normolipidemia and the risk of multivessel CAC is underinvestigated.Objectives.To determine whether there is an association between common dyslipidemias compared with normolipidemia, and the extent of coronary artery involvement among MESA participants who were free of clinical cardiovascular disease at baseline.Methods.In a cross-sectional analysis, 4,917 MESA participants were classified into six groups defined by specific LDL-c, HDL-c, or triglyceride cutoff points. Multivessel CAC was defined as involvement of at least 2 coronary arteries. Multivariate Poisson regression analysis evaluated the association of each group with multivessel CAC after adjusting for CVD risk factors.Results.Unadjusted analysis showed that all groups except hypertriglyceridemia had statistically significant prevalence ratios of having multivessel CAC as compared to the normolipidemia group. The same groups maintained statistical significance prevalence ratios with multivariate analysis adjusting for other risk factors including Agatston CAC score [combined hyperlipidemia 1.41 (1.06–1.87), hypercholesterolemia 1.55 (1.26–1.92), MetS 1.28 (1.09–1.51), and low HDL-c 1.20 (1.02–1.40)].Conclusion.Combined hyperlipidemia, simple hypercholesterolemia, MetS, and low HDL-c were associated with multivessel coronary artery disease independent of CVD risk factors and CAC score. These findings may lay the groundwork for further analysis of the underlying mechanisms in the observed relationship, as well as for the development of clinical strategies for primary prevention.

scholarly journals Mechanisms Linking Inflammation to Insulin Resistance

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Li Chen ◽  
Rui Chen ◽  
Hua Wang ◽  
Fengxia Liang
Keyword(s):  
Insulin Resistance ◽  
Signaling Pathways ◽  
Insulin Signaling ◽  
Experimental Studies ◽  
Low Grade ◽  
The World ◽  
The Status ◽  
Specific Factors ◽  
Low Grade Inflammation

Obesity is now widespread around the world. Obesity-associated chronic low-grade inflammation is responsible for the decrease of insulin sensitivity, which makes obesity a major risk factor for insulin resistance and related diseases such as type 2 diabetes mellitus and metabolic syndromes. The state of low-grade inflammation is caused by overnutrition which leads to lipid accumulation in adipocytes. Obesity might increase the expression of some inflammatory cytokines and activate several signaling pathways, both of which are involved in the pathogenesis of insulin resistance by interfering with insulin signaling and action. It has been suggested that specific factors and signaling pathways are often correlated with each other; therefore, both of the fluctuation of cytokines and the status of relevant signaling pathways should be considered during studies analyzing inflammation-related insulin resistance. In this paper, we discuss how these factors and signaling pathways contribute to insulin resistance and the therapeutic promise targeting inflammation in insulin resistance based on the latest experimental studies.

scholarly journals Lipoprotein Particle Size Distributions in Response to a 6-Week Dietary Intervention Using Different Dairy Food Matrices Including Cheese and Butter

2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 582-582
Author(s):  
Simone Dunne ◽  
Eileen Gibney ◽  
Fiona McGillicuddy ◽  
Emma Feeney
Keyword(s):  
Particle Size ◽  
Particle Size Distribution ◽  
Size Distribution ◽  
Cvd Risk ◽  
Dairy Food ◽  
Dairy Fat ◽  
Lipoprotein Particle ◽  
Cholesterol Levels ◽  
Ldl Particles ◽  
Lipoprotein Particle Size

Abstract Objectives Most dietary guidelines recommend saturated fat (SFA) intakes to be < 10% of total energy intake, since SFA increase low-density lipoprotein cholesterol (LDL-c) levels, a known risk factor for cardiovascular disease (CVD). However, within LDL-c, small, dense LDL particles are more strongly related to CVD risk than large buoyant particles, and response to SFA vary for different foods. Dairy fat, when eaten as cheese, significantly lowers total cholesterol compared to butter. Here, we aimed to test the effect of the cheese matrix on lipoprotein particle size distribution response in overweight adults aged ≥ 50 years. Methods In this secondary analysis of a 6-week randomised parallel intervention(1); participants received ∼40g dairy fat in 1 of 4 treatments: (A) 120 g of full-fat cheddar cheese (FFCC); (B) reduced-fat cheese plus butter (RFC + B); (C) butter, calcium caseinate powder, and calcium supplement (CaCO3) (BCC); or (D) 120 g FFCC as per (A). Fasting EDTA blood samples at wk. 0 (baseline) and wk. 6 were analysed for lipoprotein particle size distribution via nuclear magnetic resonance (NMR) spectroscopy. To examine extremes in response, those with greatest reduction in LDL-c (n = 15, ‘positive’ responders) were compared to those with the greatest increase in LDL-c (n = 15, ‘negative’ responders). Results Correlation analyses between the change in cholesterol levels and change in particle size distribution suggest a relationship between change in LDL-c, HDL-c, and corresponding particle sizes, which differs dependent on the dairy fat matrix. The correlation of LDL-c and LDL particle (LDL-p) concentration weakened as less fat was present within a cheese matrix, as LDL-c decreased so did total LDL-p, due to larger LDL particles. The positive responders displayed a stronger relationship between change in cholesterol and lipoprotein levels, with the changes in cholesterol driven by the large LDL-p and large HDL-p. Conclusions Lipoprotein particle distribution is correlated with change in cholesterol levels after a 6-week intervention of dairy fat. The changes in LDL-c and HDL-c were driven by the less atherogenic, large LDL-p and large HDL-p which are inversely associated with CVD risk. The overall response in LDL-p to SFA appears to vary, dependent on the dairy food matrix in which the fat was eaten. Funding Sources Food for Health Ireland (FHI). Enterprise Ireland.

Sandalwood seed oil ameliorates hepatic insulin resistance by regulating the JNK/NF-κB inflammatory and PI3K/AKT insulin signaling pathways

2021 ◽  
Author(s):  
Huijun Zhang ◽  
Xiang Gao ◽  
Kelei Li ◽  
Yandi Liu ◽  
Dhanushka S. Hettiarachichi ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Insulin Signaling ◽  
Seed Oil ◽  
Insulin Signaling Pathway ◽  
Hepatic Insulin Resistance ◽  
Inflammatory Signaling

Sandalwood seed oil improved insulin resistance by activating the PI3K/AKT insulin signaling pathway and by down-regulating the JNK/NF-κB inflammatory signaling pathway in the liver.

Sign in / Sign up

Export Citation Format

Share Document