Biallelic CAV1 null variants induce Congenital Generalized Lipodystrophy with achalasia

2021 ◽  
Author(s):  
Asuman Nur Karhan ◽  
Jamila Zammouri ◽  
Martine Auclair ◽  
Emilie Capel ◽  
Feramuz Demir Apaydın ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Hdl Cholesterol ◽  
Membrane Microdomains ◽  
Phenotypic Traits ◽  
Major Protein ◽  
Genetic Transmission ◽  
Caveolin 1 ◽  
Congenital Generalized Lipodystrophy ◽  
Pathogenic Variants ◽  
Low Hdl

Objective : CAV1 encodes caveolin-1, a major protein of plasma membrane microdomains called caveolae, involved in several signalling pathways. Caveolin-1 is also located at the adipocyte lipid droplet. Heterozygous pathogenic variants of CAV1 induce rare heterogeneous disorders including pulmonary arterial hypertension and neonatal progeroid syndrome. Only one patient was previously reported with a CAV1 homozygous pathogenic variant, associated with congenital generalized lipodystrophy (CGL3). We aimed to further delineate genetic transmission, clinical, metabolic and cellular characteristics of CGL3. Design/Methods: In a large consanguineous kindred referred for CGL, we performed next-generation sequencing, as well as clinical, imagery and metabolic investigations. We studied skin fibroblasts from the index case and the previously reported patient with CGL3. Results: Four patients, aged 8 months to 18 years, carried a new homozygous p.(His79Glnfs*3) CAV1 variant. They all displayed generalized lipodystrophy since infancy, insulin resistance, low HDL-cholesterol and/or high triglycerides, but no pulmonary hypertension. Two patients also presented at the age of 15 and 18 years with dysphagia due to achalasia, and one patient had retinitis pigmentosa. Heterozygous parents and relatives (n=9) were asymptomatic, without any metabolic abnormality. Patients’ fibroblasts showed a complete loss of caveolae and no protein expression of caveolin-1 and its caveolin-2 and cavin-1 partners. Patients’ fibroblasts also displayed insulin resistance, increased oxidative stress and premature senescence. Conclusions: The CAV1 null variant investigated herein leads to an autosomal recessive congenital lipodystrophy syndrome. Loss of caveolin-1 and/or caveolae induces specific manifestations including achalasia which requires specific management. Overlapping phenotypic traits between the different CAV1-related diseases require further studies.

scholarly journals Correlation of Uric Acid Levels and Parameters of Metabolic Syndrome

2017 ◽  
pp. 481-487 ◽  
Author(s):  
L. CIBIČKOVÁ ◽  
K. LANGOVÁ ◽  
H. VAVERKOVÁ ◽  
V. KUBÍČKOVÁ ◽  
D. KARÁSEK
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Uric Acid ◽  
Hdl Cholesterol ◽  
Cross Sectional Study ◽  
Anthropometric Parameters ◽  
Cross Sectional ◽  
Hypertriglyceridemic Waist ◽  
Low Hdl ◽  
Hypertriglyceridemic Waist Phenotype

Hyperuricemia has been described as associated with the risk of development metabolic syndrome; however the relationship between the uric acid level and particular parameters of metabolic syndrome remained unclear. We performed a cross-sectional study on a cohort of 833 dyslipidemic patients and correlated their levels of uric acid with parameters of insulin resistance, lipid metabolism, C-reactive protein, anthropometric parameters. We also defined patients with hypertriglyceridemic waist phenotype and compered their uric acid levels with those without this phenotype. We found that levels of uric acid are associated with parameters of metabolic syndrome. Specifically, dyslipidemia characteristic for metabolic syndrome (low HDL cholesterol and high triglycerides) correlates better with uric acid levels than parameters of insulin resistance. Also waist circumference correlates better with uric acid levels than body mass index. Patients with hypertriglyceridemic waist phenotype had higher levels of uric acid when compared with patients without this phenotype. Serum uric acid levels are even in low levels linearly correlated with parameters of metabolic syndrome (better with typical lipid characteristics than with parameters of insulin resistance) and could be associated with higher cardiovascular risk.

scholarly journals A Contemporary Overview of PPARα/γ Dual Agonists for the Management of Diabetic Dyslipidemia

2019 ◽  
Vol 12 (3) ◽  
pp. 195-201 ◽  
Author(s):  
Pitchai Balakumar ◽  
Nanjaian Mahadevan ◽  
Ramanathan Sambathkumar
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Therapeutic Option ◽  
Hdl Cholesterol ◽  
High Plasma ◽  
Cholesterol Concentration ◽  
Current Status ◽  
Peroxisome Proliferator ◽  
Diabetic Dyslipidemia ◽  
Low Hdl

Background: Diabetes mellitus and concomitant dyslipidemia, being referred to as ‘diabetic dyslipidemia’, are the foremost detrimental factors documented to play a pivotal role in cardiovascular illness. Diabetic dyslipidemia is associated with insulin resistance, high plasma triglyceride levels, low HDL-cholesterol concentration and elevated small dense LDL-cholesterol particles. Maintaining an optimal glucose and lipid levels in patients afflicted with diabetic dyslipidemia could be a major task that might require a well-planned diet-management system and regular physical activity, or otherwise an intake of combined antidiabetic and antihyperlipidemic medications. Synchronized treatment which efficiently controls insulin resistance-associated diabetes mellitus and co-existing dyslipidemia could indeed be a fascinating therapeutic option in the management of diabetic dyslipidemia. Peroxisome proliferator-activated receptors α/γ (PPARα/γ) dual agonists are such kind of drugs which possess therapeutic potentials to treat diabetic dyslipidemia. Nevertheless, PPARα/γ dual agonists like muraglitazar, naveglitazar, tesaglitazar, ragaglitazar and aleglitazar have been reported to have undesirable adverse effects, and their developments have been halted at various stages. On the other hand, a recently introduced PPARα/γ dual agonist, saroglitazar is an emerging therapeutic agent of glitazar class approved in India for the management of diabetic dyslipidemia, and its treatment has been reported to be generally safe and well tolerated. Conclusion: Some additional and new compounds, at initial and preclinical stages, have been recently reported to possess PPARα/γ dual agonistic potentials with considerable therapeutic efficacy and reduced adverse profile. This review sheds light on the current status of various PPARα/γ dual agonists for the management of diabetic dyslipidemia.

scholarly journals Insulin Resistance and Cardiovascular Events With Low HDL Cholesterol: The Veterans Affairs HDL Intervention Trial (VA-HIT)

Diabetes Care ◽  
2003 ◽  
Vol 26 (5) ◽  
pp. 1513-1517 ◽  
Author(s):  
S. J. Robins ◽  
H. B. Rubins ◽  
F. H. Faas ◽  
E. J. Schaefer ◽  
M. B. Elam ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Cardiovascular Events ◽  
Hdl Cholesterol ◽  
Veterans Affairs ◽  
Intervention Trial ◽  
Low Hdl

scholarly journals Unacylated Ghrelin is associated with the isolated low HDL-cholesterol obese phenotype independently of insulin resistance and CRP level

2012 ◽  
Vol 9 (1) ◽  
pp. 17 ◽  
Author(s):  
Juan-Patricio Nogueira ◽  
Marie Maraninchi ◽  
Sophie Beliard ◽  
Anne Marie Lorec ◽  
Bruno Berthet ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Hdl Cholesterol ◽  
Unacylated Ghrelin ◽  
Low Hdl ◽  
Obese Phenotype

Abstract 506: Hepatic Insulin Signaling Regulates ApoAI Expression Through Type I Deiodinase

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Jing Liu ◽  
Antonio Hernandez-Ono ◽  
Valerie A Galton ◽  
Henry N Ginsberg
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Signaling ◽  
Knockout Mice ◽  
Luciferase Activity ◽  
Hdl Cholesterol ◽  
Mrna Levels ◽  
Cholesterol Levels ◽  
Low Hdl

Low HDL cholesterol is a common feature of insulin resistant states such as type 2 diabetes, but little is known about the regulation of HDL cholesterol and apoAI levels by insulin signaling. In prior studies, we observed that liver insulin receptor (Insr) knockout mice (LIRKO) had very low plasma HDL cholesterol and apoAI levels compared with their controls. HDL cholesterol levels were normalized when we restored insulin signaling by expression of constitutively active (CA) AKT1. Acute knock down of hepatic Insr by adenovirus-mediated expression of albumin-Cre in Insr flox/flox mice resulted in a marked decrease in the levels of ApoAI and Dio1 mRNA in the liver. Dio1 encodes the Type 1 deiodinase (D1), which can convert thyroxine to 3,5,3’-triiodothyronine. Adenovirus mediated overexpression of Dio1 increased HDL cholesterol and apoAI levels in LIRKO mice. D1 knockout mice exhibited a significant reduction in hepatic ApoAI mRNA levels. In McArdle cells, short interfering (si) RNA-mediated knockdown of Insr reduced both Dio1 and ApoAI mRNA levels. Knockdown of Insr by siRNA reduced luciferase activity of both hDio1 and hApoAI promoter constructs in HepG2 cells. Furthermore, siRNA-mediated knockdown of Dio1 expression also decreased hApoAI luciferase activity. These findings indicate that insulin signaling regulates the expression of both Dio1 and ApoAI, and that Dio1 regulates ApoAI expression. Reductions in ApoAI gene expression may play a role in the etiology of low HDL cholesterol levels commonly present in states of insulin resistance. Targeting D1 may be a novel way to increase apoAI and HDL cholesterol levels in people with insulin resistance or type 2 diabetes mellitus.

scholarly journals Relationship of TSH levels with cardiometabolic risk factors in US youth and reference percentiles for thyroid function

2020 ◽  
Author(s):  
Xinlei Chen ◽  
Shuliang Deng ◽  
Cecilia Sena ◽  
Chuhan Zhou ◽  
Vidhu V Thaker
Keyword(s):  
Risk Factors ◽  
Insulin Resistance ◽  
Abdominal Obesity ◽  
Cardiometabolic Risk ◽  
Hdl Cholesterol ◽  
Cross Sectional Study ◽  
Cardiometabolic Risk Factors ◽  
Cross Sectional ◽  
Low Hdl ◽  
Tsh Levels

Abstract Context Thyroid hormones play an important role in the metabolic homeostasis and higher levels have been associated with cardiometabolic risk. Objective To examine the association of cardiometabolic risk factors with TSH levels in US youth. Design & Setting Cross-sectional study of youth aged 12-18 years without known thyroid abnormalities from five National Health and Nutrition Examination Survey cycles (n=2,818) representing 15.4 million US children. Subclinical hypothyroidism (SH) was defined as TSH levels 4.5-10 mIU/L. Assessed cardiometabolic risk factors include abdominal obesity (waist circumference > 90 th percentile), hypertriglyceridemia (TG ≥130 mg/dL), low HDL cholesterol (HDL-C < 40 mg/dL), elevated blood pressure (SBP and DBP ≥90 th percentile), hyperglycemia (FBG ≥100 mg/dL, or known diabetes), insulin resistance (HOMA-IR > 3.16) and elevated alanine transferase (ALT ≥ 50 U/L for boys and ≥ 44 U/L for girls). Age and sex- specific percentiles for thyroid parameters were calculated. Results In this cohort of youth (51.3% male), 31.2% had overweight/obesity. The prevalence of SH was 2.0 % (95% CI 1.2-3.1). The median TSH levels were higher in youth with overweight/obesity (p<.001). Adjusting for age, sex, race/ethnicity and obesity, youth with TSH in the 4 th quantile had higher odds of abdominal obesity (OR 2.53 [1.43-4.46], p = .002), insulin resistance (OR 2.82 [1.42-5.57], p=.003) and ≥ 2 CMRF (OR 2.20 [1.23-3.95], p=.009). Conclusions The prevalence of SH is low in US youth. The higher odds of insulin resistance and cardiometabolic risk factors in youth with TSH levels > 75 th percentile requires further study.

scholarly journals Hypertriglyceridemia, Metabolic Syndrome, and Cardiovascular Disease in HIV-Infected Patients: Effects of Antiretroviral Therapy and Adipose Tissue Distribution

2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Jeroen P. H. van Wijk ◽  
Manuel Castro Cabezas
Keyword(s):  
Risk Factors ◽  
Insulin Resistance ◽  
Cardiovascular Disease ◽  
Cardiovascular Risk ◽  
Antiretroviral Therapy ◽  
Hdl Cholesterol ◽  
Postprandial Hyperlipidemia ◽  
Dramatic Decline ◽  
Low Hdl ◽  
Related Mortality

The use of combination antiretroviral therapy (CART) in HIV-infected patients has resulted in a dramatic decline in AIDS-related mortality. However, mortality due to non-AIDS conditions, particularly cardiovascular disease (CVD) seems to increase in this population. CART has been associated with several metabolic risk factors, including insulin resistance, low HDL-cholesterol, hypertriglyceridemia and postprandial hyperlipidemia. In addition, HIV itself, as well as specific antiretroviral agents, may further increase cardiovascular risk by interfering with endothelial function. As the HIV population is aging, CVD may become an increasingly growing health problem in the future. Therefore, early diagnosis and treatment of cardiovascular risk factors is warranted in this population. This paper reviews the contribution of both, HIV infection and CART, to insulin resistance, postprandial hyperlipidemia and cardiovascular risk in HIV-infected patients. Strategies to reduce cardiovascular risk are also discussed.

scholarly journals Glucocorticoids and Type 2 Diabetes: From Physiology to Pathology

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Guido Di Dalmazi ◽  
Uberto Pagotto ◽  
Renato Pasquali ◽  
Valentina Vicennati
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Hdl Cholesterol ◽  
Overweight And Obesity ◽  
Metabolic Disturbances ◽  
Counterregulatory Hormones ◽  
The Metabolic Syndrome ◽  
Low Hdl ◽  
Glucagon Like Peptide 1

Type 2 diabetes mellitus is the result of interaction between genetic and environmental factors, leading to heterogeneous and progressive pancreaticβ-cell dysfunction. Overweight and obesity are major contributors to the development of insulin resistance and impaired glucose tolerance. The inability ofβcells to secrete enough insulin produces type 2 diabetes. Abnormalities in other hormones such as reduced secretion of the incretin glucagon-like peptide 1 (GLP-1), hyperglucagonemia, and raised concentrations of other counterregulatory hormones also contribute to insulin resistance, reduced insulin secretion, and hyperglycaemia in type 2 diabetes. Clinical-overt and experimental cortisol excess is associated with profound metabolic disturbances of intermediate metabolism resulting in abdominal obesity, insulin resistance, and low HDL-cholesterol levels, which can lead to diabetes. It was therefore suggested that subtle abnormalities in cortisol secretion and action are one of the missing links between insulin resistance and other features of the metabolic syndrome. The aim of this paper is to address the role of glucocorticoids on glucose homeostasis and to explain the relationship between hypercortisolism and type 2 diabetes.

scholarly journals Low HDL cholesterol is associated with increased atherogenic lipoproteins and insulin resistance in women classified with metabolic syndrome

2010 ◽  
Vol 4 (6) ◽  
pp. 492 ◽  
Author(s):  
Maria Luz Fernandez ◽  
Jennifer J Jones ◽  
Daniela Ackerman ◽  
Jacqueline Barona ◽  
Mariana Calle ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Hdl Cholesterol ◽  
Low Hdl
Sign in / Sign up

Export Citation Format

Share Document