|
1
|
Zhang Z, Chen H, Chen L, Liang W, Hu T, Sun N, Zhao Y, Wei X. Association of total cholesterol to high-density lipoprotein cholesterol ratio with diabetes risk: a retrospective study of Chinese individuals. Sci Rep 2025; 15:16261. [PMID: 40346160 PMCID: PMC12064768 DOI: 10.1038/s41598-025-87277-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2024] [Accepted: 01/17/2025] [Indexed: 05/11/2025] Open
Abstract
A common complication of type 2 diabetes is hypercholesterolemia in many patients. It is still unclear, nevertheless, how high-density lipoprotein cholesterol ratio (TC/HDL-C), total cholesterol, and diabetes are related. The purpose of this study is to look at the prediction ability and causal relationship between TC/HDL-C and diabetes. This study included 117,268 subjects who were undergoing physical examinations. The subjects were grouped into four equal groups according to the TC/HDL-C quartiles; the main outcome was the occurrence of diabetes events. TC/HDL-C is calculated as total cholesterol divided by high-density lipoprotein cholesterol. In 3.1 years (± 0.95) of follow-up, 795 women (0.68%) and 1,894 men (1.62%) received new diabetes diagnoses. TC/HDL-C is an independent predictor of new-onset diabetes, according to multivariable Cox regression analysis (HR 1.27 per SD increase, 95% CI: 1.09-1.48, P for trend < 0.001). It turned out that a cutoff value of 3.55 (area under the curve 0.64, sensitivity 0.66, specificity 0.56), was ideal for TC/HDL-C in predicting new-onset diabetes. A subgroup analysis demonstrated that the younger population had a significantly higher risk of TC/HDL-C-related diabetes than the middle-aged group (interaction P < 0.05). After controlling for confounding variables, this Chinese cohort study reveals a direct correlation between TC/HDL-C and diabetes, with a stronger independent association observed in younger and middle-aged individuals.
Collapse
Affiliation(s)
- Zhiqiang Zhang
- Department of Cardiology, Affiliated Hospital of Jining Medical University, Clinical Medical College, Jining Medical University, Jining, 272000, China
- Shandong Key Laboratory for Diagnosis and Treatment of Cardiovascular Diseases, Jining, 272000, Shandong, China
- Shandong Provincial Key Medical and Health Discipline of Cardiology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, 272000, Shandong, China
- Graduate School of Tianjin Medical University, Tianjin Medical University, Tianjin, 300070, Tianjin, China
| | - Hejun Chen
- Graduate School of Tianjin Medical University, Tianjin Medical University, Tianjin, 300070, Tianjin, China
| | - Lei Chen
- Department of Cardiology, Affiliated Hospital of Jining Medical University, Clinical Medical College, Jining Medical University, Jining, 272000, China
- Shandong Key Laboratory for Diagnosis and Treatment of Cardiovascular Diseases, Jining, 272000, Shandong, China
- Shandong Provincial Key Medical and Health Discipline of Cardiology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, 272000, Shandong, China
- Department of Cardiology, Fujian Medical University Union Hospital, Fuzhou, 350004, Fujian, China
| | - Wenyan Liang
- Department of Cardiology, Affiliated Hospital of Jining Medical University, Clinical Medical College, Jining Medical University, Jining, 272000, China
- Shandong Key Laboratory for Diagnosis and Treatment of Cardiovascular Diseases, Jining, 272000, Shandong, China
- Shandong Provincial Key Medical and Health Discipline of Cardiology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, 272000, Shandong, China
| | - Tenglong Hu
- Department of Cardiology, Affiliated Hospital of Jining Medical University, Clinical Medical College, Jining Medical University, Jining, 272000, China
- Shandong Key Laboratory for Diagnosis and Treatment of Cardiovascular Diseases, Jining, 272000, Shandong, China
- Shandong Provincial Key Medical and Health Discipline of Cardiology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, 272000, Shandong, China
| | - Na Sun
- Department of Cardiology, Affiliated Hospital of Jining Medical University, Clinical Medical College, Jining Medical University, Jining, 272000, China
- Shandong Key Laboratory for Diagnosis and Treatment of Cardiovascular Diseases, Jining, 272000, Shandong, China
- Shandong Provincial Key Medical and Health Discipline of Cardiology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, 272000, Shandong, China
| | - Yangyu Zhao
- Department of Cardiology, Affiliated Hospital of Jining Medical University, Clinical Medical College, Jining Medical University, Jining, 272000, China
- Shandong Key Laboratory for Diagnosis and Treatment of Cardiovascular Diseases, Jining, 272000, Shandong, China
- Shandong Provincial Key Medical and Health Discipline of Cardiology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, 272000, Shandong, China
| | - Xiqing Wei
- Department of Cardiology, Affiliated Hospital of Jining Medical University, Clinical Medical College, Jining Medical University, Jining, 272000, China.
- Shandong Key Laboratory for Diagnosis and Treatment of Cardiovascular Diseases, Jining, 272000, Shandong, China.
- Shandong Provincial Key Medical and Health Discipline of Cardiology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, 272000, Shandong, China.
| |
Collapse
|
|
2
|
Ramakrishnan K, Rajan R, Nachimuthu L, Jayaraj P, Narasimhulu CA, Deme P, Rajagopalan S, Sivaramakrishna A, Karthikeyan S, Desikan R. Development of Novel α-Amylase Inhibitors: Synthesis, Molecular Docking, and Biochemical Studies. Cell Biochem Biophys 2025:10.1007/s12013-025-01759-6. [PMID: 40299205 DOI: 10.1007/s12013-025-01759-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/08/2025] [Indexed: 04/30/2025]
Abstract
The rising prevalence of diabetes as a major non-communicable disease underscores the critical need for effective anti-diabetic agents. The new analogs designed 3a-3j were effectively synthesised and thoroughly characterised using (1H, 13C NMR, FT-IR, GCMS, and HRMS) to investigate their structural biochemical properties. The novel analogs were investigated thoroughly by in silico (molecular docking) and in vitro (anti-oxidant (DPPH, ABTS) activity, anti-inflammation (RBC), modifications of LDL and HDL, thiobarbituric substances, cholesterol efflux assay, and anti-diabetic) assays, validated for α-amylase inhibition. Enzyme inhibition results showed α-amylase IC50 values of 1.79 ± 0.12 μg for compound 3d, 1.75 ± 0.05 μg for compound 3e, and 1.53 ± 0.20 μg for the standard drug acarbose. Among the new molecules, compounds 3c and 3d exhibited the highest inhibitory activity in all performed in silico and in vitro studies. The study demonstrated that inhibitors 3a-3j bind strongly to the active site of human pancreatic α-amylase, highlighting their potential as effective inhibitors. These research findings help to improve the field of developing lead molecules for anti-diabetic agents.
Collapse
Affiliation(s)
- K Ramakrishnan
- Department of Chemistry, School of Advanced Sciences, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Reshma Rajan
- Department of Chemistry, School of Advanced Sciences, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Lenin Nachimuthu
- Department of Chemistry, School of Advanced Sciences, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Premkumar Jayaraj
- Department of Chemistry, School of Advanced Sciences, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Chandrakala A Narasimhulu
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, USA
| | - Pragney Deme
- Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Sanjay Rajagopalan
- Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
| | - Akella Sivaramakrishna
- Department of Chemistry, School of Advanced Sciences, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - S Karthikeyan
- Department of Chemistry, School of Advanced Sciences, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Rajagopal Desikan
- Department of Chemistry, School of Advanced Sciences, Vellore Institute of Technology, Vellore, Tamil Nadu, India.
| |
Collapse
|
|
3
|
Kron V, Verner M, Smetana P, Vrzalova R, Friebergerova E, Martinik D, Horakova D, Stepanek L, Hamplova L, Kotrbova K. Changes in glucose-related parameters according to LDL-cholesterol concentration ranges in non-diabetic patients. J Appl Biomed 2025; 23:26-35. [PMID: 40145883 DOI: 10.32725/jab.2025.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Accepted: 02/24/2025] [Indexed: 03/28/2025] Open
Abstract
The study focused on the changes in C-peptide, glycemia, insulin concentration, and insulin resistance according to LDL-cholesterol concentration ranges. The metabolic profile of individuals in the Czech Republic (n = 1840) was classified by quartiles of LDL-cholesterol into four groups with the following ranges: 0.46-2.45 (n = 445), 2.46-3.00 (n = 474), 3.01-3.59 (n = 459), and 3.60-7.18 mmol/l (n = 462). The level of glucose, C-peptide, insulin, and area of parameters during OGTT and HOMA IR were compared with a relevant LDL-cholesterol range. The evaluation involved correlations between LDL-cholesterol and the above parameters, F-test and t-test. Generally, mean values of glucose homeostasis-related parameters were higher with increasing LDL-cholesterol levels, except for mean HOMA IR values which rapidly increased (2.7-3.4) between LDL-cholesterol ranges of 3.00-3.59 and 3.60-7.18 mmol/l. Glucose, C-peptide, insulin concentrations, and the area of parameters reached greater changes especially after glucose load during OGTT (p ≤ 0.001). Considerable changes were already observed for the above parameters between groups with LDL-cholesterol ranges of 2.46-3.00 and 3.01-3.59 mmol/l. HOMA IR increased with higher LDL-cholesterol concentrations, but the differences in mean values were not statistically significant. Most important differences appeared in glucose metabolism at LDL-cholesterol concentrations of 3.60-7.18 mmol/l in comparison to LDL-cholesterol lower ranges. In particular, the areas of C-peptide, glucose, and insulin ranges showed statistically significant differences between all groups with growing LDL-cholesterol ranges. The variances of HOMA IR statistically differed between groups created according to LDL-cholesterol concentrations ranges.
Collapse
Affiliation(s)
- Vladimir Kron
- University of South Bohemia in Ceske Budejovice, Faculty of Agriculture and Technology, Department of Food, Biotechnologies and Agricultural Products Quality, Ceske Budejovice, Czech Republic
- Ambulance for Metabolic Assessment of prof. MUDr. Karel Martinik, DrSc., s.r.o., Hradec Kralove, Czech Republic
- University of South Bohemia in Ceske Budejovice, Faculty of Science, Department of Medical Biology, Ceske Budejovice, Czech Republic
| | - Miroslav Verner
- Hospital of Ceske Budejovice, a. s., Central Laboratories, Ceske Budejovice, Czech Republic
- University of South Bohemia in Ceske Budejovice, Faculty of Science, Department of Medical Biology, Ceske Budejovice, Czech Republic
| | - Pavel Smetana
- University of South Bohemia in Ceske Budejovice, Faculty of Agriculture and Technology, Department of Food, Biotechnologies and Agricultural Products Quality, Ceske Budejovice, Czech Republic
| | - Radka Vrzalova
- University of South Bohemia in Ceske Budejovice, Faculty of Agriculture and Technology, Department of Food, Biotechnologies and Agricultural Products Quality, Ceske Budejovice, Czech Republic
| | - Eliska Friebergerova
- University of South Bohemia in Ceske Budejovice, Faculty of Agriculture and Technology, Department of Food, Biotechnologies and Agricultural Products Quality, Ceske Budejovice, Czech Republic
| | - Daniel Martinik
- Ambulance for Metabolic Assessment of prof. MUDr. Karel Martinik, DrSc., s.r.o., Hradec Kralove, Czech Republic
| | - Dagmar Horakova
- Palacky University Olomouc, Faculty of Medicine and Dentistry, Department of Public Health, Olomouc, Czech Republic
| | - Ladislav Stepanek
- Palacky University Olomouc, Faculty of Medicine and Dentistry, Department of Public Health, Olomouc, Czech Republic
| | | | - Kvetoslava Kotrbova
- Institute of Laboratory Diagnostics and Public Health, Ceske Budejovice, Czech Republic
| |
Collapse
|
|
4
|
Liu K, Cooper ME, Chai Z, Liu F. High-Density Lipoprotein in Patients with Diabetic Kidney Disease: Friend or Foe? Int J Mol Sci 2025; 26:1683. [PMID: 40004147 PMCID: PMC11855193 DOI: 10.3390/ijms26041683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Revised: 02/10/2025] [Accepted: 02/12/2025] [Indexed: 02/27/2025] Open
Abstract
High-density lipoprotein (HDL) exhibits multiple metabolic protective functions, such as facilitating cellular cholesterol efflux, antioxidant, anti-inflammatory, anti-apoptotic and anti-thrombotic properties, showing antidiabetic and renoprotective potential. Diabetic kidney disease (DKD) is considered to be associated with high-density lipoprotein cholesterol (HDL-C). The hyperglycemic environment, non-enzymatic glycosylation, carbamylation, oxidative stress and systemic inflammation can cause changes in the quantity and quality of HDL, resulting in reduced HDL levels and abnormal function. Dysfunctional HDL can also have a negative impact on pancreatic β cells and kidney cells, leading to the progression of DKD. Based on these findings, new HDL-related DKD risk predictors have gradually been proposed. Interventions aiming to improve HDL levels and function, such as infusion of recombinant HDL (rHDL) or lipid-poor apolipoprotein A-I (apoA-I), can significantly improve glycemic control and also show renal protective effects. However, recent studies have revealed a U-shaped relationship between HDL-C levels and DKD, and the loss of protective properties of high levels of HDL may be related to changes in composition and the deposition of dysfunctional particles that exacerbate damage. Further research is needed to fully elucidate the complex role of HDL in DKD. Given the important role of HDL in metabolic health, developing HDL-based therapies that augment HDL function, rather than simply increasing its level, is a critical step in managing the development and progression of DKD.
Collapse
Affiliation(s)
- Ke Liu
- Department of Nephrology, West China Hospital of Sichuan University, Chengdu 610041, China;
- Laboratory of Diabetic Kidney Disease, Kidney Research Institute, Department of Nephrology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Mark E. Cooper
- Department of Diabetes, School of Translational Medicine, Monash University, Melbourne, VIC 3004, Australia;
| | - Zhonglin Chai
- Department of Diabetes, School of Translational Medicine, Monash University, Melbourne, VIC 3004, Australia;
| | - Fang Liu
- Department of Nephrology, West China Hospital of Sichuan University, Chengdu 610041, China;
- Laboratory of Diabetic Kidney Disease, Kidney Research Institute, Department of Nephrology, West China Hospital, Sichuan University, Chengdu 610041, China
| |
Collapse
|
|
5
|
Herrerías-García A, Jacobo-Tovar E, Hernández-Robles CM, Guardado-Mendoza R. Pancreatic beta cell function and insulin resistance profiles in first-degree relatives of patients with prediabetes and type 2 diabetes. Acta Diabetol 2025; 62:253-261. [PMID: 39150512 DOI: 10.1007/s00592-024-02352-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Accepted: 07/30/2024] [Indexed: 08/17/2024]
Abstract
AIMS To evaluate insulin secretion and insulin resistance profiles in individuals with family history of prediabetes and type 2 diabetes. METHODS This was a cross-sectional study to evaluate clinical and metabolic profiles between individuals with type 2 diabetes, prediabetes and their relatives. There were 911 subjects divided into five groups: (i) normoglycemic (NG), (ii) type 2 diabetes, (iii) prediabetes, (iv) first-degree relatives of patients with type 2 diabetes (famT2D), and (v) first-degree relatives of patients with prediabetes (famPD); anthropometrical, biochemical and nutritional evaluation, as well as insulin resistance and pancreatic beta cell function measurement was performed by oral glucose tolerance to compare between groups. RESULTS The most prevalent type 2 diabetes risk factors were dyslipidemia (81%), family history of type 2 diabetes (76%), central obesity (73%), male sex (63%), and sedentary lifestyle (60%), and most of them were progressively associated to prediabetes and type 2 diabetes groups. Insulin sensitivity was lower in famT2D groups in comparison to NG group (p < 0.0001). FamPD and famT2D had a 10% lower pancreatic beta cell function (DI) than the NG group (NG group 2.78 ± 1.0, famPD 2.5 ± 0.85, famT2D 2.4 ± 0.75, p˂0.001). CONCLUSIONS FamPD and famT2D patients had lower pancreatic beta cell function than NG patients, highlighting that defects in insulin secretion and insulin sensitivity appear long time before the development of hyperglycemia in patients genetically predisposed.
Collapse
Affiliation(s)
- Anaid Herrerías-García
- Metabolic Research Laboratory, Department of Medicine and Nutrition, University of Guanajuato, Blvd. Milenio 1001, Predio San Carlos, 37670, León, Guanajuato, Mexico
| | - Emmanuel Jacobo-Tovar
- Metabolic Research Laboratory, Department of Medicine and Nutrition, University of Guanajuato, Blvd. Milenio 1001, Predio San Carlos, 37670, León, Guanajuato, Mexico
| | - Claudia Mariana Hernández-Robles
- Metabolic Research Laboratory, Department of Medicine and Nutrition, University of Guanajuato, Blvd. Milenio 1001, Predio San Carlos, 37670, León, Guanajuato, Mexico
| | - Rodolfo Guardado-Mendoza
- Metabolic Research Laboratory, Department of Medicine and Nutrition, University of Guanajuato, Blvd. Milenio 1001, Predio San Carlos, 37670, León, Guanajuato, Mexico.
| |
Collapse
|
|
6
|
Liu D, Yin M, Chen J, Fu C, Schneider M, Nickel D, Yao X. Fatty acid composition evaluation of abdominal adipose tissue using chemical shiftencoded MRI: Association with diabetes. NMR IN BIOMEDICINE 2025; 38:e5290. [PMID: 39511916 DOI: 10.1002/nbm.5290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 09/26/2024] [Accepted: 10/21/2024] [Indexed: 11/15/2024]
Abstract
This study investigated the association between the fatty acid composition of abdominal adipose tissue in NAFLD patients using chemical shift-encoded MRI and the development of insulin resistance and T2DM. We enrolled 231 subjects with NAFLD who underwent both abdominal magnetic resonance spectroscopy and chemical shift-encoded MRI: comprising of 49 T2DM patients and 182 subjects without. MRI- and MRS-based liver fat fraction was measured from a circular region of interest on the right lobe of the liver. The abdominal fatty acid compositions were measured at the umbilical level with chemical shift-encoded MRI. Bland-Altman analysis, Student's t test, Mann-Whitney U test, and Spearman correlation analysis were performed. The logistic regression was applied to identify the independent factors for T2DM. Then, the predictive performance was assessed by Receiver operating characteristic curve analyses. An excellent agreement was found between liver fat fraction measured by MRS and MRI. (slope = 0.8; bias =-0.92%). In, patients with T2DM revealed lower fractions of mono-unsaturated fatty acid (Fmufa) (33.68 ± 10.62 vs 38.62 ± 12.21, P =.0089) and higher fractions of saturated fatty acid (Fsfa) (34.11 ± 9.746 vs 31.25 ± 8.66, P =.0351) of visceral fat tissue compared with patients without. BMI, HDL-c, Fmufa and Fsfa of visceral fat were independent factors for T2DM. Furthermore, Fsfa-S% was positively correlated with liver enzyme levels (P =.003 and 0.04). However, Fmufa-V% was negatively correlated with fasting blood glucose, HbA1c and HOMA-IR (P =.004, P =.001 and P =.03 respectively). Hence, the evaluation of fatty acid compositions of abdominal fat tissue using chemical shift-encoded MRI may have a predictive value for T2DM in patients with NAFLD.
Collapse
Affiliation(s)
- Dingxia Liu
- Shanghai Institute of Medical Imaging, Dept. of Radiology, Zhongshan Hospital of Fudan University, Fudan University, Shanghai, China
| | - Minyan Yin
- Shanghai Institute of Medical Imaging, Dept. of Radiology, Zhongshan Hospital of Fudan University, Fudan University, Shanghai, China
| | - Jiejun Chen
- Shanghai Institute of Medical Imaging, Dept. of Radiology, Zhongshan Hospital of Fudan University, Fudan University, Shanghai, China
| | - Caixia Fu
- Application Development, Siemens Shenzhen Magnetic Resonance Ltd, Shenzhen, China
| | - Manuel Schneider
- MR Application Predevelopment, Siemens Healthcare GmbH, Erlangen, Germany
| | - Dominik Nickel
- MR Application Predevelopment, Siemens Healthcare GmbH, Erlangen, Germany
| | - Xiuzhong Yao
- Shanghai Institute of Medical Imaging, Dept. of Radiology, Zhongshan Hospital of Fudan University, Fudan University, Shanghai, China
| |
Collapse
|
|
7
|
Jiménez-Sánchez C, Oberhauser L, Maechler P. Role of fatty acids in the pathogenesis of ß-cell failure and Type-2 diabetes. Atherosclerosis 2024; 398:118623. [PMID: 39389828 DOI: 10.1016/j.atherosclerosis.2024.118623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 10/02/2024] [Accepted: 10/03/2024] [Indexed: 10/12/2024]
Abstract
Pancreatic ß-cells are glucose sensors in charge of regulated insulin delivery to the organism, achieving glucose homeostasis and overall energy storage. The latter function promotes obesity when nutrient intake chronically exceeds daily expenditure. In case of ß-cell failure, such weight gain may pave the way for the development of Type-2 diabetes. However, the causal link between excessive body fat mass and potential degradation of ß-cells remains largely unknown and debated. Over the last decades, intensive research has been conducted on the role of lipids in the pathogenesis of ß-cells, also referred to as lipotoxicity. Among various lipid species, the usual suspects are essentially the non-esterified fatty acids (NEFA), in particular the saturated ones such as palmitate. This review describes the fundamentals and the latest advances of research on the role of fatty acids in ß-cells. This includes intracellular pathways and receptor-mediated signaling, both participating in regulated glucose-stimulated insulin secretion as well as being implicated in ß-cell dysfunction. The discussion extends to the contribution of high glucose exposure, or glucotoxicity, to ß-cell defects. Combining glucotoxicity and lipotoxicity results in the synergistic and more deleterious glucolipotoxicity effect. In recent years, alternative roles for intracellular lipids have been uncovered, pointing to a protective function in case of nutrient overload. This requires dynamic storage of NEFA as neutral lipid droplets within the ß-cell, along with active glycerolipid/NEFA cycle allowing subsequent recruitment of lipid species supporting glucose-stimulated insulin secretion. Overall, the latest studies have revealed the two faces of the same coin.
Collapse
Affiliation(s)
- Cecilia Jiménez-Sánchez
- Department of Cell Physiology and Metabolism & Faculty Diabetes Center, University of Geneva Medical Center, Geneva, Switzerland
| | - Lucie Oberhauser
- Department of Cell Physiology and Metabolism & Faculty Diabetes Center, University of Geneva Medical Center, Geneva, Switzerland
| | - Pierre Maechler
- Department of Cell Physiology and Metabolism & Faculty Diabetes Center, University of Geneva Medical Center, Geneva, Switzerland.
| |
Collapse
|
|
8
|
Zhang X, van der Vorst EPC. High-Density Lipoprotein Modifications: Causes and Functional Consequences in Type 2 Diabetes Mellitus. Cells 2024; 13:1113. [PMID: 38994965 PMCID: PMC11240616 DOI: 10.3390/cells13131113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 06/22/2024] [Accepted: 06/24/2024] [Indexed: 07/13/2024] Open
Abstract
High-density lipoprotein (HDL) is a group of small, dense, and protein-rich lipoproteins that play a role in cholesterol metabolism and various cellular processes. Decreased levels of HDL and HDL dysfunction are commonly observed in individuals with type 2 diabetes mellitus (T2DM), which is also associated with an increased risk for cardiovascular disease (CVD). Due to hyperglycemia, oxidative stress, and inflammation that develop in T2DM, HDL undergoes several post-translational modifications such as glycation, oxidation, and carbamylation, as well as other alterations in its lipid and protein composition. It is increasingly recognized that the generation of HDL modifications in T2DM seems to be the main cause of HDL dysfunction and may in turn influence the development and progression of T2DM and its related cardiovascular complications. This review provides a general introduction to HDL structure and function and summarizes the main modifications of HDL that occur in T2DM. Furthermore, the potential impact of HDL modifications on the pathogenesis of T2DM and CVD, based on the altered interactions between modified HDL and various cell types that are involved in glucose homeostasis and atherosclerotic plaque generation, will be discussed. In addition, some perspectives for future research regarding the T2DM-related HDL modifications are addressed.
Collapse
Affiliation(s)
- Xiaodi Zhang
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, 52074 Aachen, Germany;
- Aachen-Maastricht Institute for CardioRenal Disease (AMICARE), RWTH Aachen University, 52074 Aachen, Germany
| | - Emiel P. C. van der Vorst
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, 52074 Aachen, Germany;
- Aachen-Maastricht Institute for CardioRenal Disease (AMICARE), RWTH Aachen University, 52074 Aachen, Germany
- Interdisciplinary Center for Clinical Research (IZKF), RWTH Aachen University, 52074 Aachen, Germany
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich (LMU), 80336 Munich, Germany
| |
Collapse
|
|
9
|
Hashemy H, Nguyen A, Khafagy R, Roshandel D, Paterson AD, Dash S. Analyses of potential causal contributors to increased waist/hip ratio-associated cardiometabolic disease: A combined and sex-stratified Mendelian randomization study. Diabetes Obes Metab 2024; 26:2284-2291. [PMID: 38488265 DOI: 10.1111/dom.15542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 02/21/2024] [Accepted: 02/22/2024] [Indexed: 05/09/2024]
Abstract
BACKGROUND Increased waist/hip ratio (WHR) contributes to type 2 diabetes, fatty liver, dyslipidaemia, hypertension and coronary artery disease, with potential sex-differential effects. Postulated mediators include increased lipid flux, branched-chain amino acids, glycine and glycoprotein acetyl, but their relative contributions and sex-specific impact on WHR-associated cardiometabolic disease (CMD) are not established. METHODS We therefore undertook combined and sex-stratified Mendelian randomization (MR) to assess the relative causal contributions of these mediators to WHR-associated CMD using summary statistics from the largest genome-wide association studies in European ancestries. RESULTS In sex-combined MR analyses, increased WHR significantly reduces high-density lipoprotein (beta = -0.416, SE = 0.029, p = 2.87E-47), increases triglyceride (beta = 0.431, SE = 0.029, p = 1.87E-50), type 2 diabetes (odds ratio = 2.747, SE = 0.09, p = 26E-23), coronary artery disease (odds ratio = 1.478, SE = 0.045, p = 6.96E-18), alanine transaminase (beta = 0.062, SE = 0.004, p = 6.88E-67), and systolic (beta = 0.134, SE = 0.022, p = 7.81E-10) and diastolic blood pressure (beta = 0.162, SE = 0.026, p = 5.38E-10). Adjustment for the mediators attenuated WHR's effects, but the associations remained significant with concordant results in females. In males, a similar pattern was seen, except after adjusting for the effect of the ratio of monounsaturated fatty acid to total free fatty acid, the potential causal effect of WHR was no longer significant: high-density lipoprotein (beta = -0.117, SE = 0.069, p = .09) and triglyceride (beta = 0.051, SE = 0.068, p = .459). CONCLUSIONS MR suggests WHR increases the risk of CMD independent of these mediators, with the exception of dyslipidaemia in males, which is largely driven by the monounsaturated fatty acid to total free fatty acid ratio.
Collapse
Affiliation(s)
- Habiba Hashemy
- Department of Medicine, University Health Network, Toronto & University of Toronto, Toronto, Ontario, Canada
| | - Anthony Nguyen
- Department of Medicine, University Health Network, Toronto & University of Toronto, Toronto, Ontario, Canada
| | - Rana Khafagy
- Department of Medicine, University Health Network, Toronto & University of Toronto, Toronto, Ontario, Canada
- Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
- Divisions of Epidemiology and Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
| | - Delnaz Roshandel
- Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Andrew D Paterson
- Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
- Divisions of Epidemiology and Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
| | - Satya Dash
- Department of Medicine, University Health Network, Toronto & University of Toronto, Toronto, Ontario, Canada
| |
Collapse
|
|
10
|
Emamian A, Emamian MH, Hashemi H, Fotouhi A. The association of ALT to HDL-C ratio with type 2 diabetes in 50-74 years old adults: a population-based study. Sci Rep 2024; 14:9390. [PMID: 38658745 PMCID: PMC11043380 DOI: 10.1038/s41598-024-60092-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 04/18/2024] [Indexed: 04/26/2024] Open
Abstract
There is limited information about the relationship between diabetes mellitus (DM) and ALT to HDL-C ratio. This study aims to investigate this relationship for the first time in Iran. The data of this study were taken from the third phase of the Shahroud Eye Cohort Study, which was conducted in 2019 with the participation of 4394 people aged 50-74. ALT and HDL-C levels were measured using a BT-1500 autoanalyzer. The mean ALT/HDL-C ratio was reported along with 95% confidence intervals (CI). The multiple logistic regression was used to examine the association between this ratio and DM, while controlling for the effects of other independent variables. The mean and standard deviation of the ALT/HDL-C ratio in all participants were 16.62 ± 11.22 (95% CI 16.28-16.96). The prevalence of DM was 34.7% and individuals with DM had a mean ALT/HDL-C ratio that was 1.80 units higher than those without diabetes (P < 0.001). Also, in individuals with DM, the HDL-C was found to be 0.035 (mmol/L) lower (P < 0.001), while ALT was 1.13 (IU/L) higher (P < 0.001) compared to those without diabetes. Additionally, after controlling for confounding factors, the odds of developing DM increased in a non-linear manner with an increase in the ALT/HDL-C ratio. Abdominal obesity, advanced age, female gender, and hypertension were also found to be associated with increased odds of DM. In conclusion, an increase in the ALT/ HDL-C ratiowas associated with higher odds of DM. This ratio can serve as an important predictor for diabetes mellitus.
Collapse
Affiliation(s)
- Abolfazl Emamian
- Student Research Committee, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Mohammad Hassan Emamian
- Ophthalmic Epidemiology Research Center, Shahroud University of Medical Sciences, Shahroud, Iran.
| | - Hassan Hashemi
- Noor Research Center for Ophthalmic Epidemiology, Noor Eye Hospital, Tehran, Iran
| | - Akbar Fotouhi
- Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
11
|
Mineo C, Shaul PW. New Player in an Old Field? Ecto-F 1-ATPase in Antidiabetic Actions of HDL in Pancreatic β-Cells. Arterioscler Thromb Vasc Biol 2024; 44:419-422. [PMID: 38095108 PMCID: PMC10842905 DOI: 10.1161/atvbaha.123.320426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2024]
Affiliation(s)
- Chieko Mineo
- Center for Pulmonary and Vascular Biology, Dept. of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA
- Dept. of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA
| | - Philip W. Shaul
- Center for Pulmonary and Vascular Biology, Dept. of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA
| |
Collapse
|
|
12
|
Mohsin S, Elabadlah H, Alotaiba MK, AlAmry S, Almehairbi SJ, Harara MMK, Almuhsin AMH, Tariq S, Howarth FC, Adeghate EA. High-Density Lipoprotein Is Located Alongside Insulin in the Islets of Langerhans of Normal and Rodent Models of Diabetes. Nutrients 2024; 16:313. [PMID: 38276551 PMCID: PMC10818677 DOI: 10.3390/nu16020313] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Revised: 01/10/2024] [Accepted: 01/16/2024] [Indexed: 01/27/2024] Open
Abstract
Recent studies have implicated pre-beta and beta lipoproteins (VLDL and LDL) in the etiopathogenesis of complications of diabetes mellitus (DM). In contrast, alpha lipoprotein (HDL) is protective of the beta cells of the pancreas. This study examined the distribution of HDL in the islets of Langerhans of murine models of type 1 diabetic rats (streptozotocin (STZ)-induced DM in Wistar rats) and type 2 models of DM rats (Goto-Kakizaki (GK), non-diabetic Zucker lean (ZL), and Zucker diabetic and fatty (ZDF)). The extent by which HDL co-localizes with insulin or glucagon in the islets of the pancreas was also investigated. Pancreatic tissues of Wistar non-diabetic, diabetic Wistar, GK, ZL, and ZDF rats were processed for immunohistochemistry. Pancreatic samples of GK rats fed with either a low-fat or a high-fat diet were prepared for transmission immune-electron microscopy (TIEM) to establish the cytoplasmic localization of HDL in islet cells. HDL was detected in the core and periphery of pancreatic islets of Wistar non-diabetic and diabetic, GK, ZL, and ZDF rats. The average total of islet cells immune positive for HDL was markedly (<0.05) reduced in GK and ZDF rats in comparison to Wistar controls. The number of islet cells containing HDL was also remarkably (p < 0.05) reduced in Wistar diabetic rats and GK models fed on high-fat food. The co-localization study using immunofluorescence and TIEM techniques showed that HDL is detected alongside insulin within the secretory granules of β-cells. HDL did not co-localize with glucagon. This observation implies that HDL may contribute to the metabolism of insulin.
Collapse
Affiliation(s)
- Sahar Mohsin
- Department of Anatomy, College of Medicine & Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates; (S.M.)
| | - Haba Elabadlah
- Department of Anatomy, College of Medicine & Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates; (S.M.)
- Cambridge Medical and Rehabilitation Center, Al Ain P.O. Box 222297, United Arab Emirates
| | - Mariam K. Alotaiba
- Department of Anatomy, College of Medicine & Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates; (S.M.)
| | - Suhail AlAmry
- Department of Anatomy, College of Medicine & Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates; (S.M.)
| | - Shamma J. Almehairbi
- Department of Anatomy, College of Medicine & Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates; (S.M.)
| | - Maha M. K. Harara
- Department of Anatomy, College of Medicine & Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates; (S.M.)
| | - Aisha M. H. Almuhsin
- Department of Anatomy, College of Medicine & Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates; (S.M.)
| | - Saeed Tariq
- Department of Anatomy, College of Medicine & Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates; (S.M.)
| | - Frank Christopher Howarth
- Department of Physiology, College of Medicine & Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates;
| | - Ernest A. Adeghate
- Department of Anatomy, College of Medicine & Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates; (S.M.)
- Zayed Centre for Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| |
Collapse
|
|
13
|
Rotllan N, Julve J, Escolà-Gil JC. Type 2 Diabetes and HDL Dysfunction: A Key Contributor to Glycemic Control. Curr Med Chem 2024; 31:280-285. [PMID: 36722477 DOI: 10.2174/0929867330666230201124125] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 10/31/2022] [Accepted: 12/08/2022] [Indexed: 02/02/2023]
Abstract
High-density lipoproteins (HDL) have been shown to exert multiple cardioprotective and antidiabetic functions, such as their ability to promote cellular cholesterol efflux and their antioxidant, anti-inflammatory, and antiapoptotic properties. Type 2 diabetes (T2D) is usually associated with low high-density lipoprotein cholesterol (HDL-C) levels as well as with significant alterations in the HDL composition, thereby impairing its main functions. HDL dysfunction also negatively impacts both pancreatic β-cell function and skeletal muscle insulin sensitivity, perpetuating this adverse self-feeding cycle. The impairment of these pathways is partly dependent on cellular ATP-binding cassette transporter (ABC) A1-mediated efflux to lipid-poor apolipoprotein (apo) A-I in the extracellular space. In line with these findings, experimental interventions aimed at improving HDL functions, such as infusions of synthetic HDL or lipid-poor apoA-I, significantly improved glycemic control in T2D patients and experimental models of the disease. Cholesteryl ester transfer protein (CETP) inhibitors are specific drugs designed to increase HDLC and HDL functions. Posthoc analyses of large clinical trials with CETP inhibitors have demonstrated their potential anti-diabetic properties. Research on HDL functionality and HDL-based therapies could be a crucial step toward improved glycemic control in T2D subjects.
Collapse
Affiliation(s)
- Noemi Rotllan
- Institut de recerca de l'Hospital de la Santa Creu i Sant Pau, Institut d'Investigacions Biomèdiques (IIB) Sant Pau, Barcelona, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain
| | - Josep Julve
- Institut de recerca de l'Hospital de la Santa Creu i Sant Pau, Institut d'Investigacions Biomèdiques (IIB) Sant Pau, Barcelona, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain
| | - Joan Carles Escolà-Gil
- Institut de recerca de l'Hospital de la Santa Creu i Sant Pau, Institut d'Investigacions Biomèdiques (IIB) Sant Pau, Barcelona, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain
| |
Collapse
|
|
14
|
Bodaghi AB, Ebadi E, Gholami MJ, Azizi R, Shariati A. A decreased level of high-density lipoprotein is a possible risk factor for type 2 diabetes mellitus: A review. Health Sci Rep 2023; 6:e1779. [PMID: 38125279 PMCID: PMC10731824 DOI: 10.1002/hsr2.1779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 10/19/2023] [Accepted: 12/04/2023] [Indexed: 12/23/2023] Open
Abstract
Introduction Type 2 diabetes mellitus (T2DM) is characterized primarily by dyslipidemia and hyperglycemia due to insulin resistance. High-density lipoprotein (HDL) play a significant role in preventing the incidence of dyslipidemia and its complications. HDL has different protective functions, such as reducing oxidation, vascular inflammation, and thrombosis; additionally, its anti-diabetic role is one of the most significant recent discoveries about HDL and some of its constituent lipoproteins. Methods This research reviews ongoing studies and preliminary investigations into the assessment of relation between decreased level of HDL and T2DM. Results The levels of HDL and its functions contribute to glucose hemostasis and the development of T2DM through four possible mechanisms, including insulin secretion by beta cells, peripheral insulin sensitivity, non-insulin-dependent glucose uptake, and adipose tissue metabolic activity. Additionally, the anti-oxidant properties of HDL protect beta cells from apoptosis caused by oxidative stress and inflammation induced by low-density lipoprotein, which facilitate insulin secretion. Conclusion Therefore, HDL and its compositions, especially Apo A-I, play an important role in regulating glucose metabolism, and decreased levels of HDL can be considered a risk factor for DM. Different factors, such as hypoalphalipoproteinemia that manifests as a consequence of genetic factors, such as Apo A-I deficiency, as well as secondary causes arising from lifestyle choices and underlying medical conditions that decrease the level of HDL, could be associated with DM. Moreover, intricate connections between HDL and diabetic complications extend beyond glucose metabolism to encompass complications like cardiovascular disease and kidney disease. Therefore, the exact interactions between HDL level and DM should be evaluated in future studies.
Collapse
Affiliation(s)
- Ali Bayat Bodaghi
- Student Research CommitteeKhomein University of Medical SciencesKhomeinIran
- Molecular and Medicine Research CentreKhomein University of Medical SciencesKhomeinIran
| | - Erfan Ebadi
- Student Research CommitteeKhomein University of Medical SciencesKhomeinIran
- Molecular and Medicine Research CentreKhomein University of Medical SciencesKhomeinIran
| | - Mohammad Javad Gholami
- Student Research CommitteeKhomein University of Medical SciencesKhomeinIran
- Molecular and Medicine Research CentreKhomein University of Medical SciencesKhomeinIran
| | - Reza Azizi
- Molecular and Medicine Research CentreKhomein University of Medical SciencesKhomeinIran
| | - Aref Shariati
- Molecular and Medicine Research CentreKhomein University of Medical SciencesKhomeinIran
| |
Collapse
|
|
15
|
Mehta N, Dangas K, Ditmarsch M, Rensen PCN, Dicklin MR, Kastelein JJP. The evolving role of cholesteryl ester transfer protein inhibition beyond cardiovascular disease. Pharmacol Res 2023; 197:106972. [PMID: 37898443 DOI: 10.1016/j.phrs.2023.106972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 09/21/2023] [Accepted: 10/25/2023] [Indexed: 10/30/2023]
Abstract
The main role of cholesteryl ester transfer protein (CETP) is the transfer of cholesteryl esters and triglycerides between high-density lipoprotein (HDL) particles and triglyceride-rich lipoprotein and low-density lipoprotein (LDL) particles. There is a long history of investigations regarding the inhibition of CETP as a target for reducing major adverse cardiovascular events. Initially, the potential effect on cardiovascular events of CETP inhibitors was hypothesized to be mediated by their ability to increase HDL cholesterol, but, based on evidence from anacetrapib and the newest CETP inhibitor, obicetrapib, it is now understood to be primarily due to reducing LDL cholesterol and apolipoprotein B. Nevertheless, evidence is also mounting that other roles of HDL, including its promotion of cholesterol efflux, as well as its apolipoprotein composition and anti-inflammatory, anti-oxidative, and anti-diabetic properties, may play important roles in several diseases beyond cardiovascular disease, including, but not limited to, Alzheimer's disease, diabetes, and sepsis. Furthermore, although Mendelian randomization analyses suggested that higher HDL cholesterol is associated with increased risk of age-related macular degeneration (AMD), excess risk of AMD was absent in all CETP inhibitor randomized controlled trial data comprising over 70,000 patients. In fact, certain HDL subclasses may, in contrast, be beneficial for treating the retinal cholesterol accumulation that occurs with AMD. This review describes the latest biological evidence regarding the relationship between HDL and CETP inhibition for Alzheimer's disease, type 2 diabetes mellitus, sepsis, and AMD.
Collapse
Affiliation(s)
- Nehal Mehta
- Mobius Scientific, Inc., JLABS @ Washington, DC, Washington, DC, USA
| | | | | | - Patrick C N Rensen
- Department of Medicine, Division of Endocrinology, and Einthoven Laboratory of Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | | | - John J P Kastelein
- Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, the Netherlands.
| |
Collapse
|
|
16
|
Xu Q, Fan K, Wei D, Wang L, Wang J, Song Y, Wang M, Zhao M, Liu X, Huo W, Li L, Hou J, Jing T, Wang C, Mao Z. Higher HDL-C levels attenuated the association of plasma polybrominated diphenyl ethers with prediabetes and type 2 diabetes mellitus in rural Chinese adults. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2023; 265:115524. [PMID: 37776820 DOI: 10.1016/j.ecoenv.2023.115524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 09/21/2023] [Accepted: 09/24/2023] [Indexed: 10/02/2023]
Abstract
BACKGROUND Plasma polybrominated diphenyl ethers (PBDE) were used as flame retardants widely, however, epidemiological evidence for the association between PBDEs and type 2 diabetes mellitus (T2DM) is inconsistent. Moreover, the combined effects of PBDEs and blood lipid indicators on impaired fasting glucose (IFG) and T2DM remains largely unknown in rural areas lacking good waste recycling infrastructure. METHODS In this study, a total of 2607 subjects aged 18-79 years were included from the Henan Rural Cohort. Generalized linear and logistic regression models were applied to evaluate the associations of various PBDE pollutants on IFG and T2DM. Quantile g-computation regression and PBDE pollution score created by the adaptive elastic net were applied to evaluate the impact of PBDEs mixtures on IFG and T2DM. Interaction effects of individual PBDE pollutants and blood lipid indicators on IFG and T2DM were assessed by using Interaction plots. RESULTS The geometric mean concentrations (detection rates) were 0.09 ng/mL (100.0%), 0.12 ng/mL (97.8%), 0.22 ng/mL (94.7%), 0.16 ng/mL (99.2%) and 0.28 ng/mL (100.0%) for PBDE-28, PBDE-47, PBDE-99, and PBDE-153 respectively. However, PBDE-28, PBDE-99, PBDE-100, and ΣPBDEs were positively associated with IFG (odds ratios (ORs) (95% confidence intervals (CIs)): 1.14 (1.06, 1.23), 1.16 (1.04, 1.29), 1.25 (1.14, 1.37), and 1.27 (1.08, 1.50)). Similarly, PBDE-28, PBDE-47, PBDE-99, PBDE-100, and ΣPBDEs were positively associated with T2DM (ORs (95% CIs): 1.30 (1.10, 1.54), 1.13 (1.06, 1.22), 1.27 (1.13, 1.43), 1.27 (1.15, 1.40), and 1.30 (1.10, 1.54)). Moreover, five PBDE mixtures or jointly as PBDE pollution score, were significantly associated with an increased risk of T2DM (P < 0.05 for all). In addition, the harmful effect of PBDE exposure on T2DM was decreased with accompanying high-density lipoprotein cholesterol (HDL-C) levels increased. CONCLUSIONS Our findings highlight the importance of managing PBDEs contamination and suggest that HDL-C may be a novel way to prevent T2DM.
Collapse
Affiliation(s)
- Qingqing Xu
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, PR China
| | - Keliang Fan
- Teaching and Training Department, Affiliated Hospital of Jiaxing University/ The First Hospital of Jiaxing, 314000 Zhejiang, China
| | - Dandan Wei
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, PR China
| | - Lulu Wang
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, PR China
| | - Juan Wang
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, PR China
| | - Yu Song
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, PR China
| | - Mian Wang
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, PR China
| | - Mengzhen Zhao
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, PR China
| | - Xiaotian Liu
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, PR China
| | - Wenqian Huo
- Department of Occupational and Environmental Health Sciences, College of Public Health, Zhengzhou University, Zhengzhou, Henan, PR China
| | - Linlin Li
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, PR China
| | - Jian Hou
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, PR China
| | - Tao Jing
- School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Chongjian Wang
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, PR China
| | - Zhenxing Mao
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, PR China.
| |
Collapse
|
|
17
|
Al‐kuraishy HM, Hussien NR, Al‐Niemi MS, Fahad EH, Al‐Buhadily AK, Al‐Gareeb AI, Al‐Hamash SM, Tsagkaris C, Papadakis M, Alexiou A, Batiha GE. SARS-CoV-2 induced HDL dysfunction may affect the host's response to and recovery from COVID-19. Immun Inflamm Dis 2023; 11:e861. [PMID: 37249296 PMCID: PMC10187021 DOI: 10.1002/iid3.861] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 04/18/2023] [Accepted: 04/21/2023] [Indexed: 05/31/2023] Open
Abstract
INTRODUCTION Covid-19 is linked with the development of cardio-metabolic disorders, including dyslipidemia, dysregulation of high-density lipoprotein (HDL), and low-density lipoprotein (LDL). Furthermore, SARS-Co-2 infection is associated with noteworthy changes in lipid profile, which is suggested as a possible biomarker to support the diagnosis and management of Covid-19. METHODS This paper adopts the literature review method to obtain information about how Covid-19 affects high-risk group patients and may cause severe and critical effects due to the development of acute lung injury and acute respiratory distress syndrome. A narrative and comprehensive review is presented. RESULTS Reducing HDL in Covid-19 is connected to the disease severity and poor clinical outcomes, suggesting that high HDL serum levels could benefit Covid-19. SARS-CoV-2 binds HDL, and this complex is attached to the co-localized receptors, facilitating viral entry. Therefore, SARS-CoV-2 infection may induce the development of dysfunctional HDL through different mechanisms, including induction of inflammatory and oxidative stress with activation of inflammatory signaling pathways. In turn, the induction of dysfunctional HDL induces the activation of inflammatory signaling pathways and oxidative stress, increasing Covid-19 severity. CONCLUSIONS Covid-19 is linked with the development of cardio-metabolic disorders, including dyslipidemia in general and dysregulation of high-density lipoprotein and low-density lipoprotein. Therefore, the present study aimed to overview the causal relationship between dysfunctional high-density lipoprotein and Covid-19.
Collapse
Affiliation(s)
- Hayder M. Al‐kuraishy
- Department of Pharmacology, ToxicologyMedicine College of Medicine Al‐Mustansiriyah UniversityBaghdadIraq
| | - Nawar R. Hussien
- Department of Clinical Pharmacy, College of PharmacyAl‐Farahidi UniversityBagdadIraq
| | - Marwa S. Al‐Niemi
- Department of Clinical Pharmacy, College of PharmacyAl‐Farahidi UniversityBagdadIraq
| | | | - Ali K. Al‐Buhadily
- Department of Clinical Pharmacology, Medicine and Therapeutic, Medical Faculty, College of MedicineAl‐Mustansiriya UniversityBaghdadIraq
| | - Ali I. Al‐Gareeb
- Department of Pharmacology, ToxicologyMedicine College of Medicine Al‐Mustansiriyah UniversityBaghdadIraq
| | | | - Christos Tsagkaris
- Department of Health SciencesNovel Global Community Educational FoundationHebershamNew South WalesAustralia
| | - Marios Papadakis
- Department of Surgery II, University Hospital Witten‐HerdeckeUniversity of Witten‐HerdeckeWuppertalGermany
| | - Athanasios Alexiou
- Department of Science and EngineeringNovel Global Community Educational FoundationHebershamNew South WalesAustralia
- AFNP Med AustriaWienAustria
| | - Gaber El‐Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary MedicineDamanhour UniversityDamanhourAlBeheiraEgypt
| |
Collapse
|
|
18
|
Barrera Echegoyen FX, Szeto A, Mendez AJ, Garg R, Goldberg RB. The nature and characteristics of hypertriglyceridemia in a large cohort with type 2 diabetes. J Diabetes Complications 2023; 37:108387. [PMID: 36669323 DOI: 10.1016/j.jdiacomp.2022.108387] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 12/15/2022] [Accepted: 12/22/2022] [Indexed: 12/29/2022]
Abstract
AIMS To determine the prevalence of mild, moderate and severe hypertriglyceridemia (HTG) in a large, diverse healthcare system cohort with type 2 diabetes (T2D) and to study associations between triglyceride levels and demographic factors, glycemic control, body weight and to investigate whether triglyceride levels associate with markers of fatty liver and renal disease. METHODS 19,086 individuals with T2D were studied between 2015 and 2020. We compared groups with normotriglyceridemia (<150 mg/dl [<1.7 mmol/l]), mild (150-199 mg/dl [1.7-2.25 mmol/l]), moderate (200-499 mg/dl [2.26-5.64 mmol/l]) or severe HTG (>499 mg/dl [>5.64 mmol/l]). We also performed univariate and multivariate correlational analyses with triglyceride level as a continuous variable. RESULTS 39 % had triglyceride levels ≥150 mg/dl (<1.7 mmol/l), 19 % had moderate and 2 % had severe HTG. There was a lower proportion of Blacks in all HTG categories compared to Whites. There was no overall gender difference in prevalence except that severe HTG was more common in men and as HTG severity worsened mean age fell. Triglycerides correlated with HbA1c and associated with BMI, LDL-C, diastolic BP, transaminases and urine albumin/creatinine ratio, independent of HbA1c. CONCLUSION This study fills gaps in our knowledge of the distribution and clinical associations of HTG in T2D and characterizes the features of the small but important group with severe HTG. We demonstrate the influence of age, sex and race, confirm the moderate effects of glycemic control and obesity on triglyceride level, and provide evidence that triglyceride levels may be a marker for fatty liver and nephropathy independent of glycemic control.
Collapse
Affiliation(s)
- Francisco X Barrera Echegoyen
- Division of Endocrinology Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Angela Szeto
- Department of Psychology, University of Miami, Coral Gables, FL, USA.
| | - Armando J Mendez
- Division of Endocrinology Diabetes and Metabolism, Department of Medicine, Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA.
| | - Rajesh Garg
- Division of Endocrinology Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.
| | - Ronald B Goldberg
- Division of Endocrinology Diabetes and Metabolism, Department of Medicine, Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA.
| |
Collapse
|
|
19
|
Galli A, Arunagiri A, Dule N, Castagna M, Marciani P, Perego C. Cholesterol Redistribution in Pancreatic β-Cells: A Flexible Path to Regulate Insulin Secretion. Biomolecules 2023; 13:224. [PMID: 36830593 PMCID: PMC9953638 DOI: 10.3390/biom13020224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 01/17/2023] [Accepted: 01/21/2023] [Indexed: 01/26/2023] Open
Abstract
Pancreatic β-cells, by secreting insulin, play a key role in the control of glucose homeostasis, and their dysfunction is the basis of diabetes development. The metabolic milieu created by high blood glucose and lipids is known to play a role in this process. In the last decades, cholesterol has attracted significant attention, not only because it critically controls β-cell function but also because it is the target of lipid-lowering therapies proposed for preventing the cardiovascular complications in diabetes. Despite the remarkable progress, understanding the molecular mechanisms responsible for cholesterol-mediated β-cell function remains an open and attractive area of investigation. Studies indicate that β-cells not only regulate the total cholesterol level but also its redistribution within organelles, a process mediated by vesicular and non-vesicular transport. The aim of this review is to summarize the most current view of how cholesterol homeostasis is maintained in pancreatic β-cells and to provide new insights on the mechanisms by which cholesterol is dynamically distributed among organelles to preserve their functionality. While cholesterol may affect virtually any activity of the β-cell, the intent of this review is to focus on early steps of insulin synthesis and secretion, an area still largely unexplored.
Collapse
Affiliation(s)
- Alessandra Galli
- Department of Pharmacological and Biomolecular Sciences (DiSFeB), Università degli Studi di Milano, 20134 Milan, Italy
| | - Anoop Arunagiri
- Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MA 48106, USA
| | - Nevia Dule
- Department of Pharmacological and Biomolecular Sciences (DiSFeB), Università degli Studi di Milano, 20134 Milan, Italy
| | - Michela Castagna
- Department of Pharmacological and Biomolecular Sciences (DiSFeB), Università degli Studi di Milano, 20134 Milan, Italy
| | - Paola Marciani
- Department of Pharmacological and Biomolecular Sciences (DiSFeB), Università degli Studi di Milano, 20134 Milan, Italy
| | - Carla Perego
- Department of Pharmacological and Biomolecular Sciences (DiSFeB), Università degli Studi di Milano, 20134 Milan, Italy
| |
Collapse
|
|
20
|
Dangas K, Navar AM, Kastelein JJP. The effect of CETP inhibitors on new-onset diabetes: a systematic review and meta-analysis. EUROPEAN HEART JOURNAL. CARDIOVASCULAR PHARMACOTHERAPY 2022; 8:622-632. [PMID: 35441656 PMCID: PMC9729761 DOI: 10.1093/ehjcvp/pvac025] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 03/16/2022] [Accepted: 04/24/2022] [Indexed: 12/15/2022]
Abstract
BACKGROUND Despite the increasing prevalence of type 2 diabetes mellitus (T2DM), limited pharmacologic options are available for prevention. Cholesteryl ester transfer protein inhibitors (CETPis) have been studied primarily as a therapy to reduce cardiovascular disease, but have also been shown to reduce new-onset diabetes. As new trial data have become available, this meta-analysis examines the effect of CETP inhibitors on new-onset diabetes and related glycaemic measures. METHODS AND RESULTS We searched MEDLINE, EMBASE, and Cochrane databases (all articles until 4 March, 2021) for randomised controlled trials (RCT) ≥1-year duration, with at least 500 participants, comparing CETPi to placebo, and that reported data on new-onset diabetes or related glycaemic measures [haemoglobin A1C (HbA1C), fasting plasma glucose, insulin, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)]. A fixed effects meta-analysis model was applied to all eligible studies to quantify the effect of CETPi therapy on new-onset diabetes. Four RCTs (n = 75 102) were eligible for quantitative analysis of the effect of CETPi on new-onset diabetes. CETPis were found to significantly decrease the risk of new-onset diabetes by 16% (RR: 0.84; 95% CI: 0.78, 0.91; P < 0.001), with low between-trial heterogeneity (I2 = 4.1%). Glycaemic measures were also significantly improved or trended towards improvement in those with and without diabetes across most trials. CONCLUSION Although RCTs have shown mixed results regarding the impact of CETPi on cardiovascular disease, they have shown a consistent reduction in the risk of new-onset diabetes with CETPi therapy. Future trials of CETPis and potentially other HDL-raising agents should therefore specify new-onset diabetes and reversal of existing T2DM as secondary endpoints.
Collapse
Affiliation(s)
| | - Ann-Marie Navar
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - John J P Kastelein
- Department of Vascular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam 1081, Netherlands
| |
Collapse
|
|
21
|
Bin Saleh FS, Alharbi WS, Alanazi GB, Aldughaither A. Prevalence and Regulation of Dyslipidemia Among Adults With Type 2 Diabetes From Three Primary Health Care Centers in Riyadh. Cureus 2022; 14:e27573. [PMID: 35923815 PMCID: PMC9342933 DOI: 10.7759/cureus.27573] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/01/2022] [Indexed: 12/20/2022] Open
Abstract
Background Dyslipidemia is an added risk factor in patients with type 2 diabetes who are more prone to develop cardiovascular diseases as it implies an alteration of the lipid level leading to serious health complications. Objective This study aimed at assessing the prevalence of dyslipidemia among patients with type 2 diabetes and comparing the lipid profile measurements between controlled and uncontrolled type 2 diabetic patients. Method A cross-sectional retrospective study was performed in three primary health care centers in Saudi Arabia. A sample of 418 patients with type 2 diabetes was enrolled in this study. To collect data, the researcher used a structured questionnaire and retrieved patients' data from the electronic medical records in the study setting. Results The findings of the study showed that 82.1% of type 2 diabetes mellitus (DM) patients recruited in this study were dyslipidemic. In addition, it was found that there was a significant difference in triglycerides, fasting blood sugar (FBS), and high-density lipoprotein (HDL) between controlled and uncontrolled diabetic patients (p≤0.05). Moreover, a significant interaction was found between gender, HbA1c control, educational level, and frequency of exercising on one hand and dyslipidemia on the other hand (p≤0.05). Conclusion The study concluded that there is a high prevalence of dyslipidemia among type 2 diabetic patients in Saudi Arabia and a significant interaction between dyslipidemia and diabetic patients' gender, HbA1c control, educational level, and frequency of exercising. The study recommends increasing type 2 diabetic patients' awareness regarding the management of diabetes and dyslipidemia and the importance of providing educational intervention regarding diabetes self-care activities.
Collapse
|
|
22
|
Kostara CE, Karakitsou KS, Florentin M, Bairaktari ET, Tsimihodimos V. Progressive, Qualitative, and Quantitative Alterations in HDL Lipidome from Healthy Subjects to Patients with Prediabetes and Type 2 Diabetes. Metabolites 2022; 12:metabo12080683. [PMID: 35893251 PMCID: PMC9331261 DOI: 10.3390/metabo12080683] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 07/19/2022] [Accepted: 07/22/2022] [Indexed: 12/16/2022] Open
Abstract
Prediabetes is a clinically silent, insulin-resistant state with increased risk for the development of type 2 diabetes (T2D) and cardiovascular disease (CVD). Since glucose homeostasis and lipid metabolism are highly intersected and interrelated, an in-depth characterization of qualitative and quantitative abnormalities in lipoproteins could unravel the metabolic pathways underlying the progression of prediabetes to T2D and also the proneness of these patients to developing premature atherosclerosis. We investigated the HDL lipidome in 40 patients with prediabetes and compared it to that of 40 normoglycemic individuals and 40 patients with established T2D using Nuclear Magnetic Resonance (NMR) spectroscopy. Patients with prediabetes presented significant qualitative and quantitative alterations, potentially atherogenic, in HDL lipidome compared to normoglycemic characterized by higher percentages of free cholesterol and triglycerides, whereas phospholipids were lower. Glycerophospholipids and ether glycerolipids were significantly lower in prediabetic compared to normoglycemic individuals, whereas sphingolipids were significantly higher. In prediabetes, lipids were esterified with saturated rather than unsaturated fatty acids. These changes are qualitatively similar, but quantitatively milder, than those found in patients with T2D. We conclude that the detailed characterization of the HDL lipid profile bears a potential to identify patients with subtle (but still proatherogenic) abnormalities who are at high risk for development of T2D and CVD.
Collapse
Affiliation(s)
- Christina E. Kostara
- Laboratory of Clinical Chemistry, Faculty of Medicine, University of Ioannina, 45500 Ioannina, Greece; (C.E.K.); (K.S.K.); (E.T.B.)
| | - Kiriaki S. Karakitsou
- Laboratory of Clinical Chemistry, Faculty of Medicine, University of Ioannina, 45500 Ioannina, Greece; (C.E.K.); (K.S.K.); (E.T.B.)
| | - Matilda Florentin
- Department of Internal Medicine, Faculty of Medicine, University of Ioannina, 45110 Ioannina, Greece;
| | - Eleni T. Bairaktari
- Laboratory of Clinical Chemistry, Faculty of Medicine, University of Ioannina, 45500 Ioannina, Greece; (C.E.K.); (K.S.K.); (E.T.B.)
| | - Vasilis Tsimihodimos
- Department of Internal Medicine, Faculty of Medicine, University of Ioannina, 45110 Ioannina, Greece;
- Correspondence: ; Tel.: +30-2651007362
| |
Collapse
|
|
23
|
Zhou M, Li R, Venkat P, Qian Y, Chopp M, Zacharek A, Landschoot-Ward J, Powell B, Jiang Q, Cui X. Post-Stroke Administration of L-4F Promotes Neurovascular and White Matter Remodeling in Type-2 Diabetic Stroke Mice. Front Neurol 2022; 13:863934. [PMID: 35572941 PMCID: PMC9100936 DOI: 10.3389/fneur.2022.863934] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 03/21/2022] [Indexed: 02/02/2023] Open
Abstract
Patients with type 2 diabetes mellitus (T2DM) exhibit a distinct and high risk of ischemic stroke with worse post-stroke neurovascular and white matter (WM) prognosis than the non-diabetic population. In the central nervous system, the ATP-binding cassette transporter member A 1 (ABCA1), a reverse cholesterol transporter that efflux cellular cholesterol, plays an important role in high-density lipoprotein (HDL) biogenesis and in maintaining neurovascular stability and WM integrity. Our previous study shows that L-4F, an economical apolipoprotein A member I (ApoA-I) mimetic peptide, has neuroprotective effects via alleviating neurovascular and WM impairments in the brain of db/db-T2DM stroke mice. To further investigate whether L-4F has neurorestorative benefits in the ischemic brain after stroke in T2DM and elucidate the underlying molecular mechanisms, we subjected middle-aged, brain-ABCA1 deficient (ABCA1-B/-B), and ABCA1-floxed (ABCA1fl/fl) T2DM control mice to distal middle cerebral artery occlusion. L-4F (16 mg/kg, subcutaneous) treatment was initiated 24 h after stroke and administered once daily for 21 days. Treatment of T2DM-stroke with L-4F improved neurological functional outcome, and decreased hemorrhage, mortality, and BBB leakage identified by decreased albumin infiltration and increased tight-junction and astrocyte end-feet densities, increased cerebral arteriole diameter and smooth muscle cell number, and increased WM density and oligodendrogenesis in the ischemic brain in both ABCA1-B/-B and ABCA1fl/fl T2DM-stroke mice compared with vehicle-control mice, respectively (p < 0.05, n = 9 or 21/group). The L-4F treatment reduced macrophage infiltration and neuroinflammation identified by decreases in ED-1, monocyte chemoattractant protein-1 (MCP-1), and toll-like receptor 4 (TLR4) expression, and increases in anti-inflammatory factor Insulin-like growth factor 1 (IGF-1) and its receptor IGF-1 receptor β (IGF-1Rβ) in the ischemic brain (p < 0.05, n = 6/group). These results suggest that post-stroke administration of L-4F may provide a restorative strategy for T2DM-stroke by promoting neurovascular and WM remodeling. Reducing neuroinflammation in the injured brain may contribute at least partially to the restorative effects of L-4F independent of the ABCA1 signaling pathway.
Collapse
Affiliation(s)
- Min Zhou
- Department of Neurology, Henry Ford Hospital, Detroit, MI, United States
| | - Rongwen Li
- Department of Neurology, Henry Ford Hospital, Detroit, MI, United States
| | - Poornima Venkat
- Department of Neurology, Henry Ford Hospital, Detroit, MI, United States
| | - Yu Qian
- Department of Neurology, Henry Ford Hospital, Detroit, MI, United States
| | - Michael Chopp
- Department of Neurology, Henry Ford Hospital, Detroit, MI, United States
- Department of Physics, Oakland University, Rochester, MI, United States
| | - Alex Zacharek
- Department of Neurology, Henry Ford Hospital, Detroit, MI, United States
| | | | - Brianna Powell
- Department of Neurology, Henry Ford Hospital, Detroit, MI, United States
| | - Quan Jiang
- Department of Neurology, Henry Ford Hospital, Detroit, MI, United States
- Department of Physics, Oakland University, Rochester, MI, United States
| | - Xu Cui
- Department of Neurology, Henry Ford Hospital, Detroit, MI, United States
| |
Collapse
|
|
24
|
Szili-Torok T, Sokooti S, Osté MCJ, Gomes-Neto AW, Dullaart RPF, Bakker SJL, Tietge UJF. Remnant lipoprotein cholesterol is associated with incident new onset diabetes after transplantation (NODAT) in renal transplant recipients: results of the TransplantLines Biobank and cohort Studies. Cardiovasc Diabetol 2022; 21:41. [PMID: 35296331 PMCID: PMC8925054 DOI: 10.1186/s12933-022-01475-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 03/02/2022] [Indexed: 01/04/2023] Open
Abstract
Background New onset diabetes after transplantation (NODAT) is a frequent and serious complication of renal transplantation resulting in worse graft and patient outcomes. The pathophysiology of NODAT is incompletely understood, and no prospective biomarkers have been established to predict NODAT risk in renal transplant recipients (RTR). The present work aimed to determine whether remnant lipoprotein (RLP) cholesterol could serve as such a biomarker that would also provide a novel target for therapeutic intervention. Methods This longitudinal cohort study included 480 RTR free of diabetes at baseline. 53 patients (11%) were diagnosed with NODAT during a median [interquartile range, IQR] follow-up of 5.2 [4.1–5.8] years. RLP cholesterol was calculated by subtracting HDL and LDL cholesterol from total cholesterol values (all directly measured). Results Baseline remnant cholesterol values were significantly higher in RTR who subsequently developed NODAT (0.9 [0.5–1.2] mmol/L vs. 0.6 [0.4–0.9] mmol/L, p = 0.001). Kaplan-Meier analysis showed that higher RLP cholesterol values were associated with an increased risk of incident NODAT (log rank test, p < 0.001). Cox regression demonstrated a significant longitudinal association between baseline RLP cholesterol levels and NODAT (HR, 2.27 [1.64–3.14] per 1 SD increase, p < 0.001) that remained after adjusting for plasma glucose and HbA1c (p = 0.002), HDL and LDL cholesterol (p = 0.008) and use of immunosuppressive medication (p < 0.001), among others. Adding baseline remnant cholesterol to the Framingham Diabetes Risk Score significantly improved NODAT prediction (change in C-statistic, p = 0.01). Conclusions This study demonstrates that baseline RLP cholesterol levels strongly associate with incident NODAT independent of several other recognized risk factors.
Collapse
Affiliation(s)
- Tamas Szili-Torok
- Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Sara Sokooti
- Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Maryse C J Osté
- Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Antonio W Gomes-Neto
- Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Robin P F Dullaart
- Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Stephan J L Bakker
- Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Uwe J F Tietge
- Division of Clinical Chemistry, Department of Laboratory Medicine (LABMED), H5, Alfred Nobels Alle 8, Karolinska Institutet, 141 83, Stockholm, Sweden. .,Clinical Chemistry, Karolinska University Laboratory, Karolinska University Hospital, Stockholm, Sweden.
| |
Collapse
|
|
25
|
Duan MJ, Dekker LH, Carrero JJ, Navis G. Using Structural Equation Modeling to Untangle Pathways of Risk Factors Associated with Incident Type 2 Diabetes: the Lifelines Cohort Study. PREVENTION SCIENCE : THE OFFICIAL JOURNAL OF THE SOCIETY FOR PREVENTION RESEARCH 2022; 23:1090-1100. [PMID: 35230614 PMCID: PMC9489566 DOI: 10.1007/s11121-022-01357-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/17/2022] [Indexed: 12/30/2022]
Abstract
Risk factors for type 2 diabetes are multifaceted and interrelated. Unraveling the complex pathways of modifiable risk factors related to incident type 2 diabetes will help prioritize prevention targets. The current analysis extended a previously proposed conceptual model by Bardenheier et al. (Diabetes Care, 36(9), 2655–2662, 2013) on prediabetes with a cross-sectional design. The model described the pathways of four aspects of modifiable risk factors in relation to incident type 2 diabetes, including socioeconomic status (income and education); lifestyle behaviors (diet quality, physical activity, TV watching, smoking, risk drinking, and unhealthy sleep duration); clinical markers (HDL-cholesterol, triglycerides, BMI, and waist circumference); and blood pressure. We performed structural equation modeling to test this conceptual model using a prospective population-based sample of 68,649 participants (35–80 years) from the Lifelines cohort study. During a median follow-up of 41 months, 1124 new cases of type 2 diabetes were identified (incidence 1.6%). The best-fitting model indicated that among all modifiable risk factors included, waist circumference had the biggest direct effect on type 2 diabetes (standardized β-coefficient 0.214), followed by HDL-cholesterol (standardized β-coefficient − 0.134). Less TV watching and more physical activity were found to play an important role in improving clinical markers that were directly associated with type 2 diabetes. Education had the biggest positive effects on all lifestyle behaviors except for unhealthy sleep duration. Our analysis provides evidence to support that structural equation modeling enables a holistic assessment of the interplay of type 2 diabetes risk factors, which not only allows the estimation of their total effects but also prioritization of prevention targets. Regarding the current guideline for diabetes prevention, waist management in addition to BMI control (clinical level), as well as less TV watching in addition to more physical activity (behavioral level), may provide additional public health benefits. Better education would be the main societal goal for the prevention of type 2 diabetes.
Collapse
Affiliation(s)
- Ming-Jie Duan
- Department of Internal Medicine, University Medical Center Groningen, Hanzeplein 1, P.O. Box 30 001, 9700RB, Groningen, The Netherlands.
| | - Louise H Dekker
- Department of Internal Medicine, University Medical Center Groningen, Hanzeplein 1, P.O. Box 30 001, 9700RB, Groningen, The Netherlands.,National Institute for Public Health and the Environment, Bilthoven, The Netherlands
| | - Juan-Jesus Carrero
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Gerjan Navis
- Department of Internal Medicine, University Medical Center Groningen, Hanzeplein 1, P.O. Box 30 001, 9700RB, Groningen, The Netherlands
| |
Collapse
|
|
26
|
Papuc C, Goran GV, Predescu CN, Tudoreanu L, Ștefan G. Plant polyphenols mechanisms of action on insulin resistance and against the loss of pancreatic beta cells. Crit Rev Food Sci Nutr 2022; 62:325-352. [PMID: 32901517 DOI: 10.1080/10408398.2020.1815644] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Diabetes mellitus describes a group of metabolic disorders characterized by a prolonged period hyperglycemia with long-lasting detrimental effects on the cardiovascular and nervous systems, kidney, vision, and immunity. Many plant polyphenols are shown to have beneficial activity for the prevention and treatment of diabetes, by different mechanisms. This review article is focused on synthesizing the mechanisms by which polyphenols decrease insulin resistance and inhibit loss of pancreatic islet β-cell mass and function. To achieve the objectives, this review summarizes the results of the researches realized in recent years in clinical trials and in various experimental models, on the effects of foods rich in polyphenols, polyphenolic extracts, and commercially polyphenols on insulin resistance and β-cells death. Dietary polyphenols are able to reduce insulin resistance alleviating the IRS-1/PI3-k/Akt signaling pathway, and to reduce the loss of pancreatic islet β-cell mass and function by several molecular mechanisms, such as protection of the surviving machinery of cells against the oxidative insult; increasing insulin secretion in pancreatic β-cells through activation of the FFAR1; cytoprotective effect on β-cells by activation of autophagy; protection of β-cells to act as activators for anti-apoptotic pathways and inhibitors for apoptotic pathway; stimulating of insulin release, presumably by transient ATP-sensitive K+ channel inhibition and whole-cell Ca2+ stimulation; involvement in insulin release that act on ionic currents and membrane potential as inhibitor of delayed-rectifier K+ current (IK(DR)) and activator of current. dietary polyphenols could be used as potential anti-diabetic agents to prevent and alleviate diabetes and its complications, but further studies are needed.
Collapse
Affiliation(s)
- Camelia Papuc
- Faculty of Veterinary Medicine, UASVM of Bucharest, Bucharest, Romania
| | - Gheorghe V Goran
- Faculty of Veterinary Medicine, UASVM of Bucharest, Bucharest, Romania
| | - Corina N Predescu
- Faculty of Veterinary Medicine, UASVM of Bucharest, Bucharest, Romania
| | - Liliana Tudoreanu
- Faculty of Veterinary Medicine, UASVM of Bucharest, Bucharest, Romania
| | - Georgeta Ștefan
- Faculty of Veterinary Medicine, UASVM of Bucharest, Bucharest, Romania
| |
Collapse
|
|
27
|
Nurmohamed NS, Ditmarsch M, Kastelein JJP. CETP-inhibitors: from HDL-C to LDL-C lowering agents? Cardiovasc Res 2021; 118:2919-2931. [PMID: 34849601 PMCID: PMC9648826 DOI: 10.1093/cvr/cvab350] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 11/20/2021] [Indexed: 11/29/2022] Open
Abstract
Cholesteryl ester transfer protein (CETP) is a liver-synthesized glycoprotein whose main functions are facilitating transfer of both cholesteryl esters from high-density lipoprotein (HDL) particles to apolipoprotein B (apoB)-containing particles as well as transfer of triglycerides from apoB-containing particles to HDL particles. Novel crystallographic data have shown that CETP exchanges lipids in the circulation by a dual molecular mechanism. Recently, it has been suggested that the atherosclerotic cardiovascular disease (ASCVD) benefit from CETP inhibition is the consequence of the achieved low-density lipoprotein cholesterol (LDL-C) and apoB reduction, rather than through the HDL cholesterol (HDL-C) increase. The use of CETP inhibitors is supported by genetic evidence from Mendelian randomization studies, showing that LDL-C lowering by CETP gene variants achieves equal ASCVD risk reduction as LDL-C lowering through gene proxies for statins, ezetimibe, and proprotein convertase subtilisin–kexin Type 9 inhibitors. Although first-generation CETP inhibitors (torcetrapib, dalcetrapib) were mainly raising HDL-C or had off-target effects, next generation CETP inhibitors (anacetrapib, evacetrapib) were also effective in reducing LDL-C and apoB and have been proven safe. Anacetrapib was the first CETP inhibitor to be proven effective in reducing ASCVD risk. In addition, CETP inhibitors have been shown to lower the risk of new-onset diabetes, improve glucose tolerance, and insulin sensitivity. The newest-generation CETP inhibitor obicetrapib, specifically designed to lower LDL-C and apoB, has achieved significant reductions of LDL-C up to 45%. Obicetrapib, about to enter phase III development, could become the first CETP inhibitor as add-on therapy for patients not reaching their guideline LDL-C targets.
Collapse
Affiliation(s)
- Nick S Nurmohamed
- Department of Vascular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.,Department of Cardiology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | | | - John J P Kastelein
- Department of Vascular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| |
Collapse
|
|
28
|
Xepapadaki E, Nikdima I, Sagiadinou EC, Zvintzou E, Kypreos KE. HDL and type 2 diabetes: the chicken or the egg? Diabetologia 2021; 64:1917-1926. [PMID: 34255113 DOI: 10.1007/s00125-021-05509-0] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 05/05/2021] [Indexed: 12/17/2022]
Abstract
HDL is a complex macromolecular cluster of various components, such as apolipoproteins, enzymes and lipids. Quality evidence from clinical and epidemiological studies led to the principle that HDL-cholesterol (HDL-C) levels are inversely correlated with the risk of CHD. Nevertheless, the failure of many cholesteryl ester transfer protein inhibitors to protect against CVD casts doubts on this principle and highlights the fact that HDL functionality, as dictated by its proteome and lipidome, also plays an important role in protecting against metabolic disorders. Recent data indicate that HDL-C levels and HDL particle functionality are correlated with the pathogenesis and prognosis of type 2 diabetes mellitus, a major risk factor for CVD. Hyperglycaemia leads to reduced HDL-C levels and deteriorated HDL functionality, via various alterations in HDL particles' proteome and lipidome. In turn, reduced HDL-C levels and impaired HDL functionality impact the performance of key organs related to glucose homeostasis, such as pancreas and skeletal muscles. Interestingly, different structural alterations in HDL correlate with distinct metabolic abnormalities, as indicated by recent data evaluating the role of apolipoprotein A1 and lecithin-cholesterol acyltransferase deficiency in glucose homeostasis. While it is becoming evident that not all HDL disturbances are causatively associated with the development and progression of type 2 diabetes, a bidirectional correlation between these two conditions exists, leading to a perpetual self-feeding cycle.
Collapse
Affiliation(s)
- Eva Xepapadaki
- Pharmacology Laboratory, Department of Medicine, School of Health Sciences, University of Patras, Rio Achaias, Greece
| | - Ioanna Nikdima
- Pharmacology Laboratory, Department of Medicine, School of Health Sciences, University of Patras, Rio Achaias, Greece
| | - Eleftheria C Sagiadinou
- Pharmacology Laboratory, Department of Medicine, School of Health Sciences, University of Patras, Rio Achaias, Greece
| | - Evangelia Zvintzou
- Pharmacology Laboratory, Department of Medicine, School of Health Sciences, University of Patras, Rio Achaias, Greece
| | - Kyriakos E Kypreos
- Pharmacology Laboratory, Department of Medicine, School of Health Sciences, University of Patras, Rio Achaias, Greece.
- Department of Life Sciences, School of Sciences, European University Cyprus, Nicosia, Cyprus.
| |
Collapse
|
|
29
|
Gendaszewska-Darmach E, Garstka MA, Błażewska KM. Targeting Small GTPases and Their Prenylation in Diabetes Mellitus. J Med Chem 2021; 64:9677-9710. [PMID: 34236862 PMCID: PMC8389838 DOI: 10.1021/acs.jmedchem.1c00410] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
![]()
A fundamental role
of pancreatic β-cells to maintain proper
blood glucose level is controlled by the Ras superfamily of small
GTPases that undergo post-translational modifications, including prenylation.
This covalent attachment with either a farnesyl or a geranylgeranyl
group controls their localization, activity, and protein–protein
interactions. Small GTPases are critical in maintaining glucose homeostasis
acting in the pancreas and metabolically active tissues such as skeletal
muscles, liver, or adipocytes. Hyperglycemia-induced upregulation
of small GTPases suggests that inhibition of these pathways deserves
to be considered as a potential therapeutic approach in treating T2D.
This Perspective presents how inhibition of various points in the
mevalonate pathway might affect protein prenylation and functioning
of diabetes-affected tissues and contribute to chronic inflammation
involved in diabetes mellitus (T2D) development. We also demonstrate
the currently available molecular tools to decipher the mechanisms
linking the mevalonate pathway’s enzymes and GTPases with diabetes.
Collapse
Affiliation(s)
- Edyta Gendaszewska-Darmach
- Institute of Molecular and Industrial Biotechnology, Faculty of Biotechnology and Food Sciences, Lodz University of Technology, Stefanowskiego Street 4/10, 90-924 Łódź, Poland
| | - Malgorzata A Garstka
- Core Research Laboratory, Department of Endocrinology, Department of Tumor and Immunology, Precision Medical Institute, Western China Science and Technology Innovation Port, School of Medicine, the Second Affiliated Hospital of Xi'an Jiaotong University, DaMingGong, Jian Qiang Road, Wei Yang district, Xi'an 710016, China
| | - Katarzyna M Błażewska
- Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, Żeromskiego Street 116, 90-924 Łódź, Poland
| |
Collapse
|
|
30
|
Shetty SS, Kumari NS. Fatty acid desaturase 2 (FADS 2) rs174575 (C/G) polymorphism, circulating lipid levels and susceptibility to type-2 diabetes mellitus. Sci Rep 2021; 11:13151. [PMID: 34162950 PMCID: PMC8222307 DOI: 10.1038/s41598-021-92572-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 06/02/2021] [Indexed: 12/17/2022] Open
Abstract
Several factors influence an individual's susceptibility in inter-individual lipid changes and its role in the onset of type-2 diabetes mellitus (T2DM). Considering the above fact, the present investigation focuses on determining the association between fatty acid desaturase 2 (FADS2) rs174575 (C/G) polymorphism, circulating lipid levels and susceptibility to type-2 diabetes mellitus. As per the inclusion and exclusion criteria a total of 429 subjects (non-diabetic-216; diabetic-213) were recruited for the study. Glycemic and lipid profile status were assessed using commercially available kits. Based on the previous reports SNP rs174575 of fatty acid desaturase gene (FADS2) was selected and identified using the dbSNP database. The amplified products were sequenced by means of Sanger sequencing method. Lipid profile status and apolipoprotein levels revealed statistically significant difference between the groups. Three models were assessed namely, recessive model (CC vs CG + GG), dominant model (CC + CG vs GG) and additive model (CC vs CG vs GG). The recessive model, displayed a statistically significant variations between the circulating lipid levels in T2DM. The multivariate model with genotype (G allele carriers), triglyceride (TG) and insulin served as a predictive model. The study results potentiate the functional link between FADS2 gene polymorphism, lipid levels and type-2 diabetes mellitus.
Collapse
Affiliation(s)
- Shilpa S Shetty
- Central Research Laboratory, K.S.Hegde Medical Academy, Nitte (Deemed To Be University), Deralakatte, Mangalore, India
| | - N Suchetha Kumari
- Department of Biochemistry, K.S.Hegde Medical Academy, Nitte (Deemed To Be University), Deralakatte, Mangalore, India.
| |
Collapse
|
|
31
|
Duan MJ, Dekker LH, Carrero JJ, Navis G. Blood lipids-related dietary patterns derived from reduced rank regression are associated with incident type 2 diabetes. Clin Nutr 2021; 40:4712-4719. [PMID: 34237698 DOI: 10.1016/j.clnu.2021.04.046] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 01/12/2021] [Accepted: 04/30/2021] [Indexed: 01/10/2023]
Abstract
BACKGROUND & AIMS Blood lipids play a critical role in the pathogenesis of type 2 diabetes, and they are closely related to dietary factors. However, the associations between blood lipids-related dietary patterns and risk of type 2 diabetes are controversial and not fully clear. In this study, we aimed to derive dietary patterns that explained variation in blood lipids and to investigate their associations with incident type 2 diabetes. METHODS The analysis was based on 39,000 women and 25,777 men participating in the Lifelines cohort study (aged 18-65 years, mean 43.2 years for women and 43.5 years for men). Dietary intake was measured using a 110-item semi-quantitative food frequency questionnaire. Reduced rank regression was used to derive dietary patterns with blood lipids (HDL-cholesterol, LDL-cholesterol, triglycerides, total cholesterol, and total cholesterol:HDL-cholesterol ratio) as response variables for women and men separately. The first dietary pattern identified for each sex was selected because they explained the largest variance in blood lipids. The associations between the identified dietary patterns and incident type 2 diabetes were subsequently investigated using multivariate logistic regression models. All analyses were performed separately for women and men. RESULTS During an average follow-up of 43 months, 479 new cases (incidence 0.74%) of type 2 diabetes were identified. Using reduced rank regression, we identified two sex-specific blood lipids-associated dietary patterns characterized by high intake of sugary beverages, added sugar, and low intake of vegetables, fruits, tea, and nuts/seeds. These two sex-specific dietary patterns were similar in food groups but differed in factor loadings. High dietary pattern scores were associated with increased risk of type 2 diabetes after adjustment for age, total energy intake, body mass index, waist-hip ratio, and blood pressure (ORs for the fifth quintile [Q5] using the first quintile [Q1] as reference, 1.87 [95% CI 1.23, 2.83] for women [P-trend < 0.001], and 1.72 [95% CI 1.11, 2.66] for men [P-trend = 0.018]). The associations were attenuated but remained significant after further adjustment for lifestyle and socio-economic factors. CONCLUSIONS Dietary patterns associated with adverse blood lipids are associated with incidence of type 2 diabetes. The present study provides new insights in optimizing blood lipids for the prevention of type 2 diabetes through dietary approaches.
Collapse
Affiliation(s)
- Ming-Jie Duan
- Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
| | - Louise H Dekker
- Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Aletta Jacobs School of Public Health, Groningen, the Netherlands; National Institute for Public Health and the Environment, Bilthoven, the Netherlands
| | - Juan-Jesus Carrero
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Gerjan Navis
- Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| |
Collapse
|
|
32
|
Di Bartolo BA, Cartland SP, Genner S, Manuneedhi Cholan P, Vellozzi M, Rye KA, Kavurma MM. HDL Improves Cholesterol and Glucose Homeostasis and Reduces Atherosclerosis in Diabetes-Associated Atherosclerosis. J Diabetes Res 2021; 2021:6668506. [PMID: 34095317 PMCID: PMC8163542 DOI: 10.1155/2021/6668506] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 02/11/2021] [Accepted: 02/17/2021] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND AND AIMS Apolipoprotein A-I (ApoA-I), the main component of high-density lipoprotein (HDL), not only promotes reverse cholesterol transport (RCT) in atherosclerosis but also increases insulin secretion in pancreatic β-cells, suggesting that interventions which raise HDL levels may be beneficial in diabetes-associated cardiovascular disease (CVD). Previously, we showed that TNF-related apoptosis-inducing ligand (TRAIL) deletion in Apolipoprotein Eknockout (Apoe-/- ) mice results in diabetes-accelerated atherosclerosis in response to a "Western" diet. Here, we sought to identify whether reconstituted HDL (rHDL) could improve features of diabetes-associated CVD in Trail-/-Apoe-/- mice. METHODS AND RESULTS Trail-/-Apoe-/- and Apoe-/- mice on a "Western" diet for 12 weeks received 3 weekly infusions of either PBS (vehicle) or rHDL (containing ApoA-I (20 mg/kg) and 1-palmitoyl-2-linoleoyl phosphatidylcholine). Administration of rHDL reduced total plasma cholesterol, triglyceride, and glucose levels in Trail-/-Apoe-/- but not in Apoe-/- mice, with no change in weight gain observed. rHDL treatment also improved glucose clearance in response to insulin and glucose tolerance tests. Immunohistological analysis of pancreata revealed increased insulin expression/production and a reduction in macrophage infiltration in mice with TRAIL deletion. Furthermore, atherosclerotic plaque size in Trail-/-Apoe-/- mice was significantly reduced associating with increased expression of the M2 macrophage marker CD206, suggesting HDL's involvement in the polarization of macrophages. rHDL also increased vascular mRNA expression of RCT transporters, ABCA1 and ABCG1, in Trail-/-Apoe-/- but not in Apoe-/- mice. Conclusions. rHDL improves features of diabetes-associated atherosclerosis in mice. These findings support the therapeutic potential of rHDL in the treatment of atherosclerosis and associated diabetic complications. More studies are warranted to understand rHDL's mechanism of action.
Collapse
MESH Headings
- ATP Binding Cassette Transporter 1/genetics
- ATP Binding Cassette Transporter 1/metabolism
- ATP Binding Cassette Transporter, Subfamily G, Member 1/genetics
- ATP Binding Cassette Transporter, Subfamily G, Member 1/metabolism
- Animals
- Anticholesteremic Agents/administration & dosage
- Apolipoprotein A-I/administration & dosage
- Atherosclerosis/blood
- Atherosclerosis/drug therapy
- Atherosclerosis/genetics
- Biomarkers/blood
- Blood Glucose/drug effects
- Blood Glucose/metabolism
- Cholesterol/blood
- Diabetes Mellitus/blood
- Diabetes Mellitus/drug therapy
- Diet, Western
- Disease Models, Animal
- Dyslipidemias/blood
- Dyslipidemias/drug therapy
- Dyslipidemias/genetics
- Homeostasis
- Humans
- Hypoglycemic Agents/administration & dosage
- Lipoproteins, HDL/administration & dosage
- Macrophages/drug effects
- Macrophages/metabolism
- Male
- Mice, Knockout, ApoE
- Phosphatidylcholines/administration & dosage
- Plaque, Atherosclerotic
- TNF-Related Apoptosis-Inducing Ligand/genetics
- TNF-Related Apoptosis-Inducing Ligand/metabolism
- Mice
Collapse
Affiliation(s)
- Belinda A. Di Bartolo
- The University of Sydney, Kolling Institute of Medical Research, Sydney, Australia
- Faculty of Medicine and Health, Sydney, Australia
- Heart Research Institute, Sydney, Australia
- The University of New South Wales, Faculty of Medicine, Sydney, Australia
| | - Siân P. Cartland
- Faculty of Medicine and Health, Sydney, Australia
- Heart Research Institute, Sydney, Australia
- The University of New South Wales, Faculty of Medicine, Sydney, Australia
| | | | | | | | - Kerry-Anne Rye
- The University of New South Wales, Faculty of Medicine, Sydney, Australia
| | - Mary M. Kavurma
- Faculty of Medicine and Health, Sydney, Australia
- Heart Research Institute, Sydney, Australia
- The University of New South Wales, Faculty of Medicine, Sydney, Australia
| |
Collapse
|
|
33
|
Haxhi J, Thompson PD. Rationale for the use of metformin and exercise to counteract statin-associated side effects. Int J Clin Pract 2021; 75:e13900. [PMID: 33277775 DOI: 10.1111/ijcp.13900] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 12/01/2020] [Indexed: 12/16/2022] Open
Abstract
INTRODUCTION Statins are the most widely prescribed drugs for lowering low-density lipoprotein cholesterol (LDL-C) and reducing cardiovascular morbidity and mortality. They are usually well-tolerated, but have two main safety concerns: statin-associated muscle symptoms (SAMS) and new-onset type 2 diabetes (NOD). METHODS A PubMed search was carried out using the following key words were used: statins, statin-associated muscle symptoms, statin myalgia, statin-associated diabetes, metformin and statins, exercise and statins. RESULTS Mitochondrial damage and muscle atrophy are likely the central mechanisms producing SAMS, whereas decreased glucose transport, fatty acid oxidation and insulin secretion are likely involved in the development of NOD. Metformin and exercise training share many pathways that could potentially contrast SAMS and NOD. Clinical evidence also supports the combination of statins with metformin and exercise. CONCLUSION This combination appears attractive both from a clinical and an economical viewpoint, since all three therapies are highly cost-effective and their combination could result in diabetes and cardiovascular disease prevention.
Collapse
Affiliation(s)
- Jonida Haxhi
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
- Division of Cardiology, Hartford Hospital, Hartford, CT, USA
| | - Paul D Thompson
- Division of Cardiology, Hartford Hospital, Hartford, CT, USA
| |
Collapse
|
|
34
|
Ramin-Mangata S, Thedrez A, Nativel B, Diotel N, Blanchard V, Wargny M, Aguesse A, Billon-Crossouard S, Vindis C, Le May C, Hulin P, Armanet M, Gmyr V, Pattou F, Croyal M, Meilhac O, Nobécourt E, Cariou B, Lambert G. Effects of proprotein convertase subtilisin kexin type 9 modulation in human pancreatic beta cells function. Atherosclerosis 2021; 326:47-55. [PMID: 33933263 DOI: 10.1016/j.atherosclerosis.2021.03.044] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 03/09/2021] [Accepted: 03/30/2021] [Indexed: 10/21/2022]
Abstract
BACKGROUND AND AIMS Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) is an endogenous inhibitor of the LDL receptor (LDLR). Mendelian randomization studies suggest that PCSK9 deficiency increases diabetes risk, but the underlying mechanisms remain unknown. The aim of our study was to investigate whether PCSK9 or its inhibition may modulate beta cell function. METHODS We assessed PCSK9 and insulin colocalization in human pancreatic sections by epifluorescent and confocal microscopy. We also investigated the expression and the function of PCSK9 in the human EndoC-βH1 beta cell line, by ELISA and flow cytometry, respectively. PCSK9 was inhibited with Alirocumab or siRNA. LDLR expression and LDL uptake were assessed by flow cytometry. RESULTS PCSK9 was expressed and secreted from beta cells isolated from human pancreas as well as from EndoC-βH1 cells. PCSK9 secretion was enhanced by statin treatment. Recombinant PCSK9 decreased LDLR abundance at the surface of these cells, an effect abrogated by Alirocumab. Alirocumab as well as PCSK9 silencing increased LDLR expression at the surface of EndoC-βH1 cells. Neither exogenous PCSK9, nor Alirocumab, nor PCSK9 silencing significantly altered glucose-stimulated insulin secretion (GSIS) from these cells. High-low density lipoproteins (LDL) concentrations decreased GSIS, but the addition of PCSK9 or its inhibition did not modulate this phenomenon. CONCLUSIONS While PCSK9 regulates LDLR abundance in beta cells, inhibition of exogenous or endogenous PCSK9 does not appear to significantly impact insulin secretion. This is reassuring for the safety of PCSK9 inhibitors in terms of beta cell function.
Collapse
Affiliation(s)
| | - Aurélie Thedrez
- Université de Nantes, CRNH Ouest, Inra UMR 1280 PhAN, Nantes, France; L'institut du Thorax, INSERM, CNRS, UNIV Nantes, CHU Nantes, Nantes, France
| | - Brice Nativel
- Université de La Réunion, Inserm UMR 1188 DéTROI, Sainte Clotilde, France
| | - Nicolas Diotel
- Université de La Réunion, Inserm UMR 1188 DéTROI, Sainte Clotilde, France
| | - Valentin Blanchard
- Université de La Réunion, Inserm UMR 1188 DéTROI, Sainte Clotilde, France
| | - Matthieu Wargny
- L'institut du Thorax, INSERM, CNRS, UNIV Nantes, CHU Nantes, Nantes, France; CHU Nantes, INSERM, CIC 1413, Pôle Hospitalo-Universitaire 11: Santé Publique, Clinique des Données, Nantes, F-44093, France
| | - Audrey Aguesse
- Université de Nantes, CRNH Ouest, Inra UMR 1280 PhAN, Nantes, France
| | | | | | - Cédric Le May
- L'institut du Thorax, INSERM, CNRS, UNIV Nantes, CHU Nantes, Nantes, France
| | - Philippe Hulin
- Université de Nantes, CHU de Nantes, Inserm UMS 016, Cnrs UMS 3556, Structure Fédérative de Recherche François Bonamy, Micropicell Facility, Nantes, France
| | - Mathieu Armanet
- Cell Therapy Unit, Hôpital Saint Louis, AP-HP, Université Paris Diderot, Paris, France
| | - Valery Gmyr
- European Genomic Institute for Diabetes, Inserm UMR 1190 Translational Research for Diabetes, University of Lille 2, Lille, France
| | - François Pattou
- European Genomic Institute for Diabetes, Inserm UMR 1190 Translational Research for Diabetes, University of Lille 2, Lille, France; Lille University Hospital, Lille, France
| | - Mikaël Croyal
- Université de Nantes, CRNH Ouest, Inra UMR 1280 PhAN, Nantes, France
| | - Olivier Meilhac
- Université de La Réunion, Inserm UMR 1188 DéTROI, Sainte Clotilde, France
| | - Estelle Nobécourt
- Université de La Réunion, Inserm UMR 1188 DéTROI, Sainte Clotilde, France; CHU de La Réunion, Service d'Endocrinologie Nutrition, Saint-Pierre, France
| | - Bertrand Cariou
- L'institut du Thorax, INSERM, CNRS, UNIV Nantes, CHU Nantes, Nantes, France
| | - Gilles Lambert
- Université de La Réunion, Inserm UMR 1188 DéTROI, Sainte Clotilde, France.
| |
Collapse
|
|
35
|
Ji XW, Feng GS, Li HL, Fang J, Wang J, Shen QM, Han LH, Liu DK, Xiang YB. Gender differences of relationship between serum lipid indices and type 2 diabetes mellitus: a cross-sectional survey in Chinese elderly adults. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:115. [PMID: 33569417 PMCID: PMC7867915 DOI: 10.21037/atm-20-2478] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Background To investigate the gender differences of the relationships between clinical serum lipid indices and type 2 diabetes mellitus (T2DM) in Chinese elderly adults. Methods Between 2014 and 2016, participants selected from three communities in an urban district of Shanghai were measured for serum lipid indices of low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), total cholesterol (TC), and triglyceride (TG). Age and multivariate adjusted logistic regression models were utilized to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) of serum lipid indices on T2DM prevalence. Results In total, 4,023 male and 3,862 female participants were included in this study, with the T2DM prevalence proportions of 13.03% and 11.73%, respectively. In association analysis, the serum levels of LDL-c, HDL-c, TC were significant between non-T2DM individuals and T2DM patients in men, but the HDL-c and TG in women. LDL-c/HDL-c, TG/HDL-c, and TC/HDL-c ratios were associated with the T2DM prevalence only in women. In the multivariate analysis, a higher serum LDL-c level was positively associated with a reduced risk of T2DM prevalence in men with OR (95% CI) of 0.57 (0.39–0.85) (P=0.006). Higher ratios of LDL-c/HDL-c, TG/HDL-c, and TC/HDL-c were all more likely associated with the decreased risks of T2DM prevalence with the ORs ranging from 0.45 to 0.62 in men (all P<0.05), but not in women. Conclusions High LDL-c concentration was significantly associated with a lower T2DM prevalence in men. A gender difference of the associations between the lipid ratios and T2DM prevalence was observed for LDL-c/HDL-c and TC/HDL-c ratios, which might be validated in female T2DM prevalence in the future.
Collapse
Affiliation(s)
- Xiao-Wei Ji
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,State Key Laboratory of Oncogene and Related Genes & Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guo-Shan Feng
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,State Key Laboratory of Oncogene and Related Genes & Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hong-Lan Li
- State Key Laboratory of Oncogene and Related Genes & Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jie Fang
- State Key Laboratory of Oncogene and Related Genes & Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing Wang
- State Key Laboratory of Oncogene and Related Genes & Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qiu-Ming Shen
- State Key Laboratory of Oncogene and Related Genes & Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Li-Hua Han
- State Key Laboratory of Oncogene and Related Genes & Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Da-Ke Liu
- State Key Laboratory of Oncogene and Related Genes & Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yong-Bing Xiang
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,State Key Laboratory of Oncogene and Related Genes & Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| |
Collapse
|
|
36
|
Statin Treatment-Induced Development of Type 2 Diabetes: From Clinical Evidence to Mechanistic Insights. Int J Mol Sci 2020; 21:ijms21134725. [PMID: 32630698 PMCID: PMC7369709 DOI: 10.3390/ijms21134725] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 06/29/2020] [Accepted: 06/30/2020] [Indexed: 12/17/2022] Open
Abstract
Statins are the gold-standard treatment for the prevention of primary and secondary cardiovascular disease, which is the leading cause of mortality worldwide. Despite the safety and relative tolerability of statins, observational studies, clinical trials and meta-analyses indicate an increased risk of developing new-onset type 2 diabetes mellitus (T2DM) after long-term statin treatment. It has been shown that statins can impair insulin sensitivity and secretion by pancreatic β-cells and increase insulin resistance in peripheral tissues. The mechanisms involved in these processes include, among others, impaired Ca2+ signaling in pancreatic β-cells, down-regulation of GLUT-4 in adipocytes and compromised insulin signaling. In addition, it has also been described that statins’ impact on epigenetics may also contribute to statin-induced T2DM via differential expression of microRNAs. This review focuses on the evidence and mechanisms by which statin therapy is associated with the development of T2DM. This review describes the multifactorial combination of effects that most likely contributes to the diabetogenic effects of statins. Clinically, these findings should encourage clinicians to consider diabetes monitoring in patients receiving statin therapy in order to ensure early diagnosis and appropriate management.
Collapse
|
|
37
|
Castaño D, Rattanasopa C, Monteiro-Cardoso VF, Corlianò M, Liu Y, Zhong S, Rusu M, Liehn EA, Singaraja RR. Lipid efflux mechanisms, relation to disease and potential therapeutic aspects. Adv Drug Deliv Rev 2020; 159:54-93. [PMID: 32423566 DOI: 10.1016/j.addr.2020.04.013] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 04/29/2020] [Accepted: 04/30/2020] [Indexed: 02/06/2023]
Abstract
Lipids are hydrophobic and amphiphilic molecules involved in diverse functions such as membrane structure, energy metabolism, immunity, and signaling. However, altered intra-cellular lipid levels or composition can lead to metabolic and inflammatory dysfunction, as well as lipotoxicity. Thus, intra-cellular lipid homeostasis is tightly regulated by multiple mechanisms. Since most peripheral cells do not catabolize cholesterol, efflux (extra-cellular transport) of cholesterol is vital for lipid homeostasis. Defective efflux contributes to atherosclerotic plaque development, impaired β-cell insulin secretion, and neuropathology. Of these, defective lipid efflux in macrophages in the arterial walls leading to foam cell and atherosclerotic plaque formation has been the most well studied, likely because a leading global cause of death is cardiovascular disease. Circulating high density lipoprotein particles play critical roles as acceptors of effluxed cellular lipids, suggesting their importance in disease etiology. We review here mechanisms and pathways that modulate lipid efflux, the role of lipid efflux in disease etiology, and therapeutic options aimed at modulating this critical process.
Collapse
|
|
38
|
Lin Z, Guo D, Chen J, Zheng B. A nomogram for predicting 5-year incidence of type 2 diabetes in a Chinese population. Endocrine 2020; 67:561-568. [PMID: 31820309 DOI: 10.1007/s12020-019-02154-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Accepted: 11/27/2019] [Indexed: 02/08/2023]
Abstract
PURPOSE To develop a nomogram for predicting 5-year incidence of type 2 diabetes (T2D) in Chinese adults. METHODS This is a retrospective cohort study from a prospectively collected database. We included a total 32,766 adults free of T2D at baseline with a median follow-up of 3 years. Univariate and multivariate Cox regression analyses were applied to identify independent predictors. A nomogram was constructed to predict 5-year incident rate of T2D based on the multivariate analysis results. Harrell's C-indexes and calibration plots were used to evaluate the accuracy of the nomogram in both internal and external validations. RESULTS The overall prevalence of T2D was 2.1%. Participants were randomly divided into a training set (n = 21,844) and a validation set (n = 10,922). After multivariate analysis in the training set, age, sex, BMI, hypertension, dyslipidemia, smoking status, and family history were found as risk predictors and integrated into the nomogram. Harrell's C-indexes were 0.815 (95% CI: 0.797-0.834) and 0.779 (95% CI: 0.747-0.811) in the training and validation sets, respectively. The calibration plots demonstrated good agreement between the estimated probability and the actual observation. CONCLUSION Our nomogram could be a simple and reliable tool for predicting 5-year risk of developing T2D in high-risk Chinese. Through the model, early identifying high-risk individuals is helpful for timely intervention to reduce the incidence of T2D.
Collapse
Affiliation(s)
- Zeyin Lin
- Department of Ultrasound, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Dongming Guo
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Juntian Chen
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Baoqun Zheng
- Department of Ultrasound, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.
| |
Collapse
|
|
39
|
Ursino GM, Fu Y, Cottle DL, Mukhamedova N, Jones LK, Low H, Tham MS, Gan WJ, Mellett NA, Das PP, Weir JM, Ditiatkovski M, Fynch S, Thorn P, Thomas HE, Meikle PJ, Parkington HC, Smyth IM, Sviridov D. ABCA12 regulates insulin secretion from β-cells. EMBO Rep 2020; 21:e48692. [PMID: 32072744 DOI: 10.15252/embr.201948692] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 12/12/2019] [Accepted: 01/08/2020] [Indexed: 12/18/2022] Open
Abstract
Dysregulation of lipid homeostasis is intimately associated with defects in insulin secretion, a key feature of type 2 diabetes. Here, we explore the role of the putative lipid transporter ABCA12 in regulating insulin secretion from β-cells. Mice with β-cell-specific deletion of Abca12 display impaired glucose-stimulated insulin secretion and eventual islet inflammation and β-cell death. ABCA12's action in the pancreas is independent of changes in the abundance of two other cholesterol transporters, ABCA1 and ABCG1, or of changes in cellular cholesterol or ceramide content. Instead, loss of ABCA12 results in defects in the genesis and fusion of insulin secretory granules and increases in the abundance of lipid rafts at the cell membrane. These changes are associated with dysregulation of the small GTPase CDC42 and with decreased actin polymerisation. Our findings establish a new, pleiotropic role for ABCA12 in regulating pancreatic lipid homeostasis and insulin secretion.
Collapse
Affiliation(s)
- Gloria M Ursino
- Department of Anatomy and Developmental Biology, Department of Biochemistry and Molecular Biology, Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Vic., Australia
| | - Ying Fu
- Baker Heart and Diabetes Institute, Melbourne, Vic., Australia
| | - Denny L Cottle
- Department of Anatomy and Developmental Biology, Department of Biochemistry and Molecular Biology, Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Vic., Australia
| | | | - Lynelle K Jones
- Department of Anatomy and Developmental Biology, Department of Biochemistry and Molecular Biology, Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Vic., Australia
| | - Hann Low
- Baker Heart and Diabetes Institute, Melbourne, Vic., Australia
| | - Ming Shen Tham
- Department of Anatomy and Developmental Biology, Department of Biochemistry and Molecular Biology, Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Vic., Australia
| | - Wan Jun Gan
- Charles Perkins Centre, Camperdown, NSW, Australia
| | | | - Partha P Das
- Department of Anatomy and Developmental Biology, Department of Biochemistry and Molecular Biology, Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Vic., Australia
| | | | | | - Stacey Fynch
- St Vincent's Institute, Fitzroy, Vic., Australia
| | - Peter Thorn
- Charles Perkins Centre, Camperdown, NSW, Australia
| | | | - Peter J Meikle
- Baker Heart and Diabetes Institute, Melbourne, Vic., Australia
| | - Helena C Parkington
- Department of Physiology, Neuroscience Discovery Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Vic., Australia
| | - Ian M Smyth
- Department of Anatomy and Developmental Biology, Department of Biochemistry and Molecular Biology, Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Vic., Australia
| | - Dmitri Sviridov
- Baker Heart and Diabetes Institute, Melbourne, Vic., Australia
| |
Collapse
|
|
40
|
Wang X, Li R, Zacharek A, Landschoot-Ward J, Chopp M, Chen J, Cui X. ApoA-I Mimetic Peptide Reduces Vascular and White Matter Damage After Stroke in Type-2 Diabetic Mice. Front Neurosci 2019; 13:1127. [PMID: 31708728 PMCID: PMC6823666 DOI: 10.3389/fnins.2019.01127] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Accepted: 10/04/2019] [Indexed: 01/04/2023] Open
Abstract
Diabetes leads to an elevated risk of stroke and worse functional outcome compared to the general population. We investigate whether L-4F, an economical ApoA-I mimetic peptide, reduces neurovascular and white-matter damage in db/db type-2 diabetic (T2DM) stroke mice. L-4F (16 mg/kg, subcutaneously administered initially 2 h after stroke and subsequently daily for 4 days) reduced hemorrhagic transformation, decreased infarct-volume and mortality, and treated mice exhibited increased cerebral arteriole diameter and smooth muscle cell number, decreased blood-brain barrier leakage and white-matter damage in the ischemic brain as well as improved neurological functional outcome after stroke compared with vehicle-control T2DM mice (p < 0.05, n = 11/group). Moreover, administration of L-4F mitigated macrophage infiltration, and reduced the level of proinflammatory mediators tumor necrosis factor alpha (TNFα), high-mobility group box-1 (HMGB-1)/advanced glycation end-product receptor (RAGE) and plasminogen activator inhibitor-1 (PAI-1) in the ischemic brain in T2DM mice (p < 0.05, n = 6/group). In vitro, L-4F treatment did not increase capillary-like tube formation in mouse-brain endothelial cells, but increased primary artery explant cell migration derived from C57BL/6-aorta 1 day after middle cerebral artery occlusion (MCAo), and enhanced neurite-outgrowth after 2 h of oxygen-glucose deprivation and axonal-outgrowth in primary cortical neurons derived from the C57BL/6-embryos subjected to high-glucose condition. This study suggests that early treatment with L-4F provides a potential strategy to reduce neuroinflammation and vascular and white-matter damage in the T2DM stroke population.
Collapse
Affiliation(s)
- Xiaohui Wang
- Department of Neurology, Henry Ford Hospital, Detroit, MI, United States
| | - Rongwen Li
- Department of Neurology, Henry Ford Hospital, Detroit, MI, United States
| | - Alex Zacharek
- Department of Neurology, Henry Ford Hospital, Detroit, MI, United States
| | | | - Michael Chopp
- Department of Neurology, Henry Ford Hospital, Detroit, MI, United States.,Department of Physics, Oakland University, Rochester, MI, United States
| | - Jieli Chen
- Department of Neurology, Henry Ford Hospital, Detroit, MI, United States
| | - Xu Cui
- Department of Neurology, Henry Ford Hospital, Detroit, MI, United States
| |
Collapse
|
|
41
|
Szili-Torok T, Annema W, Anderson JLC, Bakker SJL, Tietge UJF. HDL Cholesterol Efflux Predicts Incident New-Onset Diabetes After Transplantation (NODAT) in Renal Transplant Recipients Independent of HDL Cholesterol Levels. Diabetes 2019; 68:1915-1923. [PMID: 31375510 DOI: 10.2337/db18-1267] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Accepted: 07/29/2019] [Indexed: 11/13/2022]
Abstract
In renal transplant recipients (RTRs), new-onset diabetes after transplantation (NODAT) is a frequent and serious complication limiting survival of graft and patient. However, the underlying pathophysiology remains incompletely understood. In vitro and in preclinical models, HDL can preserve β-cell function, largely by mediating cholesterol efflux, but this concept has not been evaluated in humans. This study investigated whether baseline cholesterol efflux capacity (CEC) in RTRs is associated with incident NODAT during follow-up. This prospective longitudinal study included 405 diabetes-free RTRs with a functioning graft for >1 year. During a median (interquartile range) follow-up of 9.6 (6.6-10.2) years, 57 patients (14.1%) developed NODAT. HDL CEC was quantified using incubation of human macrophage foam cells with apolipoprotein B-depleted plasma. Baseline CEC was significantly lower in patients developing NODAT during follow-up (median 6.84% [interquartile range 5.84-7.50%]) compared with the NODAT-free group (7.44% [6.46-8.60%]; P = 0.001). Kaplan-Meier analysis showed a lower risk for incident NODAT with increasing sex-stratified tertiles of HDL efflux capacity (P = 0.004). Linear regression analysis indicated that CEC is independently associated with incident NODAT (P = 0.04). In Cox regression analyses, CEC was significantly associated with NODAT (hazard ratio 0.53 [95% CI 0.38-0.76]; P < 0.001), independent of HDL cholesterol levels (P = 0.015), adiposity (P = 0.018), immunosuppressive medication (P = 0.001), and kidney function (P = 0.01). Addition of CEC significantly improved the predictive power of the Framingham Diabetes Risk Score (P = 0.004). This study establishes HDL CEC as a strong predictor of NODAT in RTRs, independent of several other recognized risk factors.
Collapse
Affiliation(s)
- Tamas Szili-Torok
- Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Wijtske Annema
- Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Josephine L C Anderson
- Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Stephan J L Bakker
- Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Uwe J F Tietge
- Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
- Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
- Clinical Chemistry, Karolinska University Laboratory, Karolinska University Hospital, Stockholm, Sweden
| |
Collapse
|
|
42
|
José GJ, Jorge E, Lujan F, Ivanna Q, Jean-Marc C. Type 2 diabetes: Prescription patterns and treatment outcomes of IDMPS survey in Argentina. Diabetes Res Clin Pract 2019; 153:86-92. [PMID: 31102686 DOI: 10.1016/j.diabres.2019.05.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 04/17/2019] [Accepted: 05/09/2019] [Indexed: 01/09/2023]
Abstract
AIM To assess prescription patterns for treatment of type 2 diabetes (T2D) and their outcomes in the IDMPS survey in Argentina. METHODS Data from 2551 people with T2D recruited from 210 physicians participating in IDMPS surveys in Argentina (2006 to 2012 waves) were recorded, including medical history, medications, glycemic control, blood pressure, and lipid status. RESULTS Most people were treated with oral glucose-lowering drugs (OGLDs) (65%), followed by combinations of these drugs plus insulin (22%) and only insulin (13%). These percentages varied according to T2D duration, the frequency of OGLDs decreasing while contrastingly and only insulin increasing (under 5 years versus over 10 years of disease duration, respectively). Average systolic blood pressure (SBP), HbA1c and LDL-c were significantly higher in patients treated with insulin either alone or associated with OGLDs. The percentage of people at target values for these parameters was also lower in these two groups. The percentage of people that reached simultaneous goal treatment values for BP, HbA1c and LDL-c levels was markedly low. CONCLUSION Prescription patterns for treatment of T2D follows a chronological trend and the percentage of people at goal values (HbA1c, BP and LDL-c values) was significantly lower in people receiving insulin. These data must be carefully considered by health and academic authorities in order to implement effective strategies to modify this situation.
Collapse
Affiliation(s)
- Gagliardino Juan José
- CENEXA Centro de Endocrinología Experimental y Aplicada (UNLP-CONICET), School of Medicine, National University of La Plata, La Plata, Argentina
| | - Elgart Jorge
- CENEXA Centro de Endocrinología Experimental y Aplicada (UNLP-CONICET), School of Medicine, National University of La Plata, La Plata, Argentina
| | - Forti Lujan
- Medical Department, Sanofi, Buenos Aires, Argentina.
| | | | | |
Collapse
|
|
43
|
Xepapadaki E, Zvintzou E, Kalogeropoulou C, Filou S, Kypreos KE. Τhe Antioxidant Function of HDL in Atherosclerosis. Angiology 2019; 71:112-121. [PMID: 31185723 DOI: 10.1177/0003319719854609] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Atherosclerosis is a multistep process that progresses over a long period of time and displays a broad range of severity. In its final form, it manifests as a lesion of the intimal layer of the arterial wall. There is strong evidence supporting that oxidative stress contributes to coronary heart disease morbidity and mortality and antioxidant high-density lipoprotein (HDL) could have a beneficial role in the prevention and prognosis of the disease. Indeed, certain subspecies of HDL may act as natural antioxidants preventing oxidation of lipids on low-density lipoprotein (LDL) and biological membranes. The antioxidant function may be attributed to inhibition of synthesis or neutralization of free radicals and reactive oxygen species by HDL lipids and associated enzymes or transfer of oxidation prone lipids from LDL and biological membranes to HDL for catabolism. A limited number of clinical trials suggest that the increased antioxidant potential of HDL correlates with decreased risk for atherosclerosis. Some nutritional interventions to increase HDL antioxidant activity have been proposed with limited success so far. The limitations in measuring and understanding HDL antioxidant function in vivo are also discussed.
Collapse
Affiliation(s)
- Eva Xepapadaki
- Department of Pharmacology, School of Medicine, University of Patras, Rio Achaias, TK, Greece
| | - Evangelia Zvintzou
- Department of Pharmacology, School of Medicine, University of Patras, Rio Achaias, TK, Greece
| | | | - Serafoula Filou
- Department of Pharmacology, School of Medicine, University of Patras, Rio Achaias, TK, Greece
| | - Kyriakos E Kypreos
- Department of Pharmacology, School of Medicine, University of Patras, Rio Achaias, TK, Greece
| |
Collapse
|
|
44
|
|
|
45
|
Sedgeman LR, Beysen C, Ramirez Solano MA, Michell DL, Sheng Q, Zhao S, Turner S, Linton MF, Vickers KC. Beta cell secretion of miR-375 to HDL is inversely associated with insulin secretion. Sci Rep 2019; 9:3803. [PMID: 30846744 PMCID: PMC6405899 DOI: 10.1038/s41598-019-40338-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Accepted: 02/08/2019] [Indexed: 12/15/2022] Open
Abstract
Extracellular microRNAs (miRNAs) are a new class of biomarkers for cellular phenotypes and disease, and are bioactive signals within intercellular communication networks. Previously, we reported that miRNAs are secreted from macrophage to high-density lipoproteins (HDL) and delivered to recipient cells to regulate gene expression. Despite the potential importance of HDL-miRNAs, regulation of HDL-miRNA export from cells has not been fully studied. Here, we report that pancreatic islets and beta cells abundantly export miR-375-3p to HDL and this process is inhibited by cellular mechanisms that promote insulin secretion. Small RNA sequencing and PCR approaches were used to quantify beta cell miRNA export to HDL. Strikingly, high glucose conditions were found to inhibit HDL-miR-375-3p export, which was dependent on extracellular calcium. Likewise, stimulation of cAMP was found to repress HDL-miR-375-3p export. Furthermore, we found that beta cell ATP-sensitive potassium channel (KATP) channels are required for HDL-miRNA export as chemical inhibition (tolbutamide) and global genetic knockout (Abcc8−/−) approaches inhibited HDL-miR-375-3p export. This process is not likely associated with cholesterol flux, as gain-of-function and loss-of-function studies for cholesterol transporters failed to alter HDL-miR-375-3p export. In conclusion, results support that pancreatic beta cells export miR-375-3p to HDL and this process is inversely regulated to insulin secretion.
Collapse
Affiliation(s)
- Leslie R Sedgeman
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | | | | | - Danielle L Michell
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Quanhu Sheng
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Shilin Zhao
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
| | | | - MacRae F Linton
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Kasey C Vickers
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA. .,Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
| |
Collapse
|
|
46
|
Nicholls SJ, Nelson AJ. HDL and cardiovascular disease. Pathology 2019; 51:142-147. [PMID: 30612759 DOI: 10.1016/j.pathol.2018.10.017] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Revised: 10/28/2018] [Accepted: 10/28/2018] [Indexed: 12/31/2022]
Abstract
High-density lipoprotein (HDL) has received increasing interest due to observations of an inverse relationship between its systemic levels and cardiovascular risk and targeted interventions in animal models that have had favourable effects on atherosclerotic plaque. In addition to its pivotal role in reverse cholesterol transport, HDL has been reported to possess a range of functional properties, which may exert a protective influence on inflammation, oxidation, angiogenesis and glucose homeostasis. This has led to the development of a range of HDL targeted therapeutics, which have undergone evaluation in clinical trials. The current state of HDL in cardiovascular prevention will be reviewed.
Collapse
Affiliation(s)
- Stephen J Nicholls
- South Australian Health and Medical Research Institute, Adelaide, SA, Australia; Monash University, Adelaide, SA, Australia.
| | - Adam J Nelson
- South Australian Health and Medical Research Institute, Adelaide, SA, Australia
| |
Collapse
|
|
47
|
Abstract
Clinical trials have unequivocally shown that inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) efficaciously and safely prevents cardiovascular events by lowering levels of LDL cholesterol. PCSK9 in the circulation is derived mainly from the liver, but the protein is also expressed in the pancreas, the kidney, the intestine and the central nervous system. Although PCSK9 modulates cholesterol metabolism by regulating LDL receptor expression in the liver, in vitro and in vivo studies have suggested that PCSK9 is involved in various other physiological processes. Although therapeutic PCSK9 inhibition could theoretically have undesired effects by interfering with these non-cholesterol-related processes, studies of individuals with genetically determined reduced PCSK9 function and clinical trials of PCSK9 inhibitors have not revealed clinically meaningful adverse consequences of almost completely eradicating PCSK9 from the circulation. The clinical implications of PCSK9 functions beyond lipid metabolism in terms of wanted or unwanted effects of therapeutic PCSK9 inhibition therefore appear to be limited. The objective of this Review is to describe the physiological role of PCSK9 beyond the LDL receptor to provide a rational basis for monitoring the effects of PCSK9 inhibition as these drugs gain traction in the clinic.
Collapse
Affiliation(s)
| | - Gilles Lambert
- Inserm UMR 1188 DéTROI, Université de La Réunion, Saint-Denis de La Réunion, France
| | - Bertrand Cariou
- L'institut du thorax, INSERM, CNRS, Université de Nantes, CHU Nantes, Nantes, France
| | - G Kees Hovingh
- Department of Vascular Medicine, Academisch Medisch Centrum, Amsterdam, Netherlands.
| |
Collapse
|
|
48
|
Sato S, Imachi H, Lyu J, Miyai Y, Fukunaga K, Dong T, Ibata T, Kobayashi T, Yoshimoto T, Kikuchi F, Yonezaki K, Yamaji N, Iwama H, Murao K. Effect of TNF-α on the expression of ABCA1 in pancreatic β-cells. J Mol Endocrinol 2018; 61:185-193. [PMID: 30131353 DOI: 10.1530/jme-18-0167] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Accepted: 08/21/2018] [Indexed: 01/19/2023]
Abstract
ATP-binding cassette transporter A1 (ABCA1), a 254-kD membrane protein, is a key regulator of lipid efflux from cells to apolipoproteins. ABCA1 in pancreatic β-cells influences insulin secretion and cholesterol homeostasis. Tumor necrosis factor (TNF)-α is a pleiotropic cytokine that elicits a wide spectrum of physiological events, including cell proliferation, differentiation, and apoptosis, and is also known to decrease glucose-dependent insulin secretion in pancreatic islets. In the present study, we examined the role of TNF-α on ABCA1 expression in rat pancreatic islets and INS-1 cells. ABCA1 protein levels decreased in response to rising concentrations of TNF-α in pancreatic islets. Real-time polymerase chain reaction analysis showed a significant decrease in ABCA1 mRNA expression. In parallel with its effect on endogenous ABCA1 mRNA levels, TNF-α suppressed the activity of a reporter construct containing the ABCA1 promoter. This effect was abrogated by BIRB796, but not by SB203580 or PD98095. The constitutively active form of p38 mitogen-activated protein kinase (MAPK) γ suppressed ABCA1 promoter activity but not p38-MAPK (α, β), while a dominant-negative mutant of p38-MAPK γ blocked the effect of TNF-α on ABCA1 promoter activity. BIRB796 inhibited the increased cholesterol ester content induced by TNF-α. However, BIRB796 had no effect on the decreased insulin content nor ABCA1 suppression caused by TNF-α in INS-1 cells. In summary, TNF-α suppressed the expression of endogenous ABCA1 in pancreatic islets and INS-1 cells. These findings raise the possibility that TNF-α may affect insulin secretion by controlling ABCA1 expression.
Collapse
Affiliation(s)
- Seisuke Sato
- Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa, Japan
| | - Hitomi Imachi
- Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa, Japan
| | - Jingya Lyu
- Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa, Japan
| | - Yumi Miyai
- Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa, Japan
| | - Kensaku Fukunaga
- Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa, Japan
| | - Tao Dong
- Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa, Japan
| | - Tomohiro Ibata
- Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa, Japan
| | - Toshihiro Kobayashi
- Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa, Japan
| | - Takuo Yoshimoto
- Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa, Japan
| | - Fumi Kikuchi
- Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa, Japan
| | - Kazuko Yonezaki
- Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa, Japan
| | - Nao Yamaji
- Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa, Japan
| | - Hisakazu Iwama
- Life Science Research Center, Kagawa University, Kita-gun, Kagawa, Japan
| | - Koji Murao
- Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa, Japan
| |
Collapse
|
|
49
|
Abstract
PURPOSE OF REVIEW Type 2 diabetes mellitus (T2DM) is associated with increased coronary heart disease (CHD) morbidity and mortality. These patients are also more prone to heart failure, arrhythmias and sudden cardiac death. Furthermore, coronary interventions performed in such high-risk patients have worse outcomes. In this narrative review, we discuss the role of diabetic dyslipidaemia on the risk of CHD in patients with T2DM. The effects of hypolipidaemic, antihypertensive and antidiabetic drugs on lipid and glucose metabolism in T2DM are also considered. RECENT FINDINGS Among CHD risk factors, diabetic dyslipidaemia characterized by moderately elevated low-density lipoprotein (LDL) cholesterol, increased triglycerides and small, dense LDL particles as well as decreased high-density lipoprotein cholesterol levels may contribute to the increased CHD risk associated with T2DM. Hypolipidaemic, antihypertensive and antidiabetic drugs can affect lipid and glucose parameters thus potentially influencing CHD risk. Such drugs may improve not only the quantity, but also the quality of LDL as well as postprandial lipaemia. SUMMARY Current data highlight the importance of treating diabetic dyslipidaemia in order to minimize CHD risk. Both fasting and postprandial lipids are influenced by drugs in patients with T2DM; physicians should take this into consideration in clinical decision making.
Collapse
|
|
50
|
Abstract
PURPOSE OF REVIEW Recent studies have demonstrated a higher risk of incident diabetes associated with statin use, causing concern among patients and clinicians. In this review, we will assess the evidence and proposed mechanisms behind statin therapy and its association with incident diabetes. We will then review the current recommendations for statin use in light of this association and suggest next steps for clinicians managing these patients and researchers exploring this phenomenon. RECENT FINDINGS The annual risk of developing new-onset diabetes with statin treatment is approximately 0.1%. In comparison, the absolute risk reduction of major coronary events with statin use is approximately 0.42% annually. Statins are associated with the development of incident diabetes, particularly among those with predisposing risk factors for diabetes. However, the benefit of statin use among these patients in preventing major coronary events strongly favors statin use despite its risk of incident diabetes.
Collapse
|