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Mohammed HR, Ben Othman R, Alghurabi H, Hussein RM, Al-Obaidi Z, Abdesselem H. Comparison of clinical characteristics, microvascular complications and inflammatory markers in type 2 diabetic patients under insulin versus metformin treatment: A cross-sectional study at Karbala Diabetic Center, Iraq. Medicine (Baltimore) 2024; 103:e40330. [PMID: 39495998 PMCID: PMC11537605 DOI: 10.1097/md.0000000000040330] [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: 08/14/2024] [Accepted: 10/11/2024] [Indexed: 11/06/2024] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a major global health issue associated with chronic inflammation, which contributes to both disease progression and its complications, including cardiovascular and microvascular disorders. Key inflammatory markers such as tumor necrosis factor-alpha, interleukin-6 (IL-6), E-selectin, and P-selectin are elevated in T2DM patients and are implicated in the development of these complications. Understanding how treatments such as insulin and metformin affect these markers is crucial for improving therapeutic strategies in T2DM. This study investigated the effects of insulin and metformin on these inflammatory markers in T2DM patients. This was a cross-sectional study involving patients with diabetes on insulin (group A), metformin only (group B), and healthy controls (group C). Participants were enrolled from the Diabetic Center in Karbala, Iraq and underwent clinical assessments including ophthalmologic examinations. Fasting blood glucose, HbA1c and lipids levels were assessed. The levels of inflammatory markers (IL-6 and TNF-α), and adhesion molecules (sE-selectin and sP-selectin) were measured using Enzyme-Linked Immunosorbent Assay (ELISA). The study included 522 patients with diabetes: 356 receiving insulin (group A), 70 receiving metformin (group B) and 96 healthy controls (group C). T2DM patients treated with insulin exhibited significantly more microvascular complications than those treated with metformin. Higher rates of retinopathy (64.3% vs 11.4%) and neuropathy (69.9% vs 11.4%) were observed in the insulin group, whereas the incidence of nephropathy did not differ significantly (14.6% vs 11.4%). Inflammatory markers were lower in the insulin group: TNF-α levels were 3-fold lower and IL-6 levels were 8-fold lower. Conversely, sE-selectin levels were 1.5-fold higher in the insulin group, and sP-selectin levels were 1.4-fold higher in the metformin group. This study highlights distinct differences in inflammatory markers and systemic complications between T2DM patients treated with insulin and those treated with metformin alone. Further research is needed to explore the mechanisms underlying these observations and optimize treatment strategies for T2DM patients.
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Affiliation(s)
- Haithem Rauf Mohammed
- University of Monastir, College of Pharmacy, Tunisia
- Department of Clinical Pharmacy, University of Kerbala, College of Medicine, Kerbala, Iraq
| | - Rym Ben Othman
- University of Tunis el Manar, Faculty of Medicine of Tunis, Tunisia
- Institut National de Nutrition et de Technologie Alimentaire de Tunis, Tunisia
| | - Hamid Alghurabi
- Department of Drug Delivery and Nano Pharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan
- Department of Pharmaceutics and Clinical Lab. Sciences, College of Pharmacy, Ahl Al Bayt University, Kerbala, Iraq
| | - Radhwan M. Hussein
- Department of Pharmaceutics and Clinical Lab. Sciences, College of Pharmacy, Ahl Al Bayt University, Kerbala, Iraq
| | - Zaid Al-Obaidi
- Department of Biosciences, College of Health and Life Sciences, Aston University, Birmingham, UK
- Department of Physiology, College of Medicine, University of Kerbala, Karbala, Iraq
| | - Haifa Abdesselem
- Institut National de Nutrition et de Technologie Alimentaire de Tunis, Tunisia
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He J, Dai P, Liu L, Yang Y, Liu X, Li Y, Liao Z. The effect of short-term intensive insulin therapy on inflammatory cytokines in patients with newly diagnosed type 2 diabetes. J Diabetes 2022; 14:192-204. [PMID: 35040554 PMCID: PMC9060141 DOI: 10.1111/1753-0407.13250] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 12/03/2021] [Accepted: 12/27/2021] [Indexed: 12/01/2022] Open
Abstract
BACKGROUND Diabetes mellitus was a chronic low-grade inflammatory disease and had increased circulating inflammatory cytokines and acute phase proteins. We aimed to identify the changes of inflammatory cytokines in newly diagnosed type 2 diabetic patients after short-term intensive insulin therapy using continuous subcutaneous insulin infusion (CSII). METHODS Thirty-three newly diagnosed type 2 diabetic patients were enrolled between September 2020 to December 2020. Expression of 40 inflammatory cytokines of the patients were tested with RayBiotech antibody array before and after 1 week of intensive insulin therapy of CSII. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was carried out to explore the signaling pathway involved in the therapy. RESULTS Five inflammatory cytokines were downregulated significantly after 1 week of CSII therapy. They were interleukin-6 receptor (IL-6R), regulated upon activation normal T-cell expressed and secreted (RANTES), intercellular adhesion molecule-1 (ICAM-1), tissue inhibitor of metalloproteinase-1 (TIMP-1), and platelet-derived growth factor type BB (PDGF-BB) (p < 0.05 and foldchange <0.83). Among patients with baseline glycated hemoglobin (HbA1c) < 10%, three proinflammatory cytokines were decreased significantly after therapy: IL-6R, RANTES, and ICAM-1. As for the patients with baseline HbA1c ≥ 10%, eight inflammatory cytokines were inhibited significantly after the treatment, including ICAM-1, IL-6R, RANTES, TIMP-1, TIMP-2, macrophage inflammatory protein-1 beta (MIP-1β), PDGF-BB, and tumor necrosis factor receptor type II (TNF RII). No matter which subgroup of baseline HbA1c level was considered, the decreased cytokines after CSII therapy were significantly involved in TNF signaling pathway. Nuclear factor-kappa B (NF-κB) signaling pathway was mainly enriched in patients with baseline HbA1c ≥ 10%. CONCLUSIONS A panel of 40 inflammatory cytokines, measured by protein microarray, were evaluated for 1 week of CSII treatment in newly diagnosed type 2 diabetic patients. After treatment, many proinflammatory cytokines decreased. In the higher baseline HbA1c subgroup, more proinflammatory cytokines improved. No matter which subgroup of HbA1c level was considered, IL-6R, RANTES, and ICAM-1, which were involved in TNF signaling pathway, decreased significantly after CSII therapy. This was the first report showing that the cytokines of IL-6R, TIMP-2, PDGF-BB, and TNF RII decreased after the CSII therapy.
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Affiliation(s)
- Junyu He
- Department of EndocrinologyThe First Affiliated Hospital, Sun Yat‐Sen UniversityGuangzhouChina
| | - Peiji Dai
- Department of EndocrinologyThe First Affiliated Hospital, Sun Yat‐Sen UniversityGuangzhouChina
| | - Liyi Liu
- Department of EndocrinologyThe First Affiliated Hospital, Sun Yat‐Sen UniversityGuangzhouChina
| | - Yanqing Yang
- Research and Development DepartmentRayBiotech, Inc.GuangzhouChina
| | - Xibo Liu
- Department of EndocrinologyThe First Affiliated Hospital, Sun Yat‐Sen UniversityGuangzhouChina
| | - Yanbing Li
- Department of EndocrinologyThe First Affiliated Hospital, Sun Yat‐Sen UniversityGuangzhouChina
| | - Zhihong Liao
- Department of EndocrinologyThe First Affiliated Hospital, Sun Yat‐Sen UniversityGuangzhouChina
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Involvement of Cdkal1 in the etiology of type 2 diabetes mellitus and microvascular diabetic complications: a review. J Diabetes Metab Disord 2022; 21:991-1001. [PMID: 35673487 PMCID: PMC9167393 DOI: 10.1007/s40200-021-00953-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 11/30/2021] [Indexed: 02/07/2023]
Abstract
Diabetes Mellitus, being a polygenic disorder, have a set of risk genes involved in the onset of the insulin resistance, obesity and impaired insulin synthesis. Recent genome wide association studies (GWAS) shows the intimacy of CDK5 regulatory subunit Associated protein 1-Like 1 (Cdkal1) with the pathophysiology of the diabetes mellitus and its complications, although the exact molecular relation is still unknown. In this short review, we have summarized all the diverse biological roles of Cdkal1 in relation to the onset of diabetes mellitus. Variations in the Cdkal1 transcript are responsible for the accumulation of misfolded insulin and thus generating oxidative and ER stress in the pancreatic β-cells, leading to their destruction. Recent studies have shown that Cdkal1 has an intrinsic thiomethyl transferase activity, which is essential for proper posttranslational processing of pre-proinsulin to produce mature insulin. Moreover, Cdkal1 has also been claimed as an endogenous inhibitor of cdk5, which prevents the cdk5-induced interruption in insulin synthesis through PDX1 translocation from nucleus to cytosol. Recent clinical studies have identified the risk single nucleotide polymorphisms (SNPs) of Cdkal1 as one of the root causes for the onset of diabetic complications. To the best of our knowledge, it is the first comprehensive review which elaborates most of the potential Cdkal1-dependent molecular mechanisms studied yet. In this review, we present a compiled and concise summary about all the diverse roles of Cdkal1 in the context of type 2 diabetes mellitus and its associated complications. This review will be helpful to target Cdkal1 as a potential option for the management of type 2 diabetes mellitus in future. Graphical abstract
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Koufakis T, Dimitriadis G, Metallidis S, Zebekakis P, Kotsa K. The role of autoimmunity in the pathophysiology of type 2 diabetes: Looking at the other side of the moon. Obes Rev 2021; 22:e13231. [PMID: 33682984 DOI: 10.1111/obr.13231] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 02/17/2021] [Accepted: 02/18/2021] [Indexed: 12/12/2022]
Abstract
Efforts to unravel the pathophysiological mechanisms of type 2 diabetes (T2D) have been traditionally trapped into a metabolic perspective. However, T2D is a phenotypically and pathophysiologically heterogenous disorder, and the need for a tailored approach in its management is becoming increasingly evident. There is emerging evidence that irregular immune responses contribute to the development of hyperglycemia in T2D and, inversely, that insulin resistance is a component of the pathogenesis of autoimmune diabetes. Nevertheless, it has not yet been fully elucidated to what extent the presence of conventional autoimmune markers, such as autoantibodies, in subjects with T2D might affect the natural history of the disease and particularly each response to various treatments. The challenge for future research in the field is the discovery of novel genetic, molecular, or phenotypical indicators that would enable the characterization of specific subpopulations of people with T2D who would benefit most from the addition of immunomodulatory therapies to standard glucose-lowering treatment. This narrative review aims to discuss the plausible mechanisms through which the immune system might be implicated in the development of metabolic disturbances in T2D and obesity and explore a potential role of immunotherapy in the future management of the disorder and its complications.
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Affiliation(s)
- Theocharis Koufakis
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
| | - George Dimitriadis
- Athens University Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Symeon Metallidis
- Infectious Diseases Division, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
| | - Pantelis Zebekakis
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece.,Infectious Diseases Division, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
| | - Kalliopi Kotsa
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
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Jensen VS, Fledelius C, Zachodnik C, Damgaard J, Nygaard H, Tornqvist KS, Kirk RK, Viuff BM, Wulff EM, Lykkesfeldt J, Hvid H. Insulin treatment improves liver histopathology and decreases expression of inflammatory and fibrogenic genes in a hyperglycemic, dyslipidemic hamster model of NAFLD. J Transl Med 2021; 19:80. [PMID: 33596938 PMCID: PMC7890970 DOI: 10.1186/s12967-021-02729-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 01/29/2021] [Indexed: 11/24/2022] Open
Abstract
Background Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are highly prevalent comorbidities in patients with Type 2 diabetes. While many of these patients eventually will need treatment with insulin, little is known about the effects of insulin treatment on histopathological parameters and hepatic gene expression in diabetic patients with co-existing NAFLD and NASH. To investigate this further, we evaluated the effects of insulin treatment in NASH diet-fed hamsters with streptozotocin (STZ) -induced hyperglycemia. Methods Forty male Syrian hamsters were randomized into four groups (n = 10/group) receiving either a NASH-inducing (high fat, fructose and cholesterol) or control diet (CTRL) for four weeks, after which they were treated with STZ or sham-injected and from week five treated with either vehicle (CTRL, NASH, NASH-STZ) or human insulin (NASH-STZ-HI) for four weeks by continuous s.c. infusion via osmotic minipumps. Results NASH-STZ hamsters displayed pronounced hyperglycemia, dyslipidemia and more severe liver pathology compared to both CTRL and NASH groups. Insulin treatment attenuated dyslipidemia in NASH-STZ-HI hamsters and liver pathology was considerably improved compared to the NASH-STZ group, with prevention/reversal of hepatic steatosis, hepatic inflammation and stellate cell activation. In addition, expression of inflammatory and fibrotic genes was decreased compared to the NASH-STZ group. Conclusions These results suggest that hyperglycemia is important for development of inflammation and profibrotic processes in the liver, and that insulin administration has beneficial effects on liver pathology and expression of genes related to inflammation and fibrosis in a hyperglycemic, dyslipidemic hamster model of NAFLD.
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Affiliation(s)
- Victoria Svop Jensen
- Section of Experimental Animal Models, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, 1870, Frederiksberg, Denmark. .,Diabetes Pharmacology, Novo Nordisk A/S, Novo Nordisk Park 1, 2760, Måløv, Denmark.
| | - Christian Fledelius
- Diabetes Pharmacology, Novo Nordisk A/S, Novo Nordisk Park 1, 2760, Måløv, Denmark
| | - Christina Zachodnik
- Diabetes Pharmacology, Novo Nordisk A/S, Novo Nordisk Park 1, 2760, Måløv, Denmark
| | - Jesper Damgaard
- Diabetes Pharmacology, Novo Nordisk A/S, Novo Nordisk Park 1, 2760, Måløv, Denmark
| | - Helle Nygaard
- Diabetes Pharmacology, Novo Nordisk A/S, Novo Nordisk Park 1, 2760, Måløv, Denmark
| | | | - Rikke Kaae Kirk
- Pathology & Imaging, Novo Nordisk A/S, Novo Nordisk Park 1, 2760, Måløv, Denmark
| | | | - Erik Max Wulff
- Gubra ApS, Hørsholm Kongevej 11B, 2970, Hørsholm, Denmark
| | - Jens Lykkesfeldt
- Section of Experimental Animal Models, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, 1870, Frederiksberg, Denmark
| | - Henning Hvid
- Pathology & Imaging, Novo Nordisk A/S, Novo Nordisk Park 1, 2760, Måløv, Denmark
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Zhao L, Li Y, Lv Q, Wang M, Luan Y, Song J, Fu G, Ge J, Zou Y, Zhang W. Insulin-Attenuated Inflammatory Response of Dendritic Cells in Diabetes by Regulating RAGE-PKC β1-IRS1-NF- κB Signal Pathway: A Study on the Anti-Inflammatory Mechanism of Insulin in Diabetes. J Diabetes Res 2020; 2020:1-15. [DOI: 10.1155/2020/1596357] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2025] Open
Abstract
Background. Diabetes is associated with chronic inflammation, and dendritic cells (DCs) have proinflammatory effect in diabetes. The anti-inflammatory effect of insulin on diabetes is not entirely clear. The study aims to examine insulin-induced effects on the inflammatory response in DCs. Methods. Twenty-one C57BL/6 mice were divided into 3 groups. Streptozotocin was injected into the diabetic mice model. The bone marrow-derived DCs (BMDCs) were obtained from C57BL/6 mice. CD83, CD86, and type II major histocompatibility complex (MHC-II) of BMDCs were measured by flow cytometry. The fluctuations in the RNA levels of cytokines and chemokines were analyzed by quantitative RT-PCR. The concentrations of IFN-γ and TNF-α were calculated using ELISA kits, and the proteins were detected using western blot. Results. In CD11c+ DCs derived from the spleens with hyperglycemia, the expression of CD83 and CD86 in diabetic mice was significantly upregulated, coupled with a higher secretion level of cytokines and chemokines, and increased phosphorylation of NF-κB and IκB. Insulin therapy was found to have a reversal effect on the inflammatory response and immune maturation in DCs. In AGEs-BSA-stimulated BMDCs, insulin repressed the immune maturation and downregulated the expression of RAGE, phospho-PKCβ1, and serine phospho-IRS1 in an adose-dependent manner. Such effects can be abolished by PMA, but not IR-neutralizing antibody. AGEs-BSA-induced BMDCs immune maturation was inhibited by the neutralizing antibody of RAGE, the PKCβ1 inhibitor, or the IRS1 siRNA. Conclusions. Insulin has the capability of attenuating the inflammatory response of DCs in diabetes, partly through the downregulation of RAGE expression followed by the inhibition of PKCβ1 phosphorylation and IRS1 serine phosphorylation, resulting in the inactivation of IR binding-independent NF-κB. This might partly explain the antiatherogenic effect of insulin on diabetes.
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Affiliation(s)
- Liding Zhao
- Department of Cardiovascular Diseases, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, China
- Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, China
| | - Ya Li
- Department of Cardiovascular Diseases, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, China
- Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, China
| | - Qingbo Lv
- Department of Cardiovascular Diseases, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, China
- Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, China
| | - Min Wang
- Department of Cardiovascular Diseases, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, China
- Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, China
| | - Yi Luan
- Department of Cardiovascular Diseases, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, China
- Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, China
| | - Jiale Song
- Department of Cardiovascular Diseases, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, China
- Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, China
| | - Guosheng Fu
- Department of Cardiovascular Diseases, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, China
- Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, China
| | - Junbo Ge
- Shanghai Institute of Cardiovascular Diseases of Zhongshan Hospital, Fudan University, Shanghai, China
- Institute of Biomedical Science, Fudan University, Shanghai, China
| | - Yunzeng Zou
- Shanghai Institute of Cardiovascular Diseases of Zhongshan Hospital, Fudan University, Shanghai, China
- Institute of Biomedical Science, Fudan University, Shanghai, China
| | - Wenbin Zhang
- Department of Cardiovascular Diseases, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, China
- Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, China
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Xourgia E, Tzouganatou EM, Papazafiropoulou A, Melidonis A. Anti-inflammatory properties of antidiabetic agents. World J Meta-Anal 2019; 7:129-141. [DOI: 10.13105/wjma.v7.i4.129] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 04/20/2019] [Accepted: 04/23/2019] [Indexed: 02/06/2023] Open
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Cheng L, Yang F, Cao X, Li GQ, Lu TT, Zhu YQ, Hu Y, Mao XM. The effect of short-term intensive insulin therapy on circulating T cell subpopulations in patients with newly diagnosed type 2 diabetes mellitus. Diabetes Res Clin Pract 2019; 149:107-114. [PMID: 30759366 DOI: 10.1016/j.diabres.2019.02.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Revised: 01/04/2019] [Accepted: 02/06/2019] [Indexed: 01/04/2023]
Abstract
AIMS To evaluate the effect of short-term intensive insulin therapy on circulating T cell subpopulations in patients with newly diagnosed type 2 diabetes mellitus (T2DM). METHODS A total of 113 patients with T2DM and 28 normal subjects were enrolled. Demographic parameters and biochemical markers were collected at baseline, and flow cytometry was applied to determine the proportion of T cell subpopulations in participants. Then the patients underwent continuous subcutaneous insulin injection (CSII) treatment with euglycemia for 2 weeks, and the T cell subpopulations were measured again after CSII treatment. RESULTS Compared with normal subjects, the proportion of Th1 cells and the ratio of Th1/Th2 increased, the proportion of Treg cells decreased in patients with T2DM (p < 0.05 for all). The ratio of Th1/Th2 was positively correlated with glycosylated hemoglobin A1c (HbA1c) and negatively correlated with high density lipoprotein cholesterol (HDL-C). Furthermore, there were negative associations between the proportion of Treg cells and fasting plasma glucose, HbA1c, triglyceride, low density lipoprotein cholesterol, and positive association between the proportion of Treg cells and HDL-C. After CSII treatment, the proportion of Th1 cells and the ratio of Th1/Th2 decreased (p < 0.05 for both), the proportion of Treg cells increased in patients with T2DM (p < 0.05). CONCLUSIONS Short-term intensive insulin therapy could modulate circulating T cell subpopulations in patients with T2DM, which might alleviate inflammatory responses caused by hyperglycemia. This study was registered with ChiCTR-OPN-17010405.
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Affiliation(s)
- Liang Cheng
- Department of Endocrinology, the Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, China; Department of Endocrinology, Huai'an Second People's Hospital and the Affiliated Huai'an Hospital of Xuzhou Medical University, Huaian, Jiangsu, China
| | - Fan Yang
- Department of Endocrinology, the Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, China; Department of Endocrinology, Yancheng City No. 1 People's Hospital, Yancheng, Jiangsu, China
| | - Xin Cao
- Department of Endocrinology, the Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, China
| | - Guo-Qing Li
- Department of Endocrinology, the Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, China
| | - Ting-Ting Lu
- Department of Endocrinology, the Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, China
| | - Yun-Qing Zhu
- Department of Endocrinology, the Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, China
| | - Yun Hu
- Department of Endocrinology, the Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, China.
| | - Xiao-Ming Mao
- Department of Endocrinology, the Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, China.
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Yadav SK, Kambis TN, Mishra PK. Regulating Inflammatory Cytokines in the Diabetic Heart. OXIDATIVE STRESS IN HEART DISEASES 2019:427-436. [DOI: 10.1007/978-981-13-8273-4_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Bianchi VE. Impact of Nutrition on Cardiovascular Function. Curr Probl Cardiol 2018; 45:100391. [PMID: 30318107 DOI: 10.1016/j.cpcardiol.2018.08.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Accepted: 08/31/2018] [Indexed: 12/11/2022]
Abstract
The metabolic sources of energy for myocardial contractility include mainly free fatty acids (FFA) for 95%, and in lesser amounts for 5% from glucose and minimal contributions from other substrates such lactate, ketones, and amino acids. However, myocardial efficiency is influenced by metabolic condition, overload, and ischemia. During cardiac stress, cardiomyocytes increase glucose oxidation and reduce FFA oxidation. In patients with ischemic coronary disease and heart failure, the low oxygen availability limits myocardial reliance on FFA and glucose utilization must increase. Although glucose uptake is fundamental to cardiomyocyte function, an excessive intracellular glucose level is detrimental. Insulin plays a fundamental role in maintaining myocardial efficiency and in reducing glycemia and inflammation; this is particularly evident in obese and type-2 diabetic patients. An excess of F availability increase fat deposition within cardiomyocytes and reduces glucose oxidation. In patients with high body mass index, a restricted diet or starvation have positive effects on cardiac metabolism and function while, in patients with low body mass index, restrictive diets, or starvation have a deleterious effect. Thus, weight loss in obese patients has positive impacts on ventricular mass and function, whereas, in underweight heart failure patients, such weight reduction adds to the risk of heart damage, predisposing to cachexia. Nutrition plays an essential role in the evolution of cardiovascular disease and should be taken into account. An energy-restricted diet improves myocardial efficiency but can represent a potential risk of heart damage, particularly in patients affected by cardiovascular disease. Micronutrient integration has a marginal effect on cardiovascular efficiency.
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Bala C, Rusu A, Ciobanu DM, Craciun AE, Roman G. The association study of high-sensitivity C-reactive protein, pentraxin 3, nitrotyrosine, and insulin dose in patients with insulin-treated type 2 diabetes mellitus. Ther Clin Risk Manag 2018; 14:955-963. [PMID: 29881277 PMCID: PMC5978465 DOI: 10.2147/tcrm.s162086] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
PURPOSE The objective of this study was to examine the association between insulin dose and high-sensitivity C-reactive protein (hsCRP), nitrotyrosine, and pentraxin 3 in patients with insulin-treated type 2 diabetes. PATIENTS AND METHODS Eighty patients with type 2 diabetes treated with insulin for >6 months and with stable insulin doses (±10%) within 3 months before inclusion were enrolled in this study. Medical history, including use of insulin and insulin doses, concomitant diseases and medication, and anthropometric and routine biochemical parameters were collected for each patient. hsCRP, nitrotyrosine, and pentraxin 3 were measured in fasting conditions. Comparison analysis was performed according to the distribution in tertiles of insulin dose/kg of body weight, and linear regression adjusted for confounding factors was used to examine the associations between markers of inflammation, oxidative stress, and insulin dose. RESULTS In the comparison analysis, no statistically significant difference was found between hsCRP, nitrotyrosine, and pentraxin 3 levels across tertiles of insulin dose expressed as IU/kg of body weight (p for trend >0.05 for all comparisons) except a significantly higher hsCRP level in tertile 3 compared to tertile 1 (3.9±3.6 vs 6.1±3.8 mg/dL, p=0.035). In regression analysis, after adjustment for age, gender, smoking, body mass index, glycated hemoglobin, C-peptide, metformin, antiplatelet, and statin use, only hsCRP levels were statistically significant associated with insulin dose/kg of body weight (β=0.237, p=0.043). CONCLUSION In this sample of patients with type 2 diabetes treated with insulin for >6 months, hsCRP was positively associated with insulin doses. No such association was found for pentraxin 3, a more specific marker of vascular inflammation, and for nitrotyrosine as a marker of oxidative stress.
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Affiliation(s)
- Cornelia Bala
- Department of Diabetes and Nutrition, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Adriana Rusu
- Department of Diabetes and Nutrition, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Dana Mihaela Ciobanu
- Department of Diabetes and Nutrition, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Anca Elena Craciun
- Department of Diabetes and Nutrition, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Gabriela Roman
- Department of Diabetes and Nutrition, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
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Endothelium-dependent vasodilation in the cerebral arterioles of rats deteriorates during acute hyperglycemia and then is restored by reducing the glucose level. J Anesth 2018; 32:531-538. [DOI: 10.1007/s00540-018-2507-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2017] [Accepted: 05/12/2018] [Indexed: 12/11/2022]
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13
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Pollack RM, Donath MY, LeRoith D, Leibowitz G. Anti-inflammatory Agents in the Treatment of Diabetes and Its Vascular Complications. Diabetes Care 2016; 39 Suppl 2:S244-52. [PMID: 27440839 DOI: 10.2337/dcs15-3015] [Citation(s) in RCA: 176] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
The association between hyperglycemia and inflammation and vascular complications in diabetes is now well established. Antidiabetes drugs may alleviate inflammation by reducing hyperglycemia; however, the anti-inflammatory effects of these medications are inconsistent and it is unknown whether their beneficial metabolic effects are mediated via modulation of chronic inflammation. Recent data suggest that immunomodulatory treatments may have beneficial effects on glycemia, β-cell function, and insulin resistance. However, the mechanisms underlying their beneficial metabolic effects are not always clear, and there are concerns regarding the specificity, safety, and efficacy of immune-based therapies. Herein, we review the anti-inflammatory and metabolic effects of current antidiabetes drugs and of anti-inflammatory therapies that were studied in patients with type 2 diabetes. We discuss the potential benefit of using anti-inflammatory treatments in diabetes and important issues that should be addressed prior to implementation of such therapeutic approaches.
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Affiliation(s)
- Rena M Pollack
- Diabetes Unit, Hadassah University Hospital, Jerusalem, Israel
| | - Marc Y Donath
- Endocrinology, Diabetes, and Metabolism, Department of Biomedicine, University Hospital Basel, Basel, Switzerland
| | - Derek LeRoith
- Diabetes and Metabolism Clinical Research Center of Excellence, Rambam Health Care Campus, Haifa, Israel
| | - Gil Leibowitz
- Diabetes Unit, Hadassah University Hospital, Jerusalem, Israel Endocrine Service, Hadassah University Hospital, Jerusalem, Israel
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Bertinat R, Westermeier F, Silva P, Shi J, Nualart F, Li X, Yáñez AJ. Anti-Diabetic Agent Sodium Tungstate Induces the Secretion of Pro- and Anti-Inflammatory Cytokines by Human Kidney Cells. J Cell Physiol 2016; 232:355-362. [PMID: 27186953 DOI: 10.1002/jcp.25429] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Accepted: 05/16/2016] [Indexed: 02/04/2023]
Abstract
Diabetic kidney disease (DKD) is the major cause of end stage renal disease. Sodium tungstate (NaW) exerts anti-diabetic and immunomodulatory activities in diabetic animal models. Here, we used primary cultures of renal proximal tubule epithelial cells derived from type-2-diabetic (D-RPTEC) and non-diabetic (N-RPTEC) subjects as in vitro models to study the effects of NaW on cytokine secretion, as these factors participate in intercellular regulation of inflammation, cell growth and death, differentiation, angiogenesis, development, and repair, all processes that are dysregulated during DKD. In basal conditions, D-RPTEC cells secreted higher levels of prototypical pro-inflammatory IL-6, IL-8, and MCP-1 than N-RPTEC cells, in agreement with their diabetic phenotype. Unexpectedly, NaW further induced IL-6, IL-8, and MCP-1 secretion in both N- and D-RPTEC, together with lower levels of IL-1 RA, IL-4, IL-10, and GM-CSF, suggesting that it may contribute to the extent of renal damage/repair during DKD. Besides, NaW induced the accumulation of IκBα, the main inhibitor protein of one major pathway involved in cytokine production, suggesting further anti-inflammatory effect in the long-term. A better understanding of the mechanisms involved in the interplay between the anti-diabetic and immunomodulatory properties of NaW will facilitate future studies about its clinical relevance. J. Cell. Physiol. 232: 355-362, 2017. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Romina Bertinat
- Centro de Microscopía Avanzada, CMA-Bío Bío, Universidad de Concepción, Concepción, Chile. .,Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile. .,Division of Gastroenterology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
| | - Francisco Westermeier
- Facultad de Ciencias Químicas y Farmacéuticas and Facultad de Medicina, Centro Avanzado de Enfermedades Crónicas (ACCDiS), Universidad de Chile, Santiago, Chile.,Facultad de Ciencia, Universidad San Sebastián, Santiago, Chile
| | - Pamela Silva
- Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
| | - Jie Shi
- Division of Gastroenterology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Francisco Nualart
- Centro de Microscopía Avanzada, CMA-Bío Bío, Universidad de Concepción, Concepción, Chile
| | - Xuhang Li
- Division of Gastroenterology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Alejandro J Yáñez
- Centro de Microscopía Avanzada, CMA-Bío Bío, Universidad de Concepción, Concepción, Chile. .,Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile.
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15
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Abstract
Current literature shows an association of diabetes and secondary complications with chronic inflammation. Evidence of these immunological changes include altered levels of cytokines and chemokines, changes in the numbers and activation states of various leukocyte populations, apoptosis, and fibrosis during diabetes. Therefore, treatment of diabetes and its complications may include pharmacological strategies to reduce inflammation. Apart from anti-inflammatory drugs, various hypoglycemic agents have also been found to reduce inflammation that could contribute to improved outcomes. Extensive studies have been carried out with thiazolidinediones (peroxisome proliferator-activated receptor-γ agonist), dipeptidyl peptidase-4 inhibitors, and metformin (AMP-activated protein kinase activator) with each of these classes of compounds showing moderate-to-strong anti-inflammatory action. Sulfonylureas and alpha glucosidase inhibitors appeared to exert modest effects, while the injectable agents, insulin and glucagon-like peptide-1 receptor agonists, may improve secondary complications due to their anti-inflammatory potential. Currently, there is a lack of clinical data on anti-inflammatory effects of sodium–glucose cotransporter type 2 inhibitors. Nevertheless, for all these glucose-lowering agents, it is essential to distinguish between anti-inflammatory effects resulting from better glucose control and effects related to intrinsic anti-inflammatory actions of the pharmacological class of compounds.
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Affiliation(s)
- Vishal Kothari
- Department of Nutrition and Dietetics, Boshell Diabetes and Metabolic Diseases Research Program, Auburn University, Auburn, AL, USA
| | - John A Galdo
- Department of Pharmacy Practice, Samford University, Birmingham, AL, USA
| | - Suresh T Mathews
- Department of Nutrition and Dietetics, Samford University, Birmingham, AL, USA
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16
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Shi L, Tan G, Zhang K. Relationship of the Serum CRP Level With the Efficacy of Metformin in the Treatment of Type 2 Diabetes Mellitus: A Meta-Analysis. J Clin Lab Anal 2016; 30:13-22. [PMID: 25277876 PMCID: PMC6807049 DOI: 10.1002/jcla.21803] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2014] [Accepted: 08/11/2014] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Metformin, an anti-diabetes drug, is always used as a first-line agent for the management of T2DM. This meta-analysis was conducted to investigate whether CRP was sensitive in predicting the efficacy of metformin in the treatment of T2DM. METHODS Potential relevant studies were identified covering the following databases: MEDLINE, Science Citation Index database, the Cochrane Library Database, PubMed, EMBASE, CINAHL, Current Contents Index, the Chinese Biomedical Database, the Chinese Journal Full-Text Database, and the Weipu Journal Database. Data from eligible studies were extracted and included into the meta-analysis using a random effects model. Statistical analyses were calculated using the version 12.0 STATA software. RESULTS A total of 33 articles including 1,433 subjects were collected for analysis. Pooled SMD of those studies revealed that serum levels of CRP and hs-CRP significantly decreased in patients with T2DM after receiving the metformin treatment. Subgroup analysis by country yielded significant different estimates in the serum levels of CRP between the baseline and after metformin treatment in the China, Israel and India subgroups; but only detected only in the China subgroup considering serum levels of hs-CRP. Follow-up time-stratified analyses indicated that serum levels of CRP were markedly reduced in the metformin-treated group in all subgroups. While differences in serum hs-CRP levels were not observed in two subgroups. CONCLUSION Decreased serum levels of CRP and hs-CRP may contribute to a more sensitive prediction in providing a more accurate efficacy reference in the metformin drug in T2DM patients.
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Affiliation(s)
- Lei Shi
- Department of PharmacyLiaochengP.R. China
| | | | - Kun Zhang
- Department of PharmacyLiaocheng Third People's HospitalLiaochengP.R. China
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17
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Antidiabetic agents: Potential anti-inflammatory activity beyond glucose control. DIABETES & METABOLISM 2015; 41:183-94. [DOI: 10.1016/j.diabet.2015.02.003] [Citation(s) in RCA: 104] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/16/2015] [Accepted: 02/09/2015] [Indexed: 12/13/2022]
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18
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Longo PL, Artese HPC, Rabelo MS, Kawamoto D, Foz AM, Romito GA, Dib SA, Mayer MPA. Serum levels of inflammatory markers in type 2 diabetes patients with chronic periodontitis. J Appl Oral Sci 2014; 22:103-8. [PMID: 24676580 PMCID: PMC3956401 DOI: 10.1590/1678-775720130540] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2013] [Accepted: 12/12/2013] [Indexed: 01/20/2023] Open
Abstract
Diabetes has been associated with periodontitis, but the mechanisms through which
periodontal diseases affect the metabolic control remain unclear.
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Affiliation(s)
- Priscila Larcher Longo
- Department of Microbiology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP, Brazil
| | - Hilana Paula Carillo Artese
- Division of Periodontics, Department of Stomatology, School of Dentistry, University of Sao Paulo, Sao Paulo, SP, Brazil
| | - Marianade Sousa Rabelo
- Division of Periodontics, Department of Stomatology, School of Dentistry, University of Sao Paulo, Sao Paulo, SP, Brazil
| | - Dione Kawamoto
- Department of Microbiology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP, Brazil
| | - Adriana Moura Foz
- Division of Periodontics, Department of Stomatology, School of Dentistry, University of Sao Paulo, Sao Paulo, SP, Brazil
| | - Giuseppe Alexandre Romito
- Division of Periodontics, Department of Stomatology, School of Dentistry, University of Sao Paulo, Sao Paulo, SP, Brazil
| | - Sergio Atala Dib
- Department of Endocrinology, School of Medicine, Federal University of Sao Paulo, Sao Paulo, SP, Brazil
| | - Marcia Pinto Alves Mayer
- Department of Microbiology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP, Brazil
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