Meta-Analysis and Network Analysis Differentially Detect Various Pro-Inflammatory Mediators and Risk Factors for Type 2 Diabetes in the Elderly

Abstract

Type 2 diabetes (T2D) has a pathophysiological component that includes inflammation. Inflammation-sensitive marker measurement may be helpful in determining the risk of complications for both older T2D patients and the public. This study aimed to investigate the association between blood pro-inflammatory mediators and the characteristics of elderly patients with T2D using meta and network analyses. The Web of Science, Scopus, PubMed, and Cochrane Library databases were selected as study methodology. The Quality in Prognosis Studies (QUIPS) tool in the meta-analysis assessed the studies’ methodological quality. The selected studies were statistically analyzed using the META-MAR tool based on the standardized mean difference (SMD). The selected studies included nine examinations involving 6399 old people [+>+55 years old, 65.9+±+4.09 (mean+±+SD)]. The meta-analysis showed that pro-inflammatory mediators (SMD 0.82) and patient-related variables [risk factors (SMD 0.71)] were significantly associated with T2D (p+<+0.05). Subgroup analysis revealed that tumor necrosis factor alpha (TNF-α; SMD 1.08), body mass index (SMD 0.64), high-density lipoprotein (HDL; SMD –0.61), body weight (SMD 0.50), and blood pressure (SMD 1.11) were factors significantly associated with T2D (p+<+0.05). Network analysis revealed that among patient characteristics, diastolic blood pressure and, among inflammatory mediators, leptin were the most closely associated factors with T2D in older adults. Moreover, network analysis showed that TNF-α and systolic blood pressure were most closely associated with leptin. Overall, alternate techniques, such as meta-analysis and network analysis, might identify different markers for T2D in older people. A therapeutic decision-making process needs to consider these differences in advance.

Keywords

geriatrics - network analysis - meta-analysis - inflammation - type 2 diabetes

Publication History

Received: 08 December 2023

Accepted after revision: 09 January 2024

Accepted Manuscript online:
09 January 2024

Article published online:
12 February 2024

• References

• 1 American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2005; 28: 37-42
• 2 Atkinson MA, Maclaren NK. The pathogenesis of insulin-dependent diabetes mellitus. N Engl J Med 1994; 331: 1428-1436
• 3 Salsali A, Nathan M. A review of types 1 and 2 diabetes mellitus and their treatment with insulin. Am J Ther 2006; 13: 349-361
• 4 Reaven G. The metabolic syndrome or the insulin resistance syndrome? Different names, different concepts and different goals. Endocrinol Metab Clin North Am 2004; 33: 283-303
• 5 Guariguata L, Whiting DR, Hambleton I. et al. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract 2014; 103: 137-149
• 6 Cusick M, Meleth AD, Agrón E. et al. Associations of mortality and diabetes complications in patients with type 1 and type 2 diabetes: early treatment diabetic retinopathy study report no. 27. Diabetes Care 2005; 28: 617-625
• 7 Alamri BN, Bahabri A, Aldereihim AA. et al. Hyperglycemia effect on red blood cells indices. Eur Rev Med Pharmacol Sci 2019; 23: 2139-2150
• 8 Kurano M, Darestani SG, Shinnakasu A. et al. mRNA expression of platelet activating factor receptor (PAFR) in peripheral blood mononuclear cells is associated with albuminuria and vascular dysfunction in patients with type 2 diabetes. Diabetes Res Clin Pract 2018; 136: 124-133
• 9 Ghavidel Darestani S, Kurano M, Shinnakasu A. et al. Association between changes in the mRNA expression of platelet-activating factor receptor in peripheral blood mononuclear cells and progression of diabetic nephropathy. Diabetol Int 2019; 11: 11-18
• 10 Cen Y, Feng D, Kowsar R. et al. Sex-specific variations in the mRNA levels of candidate genes in peripheral blood mononuclear cells from patients with diabetes: a multistep study. Endocr Res 2023; 10: 1-16
• 11 Takamura T, Honda M, Sakai Y. et al. Gene expression profiles in peripheral blood mononuclear cells reflect the pathophysiology of type 2 diabetes. Biochem Biophys Res Commun 2007; 361: 379-384
• 12 Kowsar R, Mansouri A. Multi-level analysis reveals the association between diabetes, body mass index, and HbA1c in an Iraqi population. Sci Rep 2022; 12: 21135
• 13 Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 2011; 11: 98-107
• 14 Pickup JC, Mattock MB, Chusney GD. et al. NIDDM as a disease of the innate immune system: association of acute-phase reactants and interleukin-6 with metabolic syndrome X. Diabetologia 1997; 40: 1286-1292
• 15 Spranger J, Kroke A, Möhlig M. et al. Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European prospective investigation into cancer and nutrition (EPIC)-Potsdam study. Diabetes. 2003; 52: 812-817
• 16 Pradhan AD, Manson JE, Rifai N. et al. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 2001; 286: 327-334
• 17 Sanada F, Taniyama Y, Muratsu J. et al. Source of chronic inflammation in aging. Front Cardiovasc Med 2018; 5: 12
• 18 Franceschi C, Campisi J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci 2014; 69: 4-9
• 19 Freund A, Orjalo AV, Desprez PY. et al. Inflammatory networks during cellular senescence: causes and consequences. Trends Mol Med 2010; 16: 238-246
• 20 Singh T, Newman AB. Inflammatory markers in population studies of aging. Ageing Res Rev 2011; 10: 319-329
• 21 Kojima H, Kunimoto H, Inoue T. et al. The STAT3-IGFBP5 axis is critical for IL-6/gp130-induced premature senescence in human fibroblasts. Cell Cycle 2012; 11: 730-739
• 22 West SL, Gartlehner G, Mansfield AJ. et al Comparative effectiveness review methods: Clinical Heterogeneity. Rockville (MD): Agency for Healthcare Research and Quality (US). 2010 Report No.: 10-EHC070-EF
• 23 Higgins JPT, Thomas J, Chandler J. et al. (eds). Cochrane handbook for systematic reviews of interventions version 6.4 (updated August 2023). Cochrane, 2023. Available from www.training.cochrane.org/handbook
• 24 Grooten WJA, Tseli E, Äng BO. et al. Elaborating on the assessment of the risk of bias in prognostic studies in pain rehabilitation using QUIPS-aspects of interrater agreement. Diagn Progn Res 2019; 3: 5
• 25 Riley RD, Moons KGM, Snell KIE. et al. A guide to systematic review and meta-analysis of prognostic factor studies. BMJ 2019; 364: k4597
• 26 Kowsar R, Rahimi AM, Sroka M. et al. Risk of mortality in COVID-19 patients: a meta- and network analysis. Sci Rep 2023; 13: 2138
• 27 Kowsar R, Ronasi S, Sadeghi N. et al. Epidermal growth factor alleviates the negative impact of urea on frozen-thawed bovine sperm, but the subsequent developmental competence is compromised. Sci Rep 2021; 11: 4687
• 28 Kowsar R, Mansouri A, Sadeghi N. et al. A multilevel analysis identifies the different relationships between amino acids and the competence of oocytes matured individually or in groups. Sci Rep 2020; 10: 16082
• 29 Capone F, Guerriero E, Colonna G. et al. The cytokinome profile in patients with hepatocellular carcinoma and type 2 diabetes. PLoS One 2015; 10: e0134594
• 30 Cheng M, Li B, Li X. et al. Correlation between serum lactadherin and pulse wave velocity and cardiovascular risk factors in elderly patients with type 2 diabetes mellitus. Diabetes Res Clin Pract 2012; 95: 125-131
• 31 Desfaits A-C, Serri O, Renier G. Normalization of plasma lipid peroxides, monocyte adhesion, and tumor necrosis factor-a production in NIDDM patients after gliclazide treatment. Diabetes Care 1998; 21: 487-493
• 32 Hamid S, Gul A, Hamid Q. Relationship of cytokines and AGE products in diabetic and non-diabetic patients with cataract. Int J Health Sci (Qassim) 2016; 10: 507-515
• 33 Herder C. Systemic monocyte chemoattractant protein-1 concentrations are independent of type 2 diabetes or parameters of obesity: results from the cooperative health research in the region of Augsburg survey S4 (KORA S4). Eur J Endocrinol 2006; 154: 311-317
• 34 Saukkonen T, Mutt SJ, Jokelainen J. et al. Adipokines and inflammatory markers in elderly subjects with high risk of type 2 diabetes and cardiovascular disease. Sci Rep 2018; 8: 12816
• 35 Borges L, Passos MEP, Silva MBB. et al. Dance training improves cytokine secretion and viability of neutrophils in diabetic patients. Mediators Inflamm 2019;
• 36 Wannamethee SG, Lowe GD, Rumley A. et al. Adipokines and risk of type 2 diabetes in older men. Diabetes Care 2007; 30: 1200-1205
• 37 de Rekeneire N, Peila R, Ding J. et al. Diabetes, hyperglycemia, and inflammation in older individuals: the health, aging and body composition study. Diabetes Care 2006; 29: 1902-1908
• 38 Tvarijonaviciute A, Castillo C, Ceron JJ. et al. Leptin and NGF in saliva of patients with diabetes mellitus type 2: a pilot study. J Oral Pathol Med 2017; 46: 853-855
• 39 Alexandraki KI, Piperi C, Ziakas PD. et al. Cytokine secretion in long-standing diabetes mellitus type 1 and 2: associations with low-grade systemic inflammation. J Clin Immunol 2008; 28: 314-321
• 40 Wang QY, Chen FQ. Clinical significance and different levels of urinary monocyte chemoattractant protein-1 in type 2 diabetes mellitus. Diabetes Res Clin Pract 2009; 83: 215-229
• 41 Iwamoto Y, Nishimura F, Nakagawa M. et al. The effect of antimicrobial periodontal treatment on circulating tumor necrosis factor-alpha and glycated hemoglobin level in patients with type 2 diabetes. J Periodontol 2001; 72: 774-778
• 42 Stephens JM, Pekala PH. Transcriptional repression of the GLUT4 and C/EBP genes in 3T3-L1 adipocytes by tumor necrosis factor-alpha. J Biol Chem 1991; 266: 21839-21845
• 43 Akash MSH, Rehman K, Liaqat A. Tumor necrosis factor-alpha: role in development of insulin resistance and pathogenesis of type 2 diabetes mellitus. J Cell Biochem 2018; 119: 105-110
• 44 Navarro JF, Mora-Fernández C. The role of TNF-alpha in diabetic nephropathy: pathogenic and therapeutic implications. Cytokine Growth Factor Rev 2006; 17: 441-450
• 45 Bertani T, Abbate M, Zoja C. et al. Tumor necrosis factor induces glomerular damage in the rabbit. Am J Pathol 1989; 134: 419-430
• 46 Xu F, Zhang C, Graves DT. Abnormal cell responses and role of TNF-α in impaired diabetic wound healing. Biomed Res Int 2013; 2013: 754802
• 47 Francés D, Ingaramo P, Ronco M. et al. Diabetes, an inflammatory process: Oxidative stress and TNF-alpha involved in hepatic complication. J Biomed Sci Eng 2013; 6: 645-653
• 48 Navarro JF, Mora C, Muros M. et al. Urinary tumour necrosis factor-alpha excretion independently correlates with clinical markers of glomerular and tubulointerstitial injury in type 2 diabetic patients. Nephrol Dial Transplant 2006; 21: 3428-3434
• 49 Woo YC, Tso AWK, Xu A. et al. Combined use of serum adiponectin and tumor necrosis factor-alpha receptor 2 levels was comparable to 2-hour post-load glucose in diabetes prediction. PLoS One 2012; 7: e36868
• 50 Stanley TL, Zanni MV, Johnsen S. et al. TNF-alpha antagonism with etanercept decreases glucose and increases the proportion of high molecular weight adiponectin in obese subjects with features of the metabolic syndrome. J Clin Endocrinol Metab 2011; 96: 146-150
• 51 Yazdani-Biuki B, Mueller T, Brezinschek HP. et al. Relapse of diabetes after interruption of chronic administration of anti-tumor necrosis factor-alpha antibody infliximab: a case observation. Diabetes Care 2006; 29: 1712-1713
• 52 Gonzalez-Gay MA, De Matias JM, Gonzalez-Juanatey C. et al. Anti-tumor necrosis factor-alpha blockade improves insulin resistance in patients with rheumatoid arthritis. Clin Exp Rheumatol 2006; 24: 83-86
• 53 Ofei F, Hurel S, Newkirk J. et al. Effects of an engineered human anti-TNF-alpha antibody (CDP571) on insulin sensitivity and glycemic control in patients with NIDDM. Diabetes 1996; 45: 881-885
• 54 Paquot N, Castillo MJ, Lefèbvre PJ. et al. No increased insulin sensitivity after a single intravenous administration of a recombinant human tumor necrosis factor receptor: Fc fusion protein in obese insulin-resistant patients. J Clin Endocrinol Metab 2000; 85: 1316-1319
• 55 Wen Y, Gu J, Li SL. et al. Elevated glucose and diabetes promote interleukin-12 cytokine gene expression in mouse macrophages. Endocrinology 2006; 147: 2518-2525
• 56 Cai D, Yuan M, Frantz DF. et al. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med 2005; 11: 183-190
• 57 Solinas G, Karin M. JNK1 and IKKβ: Molecular links between obesity and metabolic dysfunction. FASEB J 2010; 24: 2596-2611
• 58 Bertin E, Nguyen P, Guenounou M. et al. Plasma levels of tumor necrosis factor-alpha (TNF-alpha) are essentially dependent on visceral fat amount in type 2 diabetic patients. Diabetes Metab 2000; 26: 178-182
• 59 Hasan AU, Rahman A, Kobori H. Interactions between host PPARs and gut microbiota in health and disease. Int J Mol Sci 2019; 20: 387
• 60 Ahmad R, Al-Roub A, Kochumon S. et al. The synergy between palmitate and TNF-alpha for CCL2 production is dependent on the TRIF/IRF3 pathway: implications for metabolic inflammation. J Immunol 2018; 200: 3599-3611
• 61 Sanchez-Margalet V, Martin-Romero C, Santos-Alvarez JET. et al. Role of leptin as an immunomodulator of blood mononuclear cells: mechanisms of action. Clin Exp Immunol 2003; 133: 11-19
• 62 Lundåsen T, Liao W, Angelin B. et al. Leptin induces the hepatic high density lipoprotein receptor scavenger receptor B type I (SR-BI) but not cholesterol 7alpha-hydroxylase (Cyp7a1) in leptin-deficient (ob/ob) mice. J Biol Chem 2003; 278: 43224-43228
• 63 Seufert J. Leptin effects on pancreatic beta-cell gene expression and function. Diabetes 2004; 53: S152-S158
• 64 Beltowski J. Leptin and atherosclerosis. Atherosclerosis 2006; 189: 47-60
• 65 Beltowski J. Role of leptin in blood pressure regulation and arterial hypertension. J Hypertens 2006; 24: 789-801
• 66 Mantzoros CS, Magkos F, Brinkoetter M. et al. Leptin in human physiology and pathophysiology. Am J Physiol Endocrinol 2011; 301: 567-584
• 67 Farbstein D, Levy AP. HDL dysfunction in diabetes: causes and possible treatments. Expert Rev Cardiovasc Ther 2012; 10: 353-361
• 68 Adiels M, Olofsson SO, Taskinen MR. et al. Diabetic dyslipidaemia. Curr Opin Lipidol 2006; 17: 238-246
• 69 Vergès B, Florentin E, Baillot-Rudoni S. et al. Rosuvastatin 20 mg restores normal HDL-apoA-I kinetics in type 2 diabetes. J Lipid Res 2009; 50: 1209-1215
• 70 Dallinga-Thie GM, Dullaart RP, Van Tol A. Concerted actions of cholesteryl ester transfer protein and phospholipid transfer protein in Type 2 diabetes: effects of apolipoproteins. Curr Opin Lipidol 2007; 18: 251-257
• 71 Kontush A, Chapman MJ. Antiatherogenic small, dense HDL – guardian angel of the arterial wall?. Nat Clin Pract Cardiovasc Med 2006; 3: 144-153
• 72 Wannamethee SG, Tchernova J, Whincup P. et al. Plasma leptin: associations with metabolic, inflammatory and haemostatic risk factors for cardiovascular disease. Atherosclerosis 2007; 191: 418-426
• 73 Lundasen T, Liao W, Angelin B. et al. Leptin induces the hepatic high density lipoprotein receptor scavenger receptor B type I (SR-BI) but not cholesterol 7-hydroxylase (Cyp7a1) in leptin deficient (ob/ob) mice. J Biol Chem 2003; 278: 43224-43228
• 74 Norata GD, Pirillo A, Catapano AL. Modified HDL: Biological and physiopathological consequences. Nutr Metab Cardiovasc Dis 2006; 16: 371-386
• 75 Suzuki M, Pritchard DK, Becker L. et al. High-density lipoprotein suppresses the type I interferon response, a family of potent antiviral immunoregulators, in macrophages challenged with lipopolysaccharide. Circulation 2010; 122: 1919-1927
• 76 Schutte AE, Huisman HW, Schutte R. et al. Adipokines and cardiometabolic function: How are they interlinked?. Regul Pept 2010; 164: 133-138
• 77 Correia ML, Morgan DA, Sivitz WI. et al. Leptin acts in the central nervous system to produce dose-dependent changes in arterial pressure. Hypertension 2001; 37: 936-942
• 78 Correia ML, Morgan DA, Mitchell JL. et al. Role of corticotrophin-releasing factor in effects of leptin on sympathetic nerve activity and arterial pressure. Hypertension 2001; 38: 384-388
• 79 Greco T, Biondi-Zoccai G, Saleh O. et al. The attractiveness of network meta-analysis: a comprehensive systematic and narrative review. Heart Lung Vessel 2015; 7: 133-142
• 80 Greco T, Zangrillo A, Biondi-Zoccai G. et al. Meta-analysis: pitfalls and hints. Heart Lung Vessel 2013; 5: 219-225
• 81 Lee C, Wolever RQ, Yang Q. et al. A network analysis of the association between depressive symptoms and patient activation among those with elevated cardiovascular risk. Glob Adv Health Med 2022; 11: 1-11