{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T09:50:43Z","timestamp":1791366643108,"version":"4.3.1"},"reference-count":48,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T00:00:00Z","timestamp":1776384000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T00:00:00Z","timestamp":1776384000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Diabet Med"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Chronic kidney disease is associated with dysregulation of the insulin\u2010like growth factor (IGF) system. Alterations in IGF bioavailability, driven by IGF binding proteins (IGFBPs), may influence the decline in renal function. However, the longitudinal relationship between baseline IGF\u2010I, IGF\u2010II, IGFBPs and progression of kidney dysfunction remains unclear. We evaluated how IGF\/IGFBP profile relates to longitudinal changes in urinary albumin\/creatinine ratio (ACR) and serum creatinine level in people with type 2 diabetes (T2D).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Individuals' measurements were performed in 436 individuals with T2D recruited from primary and secondary care (2002\u20132004), from the Salford and Manchester Integrated Care Record (GMCR), for laboratory and clinical data, as well as date of death. Baseline IGF\/IGFBP profile was related to 2 primary outcomes: (i) change in albumin\u2010to\u2010creatinine ratio over time (urine ACR trend slope) and (ii) change in serum creatinine over time (creatinine trend slope). Trend slopes were derived for each participant, using repeated measures throughout follow\u2010up for up to 24\u2009years. Associations between IGF axis proteins and outcomes were evaluated with multivariate regression models. Cox proportional hazards models were constructed to determine mortality risk associated with the IGF system proteins studied.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>At baseline, 59.3% of participants were men. Age at baseline was 56.6\u2009\u00b1\u20099.4\u2009years. Mean follow\u2010up duration was 17.4\u2009\u00b1\u20095.2\u2009years.<\/jats:p>\n                    <jats:p>\n                      IGF\u2010II and IGFBP\u20103 were strongly correlated (Spearman rho\u2009=\u20090.80), and were therefore not included simultaneously in the multi\u2010variate linear regression model to avoid co\u2010linearity. Higher circulating IGFBP\u20102 was independently associated with faster rate of ACR progression (normalised beta (\u0392)\u2009=\u20090.007,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.002), while IGFBP\u20101 showed an inverse association (\n                      <jats:italic>B<\/jats:italic>\n                      \u2009=\u2009\u22120.057,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.009). IGF\u2010II also remained positively associated with ACR trend (\n                      <jats:italic>B<\/jats:italic>\n                      \u2009=\u20090.005,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.013), whereas IGF\u2010I showed no association. IGFBP\u20101 showed a significant inverse association with creatinine change when adjusted for effects of covariates (unstandardised\n                      <jats:italic>B<\/jats:italic>\n                      \u2009=\u2009\u22120.038,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.04). Survival analysis revealed that higher IGFBP\u20102 levels were independently associated with higher all\u2010cause mortality (hazard ratio [HR] per 1 standard deviation increase 1.306, 95% CI 1.151\u20131.483\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0001).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This longitudinal study indicated that higher baseline IGF\u2010II, lower IGFBP\u20101 and higher IGFBP\u20102 are associated with a greater likelihood of albuminuria progression, independent of standard risk factors; lower IGBFP\u20101 also associated with greater increase in serum creatinine. Higher circulating IGFBP\u20102 level was also associated with relatively higher mortality. This study demonstrated the relevance of the IGF system to our understanding of renal complications in diabetes and strongly suggests that further exploration of mechanisms underlying these associations is merited.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/dme.70318","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T19:09:47Z","timestamp":1776452987000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The insulin\u2010like growth factor system and the progression of renal complications of type 2 diabetes"],"prefix":"10.1111","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9537-4050","authenticated-orcid":false,"given":"Adrian","family":"Heald","sequence":"first","affiliation":[{"name":"University of Manchester  Manchester UK"},{"name":"Department of Diabetes and Endocrinology Salford Royal Hospital  Salford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasitha","family":"lllangasekera","sequence":"additional","affiliation":[{"name":"Sheffield Hallam University  Sheffield UK"},{"name":"Faculty of Medicine University of Peradeniya  Peradeniya Sri Lanka"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Matheou","sequence":"additional","affiliation":[{"name":"University of Manchester  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ram Prakash","family":"Narayanan","sequence":"additional","affiliation":[{"name":"Diabetes Centre St Helens Hospital  St Helens UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"White","sequence":"additional","affiliation":[{"name":"University of Newcastle  Newcastle UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hellena","family":"Habte\u2010Asres","sequence":"additional","affiliation":[{"name":"Kings College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail","family":"Lay","sequence":"additional","affiliation":[{"name":"University of Manchester  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liliana","family":"Shalamanova","sequence":"additional","affiliation":[{"name":"Manchester Metropolitan University  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Ollier","sequence":"additional","affiliation":[{"name":"Manchester Metropolitan University  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graham A.","family":"Hitman","sequence":"additional","affiliation":[{"name":"Queen Mary University of London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ritwika","family":"Mallik","sequence":"additional","affiliation":[{"name":"Queen Mary University of London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip A.","family":"Kalra","sequence":"additional","affiliation":[{"name":"Department of Renal Medicine Salford Royal Hospital  Salford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2897-2026","authenticated-orcid":false,"given":"Martin","family":"Whyte","sequence":"additional","affiliation":[{"name":"University of Surrey  Guildford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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