{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,29]],"date-time":"2026-03-29T13:59:51Z","timestamp":1774792791658,"version":"3.50.1"},"reference-count":117,"publisher":"Portland Press Ltd.","issue":"5","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2008,10,1]]},"abstract":"<jats:p>In healthy individuals, a hyperbolic relationship exists between whole-body insulin-sensitivity and insulin secretion. Thus, for any difference in insulin-sensitivity, a reciprocal proportionate change occurs in insulin secretion. Such a feedback loop is evident in healthy individuals ingesting diets high in saturated fat and in late pregnancy where, despite lipid-induced insulin resistance, glucose tolerance is maintained through augmented GSIS (glucose-stimulated insulin secretion). NRs (nuclear receptors) are members of a superfamily of ligand-regulated and orphan transcription factors. On activation by a cognate ligand, many ligand-activated NRs recruit the RXR (retinoid X receptor) for heterodimer formation. Such NRs include the PPARs (peroxisome-proliferator-activated receptors), which are involved in lipid sensing and liporegulation. PPARs exert important lipid-lowering effects in vivo, thereby opposing the development of lipid-induced insulin resistance by relieving the inhibition of insulin-stimulated glucose disposal by muscle and lowering the necessity for augmented GSIS to counter lipid-induced insulin resistance. Long-chain fatty acids are proposed as natural PPAR ligands and some specific endogenous pathways of lipid metabolism are believed to generate PPAR agonists. Other NRs, e.g. the LXR (liver X receptor), which senses expansion of the metabolically active pool of cholesterol, and the FXR (farnesoid X receptor; NR1H4), which, like the LXR, is involved in sterol metabolism, also modulate systemic lipid levels and insulin-sensitivity. In this review, we discuss how these NRs impact insulin secretion via effects on the insulin-sensitivity\u2013insulin secretion feedback loop and, in some cases, via direct effects on the islet itself. In addition, we discuss interactions between these nutrient\/metabolite-responsive NRs and NRs that are central to the action of metabolically important hormones, including (i) the glucocorticoid receptor, critical for maintaining glucose homoeostasis in stress, inflammation and during fasting, and (ii) the thyroid hormone receptors, vital for maintenance of oxidative functions. We present data indicating that the RXR occupies a key role in directly modulating islet function and that its heterodimerization with at least two of its partners modulates GSIS.<\/jats:p>","DOI":"10.1042\/bst0360891","type":"journal-article","created":{"date-parts":[[2008,10,6]],"date-time":"2008-10-06T11:54:55Z","timestamp":1223294095000},"page":"891-900","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Role of nuclear receptors in the modulation of insulin secretion in lipid-induced insulin resistance"],"prefix":"10.1042","volume":"36","author":[{"given":"Mary\u00a0C.","family":"Sugden","sequence":"first","affiliation":[{"name":"Centre for Diabetes and Metabolic Medicine, Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, Blizard Building, 4 Newark Street, London E1 2AT, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark\u00a0J.","family":"Holness","sequence":"additional","affiliation":[{"name":"Centre for Diabetes and Metabolic Medicine, Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, Blizard Building, 4 Newark Street, London E1 2AT, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2008,9,19]]},"reference":[{"key":"2021111720014857500_B1","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1007\/s001250051508","article-title":"Expression of peroxisome proliferator-activated receptor \u03b3 (PPAR\u03b3) in normal human pancreatic islet cells","volume":"43","author":"Dubois","year":"2000","journal-title":"Diabetologia"},{"key":"2021111720014857500_B2","doi-asserted-by":"crossref","first-page":"2748","DOI":"10.1210\/endo.139.6.6049","article-title":"Differential expression of peroxisome proliferator-activated receptor-\u03b1, -\u03b2, and -\u03b3 during rat embryonic development","volume":"139","author":"Braissant","year":"1998","journal-title":"Endocrinology"},{"key":"2021111720014857500_B3","doi-asserted-by":"crossref","first-page":"2729","DOI":"10.2337\/diabetes.50.12.2729","article-title":"Selective modification of pyruvate dehydrogenase kinase isoform expression in rat pancreatic islets elicited by starvation and activation of peroxisome proliferator-activated receptor-\u03b1: implications for glucose-stimulated insulin secretion","volume":"50","author":"Sugden","year":"2001","journal-title":"Diabetes"},{"key":"2021111720014857500_B4","doi-asserted-by":"crossref","first-page":"2350","DOI":"10.1007\/s00125-006-0366-5","article-title":"BCL-6: a possible missing link for anti-inflammatory PPAR-\u03b4 signalling in pancreatic \u03b2-cells","volume":"49","author":"Kharroubi","year":"2006","journal-title":"Diabetologia"},{"key":"2021111720014857500_B5","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.febslet.2007.11.016","article-title":"Nuclear receptors: decoding metabolic disease","volume":"582","author":"Sonoda","year":"2008","journal-title":"FEBS Lett."},{"key":"2021111720014857500_B6","doi-asserted-by":"crossref","first-page":"299","DOI":"10.2174\/157339905774574365","article-title":"Novel approach to treat insulin resistance, type\u00a02 diabetes, and the metabolic syndrome: simultaneous activation of PPAR\u03b1, PPAR\u03b3, and PPAR\u03b4","volume":"1","author":"Evans","year":"2005","journal-title":"Curr. 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