Hyperinsulinemia and insulin resistance in the obese may develop as part of a homeostatic response to elevated free fatty acids: A mechanistic case-control and a population-based cohort study

Reaven, 1988, Banting lecture 1988. Role of insulin resistance in human disease, Diabetes, 37, 1595, 10.2337/diab.37.12.1595 Czech, 2017, Insulin action and resistance in obesity and type 2 diabetes, Nat Med., 23, 804, 10.1038/nm.4350 Petersen, 2018, Mechanisms of insulin action and insulin resistance, Physiol Rev., 98, 2133, 10.1152/physrev.00063.2017 McGarry, 1992, What if Minkowski had been ageusic? An alternative angle on diabetes, Science, 258, 766, 10.1126/science.1439783 Shanik, 2008, Insulin resistance and hyperinsulinemia: is hyperinsulinemia the cart or the horse?, Diabetes care, 31, S262, 10.2337/dc08-s264 Pories, 2012, Diabetes: have we got it all wrong? Hyperinsulinism as the culprit: surgery provides the evidence, Diabetes Care, 35, 2438, 10.2337/dc12-0684 Corkey, 2012, Banting lecture 2011: hyperinsulinemia: cause or consequence?, Diabetes, 61, 4, 10.2337/db11-1483 Hauke, 2018, Endogenous fatty acids are essential signaling factors of pancreatic beta-cells and insulin secretion, Diabetes, 67, 1986, 10.2337/db17-1215 Itoh, 2003, Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40, Nature, 422, 173, 10.1038/nature01478 Dobbins, 1998, A fatty acid- dependent step is critically important for both glucose- and non-glucose-stimulated insulin secretion, J Clin Invest, 101, 2370, 10.1172/JCI1813 Kim, 2019, Adipose tissue insulin resistance in youth on the spectrum from normal weight to obese and from normal glucose tolerance to impaired glucose tolerance to type 2 diabetes, Diabetes Care, 42, 265, 10.2337/dc18-1178 Gastaldelli, 2017, Role of adipose tissue insulin resistance in the natural history of type 2 diabetes: results from the san Antonio metabolism study, Diabetes, 66, 815, 10.2337/db16-1167 Mahendran, 2013, Glycerol and fatty acids in serum predict the development of hyperglycemia and type 2 diabetes in Finnish men, Diabetes Care, 36, 3732, 10.2337/dc13-0800 Frohnert, 2013, Relation between serum free fatty acids and adiposity, insulin resistance, and cardiovascular risk factors from adolescence to adulthood, Diabetes, 62, 3163, 10.2337/db12-1122 Pankow, 2004, Fasting plasma free fatty acids and risk of type 2 diabetes: the atherosclerosis risk in communities study, Diabetes Care, 27, 77, 10.2337/diacare.27.1.77 Paolisso, 1995, A high concentration of fasting plasma non-esterified fatty acids is a risk factor for the development of NIDDM, Diabetologia, 38, 1213, 10.1007/BF00422371 Titchenell, 2017, Unraveling the regulation of hepatic metabolism by insulin, Trends Endocrinol Metab, 28, 497, 10.1016/j.tem.2017.03.003 Solinas, 2017, JNK at the crossroad of obesity, insulin resistance, and cell stress response, Mol Metab, 6, 174, 10.1016/j.molmet.2016.12.001 Hotamisligil, 2016, Cell signaling and stress responses, Cold Spring Harb Perspect Biol, 8, 10.1101/cshperspect.a006072 DeFronzo, 2015, Type 2 diabetes mellitus, Nat Rev Dis Primers, 1, 15019, 10.1038/nrdp.2015.19 Lee, 2018, An integrated view of immunometabolism, Cell, 172, 22, 10.1016/j.cell.2017.12.025 Glass, 2012, Inflammation and lipid signaling in the etiology of insulin resistance, Cell Metab, 15, 635, 10.1016/j.cmet.2012.04.001 Mottillo, 2014, Coupling of lipolysis and de novo lipogenesis in brown, beige, and white adipose tissues during chronic beta3-adrenergic receptor activation, J Lipid Res, 55, 2276, 10.1194/jlr.M050005 Solinas, 2010, JNK1 and IKKbeta: molecular links between obesity and metabolic dysfunction, FASEB J, 24, 2596, 10.1096/fj.09-151340 Randle, 1963, The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus, Lancet, 1, 785, 10.1016/S0140-6736(63)91500-9 Karpe, 2011, Fatty acids, obesity, and insulin resistance: time for a reevaluation, Diabetes, 60, 2441, 10.2337/db11-0425 van Vliet, 2020, Obesity is associated with increased basal and postprandial beta-cell insulin secretion even in the absence of insulin resistance, Diabetes, 69, 2112, 10.2337/db20-0377 Jansson, 1992, Glycerol production in subcutaneous adipose tissue in lean and obese humans, J Clin Invest, 89, 1610, 10.1172/JCI115756 Dotevall, 2004, Increased levels of triglycerides, BMI and blood pressure and low physical activity increase the risk of diabetes in Swedish women. A prospective 18-year follow-up of the BEDA study, Diabet Med, 21, 615, 10.1111/j.1464-5491.2004.01189.x Lonnroth, 1987, A microdialysis method allowing characterization of intercellular water space in humans, Am J Physiol, 253, E228 Sandqvist, 2006, Postprandial interstitial insulin concentrations in type 2 diabetes relatives, Eur J Clin Invest, 36, 383, 10.1111/j.1365-2362.2006.01647.x Sjostrand, 1999, Measurement of interstitial insulin in human muscle, Am J Physiol, 276, E151 Matsuda, 1999, Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp, Diabetes Care, 22, 1462, 10.2337/diacare.22.9.1462 Matthews, 1985, Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man, Diabetologia, 28, 412, 10.1007/BF00280883 Faizi, 2009, Evaluation of endothelial function using finger plethysmography, Clin Physiol Funct Imaging, 29, 372, 10.1111/j.1475-097X.2009.00882.x Smith, 1972, Comparison of two methods for determining human adipose cell size, J Lipid Res, 13, 822, 10.1016/S0022-2275(20)39356-1 Strindberg, 2000, Validation of an endogenous reference technique for the calibration of microdialysis catheters, Scand J Clin Lab Invest, 60, 205, 10.1080/003655100750044857 Dobin, 2013, STAR: ultrafast universal RNA-seq aligner, Bioinformatics, 29, 15, 10.1093/bioinformatics/bts635 Love, 2014, Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2, Genome Biol, 15, 550, 10.1186/s13059-014-0550-8 Lind, 2020, Impaired glucose control is associated with multiple cardiovascular impairments, Clin Physiol Funct Imaging, 40, 257, 10.1111/cpf.12634 Ahmed, 2010, An autocrine lactate loop mediates insulin-dependent inhibition of lipolysis through GPR81, Cell Metab, 11, 311, 10.1016/j.cmet.2010.02.012 Jansson, 1994, Lactate release from the subcutaneous tissue in lean and obese men, J Clin Invest, 93, 240, 10.1172/JCI116951 Jansson, 1993, Measurement by microdialysis of the insulin concentration in subcutaneous interstitial fluid. Importance of the endothelial barrier for insulin, Diabetes, 42, 1469, 10.2337/diab.42.10.1469 Chen, 2005, Krox20 stimulates adipogenesis via C/EBPbeta-dependent and -independent mechanisms, Cell Metab, 1, 93, 10.1016/j.cmet.2004.12.009 Denton, 2018, Cartilage oligomeric matrix protein is differentially expressed in human subcutaneous adipose tissue and regulates adipogenesis, Mol Metab, 16, 172, 10.1016/j.molmet.2018.07.005 Grunberg, 2017, Overexpressing the novel autocrine/endocrine adipokine WISP2 induces hyperplasia of the heart, white and brown adipose tissues and prevents insulin resistance, Sci Rep, 7, 43515, 10.1038/srep43515 Masuzaki, 2001, A transgenic model of visceral obesity and the metabolic syndrome, Science, 294, 2166, 10.1126/science.1066285 Boucher, 2005, Apelin, a newly identified adipokine up-regulated by insulin and obesity, Endocrinology, 146, 1764, 10.1210/en.2004-1427 Zhu, 2016, Connexin 43 mediates white adipose tissue beiging by facilitating the propagation of sympathetic neuronal signals, Cell Metab, 24, 420, 10.1016/j.cmet.2016.08.005 Bachman, 2002, betaAR signaling required for diet-induced thermogenesis and obesity resistance, Science, 297, 843, 10.1126/science.1073160 Bing, 2004, Zinc-alpha2-glycoprotein, a lipid mobilizing factor, is expressed in adipocytes and is up-regulated in mice with cancer cachexia, 2500 Molinaro, 2019, Insulin-driven PI3K-AKT signaling in the hepatocyte is mediated by redundant PI3Kalpha and PI3Kbeta activities and is promoted by RAS, Cell Metab, 29, 10.1016/j.cmet.2019.03.010 Edgerton, 2017, Insulin's direct hepatic effect explains the inhibition of glucose production caused by insulin secretion, JCI Insight, 2, e91863, 10.1172/jci.insight.91863 Titchenell, 2016, Direct hepatocyte insulin signaling is required for lipogenesis but is dispensable for the suppression of glucose production, Cell Metab, 23, 1154, 10.1016/j.cmet.2016.04.022 Perry, 2015, Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes, Cell, 160, 745, 10.1016/j.cell.2015.01.012 Arner, 2019, Adipose lipid turnover and long-term changes in body weight, Nat Med, 25, 1385, 10.1038/s41591-019-0565-5 Arner, 2018, Weight gain and impaired glucose metabolism in women are predicted by inefficient subcutaneous fat cell lipolysis, Cell Metab, 28, 45, 10.1016/j.cmet.2018.05.004 Arner, 2011, Dynamics of human adipose lipid turnover in health and metabolic disease, Nature, 478, 110, 10.1038/nature10426 Puri, 2008, Cidea is associated with lipid droplets and insulin sensitivity in humans, 7833 Ryden, 2019, Insulin action is severely impaired in adipocytes of apparently healthy overweight and obese subjects, J Intern Med, 285, 578, 10.1111/joim.12887 Alves-Wagner, 2019, Sympathetic regulation of Slc2a4 gene expression: participation of a putative cAMP responsive element (CRE) site in the Slc2a4 promoter, Cell Physiol Biochem, 52, 580, 10.33594/000000041 Decara, 2018, Cooperative role of the glucagon-like peptide-1 receptor and beta3-adrenergic-mediated signalling on fat mass reduction through the downregulation of PKA/AKT/AMPK signalling in the adipose tissue and muscle of rats, Acta Phys, 222, e13008, 10.1111/apha.13008 Jiang, 2017, Distinct cellular and molecular mechanisms for beta3 adrenergic receptor-induced beige adipocyte formation, eLife, 6, 10.7554/eLife.30329 Barneda, 2013, Dynamic changes in lipid droplet-associated proteins in the "browning" of white adipose tissues, Biochim Biophys Acta, 1831, 924, 10.1016/j.bbalip.2013.01.015 Kvist, 1988, Total and visceral adipose-tissue volumes derived from measurements with computed tomography in adult men and women: predictive equations, Am J Clin Nutr, 48, 1351, 10.1093/ajcn/48.6.1351 Rorsman, 2018, Pancreatic beta-cell electrical activity and insulin secretion: of mice and men, Physiol Rev, 98, 117, 10.1152/physrev.00008.2017 Trico, 2018, Identification, pathophysiology, and clinical implications of primary insulin hypersecretion in nondiabetic adults and adolescents, JCI Insight, 3, 10.1172/jci.insight.124912 Conte, 2012, Multiorgan insulin sensitivity in lean and obese subjects, Diabetes Care, 35, 1316, 10.2337/dc11-1951 McQuaid, 2011, Downregulation of adipose tissue fatty acid trafficking in obesity: a driver for ectopic fat deposition?, Diabetes, 60, 47, 10.2337/db10-0867 Schenk, 2005, Postexercise insulin sensitivity is not impaired after an overnight lipid infusion, Am J Physiol Endocrinol Metab, 288, E519, 10.1152/ajpendo.00401.2004 Balent, 2002, Acute elevation of NEFA causes hyperinsulinemia without effect on insulin secretion rate in healthy human subjects, Ann N Y Acad Sci, 967, 535, 10.1111/j.1749-6632.2002.tb04313.x Amery, 2000, Elevation of plasma fatty acids by ten-hour intralipid infusion has no effect on basal or glucose-stimulated insulin secretion in normal man, Metabolism, 49, 450, 10.1016/S0026-0495(00)80007-4 Hargreaves, 1991, Effect of increased plasma free fatty acid concentrations on muscle metabolism in exercising men, J Appl Physiol (1985), 70, 194, 10.1152/jappl.1991.70.1.194 Smiles, 2019, A single bout of strenuous exercise overcomes lipid-induced anabolic resistance to protein ingestion in overweight, middle-aged men, FASEB J, 33, 7009, 10.1096/fj.201801917R Cornford, 2013, Rapid development of systemic insulin resistance with overeating is not accompanied by robust changes in skeletal muscle glucose and lipid metabolism, Appl Physiol Nutr Metab, 38, 512, 10.1139/apnm-2012-0266 Samocha-Bonet, 2012, Overfeeding reduces insulin sensitivity and increases oxidative stress, without altering markers of mitochondrial content and function in humans, PLoS ONE, 7, e36320, 10.1371/journal.pone.0036320 Stein, 1996, Essentiality of circulating fatty acids for glucose-stimulated insulin secretion in the fasted rat, J Clin Invest, 97, 2728, 10.1172/JCI118727 Sabrautzki, 2017, Point mutation of Ffar1 abrogates fatty acid-dependent insulin secretion, but protects against HFD-induced glucose intolerance, Mol Metab, 6, 1304, 10.1016/j.molmet.2017.07.007 Dobbins, 1998, Circulating fatty acids are essential for efficient glucose-stimulated insulin secretion after prolonged fasting in humans, Diabetes, 47, 1613, 10.2337/diabetes.47.10.1613 Boden, 1998, Acute lowering of plasma fatty acids lowers basal insulin secretion in diabetic and nondiabetic subjects, Diabetes, 47, 1609, 10.2337/diabetes.47.10.1609 Balasse, 1973, Role of plasma free fatty acids in the control of insulin secretion in man, Diabetologia, 9, 145, 10.1007/BF01230695