{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T19:58:27Z","timestamp":1792180707161,"version":"4.4.0"},"reference-count":124,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2022,7,25]],"date-time":"2022-07-25T00:00:00Z","timestamp":1658707200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Recent data suggests that (pre)diabetes onset is preceded by a period of hyperinsulinemia. Consumption of the \u201cmodern\u201d Western diet, over-nutrition, genetic background, decreased hepatic insulin clearance, and fetal\/metabolic programming may increase insulin secretion, thereby causing chronic hyperinsulinemia. Hyperinsulinemia is an important etiological factor in the development of metabolic syndrome, type 2 diabetes, cardiovascular disease, polycystic ovarian syndrome, and Alzheimer\u2019s disease. Recent data suggests that the onset of prediabetes and diabetes are preceded by a variable period of hyperinsulinemia. Emerging data suggest that chromic hyperinsulinemia is also a driving force for increased activation of the hypothalamic-adrenal-pituitary (HPA) axis in subjects with the metabolic syndrome, leading to a state of \u201cfunctional hypercortisolism\u201d. This \u201cfunctional hypercortisolism\u201d by antagonizing insulin actions may prevent hypoglycemia. It also disturbs energy balance by shifting energy fluxes away from muscles toward abdominal fat stores. Synergistic effects of hyperinsulinemia and \u201cfunctional hypercortisolism\u201d promote abdominal visceral obesity and insulin resistance which are core pathophysiological components of the metabolic syndrome. It is hypothesized that hyperinsulinemia-induced increased activation of the HPA axis plays an important etiological role in the development of the metabolic syndrome and its consequences. Numerous studies have demonstrated reversibility of hyperinsulinemia with lifestyle, surgical, and pharmaceutical-based therapies. Longitudinal studies should be performed to investigate whether strategies that reduce hyperinsulinemia at an early stage are successfully in preventing increased activation of the HPA axis and the metabolic syndrome.<\/jats:p>","DOI":"10.3390\/ijms23158178","type":"journal-article","created":{"date-parts":[[2022,7,25]],"date-time":"2022-07-25T21:20:59Z","timestamp":1658784059000},"page":"8178","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":118,"title":["New Insights into the Role of Insulin and Hypothalamic-Pituitary-Adrenal (HPA) Axis in the Metabolic Syndrome"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9363-6408","authenticated-orcid":false,"given":"Joseph A. M. J. L.","family":"Janssen","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Erasmus Medical Center, Room Rg527, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3030","DOI":"10.1161\/CIRCULATIONAHA.105.504670","article-title":"Insulin resistance, type 2 diabetes mellitus, and cardiovascular disease: The end of the beginning","volume":"112","author":"Reaven","year":"2005","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"S262","DOI":"10.2337\/dc08-s264","article-title":"Insulin resistance and hyperinsulinemia: Is hyperinsulinemia the cart or the horse?","volume":"31","author":"Shanik","year":"2008","journal-title":"Diabetes Care"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2432","DOI":"10.2337\/dc12-0825","article-title":"Diabetes: Have we got it all wrong? Insulin hypersecretion and food additives: Cause of obesity and diabetes?","volume":"35","author":"Corkey","year":"2012","journal-title":"Diabetes Care"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1146\/annurev-pharmtox-052220-010446","article-title":"Central Nervous System Control of Glucose Homeostasis: A Therapeutic Target for Type 2 Diabetes?","volume":"62","author":"Mirzadeh","year":"2022","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e124912","DOI":"10.1172\/jci.insight.124912","article-title":"Identification, pathophysiology, and clinical implications of primary insulin hypersecretion in nondiabetic adults and adolescents","volume":"3","author":"Trico","year":"2018","journal-title":"JCI Insight"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2387","DOI":"10.1113\/jphysiol.2009.169078","article-title":"Impact of short-term high-fat feeding on glucose and insulin metabolism in young healthy men","volume":"587","author":"Brons","year":"2009","journal-title":"J. Physiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.1172\/JCI119628","article-title":"Insulin resistance and hypersecretion in obesity. European Group for the Study of Insulin Resistance (EGIR)","volume":"100","author":"Ferrannini","year":"1997","journal-title":"J. Clin. Investig."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4014","DOI":"10.1210\/jc.2018-01147","article-title":"High-Dose, Diazoxide-Mediated Insulin Suppression Boosts Weight Loss Induced by Lifestyle Intervention","volume":"103","author":"Loves","year":"2018","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1464","DOI":"10.2337\/dc09-0153","article-title":"Basal-state hyperinsulinemia in healthy normoglycemic adults is predictive of type 2 diabetes over a 24-year follow-up: A preliminary report","volume":"32","author":"Dankner","year":"2009","journal-title":"Diabetes Care"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1007\/BF00279918","article-title":"Production of insulin resistance by hyperinsulinaemia in man","volume":"28","author":"Rizza","year":"1985","journal-title":"Diabetologia"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4","DOI":"10.2337\/db11-1483","article-title":"Banting lecture 2011: Hyperinsulinemia: Cause or consequence?","volume":"61","author":"Corkey","year":"2012","journal-title":"Diabetes"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Janssen, J. (2021). Hyperinsulinemia and Its Pivotal Role in Aging, Obesity, Type 2 Diabetes, Cardiovascular Disease and Cancer. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22157797"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"673","DOI":"10.2337\/db14-0694","article-title":"Insulin resistance as a physiological defense against metabolic stress: Implications for the management of subsets of type 2 diabetes","volume":"64","author":"Nolan","year":"2015","journal-title":"Diabetes"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"972","DOI":"10.1111\/j.1464-5491.2012.03655.x","article-title":"Disordered insulin secretion in the development of insulin resistance and Type 2 diabetes","volume":"29","author":"Schofield","year":"2012","journal-title":"Diabet. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"E105","DOI":"10.1002\/oby.20083","article-title":"Cortisol, obesity, and the metabolic syndrome: A cross-sectional study of obese subjects and review of the literature","volume":"21","author":"Abraham","year":"2013","journal-title":"Obesity"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.psyneuen.2004.05.007","article-title":"Role of stress in the pathogenesis of the metabolic syndrome","volume":"30","author":"Rosmond","year":"2005","journal-title":"Psychoneuroendocrinology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2692","DOI":"10.1210\/jc.2009-0370","article-title":"Clinical review: The pathogenetic role of cortisol in the metabolic syndrome: A hypothesis","volume":"94","author":"Anagnostis","year":"2009","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00125-003-1284-4","article-title":"11beta-Hydroxysteroid dehydrogenase Type 1 in obesity and Type 2 diabetes","volume":"47","author":"Stulnig","year":"2004","journal-title":"Diabetologia"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1038\/oby.2005.137","article-title":"Increased cortisol bioavailability, abdominal obesity, and the metabolic syndrome in obese women","volume":"13","author":"Duclos","year":"2005","journal-title":"Obes. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1210\/jcem-70-3-729","article-title":"A patient with hypocortisolism and Cushing\u2019s syndrome-like manifestations: Cortisol hyperreactive syndrome","volume":"70","author":"Iida","year":"1990","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1507\/endocrj.43.645","article-title":"Carbohydrate and lipid metabolism in endogenous hypercortisolism: Shared features with metabolic syndrome X and NIDDM","volume":"43","author":"Friedman","year":"1996","journal-title":"Endocr. J."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Beaupere, C., Liboz, A., Feve, B., Blondeau, B., and Guillemain, G. (2021). Molecular Mechanisms of Glucocorticoid-Induced Insulin Resistance. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22020623"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1210\/er.2016-1105","article-title":"Glucose Metabolism Abnormalities in Cushing Syndrome: From Molecular Basis to Clinical Management","volume":"38","author":"Scaroni","year":"2017","journal-title":"Endocr. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1515\/hmbci-2014-0025","article-title":"5alpha-Reductase inhibitors alter steroid metabolism and may contribute to insulin resistance, diabetes, metabolic syndrome and vascular disease: A medical hypothesis","volume":"20","author":"Traish","year":"2014","journal-title":"Horm. Mol. Biol. Clin. Investig."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/S0083-6729(08)60646-9","article-title":"11 beta-Hydroxysteroid dehydrogenase","volume":"57","author":"Stewart","year":"1999","journal-title":"Vitam. Horm."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1053\/beem.2000.0119","article-title":"Cortisol metabolism and the role of 11beta-hydroxysteroid dehydrogenase","volume":"15","author":"Tomlinson","year":"2001","journal-title":"Best Pract. Res. Clin. Endocrinol. Metab."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/S0960-0760(97)00200-8","article-title":"11Beta-hydroxysteroid dehydrogenase 1 in adipocytes: Expression is differentiation-dependent and hormonally regulated","volume":"64","author":"Napolitano","year":"1998","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Ghigo, E., and Porta, M. (2014). Diabetes associated with glucocorticoid excess. Diabetes Secondary to Endocrine and Pancreatic Disorders, Karger.","DOI":"10.1159\/isbn.978-3-318-02598-9"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1111\/j.1749-6632.1995.tb44724.x","article-title":"The neural network that regulates energy balance is responsive to glucocorticoids and insulin and also regulates HPA axis responsivity at a site proximal to CRF neurons","volume":"771","author":"Dallman","year":"1995","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_30","unstructured":"Goodman, H.M. (2009). Basic Medical Endocrinology, Elsevier. [4th ed.]."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.ecl.2005.01.002","article-title":"Adrenal corticosteroid biosynthesis, metabolism, and action","volume":"34","author":"Arlt","year":"2005","journal-title":"Endocrinol. Metab. Clin. N. Am."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3553","DOI":"10.1210\/jc.2007-0445","article-title":"Effects of cortisol on carbohydrate, lipid, and protein metabolism: Studies of acute cortisol withdrawal in adrenocortical failure","volume":"92","author":"Christiansen","year":"2007","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.ecl.2013.10.005","article-title":"Mechanisms of glucocorticoid-induced insulin resistance: Focus on adipose tissue function and lipid metabolism","volume":"43","author":"Geer","year":"2014","journal-title":"Endocrinol. Metab. Clin. N. Am."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1172\/JCI115396","article-title":"Modulation of glucose regulation and insulin secretion by circadian rhythmicity and sleep","volume":"88","author":"Blackman","year":"1991","journal-title":"J. Clin. Investig."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1042\/cs0960513","article-title":"Glucocorticoids and insulin resistance: Old hormones, new targets","volume":"96","author":"Andrews","year":"1999","journal-title":"Clin. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1590\/S0100-879X1997001200003","article-title":"Food and the circadian activity of the hypothalamic-pituitary-adrenal axis","volume":"30","author":"Leal","year":"1997","journal-title":"Braz. J. Med. Biol. Res."},{"key":"ref_37","first-page":"E317","article-title":"Effects of glucocorticoids on energy metabolism and food intake in humans","volume":"271","author":"Tataranni","year":"1996","journal-title":"Am. J. Physiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1111\/j.1365-2265.2006.02488.x","article-title":"Characterization of the metabolic phenotypes of Cushing\u2019s syndrome and growth hormone deficiency: A study of body composition and energy metabolism","volume":"64","author":"Burt","year":"2006","journal-title":"Clin. Endocrinol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1016\/j.nut.2007.08.008","article-title":"Relationship between stress, eating behavior, and obesity","volume":"23","author":"Torres","year":"2007","journal-title":"Nutrition"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"155142","DOI":"10.1016\/j.metabol.2022.155142","article-title":"Insulin: The master regulator of glucose metabolism","volume":"129","author":"Norton","year":"2022","journal-title":"Metabolism"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1111\/nyas.13435","article-title":"Insulin regulation of gluconeogenesis","volume":"1411","author":"Hatting","year":"2018","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Rahman, M.S., Hossain, K.S., Das, S., Kundu, S., Adegoke, E.O., Rahman, M.A., Hannan, M.A., Uddin, M.J., and Pang, M.G. (2021). Role of Insulin in Health and Disease: An Update. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22126403"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1046\/j.1440-1681.2000.03259.x","article-title":"Circumventricular organs: Definition and role in the regulation of endocrine and autonomic function","volume":"27","author":"Ganong","year":"2000","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1824","DOI":"10.1172\/JCI116773","article-title":"Saturable transport of insulin from plasma into the central nervous system of dogs In Vivo. A mechanism for regulated insulin delivery to the brain","volume":"92","author":"Baura","year":"1993","journal-title":"J. Clin. Investig."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"86","DOI":"10.2337\/diab.45.1.86","article-title":"Insulin transport from plasma into the central nervous system is inhibited by dexamethasone in dogs","volume":"45","author":"Baura","year":"1996","journal-title":"Diabetes"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3992","DOI":"10.2337\/db14-0340","article-title":"Insulin regulates brain function, but how does it get there?","volume":"63","author":"Gray","year":"2014","journal-title":"Diabetes"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1915","DOI":"10.2337\/diabetes.48.10.1915","article-title":"No effect of insulin on glucose blood-brain barrier transport and cerebral metabolism in humans","volume":"48","author":"Hasselbalch","year":"1999","journal-title":"Diabetes"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2203","DOI":"10.2337\/diabetes.50.10.2203","article-title":"The effect of insulin on In Vivo cerebral glucose concentrations and rates of glucose transport\/metabolism in humans","volume":"50","author":"Seaquist","year":"2001","journal-title":"Diabetes"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.ejphar.2004.02.041","article-title":"Glucose transporter expression in the central nervous system: Relationship to synaptic function","volume":"490","author":"McEwen","year":"2004","journal-title":"Eur. J. Pharmacol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.2337\/diabetes.54.5.1264","article-title":"Insulin signaling in the central nervous system: A critical role in metabolic homeostasis and disease from C. elegans to humans","volume":"54","author":"Porte","year":"2005","journal-title":"Diabetes"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.1038\/nm1202-798","article-title":"Hypothalamic insulin signaling is required for inhibition of glucose production","volume":"8","author":"Obici","year":"2002","journal-title":"Nat. Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.cmet.2006.02.009","article-title":"Role of hepatic STAT3 in brain-insulin action on hepatic glucose production","volume":"3","author":"Inoue","year":"2006","journal-title":"Cell Metab."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1038\/nm980","article-title":"Role of STAT-3 in regulation of hepatic gluconeogenic genes and carbohydrate metabolism In Vivo","volume":"10","author":"Inoue","year":"2004","journal-title":"Nat. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/0303-7207(94)03423-Q","article-title":"Hypothalamic GLUT 4 expression: A glucose- and insulin-sensing mechanism?","volume":"107","author":"Livingstone","year":"1995","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1038\/jcbfm.1987.68","article-title":"Effects of insulin on local cerebral glucose utilization in the rat","volume":"7","author":"Lucignani","year":"1987","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_56","first-page":"R142","article-title":"Glucocorticoids and insulin: Reciprocal signals for energy balance","volume":"268","author":"Strack","year":"1995","journal-title":"Am. J. Physiol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.ejphar.2004.02.040","article-title":"The source of cerebral insulin","volume":"490","author":"Banks","year":"2004","journal-title":"Eur. J. Pharmacol."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Kamba, A., Daimon, M., Murakami, H., Otaka, H., Matsuki, K., Sato, E., Tanabe, J., Takayasu, S., Matsuhashi, Y., and Yanagimachi, M. (2016). Association between Higher Serum Cortisol Levels and Decreased Insulin Secretion in a General Population. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0166077"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/j.tem.2011.09.001","article-title":"Diabetes in Cushing syndrome: Basic and clinical aspects","volume":"22","author":"Mazziotti","year":"2011","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1172\/JCI119175","article-title":"Direct glucocorticoid inhibition of insulin secretion. An in vitro study of dexamethasone effects in mouse islets","volume":"99","author":"Lambillotte","year":"1997","journal-title":"J. Clin. Investig."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1111\/j.1365-2362.2008.02067.x","article-title":"Novel insights into glucocorticoid-mediated diabetogenic effects: Towards expansion of therapeutic options?","volume":"39","author":"Ouwens","year":"2009","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"3309","DOI":"10.1210\/jc.2010-0119","article-title":"Reduced glucose tolerance and insulin resistance induced by steroid treatment, relative physical inactivity, and high-calorie diet impairs the incretin effect in healthy subjects","volume":"95","author":"Hansen","year":"2010","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1499","DOI":"10.1172\/JCI108231","article-title":"Effect of dexamethasone on insulin binding, glucose transport, and glucose oxidation of isolated rat adipocytes","volume":"56","author":"Olefsky","year":"1975","journal-title":"J. Clin. Investig."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"17696","DOI":"10.1016\/S0021-9258(18)45435-X","article-title":"Dexamethasone causes translocation of glucose transporters from the plasma membrane to an intracellular site in human fibroblasts","volume":"262","author":"Horner","year":"1987","journal-title":"J. Biol. Chem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1210\/endo-103-4-1054","article-title":"Alterations in insulin binding induced by changes In Vivo in the levels of glucocorticoids and growth hormone","volume":"103","author":"Kahn","year":"1978","journal-title":"Endocrinology"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1210\/jcem-55-5-910","article-title":"Hypercortisolism and insulin resistance: Comparative effects of prednisone, hydrocortisone, and dexamethasone on insulin binding of human erythrocytes","volume":"55","author":"Yasuda","year":"1982","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1159\/000314319","article-title":"Pathophysiology of diabetes mellitus in Cushing\u2019s syndrome","volume":"92","author":"Pivonello","year":"2010","journal-title":"Neuroendocrinology"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"E654","DOI":"10.1152\/ajpendo.00453.2006","article-title":"Glucocorticoids produce whole body insulin resistance with changes in cardiac metabolism","volume":"292","author":"Qi","year":"2007","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"4969","DOI":"10.1210\/jc.2008-1297","article-title":"Changes in adenosine 5\u2032-monophosphate-activated protein kinase as a mechanism of visceral obesity in Cushing\u2019s syndrome","volume":"93","author":"Kola","year":"2008","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1210\/jcem-64-4-832","article-title":"Glucocorticoids and insulin promote the differentiation of human adipocyte precursor cells into fat cells","volume":"64","author":"Hauner","year":"1987","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1210\/jcem-51-4-877","article-title":"Epinephrine, norepinephrine, glucagon, and growth hormone release in association with physiological decrements in the plasma glucose concentration in normal and diabetic man","volume":"51","author":"Santiago","year":"1980","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"125","DOI":"10.2337\/diab.29.2.125","article-title":"Stimulation of counterregulatory hormonal responses in diabetic man by a fall in glucose concentration","volume":"29","author":"DeFronzo","year":"1980","journal-title":"Diabetes"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1970","DOI":"10.1016\/S0140-6736(00)03322-5","article-title":"Hypoglycaemic counter-regulation at normal blood glucose concentrations in patients with well controlled type-2 diabetes","volume":"356","author":"Spyer","year":"2000","journal-title":"Lancet"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.molmet.2018.08.001","article-title":"Molecular reductions in glucokinase activity increase counter-regulatory responses to hypoglycemia in mice and humans with diabetes","volume":"17","author":"Chakera","year":"2018","journal-title":"Mol. Metab."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1054\/clnu.1999.0064","article-title":"Effects of glucocorticoids on hepatic sensitivity to insulin and glucagon in man","volume":"19","author":"Dirlewanger","year":"2000","journal-title":"Clin. Nutr."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"253","DOI":"10.2337\/diabetes.49.2.253","article-title":"Beta-blockade, but not normoglycemia or hyperinsulinemia, markedly diminishes stress-induced hyperglycemia in diabetic dogs","volume":"49","author":"Rashid","year":"2000","journal-title":"Diabetes"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1016\/0026-0495(80)90024-4","article-title":"Epinephrine and the regulation of glucose metabolism: Effect of diabetes and hormonal interactions","volume":"29","author":"Sherwin","year":"1980","journal-title":"Metabolism"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1382","DOI":"10.1210\/en.2004-0607","article-title":"Insulin alone increases hypothalamo-pituitary-adrenal activity, and diabetes lowers peak stress responses","volume":"146","author":"Chan","year":"2005","journal-title":"Endocrinology"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1210\/endo-116-2-604","article-title":"Hyperinsulinemia suppresses glucose utilization in specific brain regions: In Vivo studies using the euglycemic clamp in the rat","volume":"116","author":"Grunstein","year":"1985","journal-title":"Endocrinology"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"3041","DOI":"10.1210\/jcem.84.9.5953","article-title":"Supraphysiological hyperinsulinemia acutely increases hypothalamic-pituitary-adrenal secretory activity in humans","volume":"84","author":"Kern","year":"1999","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1210\/edrv-12-2-118","article-title":"The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenocortical axis","volume":"12","author":"Jacobson","year":"1991","journal-title":"Endocr. Rev."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/0006-8993(84)91028-X","article-title":"Insulin inhibits pyramidal neurons in hippocampal slices","volume":"309","author":"Palovcik","year":"1984","journal-title":"Brain Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"S45","DOI":"10.1038\/sj.ijo.0802856","article-title":"Role of glucocorticoids in the physiopathology of excessive fat deposition and insulin resistance","volume":"28","author":"Asensio","year":"2004","journal-title":"Int. J. Obes. Relat. Metab. Disord."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1002\/j.1550-8528.1996.tb00546.x","article-title":"Inhibition of cortisol secretion by dexamethasone in relation to body fat distribution: A dose-response study","volume":"4","author":"Ljung","year":"1996","journal-title":"Obes. Res."},{"key":"ref_85","first-page":"1853","article-title":"Stress-related cortisol secretion in men: Relationships with abdominal obesity and endocrine, metabolic and hemodynamic abnormalities","volume":"83","author":"Rosmond","year":"1998","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1136\/bmj.303.6809.1019","article-title":"Fetal and infant growth and impaired glucose tolerance at age 64","volume":"303","author":"Hales","year":"1991","journal-title":"BMJ"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1046\/j.1365-2265.1996.8560864.x","article-title":"Size at birth and adrenocortical function in childhood","volume":"45","author":"Clark","year":"1996","journal-title":"Clin. Endocrinol."},{"key":"ref_88","first-page":"757","article-title":"Elevated plasma cortisol concentrations: A link between low birth weight and the insulin resistance syndrome?","volume":"83","author":"Phillips","year":"1998","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"101112","DOI":"10.1016\/j.molmet.2020.101112","article-title":"Insulin and obesity transform hypothalamic-pituitary-adrenal axis stemness and function in a hyperactive state","volume":"43","author":"Werdermann","year":"2021","journal-title":"Mol. Metab."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1806","DOI":"10.1210\/jcem.83.5.4951","article-title":"Obesity and gender influence cortisol secretion and metabolism in man","volume":"83","author":"Andrew","year":"1998","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_91","first-page":"1022","article-title":"Cortisol metabolism in human obesity: Impaired cortisone \u2192 cortisol conversion in subjects with central adiposity","volume":"84","author":"Stewart","year":"1999","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1196\/annals.1367.009","article-title":"The hypothalamic-pituitary-adrenal axis activity in obesity and the metabolic syndrome","volume":"1083","author":"Pasquali","year":"2006","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"4093","DOI":"10.1210\/jcem.85.11.6946","article-title":"Abnormalities of the hypothalamic-pituitary-adrenal axis in nondepressed women with abdominal obesity and relations with insulin resistance: Evidence for a central and a peripheral alteration","volume":"85","author":"Vicennati","year":"2000","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1038\/sj.ijo.0800838","article-title":"ACTH and cortisol response to combined corticotropin releasing hormone-arginine vasopressin stimulation in obese males and its relationship to body weight, fat distribution and parameters of the metabolic syndrome","volume":"23","author":"Pasquali","year":"1999","journal-title":"Int. J. Obes. Relat. Metab. Disord."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1007\/s00125-007-0629-9","article-title":"Cortisol clearance and associations with insulin sensitivity, body fat and fatty liver in middle-aged men","volume":"50","author":"Holt","year":"2007","journal-title":"Diabetologia"},{"key":"ref_96","first-page":"501","article-title":"Effect of fat distribution on the pharmacokinetics of cortisol in obesity","volume":"36","author":"Lottenberg","year":"1998","journal-title":"Int. J. Clin. Pharmacol. Ther."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"3192","DOI":"10.1210\/jcem.84.9.5946","article-title":"Plasma total and glycosylated corticosteroid-binding globulin levels are associated with insulin secretion","volume":"84","author":"Grasa","year":"1999","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1494","DOI":"10.2337\/dc06-1353","article-title":"Massive weight loss decreases corticosteroid-binding globulin levels and increases free cortisol in healthy obese patients: An adaptive phenomenon?","volume":"30","author":"Manco","year":"2007","journal-title":"Diabetes Care"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"2518","DOI":"10.1210\/endo-122-6-2518","article-title":"Characterization of insulin-like growth factor I and insulin receptors on cultured bovine adrenal fasciculata cells. Role of these peptides on adrenal cell function","volume":"122","author":"Penhoat","year":"1988","journal-title":"Endocrinology"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"5025","DOI":"10.1038\/s41598-018-23298-2","article-title":"Insulin Regulates Adrenal Steroidogenesis by Stabilizing SF-1 Activity","volume":"8","author":"Kinyua","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1002\/ijc.29950","article-title":"Adrenocortical tumors and insulin resistance: What is the first step?","volume":"138","author":"Altieri","year":"2016","journal-title":"Int. J. Cancer"},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Tsatsoulis, A. (2018). The Role of Insulin Resistance\/Hyperinsulinism on the Rising Trend of Thyroid and Adrenal Nodular Disease in the Current Environment. J. Clin. Med., 7.","DOI":"10.3390\/jcm7030037"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1007\/s10654-011-9585-2","article-title":"Reliability of hypothalamic-pituitary-adrenal axis assessment methods for use in population-based studies","volume":"26","author":"Golden","year":"2011","journal-title":"Eur. J. Epidemiol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"e3528","DOI":"10.1002\/dmrr.3528","article-title":"Association of MRI-based adrenal gland volume and impaired glucose metabolism in a population-based cohort study","volume":"38","author":"Askani","year":"2022","journal-title":"Diabetes Metab. Res. Rev."},{"key":"ref_105","first-page":"1","article-title":"Growth hormone, insulin-like growth factor-I and the cortisol-cortisone shuttle","volume":"56","author":"Stewart","year":"2001","journal-title":"Horm. Res."},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Ahmed, A., Rabbitt, E., Brady, T., Brown, C., Guest, P., Bujalska, I.J., Doig, C., Newsome, P.N., Hubscher, S., and Elias, E. (2012). A switch in hepatic cortisol metabolism across the spectrum of non alcoholic fatty liver disease. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0029531"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"4069","DOI":"10.1210\/en.2008-0088","article-title":"Insulin and dexamethasone dynamically regulate adipocyte 11beta-hydroxysteroid dehydrogenase type 1","volume":"149","author":"Balachandran","year":"2008","journal-title":"Endocrinology"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"2166","DOI":"10.1126\/science.1066285","article-title":"A transgenic model of visceral obesity and the metabolic syndrome","volume":"294","author":"Masuzaki","year":"2001","journal-title":"Science"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"41293","DOI":"10.1074\/jbc.M103676200","article-title":"Improved lipid and lipoprotein profile, hepatic insulin sensitivity, and glucose tolerance in 11beta-hydroxysteroid dehydrogenase type 1 null mice","volume":"276","author":"Morton","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1016\/S0140-6736(96)11222-8","article-title":"Does central obesity reflect \u201cCushing\u2019s disease of the omentum\u201d?","volume":"349","author":"Bujalska","year":"1997","journal-title":"Lancet"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1210\/er.2003-0031","article-title":"11beta-hydroxysteroid dehydrogenase type 1: A tissue-specific regulator of glucocorticoid response","volume":"25","author":"Tomlinson","year":"2004","journal-title":"Endocr. Rev."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1631","DOI":"10.1210\/jc.2012-3523","article-title":"Glucocorticoids fail to cause insulin resistance in human subcutaneous adipose tissue In Vivo","volume":"98","author":"Hazlehurst","year":"2013","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1515\/hmbci-2013-0038","article-title":"Effects of energy restriction on activity of the hypothalamo-pituitary-adrenal axis in obese humans and rodents: Implications for diet-induced changes in body composition","volume":"15","author":"Seimon","year":"2013","journal-title":"Horm. Mol. Biol. Clin. Investig."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.numecd.2004.11.004","article-title":"Impact of weight loss on cortisol secretion in obese men with and without metabolic syndrome features","volume":"16","author":"Parra","year":"2006","journal-title":"Nutr. Metab. Cardiovasc. Dis."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1055\/s-2007-1004859","article-title":"Beta-endorphin, insulin, ACTH and cortisol plasma levels during oral glucose tolerance test in obesity after weight loss","volume":"22","author":"Giovannini","year":"1990","journal-title":"Horm. Metab. Res."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1055\/s-2007-985354","article-title":"Moderate weight loss reduces renin and aldosterone but does not influence basal or stimulated pituitary-adrenal axis function","volume":"39","author":"Ho","year":"2007","journal-title":"Horm. Metab. Res."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.nut.2007.02.007","article-title":"Influence of meal time on salivary circadian cortisol rhythms and weight loss in obese women","volume":"23","author":"Bavaresco","year":"2007","journal-title":"Nutrition"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"E351","DOI":"10.1152\/ajpendo.90769.2008","article-title":"Enhanced cortisol production rates, free cortisol, and 11beta-HSD-1 expression correlate with visceral fat and insulin resistance in men: Effect of weight loss","volume":"296","author":"Purnell","year":"2009","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"426","DOI":"10.4103\/2230-8210.152793","article-title":"Sodium-glucose cotransporter-2 inhibition and the insulin: Glucagon ratio: Unexplored dimensions","volume":"19","author":"Kalra","year":"2015","journal-title":"Indian J. Endocrinol. Metab."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.cmet.2017.04.011","article-title":"Sodium-Glucose Co-transporters and Their Inhibition: Clinical Physiology","volume":"26","author":"Ferrannini","year":"2017","journal-title":"Cell Metab."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"273","DOI":"10.2337\/dci21-0050","article-title":"The Brains behind SGLT2 Inhibition","volume":"45","author":"Schlogl","year":"2022","journal-title":"Diabetes Care"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"e27638","DOI":"10.1097\/MD.0000000000027638","article-title":"Effects of tofogliflozin on adrenocorticotropic hormone, renin and aldosterone, and cortisol levels in elderly patients with diabetes mellitus: A retrospective study of a patient cohort","volume":"100","author":"Higashikawa","year":"2021","journal-title":"Medicine"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1038\/s41366-020-00688-z","article-title":"Metformin effectively restores the HPA axis function in diet-induced obese rats","volume":"45","author":"Shin","year":"2021","journal-title":"Int. J. Obes."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"8145","DOI":"10.1038\/srep08145","article-title":"Antihyperglycemic mechanism of metformin occurs via the AMPK\/LXRalpha\/POMC pathway","volume":"5","author":"Cho","year":"2015","journal-title":"Sci. Rep."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/15\/8178\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:56:02Z","timestamp":1760140562000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/15\/8178"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,25]]},"references-count":124,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["ijms23158178"],"URL":"https:\/\/doi.org\/10.3390\/ijms23158178","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,25]]}}}