{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T16:46:37Z","timestamp":1790959597595,"version":"4.1.0"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,9]],"date-time":"2025-07-09T00:00:00Z","timestamp":1752019200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Type 2 diabetes mellitus (T2DM) is associated with lower gray matter (GM) volumes. However, little is known about the impact of glycemic control on brain atrophy, especially in highly susceptible regions. Therefore, we aim to identify the effect of glycemic variability (GV) on long-term changes in brain volume among individuals with T2DM.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A longitudinal clinical, biochemical, and imaging assessment was conducted at a baseline visit on 170 individuals (85 with T2DM), from which 29 (15 with T2DM) were evaluated at a 7-year follow-up visit. Brain regional volumes were evaluated with 3\u202fT MRI, using the FreeSurfer 7 longitudinal pipeline. GV metrics such as SD, M-value, MAG (mean absolute glucose change), MAGE (mean amplitude of glycemic excursion), and CoV (coefficient of variation) were calculated in both visits.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Statistically significant negative correlations between GV metrics and symmetrized percent change (SPC) of GM volumes were found in specific cortical and subcortical regions of individuals with T2DM. MAGE was correlated with regionally specific atrophy on the temporal lobe (<jats:italic>r<\/jats:italic> =\u202f\u22120.63, <jats:italic>p<\/jats:italic>\u202f=\u202f0.021), insula (<jats:italic>\u03c1<\/jats:italic>\u202f=\u202f\u22120.62, <jats:italic>p<\/jats:italic>\u202f=\u202f0.022), thalamus (<jats:italic>r<\/jats:italic> =\u202f\u22120.64; <jats:italic>p<\/jats:italic>\u202f=\u202f0.024), hippocampus (<jats:italic>r<\/jats:italic> =\u202f\u22120.59; <jats:italic>p<\/jats:italic>\u202f=\u202f0.034), and putamen (<jats:italic>\u03c1<\/jats:italic> =\u202f\u22120.65, <jats:italic>p<\/jats:italic>\u202f=\u202f0.017). Concerning the hippocampal subregions, the presubiculum was significantly correlated with MAGE (<jats:italic>r<\/jats:italic> =\u202f\u22120.73; <jats:italic>p<\/jats:italic>\u202f=\u202f0.005). Baseline GV was consistently associated with temporal lobe SPC. Linear regression analysis showed that, for each increase of 1\u202fmmol\/L in MAGE value, the SPC of the temporal lobe decreases on average by 1.2% (higher atrophy rate).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The relationship between longitudinal GM atrophy and GV has a regionally specific pattern, suggesting localized brain susceptibility to intra-daily glucose fluctuations. Negative correlations between GV metrics and SPC volume of regions involved in habit-learning, decision-making, and memory highlight GV as a mediator of the neural impact of T2DM on the reward prediction-error circuits.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnins.2025.1430185","type":"journal-article","created":{"date-parts":[[2025,7,10]],"date-time":"2025-07-10T05:45:27Z","timestamp":1752126327000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Habit-learning and decision-making circuits are susceptible to glycemic variability in type 2 diabetes: a longitudinal study"],"prefix":"10.3389","volume":"19","author":[{"given":"Carolina","family":"Moreno","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ot\u00edlia C.","family":"d\u2019Almeida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joana","family":"Cris\u00f3stomo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N\u00e1dia","family":"Can\u00e1rio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonor","family":"Gomes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Castelo-Branco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,7,9]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1186\/1755-7682-3-24","article-title":"Dopaminergic reward system: a short integrative review","volume":"3","author":"Arias-Carri\u00f3n","year":"2010","journal-title":"Int. Arch. Med."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"e12947","DOI":"10.1111\/jne.12947","article-title":"Insulin on the brain: the role of central insulin signalling in energy and glucose homeostasis","volume":"33","author":"Beddows","year":"2021","journal-title":"J. Neuroendocrinol."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"750","DOI":"10.1038\/nn1075","article-title":"Non-invasive mapping of connections between the human thalamus and cortex using diffusion imaging","volume":"6","author":"Behrens","year":"2003","journal-title":"Nat. Neurosci."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"2244","DOI":"10.2337\/db14-0348","article-title":"Brain changes underlying cognitive dysfunction in diabetes: what can we learn from MRI?","volume":"63","author":"Biessels","year":"2014","journal-title":"Diabetes"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"116563","DOI":"10.1016\/j.neuroimage.2020.116563","article-title":"Test-retest reliability of FreeSurfer automated hippocampal subfield segmentation within and across scanners","volume":"210","author":"Brown","year":"2020","journal-title":"NeuroImage"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"3523","DOI":"10.2337\/db14-0122","article-title":"Cerebral microvascular lesions on high-resolution 7-tesla MRI in patients with type 2 diabetes","volume":"63","author":"Brundel","year":"2014","journal-title":"Diabetes"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1007\/s00125-018-4778-9","article-title":"Type 2 diabetes mellitus, brain atrophy and cognitive decline in older people: a longitudinal study","volume":"62","author":"Callisaya","year":"2019","journal-title":"Diabetologia"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"pyv014","DOI":"10.1093\/ijnp\/pyv014","article-title":"Reduced insulin sensitivity is related to less endogenous dopamine at D2\/3 receptors in the ventral striatum of healthy nonobese humans","volume":"18","author":"Caravaggio","year":"2015","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1016\/S2213-8587(18)30136-0","article-title":"Glycaemic variability in diabetes: clinical and therapeutic implications","volume":"7","author":"Ceriello","year":"2019","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1007\/s00592-012-0398-x","article-title":"Acute and chronic fluctuations in blood glucose levels can increase oxidative stress in type 2 diabetes mellitus","volume":"49","author":"Chang","year":"2012","journal-title":"Acta Diabetol."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.tins.2020.10.007","article-title":"The emerging science of Interoception: sensing, integrating, interpreting, and regulating signals within the self","volume":"44","author":"Chen","year":"2021","journal-title":"Trends Neurosci."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"e86284","DOI":"10.1371\/journal.pone.0086284","article-title":"Multi-scale glycemic variability: a link to gray matter atrophy and cognitive decline in type 2 diabetes","volume":"9","author":"Cui","year":"2014","journal-title":"PLoS One"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"e48007","DOI":"10.1371\/journal.pone.0048007","article-title":"Evidence for a role of a Cortico-subcortical network for automatic and unconscious motor inhibition of manual responses","volume":"7","author":"D\u2019Ostilio","year":"2012","journal-title":"PLoS One"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1006\/nimg.1998.0395","article-title":"Cortical surface-based analysis","volume":"9","author":"Dale","year":"1999","journal-title":"NeuroImage"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1159\/000321354","article-title":"Microvascular determinants of cognitive decline and brain volume change in elderly patients with type 2 diabetes","volume":"30","author":"de Bresser","year":"2010","journal-title":"Dement. Geriatr. Cogn. Disord."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"1604","DOI":"10.1007\/s00125-003-1235-0","article-title":"Type 2 diabetes and atrophy of medial temporal lobe structures on brain MRI","volume":"46","author":"den Heijer","year":"2003","journal-title":"Diabetologia"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1177\/1073858420907591","article-title":"Dopamine, prediction error and beyond","volume":"27","author":"Diederen","year":"2021","journal-title":"Neuroscientist"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"764","DOI":"10.2337\/dc15-2230","article-title":"Brain and white matter Hyperintensity volumes after 10 years of random assignment to lifestyle intervention","volume":"39","author":"Espeland","year":"2016","journal-title":"Diabetes Care"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"868","DOI":"10.3389\/fnins.2019.00868","article-title":"The relevance of insulin action in the dopaminergic system","volume":"13","author":"Fiory","year":"2019","journal-title":"Front. Neurosci."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1016\/S0896-6273(02)00569-X","article-title":"Whole brain segmentation","volume":"33","author":"Fischl","year":"2002","journal-title":"Neuron"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1006\/nimg.1998.0396","article-title":"Cortical surface-based analysis","volume":"9","author":"Fischl","year":"1999","journal-title":"NeuroImage"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"2131","DOI":"10.1007\/s00125-021-05539-8","article-title":"The legacy effect in diabetes: are there long-term benefits?","volume":"64","author":"Folz","year":"2021","journal-title":"Diabetologia"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/S2213-8587(14)70148-2","article-title":"Glucose regulation, cognition, and brain MRI in type 2 diabetes: a systematic review","volume":"3","author":"Geijselaers","year":"2015","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1016\/j.diabres.2011.07.002","article-title":"Association of cognitive dysfunction with hippocampal atrophy in elderly Japanese people with type 2 diabetes","volume":"94","author":"Hayashi","year":"2011","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"nsw097","DOI":"10.1093\/scan\/nsw097","article-title":"Changes in cortico-subcortical and subcortico-subcortical connectivity impact cognitive control to emotional cues across development","volume":"11","author":"Heller","year":"2016","journal-title":"Soc. Cogn. Affect. Neurosci."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"921","DOI":"10.1089\/dia.2010.0247","article-title":"Normal reference range for mean tissue glucose and glycemic variability derived from continuous glucose monitoring for subjects without diabetes in different ethnic groups","volume":"13","author":"Hill","year":"2011","journal-title":"Diabetes Technol. Ther."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"5594","DOI":"10.1523\/JNEUROSCI.0067-17.2017","article-title":"The human thalamus is an integrative hub for functional brain networks","volume":"37","author":"Hwang","year":"2017","journal-title":"J. Neurosci."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1016\/j.neuroimage.2015.04.042","article-title":"A computational atlas of the hippocampal formation using ex vivo, ultra-high resolution MRI: application to adaptive segmentation of in vivo MRI","volume":"115","author":"Iglesias","year":"2015","journal-title":"NeuroImage"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"542","DOI":"10.1016\/j.neuroimage.2016.07.020","article-title":"Bayesian longitudinal segmentation of hippocampal substructures in brain MRI using subject-specific atlases","volume":"141","author":"Iglesias","year":"2016","journal-title":"NeuroImage"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"107","DOI":"10.2991\/jegh.k.191028.001","article-title":"Epidemiology of type 2 diabetes \u2013 global burden of disease and forecasted trends","volume":"10","author":"Khan","year":"2019","journal-title":"J. Epidemiol. Glob. Health"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"1486","DOI":"10.2337\/dc06-0293","article-title":"The effect of glucose variability on the risk of microvascular complications in type 1 diabetes","volume":"29","author":"Kilpatrick","year":"2006","journal-title":"Diabetes Care"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"171","DOI":"10.3389\/fnins.2012.00171","article-title":"101 labeled brain images and a consistent human cortical labeling protocol","volume":"6","author":"Klein","year":"2012","journal-title":"Front. Neurosci."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/j.jns.2013.06.019","article-title":"Diabetes mellitus and progression of vascular brain lesions and brain atrophy in patients with symptomatic atherosclerotic disease. The SMART-MR study","volume":"332","author":"Kooistra","year":"2013","journal-title":"J. Neurol. Sci."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1111\/j.1464-5491.2007.02049.x","article-title":"Diabetes mellitus, hypertension and medial temporal lobe atrophy: the LADIS study","volume":"24","author":"Korf","year":"2007","journal-title":"Diabet. Med."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"923","DOI":"10.4093\/dmj.2021.0346","article-title":"Fasting glucose variability and the risk of dementia in individuals with diabetes: a Nationwide cohort study","volume":"46","author":"Lee","year":"2022","journal-title":"Diabetes Metab. J."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1111\/nyas.12807","article-title":"Impact of diabetes on cognitive function and brain structure","volume":"1353","author":"Moheet","year":"2015","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"1402","DOI":"10.1016\/j.neuroimage.2012.02.084","article-title":"Within-subject template estimation for unbiased longitudinal image analysis","volume":"61","author":"Reuter","year":"2012","journal-title":"NeuroImage"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"2169","DOI":"10.2337\/dc10-0389","article-title":"Relationships between daily acute glucose fluctuations and cognitive performance among aged type 2 diabetic patients","volume":"33","author":"Rizzo","year":"2010","journal-title":"Diabetes Care"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"855","DOI":"10.2337\/dc10-1684","article-title":"A decrease in glucose variability does not reduce cardiovascular event rates in type 2 diabetic patients after acute myocardial infarction","volume":"34","author":"Siegelaar","year":"2011","journal-title":"Diabetes Care"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1016\/j.ejphar.2004.02.056","article-title":"Insulin, C-peptide, hyperglycemia, and central nervous system complications in diabetes","volume":"490","author":"Sima","year":"2004","journal-title":"Eur. J. Pharmacol."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"2285","DOI":"10.2337\/dc10-1303","article-title":"Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments","volume":"33","author":"Tesfaye","year":"2010","journal-title":"Diabetes Care"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/1475-2840-12-1","article-title":"Relationship between fluctuations in glucose levels measured by continuous glucose monitoring and vascular endothelial dysfunction in type 2 diabetes mellitus","volume":"12","author":"Torimoto","year":"2013","journal-title":"Cardiovasc. Diabetol."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"930","DOI":"10.3389\/fnins.2018.00930","article-title":"Impact of metabolic syndrome on neuroinflammation and the blood\u2013brain barrier","volume":"12","author":"Van Dyken","year":"2018","journal-title":"Front. Neurosci."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"997","DOI":"10.1212\/WNL.0b013e3181f25f06","article-title":"Progression of brain atrophy and cognitive decline in diabetes mellitus: a 3-year follow-up","volume":"75","author":"van Elderen","year":"2010","journal-title":"Neurology"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1016\/S2213-8587(19)30405-X","article-title":"Cerebral microvascular complications of type 2 diabetes: stroke, cognitive dysfunction, and depression","volume":"8","author":"van Sloten","year":"2020","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref46","volume-title":"Classification of diabetes mellitus","year":"2019"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1016\/j.jns.2014.06.008","article-title":"Global brain atrophy but not hippocampal atrophy is related to type 2 diabetes","volume":"344","author":"Wisse","year":"2014","journal-title":"J. Neurol. Sci."},{"key":"ref48","doi-asserted-by":"publisher","first-page":"781","DOI":"10.4093\/dmj.2021.0189","article-title":"Association between type 2 diabetes mellitus and brain atrophy: a Meta-analysis","volume":"46","author":"Zhang","year":"2022","journal-title":"Diabetes Metab. J."},{"key":"ref49","first-page":"1","article-title":"The relationship between glucose excursion and cognitive function in aged type 2 diabetes patients","volume-title":"Biomed. Environ. Sci","author":"Zhong","year":"2012"}],"container-title":["Frontiers in Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2025.1430185\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,10]],"date-time":"2025-07-10T13:38:30Z","timestamp":1752154710000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2025.1430185\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,9]]},"references-count":49,"alternative-id":["10.3389\/fnins.2025.1430185"],"URL":"https:\/\/doi.org\/10.3389\/fnins.2025.1430185","relation":{},"ISSN":["1662-453X"],"issn-type":[{"value":"1662-453X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,9]]},"article-number":"1430185"}}