Effect of Hypoglycemia on Brain Structure in People With Type 2 Diabetes: Epidemiological Analysis of the ACCORD-MIND MRI Trial
Open accessAbstract
OBJECTIVE: The effect of hypoglycemia related to treatment of type 2 diabetes mellitus (T2DM) on brain structure remains unclear. We aimed to assess whether symptomatic severe hypoglycemia is associated with brain atrophy and/or white matter abnormalities. RESEARCH DESIGN AND METHODS: We included T2DM participants with brain MRI from the Action to Control Cardiovascular Risk in Diabetes-Memory in Diabetes (ACCORD-MIND) trial. Symptomatic severe hypoglycemia was defined as blood glucose <2.8 mmol/L or symptoms resolved with treatments that required the assistance of another person or medical assistance (hypoglycemia requiring assistance [HA]). Standardized brain MRI was performed at baseline and at 40 months. Total brain volume (TBV) and abnormal white matter (AWM) volume were calculated using an automated computer algorithm. Brain MRI scans of hypoglycemic participants were also reviewed for local disease. RESULTS: Of the 503 T2DM participants (mean age, 62 years) with successful baseline and 40-month brain MRI, 28 had at least one HA episode during the 40-month follow-up. Compared with participants without HA, those with HA had marginally significant less atrophy (less decrease in TBV) from baseline to 40 months (−9.55 [95% CI −15.21, −3.90] vs. −15.38 [95% CI −16.64, −14.12], P = 0.051), and no significant increase of AWM volume (2.06 [95% CI 1.71, 2.49] vs. 1.84 [95% CI 1.76, 1.91], P = 0.247). In addition, no unexpected local signal changes or volume loss were seen on hypoglycemic participants’ brain MRI scans. CONCLUSIONS: Our study suggests that hypoglycemia related to T2DM treatment may not accentuate brain pathology, specifically brain atrophy or white matter abnormalities.
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Lowered cognitive performance appears to be more associated with the presence of microvascular complications or poor metabolic control than with the occurrence of severe hypoglycemic episodes.
“Lowered cognitive performance appears to be more associated with the presence of microvascular complications or poor metabolic control than with the occurrence of severe hypoglycemic episodes (57,61).”
From Hypoglycemia (2018) · cites this paper as [57]
The Conclusions (page unavailable) report no additional brain atrophy or abnormal white matter after severe symptomatic hypoglycemia in treated people with type 2 diabetes, which offers indirect support for the hypoglycemia part of the claim. But the paper measures brain structure, not cognitive performance, and does not establish that microvascular complications or poor metabolic control are more strongly associated with lowered cognitive performance. It explicitly cautions that its MRI measures reflect structure, not function. (LLM, conf=0.82)
Experimental — accuracy not yet measuredProspective studies have not found an association between intensive insulin therapy and cognitive function, or between severe hypoglycemia and future cognitive function.
“Prospective studies have not found an association between intensive insulin therapy and cognitive function (58)(59)(60), or between severe hypoglycemia and future cognitive function (56,57).”
From Hypoglycemia (2018) · cites this paper as [57]
The Introduction (page not provided) reports that the DCCT found no significant correlation between treatment-related hypoglycemic events and neuropsychological function. But this paper’s own prospective analysis measured brain structure, not future cognitive function; the Conclusions explicitly caution that its MRI variables reflect structure, not function. It therefore does not establish the claimed lack of association between severe hypoglycemia and future cognitive function. (LLM, conf=0.83)
Experimental — accuracy not yet measuredThe person with cognitive disorders is at high risk of future severe hypoglycemic episodes, possibly because of medication errors.
“The person with cognitive disorders is at high risk of future severe hypoglycemic episodes, possibly because of medication errors (19,56,57)”
From Hypoglycemia (2018) · cites this paper as [57]
The Introduction discusses severe hypoglycemia as a possible antecedent of cognitive impairment, not cognitive disorders as a predictor of future episodes. The Results and Conclusions identify other factors associated with hypoglycemia, but do not establish increased risk from cognitive disorders or mention medication errors (searched: future episodes, cognitive impairment, medication errors). (LLM, conf=0.72)
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Cites
Effects of Intensive Glucose Lowering in Type 2 Diabetes
(2008) · New England Journal of Medicine · doi:10.1056/nejmoa0802743 · Cited by 7,888 · see citing works
Debette, S., & Markus, H. S. (2010) · BMJ · doi:10.1136/bmj.c3666 · Cited by 2,328 · see citing works
The clinical use of structural MRI in Alzheimer disease
Frisoni, G. B., Fox, N. C., Jack, C. R., Scheltens, P., & Thompson, P. M. (2010) · Nature Reviews Neurology · doi:10.1038/nrneurol.2009.215 · Cited by 2,113 · see citing works
Nathan, D. M., & for the DCCT/EDIC Research Group (2014) · Diabetes Care · doi:10.2337/dc13-2112 · Cited by 1,832 · see citing works
Seaquist, E. R., Anderson, J., Childs, B., Cryer, P., Dagogo-Jack, S., Fish, L., Heller, S. R., Rodriguez, H., Rosenzweig, J., & Vigersky, R. (2013) · Diabetes Care · doi:10.2337/dc12-2480 · Cited by 1,389 · see citing works
Reichard, P., Nilsson, B.-Y., & Rosenqvist, U. (1993) · New England Journal of Medicine · doi:10.1056/nejm199307293290502 · Cited by 1,202 · see citing works
Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus
Whitmer, R. A. (2009) · JAMA · doi:10.1001/jama.2009.460 · Cited by 1,128 · see citing works
Cognitive decline and dementia in diabetes—systematic overview of prospective observational studies
Cukierman, T., Gerstein, H. C., & Williamson, J. D. (2005) · Diabetologia · doi:10.1007/s00125-005-0023-4 · Cited by 1,049 · see citing works
Self-citationBonds, D. E., Miller, M. E., Bergenstal, R. M., Buse, J. B., Byington, R. P., Cutler, J. A., Dudl, R. J., Ismail-Beigi, F., Kimel, A. R., Hoogwerf, B., et al. (2010) · BMJ · doi:10.1136/bmj.b4909 · Cited by 933 · cited 3× · see citing works
“These findings are consistent with the ACCORD study and comparable with the studies of other T2DM populations (22,40,41).”
Self-citationRisk of hypoglycaemia in types 1 and 2 diabetes: Effects of treatment modalities and their duration
UK Hypoglycaemia Study Group (2007) · Diabetologia · doi:10.1007/s00125-007-0599-y · Cited by 825 · see citing works
The barrier of hypoglycemia in diabetes
Cryer, P. E. (2008) · Diabetes · doi:10.2337/db08-1084 · Cited by 725 · see citing works
Long-term effect of diabetes and its treatment on cognitive function
(2007) · New England Journal of Medicine · doi:10.1056/nejmoa066397 · Cited by 646 · see citing works
Launer, L. J., Miller, M. E., Williamson, J. D., Lazar, R. M., Gerstein, H. C., Murray, A. M., Sullivan, M., Horowitz, K. R., Ding, J., Marcovina, S., et al. (2011) · The Lancet Neurology · doi:10.1016/s1474-4422(11)70188-0 · Cited by 574 · see citing works
Self-citationLongitudinal pattern of regional brain volume change differentiates normal aging from MCI
Driscoll, I. F., Davatzikos, C. A., An, Y., Wu, X., Shen, D. G., Kraut, M. A., & Resnick, S. M. (2009) · Neurology · doi:10.1212/wnl.0b013e3181a82634 · Cited by 527 · see citing works
Self-citationHypoglycemia, functional brain failure, and brain death.
Cryer, P. E. (2007) · Journal of Clinical Investigation · doi:10.1172/jci31669 · Cited by 363 · see citing works
Brain Imaging in Patients With Diabetes
van Harten, B., de Leeuw, F., Weinstein, H. C., Scheltens, P., & Biessels, G. J. (2006) · Diabetes Care · doi:10.2337/dc06-1637 · Cited by 349 · see citing works
Radiofrequency Energy-Induced Heating During MR Procedures: A Review
Shellock, F. G. (2000) · Journal of Magnetic Resonance Imaging · doi:10.1002/1522-2586(200007)12:1 · Cited by 344 · see citing works
Correlation between rates of brain atrophy and cognitive decline in AD
Fox, N. C., Scahill, R. I., Crum, W. R., & Rossor, M. N. (1999) · Neurology · doi:10.1212/wnl.52.8.1687 · Cited by 338 · see citing works
An Image-Processing System for Qualitative and Quantitative Volumetric Analysis of Brain Images
Goldszal, A. F., Davatzikos, C. A., Pham, D. L., Yan, M., Bryan, R. N., & Resnick, S. M. (1998) · Journal of Computer Assisted Tomography · doi:10.1097/00004728-199809000-00030 · Cited by 295 · see citing works
Self-citationComputer-Assisted Segmentation of White Matter Lesions in 3D MR Images Using Support Vector Machine
Lao, Z., Shen, D. G., Liu, D., Jawad, A. F., Melhem, E. R., Launer, L. J., Bryan, R. N., & Davatzikos, C. A. (2008) · Academic Radiology · doi:10.1016/j.acra.2007.10.012 · Cited by 240 · see citing works
Self-citationHypoglycaemia and cognitive function
Warren, R. E., & Frier, B. M. (2004) · Diabetes Obesity and Metabolism · doi:10.1111/j.1463-1326.2004.00421.x · Cited by 219 · see citing works
Whole-Brain Atrophy Rate and Cognitive Decline: Longitudinal MR Study of Memory Clinic Patients
Sluimer, J. D., van der Flier, W. M., Karas, G. B., Fox, N. C., Scheltens, P., Barkhof, F., & Vrenken, H. (2008) · Radiology · doi:10.1148/radiol.2482070938 · Cited by 173 · see citing works
Permanent neuropsychological impairment after recurrent episodes of severe hypoglycaemia in man
Wredling, R., Levander, S. E., Adamson, U., & Lins, P. E. (1990) · Diabetologia · doi:10.1007/bf00404042 · Cited by 159 · see citing works
Diffusion MR Imaging of Hypoglycemic Encephalopathy
Kang, E., Jeon, S. J., Choi, S. S., Song, C. J., & Yu, I. K. (2009) · American Journal of Neuroradiology · doi:10.3174/ajnr.a1856 · Cited by 153 · see citing works
Neurocognitive Functioning in Children Diagnosed with Diabetes Before Age 10 Years
KAUFMAN, F. R., Epport, K., Engilman, R., & Halvorson, M. (1999) · Journal of Diabetes and its Complications · doi:10.1016/s1056-8727(98)00029-4 · Cited by 128 · see citing works
Akram, K., Pedersen‐Bjergaard, U., Carstensen, B., Borch‐Johnsen, K., & Thorsteinsson, B. (2006) · Diabetic Medicine · doi:10.1111/j.1464-5491.2006.01880.x · Cited by 128 · see citing works
Williamson, J. D., Miller, M. E., Bryan, R. N., Lazar, R. M., Coker, L. H., Johnson, J., Cukierman, T., Horowitz, K. R., Murray, A. M., & Launer, L. J. (2007) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2007.03.029 · Cited by 124 · see citing works
Self-citationHasegawa, Y., Formato, J. E., Latour, L. L., Gutierrez, J. A., Liu, K.-F., García, J. H., Sotak, C. H., & Fisher, M. (1996) · Stroke · doi:10.1161/01.str.27.9.1648 · Cited by 122 · see citing works
Draelos, M. T., Jacobson, A. M., Weinger, K., Widom, B., Ryan, C. M., Finkelstein, D. M., & Simonson, D. C. (1995) · The American Journal of Medicine · doi:10.1016/s0002-9343(99)80397-0 · Cited by 117 · see citing works
Reversible hyperintensity lesion on diffusion-weighted MRI in hypoglycemic coma
Aoki, T., Sato, T., Hasegawa, K., Ishizaki, R., & Saiki, M. (2004) · Neurology · doi:10.1212/01.wnl.0000130181.05016.68 · Cited by 104 · see citing works
Reversible focal splenial lesions
Gallucci, M., Limbucci, N., Paonessa, A., & Caranci, F. (2007) · Neuroradiology · doi:10.1007/s00234-007-0235-z · Cited by 91 · see citing works
Böttcher, J., Kunze, A., Kurrat, C., Schmidt, P. M., Hagemann, G., Witte, O. W., & Kaiser, W. A. (2005) · Stroke · doi:10.1161/01.str.0000155733.65215.c2 · Cited by 90 · see citing works
Diffusion-weighted MR imaging in early diagnosis and prognosis of hypoglycemia.
Lo, L. S., Tan, A. C. H., Umapathi, T. N., & Lim, C. C. T. (2006) · PubMed Central · Cited by 87 · see citing works
Hypoglycemia and Diffusion-Weighted Imaging
Chan, R., Erbay, S. H., Oljeski, S. A., Thaler, D. E., & Bhadelia, R. A. (2003) · Journal of Computer Assisted Tomography · doi:10.1097/00004728-200305000-00020 · Cited by 57 · see citing works
Neuropsychological correlates of whole brain atrophy in Alzheimer's disease
Schott, J. M., Crutch, S. J., Frost, C. D., Warrington, E. K., Rossor, M. N., & Fox, N. C. (2008) · Neuropsychologia · doi:10.1016/j.neuropsychologia.2008.02.015 · Cited by 56 · see citing works
Bonds, D. E., Kurashige, E. M., Bergenstal, R. M., Brillon, D. J., DOMANSKI, M. J., Felicetta, J. V., Fonseca, V. A., Hall, K., HRAMIAK, I. M., Miller, M. E., et al. (2007) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2007.03.026 · Cited by 51 · see citing works
Self-citationAlbayram, S., Özer, H., Gökdemir, S., Gülşen, F., Kızıltan, G., Koçer, N., & Işlak, C. (2006) · PubMed Central · Cited by 46 · see citing works
Patients with type 1 diabetes exhibit altered cerebral metabolism during hypoglycemia
van de Ven, K. C. C., Tack, C. J., Heerschap, A., van der Graaf, M., & de Galan, B. E. (2013) · Journal of Clinical Investigation · doi:10.1172/jci62742 · Cited by 39 · see citing works
Time related changes in reversible MRI findings after prolonged hypoglycemia
Maekawa, S., Aibiki, M., Kikuchi, K., Kikuchi, S., & Umakoshi, K. (2005) · Clinical Neurology and Neurosurgery · doi:10.1016/j.clineuro.2005.02.004 · Cited by 38 · see citing works
Kim, J. H., Roh, J. H., & Koh, S. (2006) · Cerebrovascular Diseases · doi:10.1159/000094330 · Cited by 30 · see citing works
American Diabetes Association Research Symposium: Diabetes and the Brain
Seaquist, E. R., Lattemann, D. F., & Dixon, R. A. (2012) · Diabetes · doi:10.2337/db12-0489 · Cited by 11 · see citing works
Maruya, J., Endoh, H., Watanabe, H., Motoyama, H., & Abe, H. (2009) · BMJ Case Reports · doi:10.1136/bcr.07.2008.0514 · Cited by 6 · see citing works
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1 of the 43 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Simó, R., Ciudin, A., Simó‐Servat, O., & Hernández, C. (2017) · Acta Diabetologica · doi:10.1007/s00592-017-0970-5 · Cited by 172 · see citing works
Neurofunctional topography of the human hippocampus
Robinson, J. L., Barron, D. S., Kirby, L. A. J., Bottenhorn, K. L., Hill, A. C., Murphy, J. E., Katz, J. S., Salibi, N., Eickhoff, S. B., & Fox, P. T. (2015) · Human Brain Mapping · doi:10.1002/hbm.22987 · Cited by 119 · see citing works
Lee, A. K., Rawlings, A. M., Lee, C. J., Gross, A. L., Huang, E. S., Sharrett, A. R., Coresh, J., & Selvin, E. (2018) · Diabetologia · doi:10.1007/s00125-018-4668-1 · Cited by 115 · see citing works
Yale, J.-F., Paty, B., & Senior, P. A. (2018) · Canadian Journal of Diabetes · doi:10.1016/j.jcjd.2017.10.010 · Cited by 105 · see citing works
Diabetes, Dementia and Hypoglycemia
Meneilly, G. S., & Tessier, D. (2016) · Canadian Journal of Diabetes · doi:10.1016/j.jcjd.2015.09.006 · Cited by 98 · see citing works
Bello‐Chavolla, O. Y., Antonio‐Villa, N. E., Vargas‐Vázquez, A., Ávila‐Funes, J. A., & Aguilar-Salinas, C. A. (2019) · Current Diabetes Reviews · doi:10.2174/1573399815666190129155654 · Cited by 93 · see citing works
Diabetes mellitus and white matter hyperintensity
Tamura, Y., & Araki, A. (2015) · Geriatrics and gerontology international/Geriatrics & gerontology international · doi:10.1111/ggi.12666 · Cited by 83 · see citing works
Glucose Control and Vascular Outcomes in Type 2 Diabetes: Is the Picture Clear?
Giorgino, F., Home, P., & Tuomilehto, J. O. (2016) · Diabetes Care · doi:10.2337/dcs15-3023 · Cited by 54 · see citing works
Avoiding or coping with severe hypoglycemia in patients with type 2 diabetes
Yun, J., & Ko, S. (2015) · The Korean Journal of Internal Medicine · doi:10.3904/kjim.2015.30.1.6 · Cited by 40 · see citing works
Espeland, M. A., Carmichael, O. T., Hayden, K. M., Neiberg, R. H., Newman, A. B., Keller, J. N., Wadden, T. A., Rapp, S. R., Hill, J. O., Horton, E. S., et al. (2017) · The Journals of Gerontology Series A · doi:10.1093/gerona/glx165 · Cited by 38 · see citing works
Ogama, N., Sakurai, T., Kawashima, S., Tanikawa, T., Tokuda, H., Satake, S., Miura, H., Shimizu, A., Kokubo, M., Niida, S., et al. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00273 · Cited by 30 · see citing works
Diabetic aggravation of stroke and animal models
Rehni, A. K., Liu, A., Pérez‐Pinzón, M. A., & Dave, K. R. (2017) · Experimental Neurology · doi:10.1016/j.expneurol.2017.03.004 · Cited by 28 · see citing works
Pandey, S., & Garabadu, D. (2016) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-016-0418-4 · Cited by 22 · see citing works
Hughes, T. M., Sink, K. M., Williamson, J. D., Hugenschmidt, C. E., Wagner, B., Whitlow, C. T., Xu, J., Smith, S. C., Launer, L. J., Barzilay, J. I., et al. (2018) · Journal of Diabetes and its Complications · doi:10.1016/j.jdiacomp.2018.05.017 · Cited by 16 · see citing works
Self-citationMetabolic pathways in the periphery and brain: Contribution to mental disorders?
Nagalski, A., Koziński, K., & Wisniewska, M. B. (2016) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2016.09.012 · Cited by 14 · see citing works
Lega, I. C., Yale, J.-F., Chadha, A., Paty, B., Roscoe, R., Snider, M., Steier, J., Bajaj, H. S., Barnes, T., Gilbert, J., et al. (2023) · Canadian Journal of Diabetes · doi:10.1016/j.jcjd.2023.08.003 · Cited by 12 · see citing works
Alkabbani, W., Maxwell, C. J., Marrie, R. A., Tyas, S. L., Lega, I. C., & Gamble, J. (2022) · International Journal of Epidemiology · doi:10.1093/ije/dyac168 · Cited by 10 · see citing works
Diabetes mellitus and the central nervous system
Surkova, E. V. (2016) · Terapevticheskii arkhiv · doi:10.17116/terarkh201688682-86 · Cited by 6 · see citing works
Putallaz, P., Seematter‐Bagnoud, L., Draganski, B., Rouaud, O., Krief, H., & Büla, C. (2024) · BMC Geriatrics · doi:10.1186/s12877-024-05025-x · Cited by 2 · see citing works
Tata Laksana Hipoglikemia pada Pasien Diabetes
Pramudya, R., & Amiralevi, S. H. (2025) · Cermin Dunia Kedokteran · doi:10.55175/cdk.v52i1.1254
Untitled work
Diabetes Canada Clinical Practice Guidelines Expert Committee (n.d.) · Diabetes Canada
- Authors
- Zhang, Z., Lovato, J., Battapady, H., Davatzikos, C., Gerstein, H. C., Ismail-Beigi, F., Launer, L. J., Murray, A., Punthakee, Z., Tirado, A. A., Williamson, J., Bryan, R. N., & Miller, M. E.
- Affiliations
- University of Pennsylvania (US)
- Wake Forest University (US)
- McMaster University (CA)
- Case Western Reserve University, Cleveland, OH
- National Institutes of Health (US)
- Hennepin County Medical Center (US)
- Columbia University (US)
- Corresponding author
- Bryan, R. Nick
- ORCID
- Venue
- Diabetes Care
- Publisher
- American Diabetes Association
- Published
- 2014-11-08
- Volume
- 37
- Issue
- 12
- Pages
- 3279-3285
- ISSN
- 0149-5992 (ISSN-L)
- 1935-5548
- PMC
- PMC4237972
- OpenAlex
- W2078416668
- Cited by
- 20
- References
- 43
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 1 · 2022: 1 · 2019: 1 · 2018: 4 · 2017: 3 · 2016: 5 · 2015: 3
- FWCI
- 2.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes Care (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (n01hc95183-23-0-0, n01hc95180-24-0-1, n01hc95184-24-0-1, n01hc95181-23-0-1, n01hc95182-23-0-1, n01hc95178-28-0-1, n01hc95179-25-0-0)
- National Institute on Aging (AG-0002)
- National Heart, Lung, and Blood Institute (N01- HC-95181, N01 HC095184, N01-HC- 95180, N01-HC-95178, N01 HC095182, N01 HC095181, N01-HC-095183, N01 HC095178, N01-HC-95184, N01HC95179, N01 HC095180, N01‐HC‐95183, N01-HC-95182, N01 HC095179)
- National Institute of Biomedical Imaging and Bioengineering (R01EB009234)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Neurological and metabolic disorders
- Keywords
- hypoglycemia, type 2 diabetes, brain atrophy, white matter abnormalities, total brain volume, brain MRI, diabetes treatment
- MeSH terms
- Adult, Aged, Atrophy, Blood Glucose, Brain, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Female, Humans, Hypoglycemia, Hypoglycemic Agents, Magnetic Resonance Imaging, Male, Memory, Middle Aged, Risk Factors
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