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Vol. 30, No. 3, 2008
Issue release date: May 2008
Free Access
Neuroepidemiology 2008;30:174–179
(DOI:10.1159/000126909)

Fasting Insulin Levels and Cognitive Decline in Older Women without Diabetes

van Oijen M.a · Okereke O.I.b, c · Kang J.H.c · Pollak M.N.f · Hu F.B.c, e · Hankinson S.E.c, d · Grodstein F.b-d
aDepartments of Epidemiology/Biostatistics and Neurology, Erasmus Medical Center, Rotterdam, The Netherlands; bDivision of Aging and cChanning Laboratory, Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, dDepartments of Epidemiology and eNutrition, Harvard School of Public Health, Boston, Mass., USA; fDepartments of Medicine and Oncology, Lady Davis Research Institute of the Jewish General Hospital and McGill University, Montreal, Que., Canada
email Corresponding Author

Abstract

Background: Type 2 diabetes has been associated with an increased risk of dementia. To assess possible independent effects of insulin, we investigated the relation of insulin levels to cognitive decline in nondiabetic women. Methods: Fasting plasma insulin levels were measured in mid-life in 1,416 nondiabetic Nurses’ Health Study participants, who also completed cognitive testing that began 10 years later (current age: 70–75 years). Over 4 years, 3 assessments of general cognition, verbal memory, category fluency and attention were administered. Primary outcomes were the Telephone Interview for Cognitive Status (TICS) performance, the global score (average of all tests) and verbal memory (average of verbal recall tests). Linear mixed-effects models were used to calculate the association between insulin and cognitive decline. Results: Higher insulin levels were associated with a faster decline on the TICS and verbal memory. For analysis, batch-specific quartiles of insulin levels were constructed. Compared to the lowest quartile, adjusted differences in the annual rates of decline (with 95% CI values in parentheses) for the second, third and fourth quartiles were: TICS, –0.06 (–0.16, 0.03), –0.14 (–0.24, –0.04), and –0.09 (–0.19, 0.01) points (p trend = 0.04); verbal memory, –0.01 (–0.04, 0.02), –0.05 (–0.08, –0.02), and –0.02 (–0.05, 0.01) units (p trend = 0.02). These associations remained after multivariable adjustment. Conclusions: Our study provides evidence for a potential role of higher fasting insulin levels in cognitive decline, possibly independent of diabetes.


 goto top of outline Key Words

  • Diabetes
  • Insulin, cognitive performance
  • Aging, cognitive decline
  • Dementia

 goto top of outline Abstract

Background: Type 2 diabetes has been associated with an increased risk of dementia. To assess possible independent effects of insulin, we investigated the relation of insulin levels to cognitive decline in nondiabetic women. Methods: Fasting plasma insulin levels were measured in mid-life in 1,416 nondiabetic Nurses’ Health Study participants, who also completed cognitive testing that began 10 years later (current age: 70–75 years). Over 4 years, 3 assessments of general cognition, verbal memory, category fluency and attention were administered. Primary outcomes were the Telephone Interview for Cognitive Status (TICS) performance, the global score (average of all tests) and verbal memory (average of verbal recall tests). Linear mixed-effects models were used to calculate the association between insulin and cognitive decline. Results: Higher insulin levels were associated with a faster decline on the TICS and verbal memory. For analysis, batch-specific quartiles of insulin levels were constructed. Compared to the lowest quartile, adjusted differences in the annual rates of decline (with 95% CI values in parentheses) for the second, third and fourth quartiles were: TICS, –0.06 (–0.16, 0.03), –0.14 (–0.24, –0.04), and –0.09 (–0.19, 0.01) points (p trend = 0.04); verbal memory, –0.01 (–0.04, 0.02), –0.05 (–0.08, –0.02), and –0.02 (–0.05, 0.01) units (p trend = 0.02). These associations remained after multivariable adjustment. Conclusions: Our study provides evidence for a potential role of higher fasting insulin levels in cognitive decline, possibly independent of diabetes.

Copyright © 2008 S. Karger AG, Basel


 goto top of outline References
  1. Ott A, Stolk RP, van Harskamp F, Pols HA, Hofman A, Breteler MM: Diabetes mellitus and the risk of dementia. The Rotterdam Study. Neurology 1999;53:1937–1942.
  2. Coker LH, Shumaker SA: Type 2 diabetes mellitus and cognition: an understudied issue in women’s health. J Psychosom Res 2003;54:129–139.
  3. Gregg EW, Yaffe K, Cauley JA, Rolka DB, Blackwell TL, Narayan KM, Cummings SR: Is diabetes associated with cognitive impairment and cognitive decline among older women? Study of Osteoporotic Fractures Research Group. Arch Intern Med 2000;160:174–180.
  4. Biessels GJ, Staekenborg S, Brunner E, Brayne C, Scheltens P: Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol 2006;5:64–74.
  5. Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, Frosch MP, Eckman CB, Tanzi RE, Selkoe DJ, Guenette S: Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci USA 2003;100:4162–4167.
  6. Luchsinger JA, Tang MX, Shea S, Mayeux R: Hyperinsulinemia and risk of Alzheimer disease. Neurology 2004;63:1187–1192.
  7. Peila R, Rodriguez BL, White LR, Launer LJ: Fasting insulin and incident dementia in an elderly population of Japanese-American men. Neurology 2004;63:228–233.
  8. Okereke O, Hankinson SE, Hu FB, Grodstein F: Plasma C peptide level and cognitive function among older women without diabetes mellitus. Arch Intern Med 2005;165:1651–1656.
  9. Brandt J, Spencer M, Folstein MF: The telephone interview for cognitive status. Neuropsychiatry Neuropsychol Behav Neurol 1988;1:111–117.
  10. Folstein MF, Folstein SE, McHugh PR: ‘Mini-mental state’: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–198.
  11. Albert M, Smith LA, Scherr PA, Taylor JO, Evans DA, Funkenstein HH: Use of brief cognitive tests to identify individuals in the community with clinically diagnosed Alzheimer’s disease. Int J Neurosci 1991;57:167–178.
  12. Chen P, Ratcliff G, Belle SH, Cauley JA, DeKosky ST, Ganguli M: Patterns of cognitive decline in presymptomatic Alzheimer disease: a prospective community study. Arch Gen Psychiatry 2001;58:853–858.
  13. Small BJ, Fratiglioni L, Viitanen M, Winblad B, Backman L: The course of cognitive impairment in preclinical Alzheimer disease: three- and 6-year follow-up of a population-based sample. Arch Neurol 2000;57:839–844.
  14. Laird NM, Ware JH: Random-effects models for longitudinal data. Biometrics 1982;38:963–974.
  15. Kalmijn S, Feskens EJ, Launer LJ, Stijnen T, Kromhout D: Glucose intolerance, hyperinsulinaemia and cognitive function in a general population of elderly men. Diabetologia 1995;38:1096–1102.
  16. Yaffe K, Blackwell T, Kanaya AM, Davidowitz N, Barrett-Connor E, Krueger K: Diabetes, impaired fasting glucose, and development of cognitive impairment in older women. Neurology 2004;63:658–663.
  17. Yaffe K, Blackwell T, Whitmer RA, Krueger K, Barrett Connor E: Glycosylated hemoglobin level and development of mild cognitive impairment or dementia in older women. J Nutr Health Aging 2006;10:293–295.
  18. Okereke O, Kang JH, Gaziano JM, Ma J, Stampfer MJ, Grodstein F: Plasma C-peptide and cognitive performance in older men without diabetes. Am J Geriatr Psychiatry 2006;14:1041–1050.
  19. Biessels GJ, Kappelle LJ: Increased risk of Alzheimer’s disease in type II diabetes: insulin resistance of the brain or insulin-induced amyloid pathology? Biochem Soc Trans 2005;33:1041–1044.
  20. Banks WA: The source of cerebral insulin. Eur J Pharmacol 2004;490:5–12.
  21. Park CR: Cognitive effects of insulin in the central nervous system. Neurosci Biobehav Rev 2001;25:311–323.
  22. Song Y, Manson JE, Tinker L, Howard BV, Kuller LH, Nathan L, Rifai N, Liu S: Insulin sensitivity and insulin secretion determined by homeostasis model assessment and risk of diabetes in a multiethnic cohort of women: the Women’s Health Initiative Observational Study. Diabetes Care 2007;30:1747–1752.
  23. Lawlor DA, Fraser A, Ebrahim S, Smith GD: Independent associations of fasting insulin, glucose, and glycated haemoglobin with stroke and coronary heart disease in older women. PLoS Med 2007;4:e263.

 goto top of outline Author Contacts

Dr. Francine Grodstein
Channing Laboratory, Department of Medicine
Brigham and Women’s Hospital, Harvard Medical School, 181 Longwood Avenue
Boston, MA 02115 (USA)
Tel. +1 617 525 2279, Fax +1 617 525 2008, E-Mail fgrodstein@partners.org


 goto top of outline Article Information

Received: October 15, 2007
Accepted: January 23, 2008
Published online: April 17, 2008
Number of Print Pages : 6
Number of Figures : 0, Number of Tables : 3, Number of References : 23


 goto top of outline Publication Details

Neuroepidemiology

Vol. 30, No. 3, Year 2008 (Cover Date: May 2008)

Journal Editor: Feigin V.L. (Auckland)
ISSN: 0251–5350 (Print), eISSN: 1423–0208 (Online)

For additional information: http://www.karger.com/NED


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Background: Type 2 diabetes has been associated with an increased risk of dementia. To assess possible independent effects of insulin, we investigated the relation of insulin levels to cognitive decline in nondiabetic women. Methods: Fasting plasma insulin levels were measured in mid-life in 1,416 nondiabetic Nurses’ Health Study participants, who also completed cognitive testing that began 10 years later (current age: 70–75 years). Over 4 years, 3 assessments of general cognition, verbal memory, category fluency and attention were administered. Primary outcomes were the Telephone Interview for Cognitive Status (TICS) performance, the global score (average of all tests) and verbal memory (average of verbal recall tests). Linear mixed-effects models were used to calculate the association between insulin and cognitive decline. Results: Higher insulin levels were associated with a faster decline on the TICS and verbal memory. For analysis, batch-specific quartiles of insulin levels were constructed. Compared to the lowest quartile, adjusted differences in the annual rates of decline (with 95% CI values in parentheses) for the second, third and fourth quartiles were: TICS, –0.06 (–0.16, 0.03), –0.14 (–0.24, –0.04), and –0.09 (–0.19, 0.01) points (p trend = 0.04); verbal memory, –0.01 (–0.04, 0.02), –0.05 (–0.08, –0.02), and –0.02 (–0.05, 0.01) units (p trend = 0.02). These associations remained after multivariable adjustment. Conclusions: Our study provides evidence for a potential role of higher fasting insulin levels in cognitive decline, possibly independent of diabetes.



 goto top of outline Author Contacts

Dr. Francine Grodstein
Channing Laboratory, Department of Medicine
Brigham and Women’s Hospital, Harvard Medical School, 181 Longwood Avenue
Boston, MA 02115 (USA)
Tel. +1 617 525 2279, Fax +1 617 525 2008, E-Mail fgrodstein@partners.org


 goto top of outline Article Information

Received: October 15, 2007
Accepted: January 23, 2008
Published online: April 17, 2008
Number of Print Pages : 6
Number of Figures : 0, Number of Tables : 3, Number of References : 23


 goto top of outline Publication Details

Neuroepidemiology

Vol. 30, No. 3, Year 2008 (Cover Date: May 2008)

Journal Editor: Feigin V.L. (Auckland)
ISSN: 0251–5350 (Print), eISSN: 1423–0208 (Online)

For additional information: http://www.karger.com/NED


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Ott A, Stolk RP, van Harskamp F, Pols HA, Hofman A, Breteler MM: Diabetes mellitus and the risk of dementia. The Rotterdam Study. Neurology 1999;53:1937–1942.
  2. Coker LH, Shumaker SA: Type 2 diabetes mellitus and cognition: an understudied issue in women’s health. J Psychosom Res 2003;54:129–139.
  3. Gregg EW, Yaffe K, Cauley JA, Rolka DB, Blackwell TL, Narayan KM, Cummings SR: Is diabetes associated with cognitive impairment and cognitive decline among older women? Study of Osteoporotic Fractures Research Group. Arch Intern Med 2000;160:174–180.
  4. Biessels GJ, Staekenborg S, Brunner E, Brayne C, Scheltens P: Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol 2006;5:64–74.
  5. Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, Frosch MP, Eckman CB, Tanzi RE, Selkoe DJ, Guenette S: Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci USA 2003;100:4162–4167.
  6. Luchsinger JA, Tang MX, Shea S, Mayeux R: Hyperinsulinemia and risk of Alzheimer disease. Neurology 2004;63:1187–1192.
  7. Peila R, Rodriguez BL, White LR, Launer LJ: Fasting insulin and incident dementia in an elderly population of Japanese-American men. Neurology 2004;63:228–233.
  8. Okereke O, Hankinson SE, Hu FB, Grodstein F: Plasma C peptide level and cognitive function among older women without diabetes mellitus. Arch Intern Med 2005;165:1651–1656.
  9. Brandt J, Spencer M, Folstein MF: The telephone interview for cognitive status. Neuropsychiatry Neuropsychol Behav Neurol 1988;1:111–117.
  10. Folstein MF, Folstein SE, McHugh PR: ‘Mini-mental state’: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–198.
  11. Albert M, Smith LA, Scherr PA, Taylor JO, Evans DA, Funkenstein HH: Use of brief cognitive tests to identify individuals in the community with clinically diagnosed Alzheimer’s disease. Int J Neurosci 1991;57:167–178.
  12. Chen P, Ratcliff G, Belle SH, Cauley JA, DeKosky ST, Ganguli M: Patterns of cognitive decline in presymptomatic Alzheimer disease: a prospective community study. Arch Gen Psychiatry 2001;58:853–858.
  13. Small BJ, Fratiglioni L, Viitanen M, Winblad B, Backman L: The course of cognitive impairment in preclinical Alzheimer disease: three- and 6-year follow-up of a population-based sample. Arch Neurol 2000;57:839–844.
  14. Laird NM, Ware JH: Random-effects models for longitudinal data. Biometrics 1982;38:963–974.
  15. Kalmijn S, Feskens EJ, Launer LJ, Stijnen T, Kromhout D: Glucose intolerance, hyperinsulinaemia and cognitive function in a general population of elderly men. Diabetologia 1995;38:1096–1102.
  16. Yaffe K, Blackwell T, Kanaya AM, Davidowitz N, Barrett-Connor E, Krueger K: Diabetes, impaired fasting glucose, and development of cognitive impairment in older women. Neurology 2004;63:658–663.
  17. Yaffe K, Blackwell T, Whitmer RA, Krueger K, Barrett Connor E: Glycosylated hemoglobin level and development of mild cognitive impairment or dementia in older women. J Nutr Health Aging 2006;10:293–295.
  18. Okereke O, Kang JH, Gaziano JM, Ma J, Stampfer MJ, Grodstein F: Plasma C-peptide and cognitive performance in older men without diabetes. Am J Geriatr Psychiatry 2006;14:1041–1050.
  19. Biessels GJ, Kappelle LJ: Increased risk of Alzheimer’s disease in type II diabetes: insulin resistance of the brain or insulin-induced amyloid pathology? Biochem Soc Trans 2005;33:1041–1044.
  20. Banks WA: The source of cerebral insulin. Eur J Pharmacol 2004;490:5–12.
  21. Park CR: Cognitive effects of insulin in the central nervous system. Neurosci Biobehav Rev 2001;25:311–323.
  22. Song Y, Manson JE, Tinker L, Howard BV, Kuller LH, Nathan L, Rifai N, Liu S: Insulin sensitivity and insulin secretion determined by homeostasis model assessment and risk of diabetes in a multiethnic cohort of women: the Women’s Health Initiative Observational Study. Diabetes Care 2007;30:1747–1752.
  23. Lawlor DA, Fraser A, Ebrahim S, Smith GD: Independent associations of fasting insulin, glucose, and glycated haemoglobin with stroke and coronary heart disease in older women. PLoS Med 2007;4:e263.