Dementia Risk in Type 2 Diabetes

1. Dementia Risk in Type 2 Diabetes Lisa Victorine DTC 601 Research Writing

2. Objectives • Identify the correlation between Type 2 diabetes (T2DM) and dementia • Examine the relationship between insulin and beta-amyloid plaque in the brain • Evaluate glucose uptake in the brain • Determine associations between dietary intake and cognitive function • Compare obesity, metabolic syndrome, and dementia

3. Dementia • Is a symptom of a degenerative brain disorder due to: • vascular occlusions • β-amyloid plaque • Identified as progressive deterioration of memory, language, problem solving, and concentration • Affects 5 million Americans, over the age of 701 • May take 15-25 years to manifest as cognitive decline • http://www.nia.nih.gov/alzheimers/topics/causes

4. Type 2 Diabetes • A chronic condition that affects glucose metabolism due to: • Insufficient insulin production in pancreas • Insulin resistance • Risk Factors • *Overweight / Obese *Abdominal Fat Stores • *Inactivity *Family History • *Age *Metabolic Syndrome • http://www.mayoclinic.com/health/diabetes-and-alzheimers/AZ00050

5. Dementia and Type 2 Diabetes Nearly one in five Americans over age 60 develops Type 2 Diabetes1

6. Dementia and Type 2 Diabetes While, one in eight Americans experience dementia due to Alzheimer’s disease1

7. Background Vascular Dementia • Occurs with: • Inadequate blood flow to the brain due to • Stroke • Damaged or impaired neural blood vessels • Causes changes in: • Cognitive function, memory loss, and confusion • Is the second most common cause of dementia • after Alzheimer’s disease

8. Background β-amyloid Dementia • Starting point… • Amyloid Precursor Protein (APP) • a large transmembrane protein in brain tissue • regulates synapses and neuron plasticity • Enzymes cleave APP into unstable β-amyloid fragments • Released outside of cell membrane for macrophage destruction • Alzheimer’s patients accumulate excess β-amyloid • forms plaque build-up between neurons

9. Problem Identified • It is unclear which component of T2DM directly increases risk for dementia. • To identify the correlation, the relationship between: • altered levels of brain insulin-degrading enzyme • insulin resistance • clearance of beta-amyloid proteins • dietary factors • Will be examined…

10. Insulin and Glucose Uptake in the brain • Interference with glycolytic activity in the brain affects: • *neurotransmitter activity • *cognitive learning • *plasticity • *cerebral blood vessel function

11. Insulin and Glucose Uptakein the brain • Cerebral vascular impairment due to T2DM complications (atherosclerosis and stroke) may • cause dementia2 • Deprives oxygen and nutrition support to neurons • Hyperglycemia accelerates advanced glycation end (AGE) products Oxidative stress

12. Insulin and Glucose Uptake in the brain • The Blood Brain Barrier • Protects the integrity of nutrient transport • Protein Receptors for Advanced Glycation End Products (RAGE) are located in the BBB. • RAGE also imports peripheral • β-amyloid protein into brain • T2DM patients have more RAGE increasingβ-amyloid plaque2 RAGE BBB RAGE Brain

13. Insulin and β-amyloid Both insulin and β-amyloid are substrates of insulin-degrading enzyme (IDE) I β-a β-a I IDE I β-a • Insulin binds with a higher affinity to IDE compared to β-amyloid • Excess release of insulin creates IDE saturation leaving • β-amyloid fragments to aggregate and cause plaque4

14. Type 3 Diabetes and Dementia • Type 3 diabetes – a hybrid term for diabetes mellitus in the brain, caused by: • Cerebral hyperglycemia • Low cerebral insulin • Presence of T2DM • Insulin is not solely produced in the pancreas. It is also produced within neurons3 • Deficient levels of neuron-synthesized insulin, insulin-like growth factor, and pancreatic insulin β-amyloid plaque and tangles. • (Hallmarks of Alzheimer’s disease)

15. Diabetics vs. Non-Diabetics University of Seattle Study Dr. Paul Crane and associates5 • 2067 subjects 65 ± with no signs of cognitive decline • (232 had T2DM at onset of study) • After seven years: • Dementia developed in 524 subjects • 74 with T2DM, 405 without T2DM • Probable cause: Alzheimer’s disease in 403 subjects • Vascular impairment in 55 subjects • Other causes in 66 subjects • Every incremental increase of blood glucose was associated with increased risk for dementia

16. Diabetics vs. Non-Diabetics Elderly Mexican Americans with a High Burden of T2DM6 • 677 T2DM subject s/ 940 subjects without diabetes • After 10 years: • T2DM subjects had a two-fold increased risk for dementia: • *typically born in the United States • *prior history of cardiovascular and renal disease • Subjects without diabetes and low risk for dementia: • * immigrants • * small waist circumference • *reduced hypertension • *low blood glucose

17. Dietary Intake and Cognitive Function • 4 year cross-sectional study examined dietary intake of 1,219 healthy elderly subjects • 10 nutrients were tracked: • saturated fatty acids • monounsaturated fatty acids • omega-3 and -6 • beta carotene • vitamins C, D, E, B-12, and folate • Findings revealed: Subjects eating omega-3 had β-amyloid 42 • and a 20-30% decreased risk for dementia7

18. Dietary Intake and Cognitive Function Eating a long-term Mediterranean diet Patients consuming increased vegetables and a high ratio of monounsaturated to saturated fatty acids have a moderateincrease in verbal memory recall and cognitive function later in life9,10

19. Dietary Intake and Cognitive Function • Vitamin D3, Omega-3, and Dementia • Macrophages that destroy β-amyloid fragments • in the brain were drawn from Alzheimer’s patients • and control group • After 12 hr. incubation • Group 1 received active vitamin D3 • Group 2 received omega-3 (resolvin D1) • Both groups increased macrophage efficiency on β-amyloid proteins

20. Obesity, Metabolic Syndrome, and Dementia Metabolic Syndrome: Risk factor for dementia characterized by obesity, hyperglycemia, and insulin resistance Obese Abdominal Tissue Lipolysis: Releases elevated levels of free fatty acids, which inhibit insulin’s ability to stimulate glucose uptake in the brain12

21. Obesity, Metabolic Syndrome, and Dementia • Westernized diets with added sweeteners increase risk for obesity and metabolic syndrome.13 • Fructose: • leptin levels • plasma triglycerides =  risk for metabolic syndrome • and obesity • uric acid = associated with vascular impairment • and dementia

22. Conclusion • Incidence of T2DM and dementia are closely correlated • The exact relationship is not clear • Evidence suggests associations between: • -Elevated blood glucose • -Insulin resistance • -β-amyloid breakdown and clearance • and neurodegenerative disease

23. Conclusion • Improved dietary measures may: • -Reduce obesity • -Reduce metabolic syndrome • -Lower blood glucose • -Improve insulin sensitivity • -Decrease vascular impairment • More clinical trials are necessary to define • relationship between T2DM and dementia

24. REFERENCES 1. U.S. Department of Health and Human Services [Internet]. Bethesda: National Institute on Aging; c2013 [cited 2013 Oct 1]. Available at: http://www.nia.nih.gov/alzheimers/topics/causes. 2. Arab L, Sadeghi R, Walker DG, Lue LF, Sabbagh MN. Consequences of aberrant insulin regulation in the brain: Can treating diabetes be effective for Alzheimer’s disease? Curr Neuropharmacol. 2011 December; 9(4): 693-705. 3. De la Monte SM, Wands JR. Alzheimer’s disease is type 3 diabetes-evidence reviewed. J Diabetes Sci Technol. 2008 November; 2(6); 1101-13. Liu Z, Zhu H, Fang GG, et al. Characterization of insulin degrading enzyme and other amyloid-ß degrading proteases in human serum: A role in Alzheimer’s disease? J Alzheimers Dis. 2012; 29(2): 329-40.

25. 5. Crane PK, Walker R, Walker R, et al. Glucose levels and risk of dementia. N Engl J Med. 2013 Aug; 369(6): 540-548. 6. MayedaER, Haan, MN, Kanaya, AM, Yaffe, K, Neuhaus J. Type 2 diabetes and 10-year risk of dementia and cognitive impairment among older Mexican Americans Diabetes Care. 2013 March; 36(9): 2600-6. 7. Gu Y, Schupf N, Consentino SA, Luchsinger JA, Scarmeas N. Nutrient intake and plasma beta-amyloid. JAMA Neurol. 2013 September; 78(23): 1832-40. 8. Cheng D, Nobel J, Tang MX, Schupf N, Mayeux R, Luchsinger JA. Type 2 diabetes and late-onset Alzheimer’s disease. Dement Geriatr Cogn Disord. 2011; 31(6): 424-30.

26. 9. SamieriC, Okereke OI, E Devore E, Grodstein F. Long-term adherence to the Mediterranean diet is associated with overall cognitive status, but not cognitive decline, in women. J Nutr. 2013 Apr; 143(4): 493-9. 10. Tsivgoulis G, Judd S, Letter AJ, et al. Adherence to a Mediterranean diet and risk of incident cognitive impairment. Neurology. 2013 Apr; 80(18): 1684-92. 11. Mizwicki MT, Liu G, Fiala M, et al. 1alpha, 25-dihydroxyvitamin D3 and resolvin D1 retune the balance between amyloid-beta phagocytosis and inflammation in Alzheimer’s disease patients. J Alzheimers Dis. 2013 Jan; 34(1): 155-70. 12. AccardiG, Caruso C, Colonna-Romano G, Camarda C, Monastero R, Candore G. Can Alzheimer disease be a form of type 3 diabetes? Rejuvenation Res. 2012 Apr; 15(2): 217-21. 13. Lakhan SH, Kirchgessner A. The emerging role of dietary fructose in obesity and cognitive decline. Nutr J. 2013 Aug;12(114): 1475-2891.