The Correlation between Diabetes Mellitus and Neurodegenerative Diseases

Abstract

Today there is no longer any doubt that diabetes mellitus is associated with cognitive impairment and neurodegenerative diseases. The two most common forms of diabetes mellitus are type 1 and type 2. Type 1 diabetes mellitus is characterized by an absolute insulin deficiency that is associated with a large number of metabolic changes. This type of diabetes requires insulin therapy. Without insulin, this disease is fatal. The far more common form of diabetes mellitus nowadays is type 2 diabetes mellitus. It is characterized by insulin resistance. For a number of years drugs have been available that can be used to treat this form of diabetes in a multimodal manner. These therapy options can not only improve metabolic control, but also prevent cardiovascular events. Different cognitive alterations associated with diabetes mellitus can be distinguished. On the one hand, the change in glucose homeostasis itself leads to cognitive alterations, i.e. blood sugar levels that are too high or acutely too low are regularly associated with significant impairments in mental performance, including loss of consciousness. But not only the momentary blood sugar levels, but also long-term changes in glucose metabolism might lead to neurodegeneration and even dementia in a way that has not yet been fully understood. Insulin or insulin-like molecules have important effects in the central nervous system. In the last decades, it has been shown that insulin receptors themselves are expressed in many regions of the brain and e.g. regulate food intake and memory formation in humans and in animal models. In the animal model, disturbances in insulin signal transduction influence the development of pathologies typical of Alzheimerʼs disease (AD). In humans, central insulin resistance is at least part of the formal pathogenesis of AD. Vascular changes (macroangiopathy) in patients with diabetes mellitus often lead to cerebral insults, microangiopathies and vascular dementia.

Key words

Diabetes mellitus - neurodegeneration - insulin

Publication History

Received: 01 December 2022

Accepted: 21 December 2022

Accepted Manuscript online:
10 January 2023

Article published online:
22 February 2023

• References/Literatur

• 1 Ott A, Stolk RP, van Harskamp F. et al. Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology 1999; 53: 1937-1942
• 2 Kopf D, Frölich L. Risk of incident Alzheimerʼs disease in diabetic patients: a systematic review of prospective trials. J Alzheimers Dis 2009; 16: 677-685
• 3 Cheng G, Huang C, Deng H. et al. Diabetes as a risk factor for dementia and mild cognitive impairment: a meta-analysis of longitudinal studies. Intern Med J 2012; 42: 484-491
• 4 Chatterjee S, Peters SAE, Woodward M. et al. Type 2 diabetes as a risk factor for dementia in women compared with men: a pooled analysis of 2.3 million people comprising more than 100,000 cases of dementia. Diabetes Care 2016; 39: 300-307
• 5 Zhang J, Chen C, Hua S. et al. An updated meta-analysis of cohort studies: Diabetes and risk of Alzheimerʼs disease. Diabetes Res Clin Pract 2017; 124: 41-47
• 6 Burillo J, Marqués P, Jiménez B. et al. Insulin Resistance and Diabetes Mellitus in Alzheimerʼs Disease. Cells 2021; 10: 1236
• 7 Ramirez A, Wolfsgruber S, Lange C. et al. Elevated HbA1c is associated with increased risk of incident dementia in primary care patients. J Alzheimers Dis 2015; 44: 1203-1212
• 8 Crane PK, Walker R, Hubbard RA. et al. Glucose levels and risk of dementia. N Engl J Med 2013; 369: 540-548
• 9 Kopf D. Diabetes mellitus and dementia. Internist (Berl) 2015; 56: 520-526
• 10 Kleinridders A, Ferris HA, Cai W. et al. Insulin action in brain regulates systemic metabolism and brain function. Diabetes 2014; 63: 2232-2243
• 11 Plum L, Schubert M, Brüning JC. The role of insulin receptor signaling in the brain. Trends Endocrinol Metab 2005; 16: 59-65
• 12 Kullmann S, Kleinridders A, Small DM. et al. Central nervous pathways of insulin action in the control of metabolism and food intake. Lancet Diabetes Endocrinol 2020; 8: 524-534
• 13 Whitmer RA, Gilsanz P, Quesenberry CP. et al. Association of Type 1 Diabetes and Hypoglycemic and Hyperglycemic Events and Risk of Dementia. Neurology 2021; 97: e275-e283
• 14 International Hypoglycaemia Study Group. Hypoglycaemia, cardiovascular disease, and mortality in diabetes: epidemiology, pathogenesis, and management. Lancet Diabetes Endocrinol 2019; 7: 385-396
• 15 Yaffe K, Falvey CM, Hamilton N. et al. Association between hypoglycemia and dementia in a biracial cohort of older adults with diabetes mellitus. JAMA Intern Med 2013; 173: 1300-1306
• 16 Whitmer RA, Karter AJ, Yaffe K. et al. Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus. JAMA 2009; 301: 1565-1572
• 17 McEwen BS, Reagan LP. Glucose transporter expression in the central nervous system: relationship to synaptic function. Eur J Pharmacol 2004; 490: 13-24
• 18 Mergenthaler P, Lindauer U, Daniel GA. et al. Sugar for the brain: the role of glucose in physiological and pathological brain function. Trends Neurosci 2013; 36: 587-597
• 19 Pomytkin I, Costa-Nunes JP, Kasatkin V. et al. Insulin receptor in the brain: Mechanisms of activation and the role in the CNS pathology and treatment. CNS Neurosci Ther 2018; 24: 763-774
• 20 White MF, Kahn CR. Insulin action at a molecular level – 100 years of progress. Mol Metab 2021; 52: 101304
• 21 Stöhr O, Hahn J, Moll L. et al. Insulin receptor substrate-1 and -2 mediate resistance to glucose-induced caspase-3 activation in human neuroblastoma cells. Biochim Biophys Acta 2011; 1812: 573-580
• 22 Schubert M, Brazil DP, Burks DJ. et al. Insulin receptor substrate-2 deficiency impairs brain growth and promotes tau phosphorylation. J Neurosci 2003; 23: 7084-7092
• 23 Brüning JC, Gautam D, Burks DJ. et al. Role of brain insulin receptor in control of body weight and reproduction. Science 2000; 289: 2122-2125
• 24 Schubert M, Gautam D, Surjo D. et al. Role for neuronal insulin resistance in neurodegenerative diseases. Proc Natl Acad Sci U S A 2004; 101: 3100-3105
• 25 Benedict C, Hallschmid M, Hatke A. et al. Intranasal insulin improves memory in humans. Psychoneuroendocrinology 2004; 29: 1326-1334
• 26 Biessels GJ, Kappelle LJ. Utrecht Diabetic Encephalopathy Study Group: Increased risk of Alzheimerʼs disease in Type II diabetes: insulin resistance of the brain or insulin-induced amyloid pathology?. Biochem Soc Trans 2005; 33: 1041-1044
• 27 Ibanez L, Cruchaga C, Fernández MV. Advances in Genetic and Molecular Understanding of Alzheimerʼs Disease. Genes (Basel) 2021; 12: 1247
• 28 Freude S, Plum L, Schnitker J. et al. Peripheral hyperinsulinemia promotes tau phosphorylation in vivo. Diabetes 2005; 54: 3343-3348
• 29 Schubert M, Brazil DP, Burks DJ. et al. Insulin receptor substrate-2 deficiency impairs brain growth and promotes tau phosphorylation. J Neurosci 2003; 23: 7084-7092
• 30 Talbot K, Wang HY, Kazi H. et al. Demonstrated brain insulin resistance in Alzheimerʼs disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest 2012; 122: 1316-1338
• 31 Liu Y, Liu F, Grundke-Iqbal I. et al. Deficient brain insulin signalling pathway in Alzheimerʼs disease and diabetes. J Pathol 2011; 225: 54-62
• 32 Frölich L, Blum-Degen D, Bernstein HG. et al. Brain insulin and insulin receptors in aging and sporadic Alzheimerʼs disease. J Neural Transm (Vienna) 1998; 105: 423-438
• 33 Hoyer S. The brain insulin signal transduction system and sporadic (type II) Alzheimer disease: an update. J Neural Transm (Vienna) 2002; 109: 341-360
• 34 Ahmed S, Mahmood Z, Zahid S. Linking insulin with Alzheimerʼs disease: emergence as type III diabetes. Neurol Sci 2015; 36: 1763-1769
• 35 Son SM, Song H, Byun J. et al. Accumulation of autophagosomes contributes to enhanced amyloidogenic APP processing under insulin-resistant conditions. Autophagy 2012; 8: 1842-1844
• 36 Craft S, Raman R, Chow TW. et al. Safety, Efficacy, and Feasibility of Intranasal Insulin for the Treatment of Mild Cognitive Impairment and Alzheimer Disease Dementia: A Randomized Clinical Trial. JAMA Neurol 2020; 77: 1099-1109
• 37 Kuan YC, Huang KW, Lin CL. et al. Effects of metformin exposure on neurodegenerative diseases in elderly patients with type 2 diabetes mellitus. Prog Neuropsychopharmacol Biol Psychiatry 2017; 79: 77-83
• 38 Areosa Sastre A, Vernooij RW, González-Colaço Harmand M. et al. Effect of the treatment of Type 2 diabetes mellitus on the development of cognitive impairment and dementia. Cochrane Database Syst Rev 2017; (06) CD003804
• 39 Koenig AM, Mechanic-Hamilton D, Xie SX. et al. Effects of the insulin sensitizer Metformin in Alzheimer disease: pilot data from a randomized placebo-controlled crossover study. Alzheimer Dis Assoc Disord 2017; 31: 107-113