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Type 3 diabetes
Type 3 diabetes
	Diagram showing late stages of Alzheimer's disease in the brain caused by type 3 diabetes
Specialty	Neurology
Symptoms	Memory loss, linguistic problems, mood and behavioural swings and motivational loss
Usual onset	From early childhood/adolescence onward
Duration	Long-term
Causes	type 1 diabetes, type 2 diabetes
Risk factors	Genetics and Lifestyle
Diagnostic method	Based on symptoms and cognitive testing after ruling out other possible causes
Prevention	Diet, physical and mental exercise, and psychological well-being
Medication	Melatonin or Glucagon-like Peptide 1 Administration (small benefit)
Frequency	Unknown

Type 3 diabetes is a proposed pathological linkage between Alzheimer's disease and certain features of type 1 and type 2 diabetes.^[1] Specifically, the term refers to a set of common biochemical and metabolic features seen in the brain in Alzheimer's disease, and in other tissues in diabetes;^[1]^[2] it may thus be considered a "brain-specific type of diabetes."^[3] It was recognized at least as early as 2005 that some features of brain function in Alzheimer's disease mimic those that underlie diabetes.^[4] However, the concept of type 3 diabetes is controversial, and as of 2021 it was not a widely or generally recognized diagnosis.^[5]

Metabolic risk factors such as hyperglycaemia, oxidative stress and lipid peroxidation are common processes thought to be contributors to the development of Alzheimer's disease in people with diabetes.^[6] But while insulin resistance is a risk factor for the development of Alzheimer's disease and some other dementias, causes of Alzheimer's disease are likely to be much more complex than being explained by insulin factors on their own, and indeed some patients with Alzheimer's disease have normal insulin metabolism.^[7]

The techniques used to prevent the disease in patients with diabetes are similar to individuals who do not show signs and symptoms of the disease.^[8] The four pillars of Alzheimer's disease prevention^[9] are used as a guide for individuals of who are at risk of developing Alzheimer's disease. As with Alzheimer's disease more broadly, there is no cure for type 3 diabetes, but disease progression may be slowed with certain drugs.^[5]

Signs and symptoms

Alzheimer's disease is associated with a progressive decline in mental faculties. At early stages, forgetfulness, poor judgment, lack of awareness of date or location, and mood disturbances may be evident. This progresses to major difficulties in performing everyday tasks and recognizing familiar people. At later stages, the ability to speak is lost, and control of basic body functions is lost or greatly diminished.^[10]

These symptoms may be exacerbated in individuals with pre-existing type 1 or type 2 diabetes. Individuals with type 1 diabetes are often diagnosed at a young age, usually between childhood and adolescence.^[6] In some cases, brain development in these patients is negatively impacted, resulting in cognitive impairment earlier in life.^[6] In type 2 diabetes, which is usually diagnosed later in life, patients often exhibit cognitive impairment that correlates with the length of time since initial type 2 diabetes onset, and with poor glycemic control.^[6]^[11]

The observation that both types 1 and 2 diabetes can contribute to the development of Alzheimer's disease led to the hypothesis that Alzheimer's disease reflects a brain-specific "type 3" of diabetes.^[11] This hypothesis is controversial and not widely accepted in the medical community;^[5] neurologist and skeptic Steven Novella remarked that "it is silly to say that [Alzheimer's disease] should now be known as Type 3 diabetes—unless you are trying to reinforce a simplistic medical narrative by massively overemphasizing the role of diet in every disease."^[12]

Cause

There are a number of mechanisms that attempt to explain the cause, progression and the link between type 1 diabetes, type 2 diabetes and Alzheimer's disease.^[13]^[6]^[1]^[14]

Insulin resistance

Insulin resistance is a reduction in the body's sensitivity to insulin, which is required for most cells to use glucose. Thus, in type 3 diabetes, the neurons lack sufficient glucose to function properly. This deficiency can lead to a decrease in memory, judgement and the ability to reason, which are key symptoms of Alzheimer's disease.^[13]

Elevated cholesterol

Elevated serum cholesterol, specifically LDL cholesterol, is a risk factor for AD,^[15] and a variant of the cholesterol transport protein apoE is the most common genetic risk factor for late-onset AD.^[16] Treatment with statins, which inhibit cholesterol synthesis in the liver, has furthermore been shown to decrease risk for dementia of various types.^[17] LDL cholesterol levels are also a known risk factor for type 2 diabetes,^[18] and type 2 diabetes itself can lead to chemically-altered LDLs and an increased residence time of LDL cholesterol in the blood.^[19]

Oxidative stress and lipid peroxidation

Hyperglycemia, which frequently occurs in diabetes, can lead to formation of advanced glycation end-products and reactive oxygen species (ROS) in the brain.^[1] The resulting oxidative stress causes chemical changes in the protein and lipid molecules that are essential to brain function.^[1] The brain, which contains a high proportion of polyunsaturated fatty acids and relatively low levels of antioxidant proteins like catalase and superoxide dismutase,^[1] is especially sensitive to this oxidative stress. One of the main biomarkers of oxidative stress is lipid peroxidation, or the presence of reactive peroxide groups on fatty acid molecules. These peroxides disrupt the integrity of cell membranes, cause harmful chemical modifications of critical membrane proteins, and may lead to disorganization of microtubules,^[20] contributing to dysfunction in brain cells.

Diagnosis

A minor to medium decline in cognitive function is found to be linked with both type 1 diabetes and type 2 diabetes.^[1] However there are substantial variances in the cognitive pathophysiology of both type 1 diabetes and type 2 diabetes, leading to impairment.^[21] Type 2 diabetes is characteristically diagnosed from within the late fifties to mid-sixties age range however it is possible to be diagnosed younger.^[22] This form of diabetes is typically related to insulin resistance, dyslipidemia, hypertension and obesity. These mechanisms have a harmful influence on brain development.^[10]

Type 1 diabetes is typically detected at a young age and may have negative impacts on cognitive growth. In both forms of diabetes, microvascular complications and hyperglycaemia are mutual risk factors that are found to contribute to the cognitive decline in patients.^[10]

Prevention

There is no evidence today supporting a definitive method for preventing the onset of Alzheimer's disease in diabetic patients. However the four pillars of Alzheimer's prevention which outlines diet, physical and mental exercise, yoga and meditation and psychological well-being is recommended to patients who are at risk.^[9]^[23]

Diet

Mediterranean diet, a diet based around fruit, vegetables, olive oil, nuts and seafood has been shown to lower the risks of Alzheimer's disease in patients.^[9] Specifically, patients who followed this diet which is modeled on particular Mediterranean nations presented decreasing amounts of amyloid-beta plaques between their nerve cells in the brain,^[23] signifying the cell connections within the brain were firing correctly. This diet also presented increases in the thickness in the memory division of the brain cortex in the formal and parietal lobes and areas of cognition such as language and memory.^[23] Updated versions of the Mediterranean diet such as the DASH diet have been recommended for patients, adding juicing and supplements to the recommendation for patients.^[23]

Physical and mental exercise

Physical exercise increases the amount of blood flow through the brain while simultaneously causing the growth of brain cells known as neurogenesis.^[9]^[24] One hundred and twenty minutes of aerobic exercise and multiple strength training sessions per week are suggested to maintain and increase memory function in the patient.^[25] Mental stimulation is also recommended for patients.^[25] Brain aerobic activities such as reading and puzzles are endorsed to test and stimulate cognitive functioning while creative activities like painting and viewing art also activate the conditioning of the brain.^[9]^[23]

Yoga and meditation

Mediation and yoga have been found to reduce stress, which is a major element in the cause of Alzheimer's disease.^[9] Stress has a negative impact on a patient's genes such as producing inflammation in the brain, a key component of Alzheimer's disease.^[26] Simple twelve minute meditation each day reduces levels of stress in patients and extends the flow of blood to key areas of the brain responsible for memory performance.^[9]^[26] Yoga also stimulates the Anterior Cingulate Gyrus, a key area in the brain which manages memory recall, stress, emotive and cognitive stability.^{[citation needed]}

Psychological well-being

Psychological well-being factors such as self-acceptance and confidence, personal growth, regular socialization and independence decrease the probability of mental decline and reduce inflammation within the brain.^[27] Purpose in Life is now considered to increase the physiological health of patients with Alzheimer's disease.^[9] Optimistic emotions such as love, appreciation and kindness are known to lessen the stress response and maintain a healthy cognition throughout the rest of the patient's life.^[27]

References

^ ^a ^b ^c ^d ^e ^f ^g Kandimalla, Ramesh; Thirumala, Vani; Reddy, P. Hemachandra (May 2017). "Is Alzheimer's disease a Type 3 Diabetes? A critical appraisal". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1863 (5): 1078–1089. doi:10.1016/j.bbadis.2016.08.018. PMC 5344773. PMID 27567931.
^ de la Monte, Suzanne M.; Wands, Jack R. (2008). "Alzheimer's Disease Is Type 3 Diabetes–Evidence Reviewed". Journal of Diabetes Science and Technology. 2 (6): 1101–1113. doi:10.1177/193229680800200619. PMC 2769828. PMID 19885299.
^ Song, Juhyun; Whitcomb, Daniel J.; Kim, Byeong C. (December 2017). "The role of melatonin in the onset and progression of type 3 diabetes". Molecular Brain. 10 (1): 35. doi:10.1186/s13041-017-0315-x. PMC 5539639. PMID 28764741.
^ Steen, Eric; Terry, Benjamin M.; Rivera, Enrique J.; Cannon, Jennifer L.; Neely, Thomas R.; Tavares, Rose; Xu, X. Julia; Wands, Jack R.; de la Monte, Suzanne M. (2005). "Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease – is this type 3 diabetes?". Journal of Alzheimer's Disease. 7 (1): 63–80. doi:10.3233/JAD-2005-7107. PMID 15750215. S2CID 28173722.
^ ^a ^b ^c "Type 3 diabetes explained". Medical News Today. July 30, 2021.
^ ^a ^b ^c ^d ^e Moheet, Amir; Mangia, Silvia; Seaquist, Elizabeth R. (September 2015). "Impact of diabetes on cognitive function and brain structure: Impact of diabetes on brain". Annals of the New York Academy of Sciences. 1353 (1): 60–71. Bibcode:2015NYASA1353...60M. doi:10.1111/nyas.12807. PMC 4837888. PMID 26132277.
^ Ferreira, Laís S. S.; Fernandes, Caroline S.; Vieira, Marcelo N. N.; De Felice, Fernanda G. (13 November 2018). "Insulin Resistance in Alzheimer's Disease". Frontiers in Neuroscience. 12: 830. doi:10.3389/fnins.2018.00830. PMC 6277874. PMID 30542257.
^ Förstl, H.; Kurz, A. (16 December 1999). "Clinical features of Alzheimer's disease". European Archives of Psychiatry and Clinical Neuroscience. 249 (6): 288–290. doi:10.1007/s004060050101. PMID 10653284. S2CID 26142779.
^ ^a ^b ^c ^d ^e ^f ^g ^h Khalsa, Dharma Singh; Perry, George (2017). "The Four Pillars of Alzheimer's Prevention". Cerebrum. v2017 (Mar–Apr): cer03–17. PMC 5501038. PMID 28698774.
^ ^a ^b ^c "What Are the Signs of Alzheimer's Disease?". National Institute on Aging. 16 May 2017.
^ ^a ^b de la Monte, Suzanne M.; Wands, Jack R. (November 2008). "Alzheimer's Disease is Type 3 Diabetes—Evidence Reviewed". Journal of Diabetes Science and Technology. 2 (6): 1101–1113. doi:10.1177/193229680800200619. PMC 2769828. PMID 19885299.
^ "What is Type 3 Diabetes?". Science Based Medicine. 3 Apr 2024.
^ ^a ^b "What is type 3 diabetes?". Diabetesaustralia.com.au. Diabetes Australia. 30 Aug 2019. Retrieved 11 Dec 2023.
^ Bae, Choon; Song, Juhyun (22 November 2017). "The Role of Glucagon-Like Peptide 1 (GLP1) in Type 3 Diabetes: GLP-1 Controls Insulin Resistance, Neuroinflammation and Neurogenesis in the Brain". International Journal of Molecular Sciences. 18 (11): 2493. doi:10.3390/ijms18112493. PMC 5713459. PMID 29165354.
^ Saiz-Vazquez, Olalla; Puente-Martinez, Alicia; Ubillos-Landa, Silvia; Pacheco-Bonrostro, Joaquin; Santabarbara, Javier (18 Jun 2020). "Cholesterol and Alzheimer's Disease Risk: A Meta-Meta-Analysis". Brain Sci. 10 (6): 386. doi:10.3390/brainsci10060386. PMC 7349210. PMID 32570800.
^ Karch, Celeste M.; Goate, Alison M. (1 Jan 2015). "Alzheimer's disease risk genes and mechanisms of disease pathogenesis". Biol. Psychiatry. 77 (1): 43–51. doi:10.1016/j.biopsych.2014.05.006. PMC 4234692. PMID 24951455.
^ Jick, H; Zornberg, G.L.; Jick, S.S.; Seshadri, S.; Drachman, D.A. (11 Nov 2000). "Statins and the Risk of Dementia". Lancet. 356 (9242): 1627–1631. doi:10.1016/S0140-6736(00)03155-X. PMID 11089820. S2CID 11414020.
^ Ichikawa, Takahiro; Okada, Hiroshi; Hamaguchi, Masahide; Kurogi, Kazushiro; Murata, Hiroaki; Ito, Masato; Fukui, Michiaki (May 2023). "Estimated small dense low-density lipoprotein-cholesterol and incipient type 2 diabetes in Japanese people: Population-based Panasonic cohort study 13". Diab. Res. Clin. Pract. 199: 110665. doi:10.1016/j.diabres.2023.110665. PMID 37031889. S2CID 258047959.
^ Verges, Bruno (Dec 2009). "Lipid modification in type 2 diabetes: the role of LDL and HDL". Fundam. Clin. Pharmacol. 23 (6): 681–685. doi:10.1111/j.1472-8206.2009.00739.x. PMID 19650852.
^ Montine, Thomas J.; Neely, M. Diana; Quinn, Joseph F.; Beal, M. Flint; Markesbery, William R.; Roberts II, L. Jackson; Morrow, Jason D. (1 Sep 2002). "Lipid peroxidation in aging brain and Alzheimer's disease". Free Radical Biology & Medicine. 33 (5): 620–626. doi:10.1016/S0891-5849(02)00807-9. PMID 12208348.
^ Srikanth, Velandai; Arvanitakis, Zoe (2018). Type 2 Diabetes and Dementia. Academic Press. ISBN 978-0-12-809694-9.^{[page needed]}
^ Srikanth, Velandai; Arvanitakis, Zoe (2018). Type 2 Diabetes and Dementia. Academic Press. ISBN 978-0-12-809694-9.^{[page needed]}
^ ^a ^b ^c ^d ^e Staubo, Sara C.; Aakre, Jeremiah A.; Vemuri, Prashanthi; Syrjanen, Jeremy A.; Mielke, Michelle M.; Geda, Yonas E.; Kremers, Walter K.; Machulda, Mary M.; Knopman, David S.; Petersen, Ronald C.; Jack, Clifford R.; Roberts, Rosebud O. (February 2017). "Mediterranean diet, micronutrients and macronutrients, and MRI measures of cortical thickness". Alzheimer's & Dementia. 13 (2): 168–177. doi:10.1016/j.jalz.2016.06.2359. PMC 5259552. PMID 27461490.
^ Miller, Emelie; Johansson, Boo (1 January 2016). "Capability to Paint and Alzheimer's Disease: Relationship to Disease Stages and Instructions". SAGE Open. 6 (1). doi:10.1177/2158244016631799.
^ ^a ^b Paillard, Thierry; Rolland, Yves; de Souto Barreto, Philipe (2015). "Protective Effects of Physical Exercise in Alzheimer's Disease and Parkinson's Disease: A Narrative Review". Journal of Clinical Neurology. 11 (3): 212–219. doi:10.3988/jcn.2015.11.3.212. PMC 4507374. PMID 26174783.
^ ^a ^b Justice, Nicholas J. (1 February 2018). "The relationship between stress and Alzheimer's disease". Neurobiology of Stress. 8: 127–133. doi:10.1016/j.ynstr.2018.04.002. PMC 5991350. PMID 29888308.
^ ^a ^b Ryff, Carol D.; Singer, Burton H.; Dienberg Love, Gayle (29 September 2004). "Positive health: connecting well–being with biology". Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences. 359 (1449): 1383–1394. doi:10.1098/rstb.2004.1521. PMC 1693417. PMID 15347530.