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Is sporadic Alzheimer’s disease a form of diabetes?

Due to the aging of the population and to unhealthy lifestyle habits, age-related metabolic and neurodegenerative diseases are a growing and alarming problem around the globe. Sporadic Alzheimer's disease (AD) and type 2 diabetes (T2D), two chronic age-related disorders, have attained epidemic proportions. In 2015, an estimated 46.8 million people worldwide were living with dementia; AD being the most common form of dementia among the elderly. This number will almost double every 20 years, reaching 74.7 million in 2030 and 131.5 million in 2050 [1]. Similarly, in 2010 about 285 million adults were living with diabetes and the number of affected individuals will increase to 439 million by 2030 [2].

To aggravate this scenario, a growing body of epidemiological and clinical studies has shown that T2D significantly increases the risk of AD [3]. It has been demonstrated that both diseases share several pathophysiological mechanisms such as altered insulin signaling, energy metabolism defects (mainly alterations in glucose metabolism and mitochondria), oxidative stress, inflammation, and amyloidosis, among others [3,4]. Due to the remarkable overlap found between AD and T2D, it has been suggested that AD might be a new form of diabetes or type 3 diabetes [5,6].

Due to the lack of effective treatments for AD, and considering the similarities between AD and T2D, it has been hypothesized that anti-diabetic medication can help treat AD patients [7]. In fact, there are several ongoing clinical trials of antidiabetic drugs in mild cognitive impairment (MCI) and AD subjects.

Promising effects of intranasally administered insulin or insulin analogues such as insulin detemir have been observed in AD and amnestic MCI subjects [8,9]. However, in carriers of the allele ε4 of apolipoprotein E (APOE-ε4) insulin administration seems to exacerbate cognitive deficits [10].

Regarding the oral antidiabetic agent metformin, a biguanide that stimulates adenosine monophosphate (AMP)-activated protein kinase (AMPK), studies have shown that in diabetic individuals, long-term treatment (>6 years) with metformin seems to reduce the risk of cognitive decline [11]. However, another study showed that individuals with T2D or impaired glucose tolerance had overall worse cognitive performance and, among the participants with T2D, those treated with metformin performed less well on the cognitive tests than those managing diabetes with other approaches [12].

Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists and potent insulin sensitizers. The best characterized PPAR-γ agonists are pioglitazone and rosiglitazone. Rosiglitazone was associated with an early increase in whole brain glucose metabolism, but not with any biological or clinical evidence for slowing progression over a 1-year follow up in the symptomatic stages of AD [13]. However, a previous trial involving mild and moderate AD patients showed that patients treated with 8 mg rosiglitazone during 6 months presented a significant improvement in cognitive function in APOE-ε4-negative patients, while individuals with the APOE-ε4 allele showed no benefit [14]. However, a recent systemic review and meta-analysis concluded that there is insufficient evidence to support the use of rosiglitazone in amnestic MCI and AD patients [15]. The same study concluded that pioglitazone may be useful in treating AD patients with comorbid diabetes [15]. A major limitation of TZDs in the prevention of AD is the side effects of edema and congestive heart failure.

Concerning the effects of glucagon-like peptide-1 (GLP-1) receptor agonists that have an insulinotropic action dependent on glucose levels, we are awaiting the results of two clinical trials; a pilot clinic trial of exendin-4 in MCI and early stage AD subjects (NCT01255163) and a phase II clinical trial assessing the safety and efficacy of liraglutide in mild AD (NCT01843075).

The discrepancies found between studies suggest that effects of antidiabetic agents possibly depends on doses and duration of treatment, and target population as defined by the stage and severity of cognitive impairment and dementia as well as APOE gene polymorphism. More studies, particularly large-scale population studies and clinical trials, must be done to evaluate the effect of dose and duration of therapy (monotherapy or combination therapy) using a standardized battery of tests and the participants must be followed over a number of years.

Based on the above, we must ask ourselves: Is antidiabetic medication the right path to achieve sporadic AD cure?

References
[1] World Alzheimer Report 2015: The Global Impact of Dementia (https://www.alz.co.uk/research/world-report-2015)
[2] Shaw JE, Sicree RA, Zimmet PZ (2010) Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract 87, 4-14.
[3] Moreira PI (2012) Alzheimer's disease and diabetes: an integrative view of the role of mitochondria, oxidative stress, and insulin. J Alzheimers Dis 30, S199-215.
[4] De Felice FG, Ferreira ST (2014) Inflammation, defective insulin signaling, and mitochondrial dysfunction as common molecular denominators connecting type 2 diabetes to Alzheimer disease. Diabetes 63, 2262-2272.
[5] Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, Xu XJ, Wands JR, de la Monte SM (2005) Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease--is this type 3 diabetes? J Alzheimers Dis 7, 63-80.
[6] de la Monte SM (2014) Type 3 diabetes is sporadic Alzheimer׳s disease: mini-review. Eur Neuropsychopharmacol 24, 1954-1960.
[7] Yarchoan M, Arnold SE (2014) Repurposing diabetes drugs for brain insulin resistance in Alzheimer disease. Diabetes 63, 2253-2261.
[8] Reger MA, Watson GS, Green PS, Wilkinson CW, Baker LD, Cholerton B, Fishel MA, Plymate SR, Breitner JC, DeGroodt W, Mehta P, Craft S (2008) Intranasal insulin improves cognition and modulates beta-amyloid in early AD. Neurology 70, 440-448.
[9] Claxton A, Baker LD, Hanson A, Trittschuh EH, Cholerton B, Morgan A, Callaghan M, Arbuckle M, Behl C, Craft S (2015) Long-acting intranasal insulin detemir improves cognition for adults with mild cognitive impairment or early-stage Alzheimer's disease dementia. J Alzheimers Dis 44, 897-906.
[10] Reger MA, Watson GS, Frey WH 2nd, Baker LD, Cholerton B, Keeling ML, Belongia DA, Fishel MA, Plymate SR, Schellenberg GD, Cherrier MM, Craft S (2006) Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype. Neurobiol Aging 27, 451-458.
[11] Ng TP, Feng L, Yap KB, Lee TS, Tan CH, Winblad B (2014) Long-term metformin usage and cognitive function among older adults with diabetes. J Alzheimers Dis 41, 61-68.
[12] Moore EM, Mander AG, Ames D, Kotowicz MA, Carne RP, Brodaty H, Woodward M, Boundy K, Ellis KA, Bush AI, Faux NG, Martins R, Szoeke C, Rowe C, Watters DA; AIBL Investigators (2013) Increased risk of cognitive impairment in patients with diabetes is associated with metformin. Diabetes Care 36, 2981-2987.
[13] Tzimopoulou S, Cunningham VJ, Nichols TE, Searle G, Bird NP, Mistry P, Dixon IJ, Hallett WA, Whitcher B, Brown AP, Zvartau-Hind M, Lotay N, Lai RY, Castiglia M, Jeter B, Matthews JC, Chen K, Bandy D, Reiman EM, Gold M, Rabiner EA, Matthews PM (2006) A multi-center randomized proof-of-concept clinical trial applying [¹⁸F]FDG-PET for evaluation of metabolic therapy with rosiglitazone XR in mild to moderate Alzheimer's disease. J Alzheimers Dis 22, 1241-1256.
[14] Risner ME, Saunders AM, Altman JF, Ormandy GC, Craft S, Foley IM, Zvartau-Hind ME, Hosford DA, Roses AD; Rosiglitazone in Alzheimer's Disease Study Group (2006) Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease. Pharmacogenomics J 6, 246-254.
[15] Liu J, Wang LN, Jia JP (2015) Peroxisome proliferator-activated receptor-gamma agonists for Alzheimer's disease and amnestic mild cognitive impairment: a systematic review and meta-analysis. Drugs Aging 32, 57-65.

Last comment on 15 July 2016 by Ana Duarte

Comments

Submitted by Russell Swerdlow, MD on

Observed relationships between Alzheimer’s disease (AD) and diabetes/insulin resistance have long been speculated about and could provide important clues about AD etiology and pathophysiology. The fact that the insulin pathway activation state appears reduced in AD has given rise to speculation that amyloid-beta perturbs insulin signaling, causing a “diabetes” of the brain, and to speculation that a central nervous system manifestation of a general insulin resistance state promotes the production or blocks the elimination of amyloid-beta. Another possibility to consider is that this could all reflect a common upstream feature that gives rise to insulin resistance in the brain, peripheral insulin resistance, and amyloid-beta production. For example, mitochondrial dysfunction is known to cause insulin resistance and to increase processing of amyloid precursor protein to amyloid-beta. Dr. Moreira nicely explains the rationale for trying to treat AD like we treat diabetes, and of summarizing past and recent clinical trials that featured such interventions. These trials have thus far not proved transformative although results from particular trials of particular agents are pending. One caution is that if insulin resistance is contributing to neurodegeneration and neurodysfunction in AD, interventions that address the actual cause of that insulin resistance would seem to make the most sense. If perturbed mitochondrial function is the root cause, the most rationale approach would arguably be to repair or reverse the perturbed mitochondrial function.

Submitted by Ana Duarte on

As posted by Paula I. Moreira, type 2 diabetes (T2D) constitutes such a public health concern that, recently, the World Health Organization considered it an epidemic of the 21st century [1,2]. This can be further aggravated by the ever-increasing population aging, modern lifestyle-related risk factors (especially the “obesity boom” in the so-called “under development” nations), and morbidity and mortality associated with its severe long-term complications [1,3,4]. Among such chronic complications, one can find severe brain dysfunction/degeneration, cognitive decline and, ultimately, neurodegenerative disorders (including Alzheimer disease, AD) [5-7].

Though it is not surprising that T2D constitutes a risk factor for AD, the opposite (i.e., the higher risk of AD patients to T2D) [8,9] seems to be more striking. Another point focused was that, despite the knowledge on the subcellular commonalities between both pathologies, their precise (inter)actions during T2D progression that culminate in AD remain debatable. On one hand, it seems highly probable that chronic hyperglycemia- and/or insulin resistance-related injury (e.g., on brain neurovascular function) may be further aggravated over patient’s aging, culminating in cognitive decline and AD [6,8,10-12]. As such, insulin could not only constitute a (or the) missing link between both pathologies, but the restoration of its brain levels/action could provide a successful therapeutic strategy [13,14]. But, on the other hand, things have shown not to be so straightforward and the opinions divide between the hypotheses that AD could be a brain-specific, type 3 diabetes, metabolic-cognitive syndrome or insulin-resistant state [15]. Apart from these controversies, it seems more consensual that, given the lack of chronically-efficient or safe anti-AD drugs, and the similarities between T2D and AD, a beneficial anti-T2D (or, at least, anti-hyperglycemic) treatment can be also beneficial against AD [9,16]. This may occur, e.g., by allowing the management/prevention (especially before midlife) or delay of T2D (or, at least, its peripheral features) and the subsequent chronic brain injury [6,17].

Among the anti-T2D drugs (or classes of drugs) with a promising potential against AD, most of them (including insulin itself) have shown contradictory results in patients. Although these can be explained by the different doses used, duration of treatment and parameters analyzed, one can also ask if the recurrent hypoglycemic episodes affecting patients brains under these treatments cannot underlie (at least partially) some of the negative effects reported. If this is true, then the very promising glucagon-like peptide-1 (GLP-1) analogues could be also the most beneficial against AD in clinical trials. This because GLP-1 mimetics were shown not only to readily cross the blood-brain barrier and exert neuroprotective effects in models of T2D and AD [5,8,14], but their hypoglycemic potential was found to be very low [6].

In sum, there is a hope for anti-T2D drugs as one (or the) “hidden secret” for the treatment of AD. But, if the clinical trials fail, a possible future “exit plan” may involve more “sophisticated” medicines, with less recurrent hypoglycemia episodes (or other adverse effects). Alternatively, one can expect that, at least by attenuating peripheral T2D hallmarks, the drugs currently available may blunt its chronic brain damage and, ultimately, the complications affecting the central nervous system.

References
[1] World Health Organization (2016) Diabetes fact sheet 312, revised June 2016 (available online: http://www.who.int/mediacentre/factsheets/fs312/en/). Accessed June 26, 2016.
[2] NCD Risk Factor Collaboration (NCD-RisC) (2016) Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4.4 million participants. Lancet 387, 1513-1530.
[3] de Visser A, Hemming A, Yang C, Zaver S, Dhaliwal R, Jawed Z, Toth C (2014) The adjuvant effect of hypertension upon diabetic peripheral neuropathy in experimental type 2 diabetes. Neurobiol Dis 62, 18-30.
[4] Shaw JE Sicree RA, Zimmet PZ (2010) Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract 87, 4–14.
[5] Candeias EM, Sebastião IC, Cardoso SM, Correia SC, Carvalho CI, Plácido AI, Santos MS, Oliveira CR, Moreira PI, Duarte AI (2015) Gut-brain connection: The neuroprotective effects of the anti-diabetic drug liraglutide. World J Diabetes 6, 807-827.
[6] Duarte AI, Candeias E, Correia SC, Santos RX, Carvalho C, Cardoso S, Plácido A, Santos MS, Oliveira CR, Moreira PI (2013) Crosstalk between diabetes and brain: glucagon-like peptide-1 mimetics as a promising therapy against neurodegeneration.Biochim Biophys Acta 1832, 527-541.
[7] Sima AA (2010) Encephalopathies: the emerging diabetic complications. Acta Diabetol 47, 279-293.
[8] Sebastião I, Candeias E, Santos MS, de Oliveira CR, Moreira PI, Duarte AI (2014) Insulin as a bridge between type 2 diabetes and Alzheimer disease - how anti-diabetics could be a solution for dementia. Front Endocrinol (Lausanne) 5, 110.
[9] Cai H, Cong WN, Ji S, Rothman S, Maudsley S, Martin B (2012) Metabolic dysfunction in Alzheimer's disease and related neurodegenerative disorders. Curr Alzheimer Res 9, 5-17.
[10] Carvalho C, Katz PS, Dutta S, Katakam PV, Moreira PI, Busija DW (2014) Increased susceptibility to amyloid-β toxicity in rat brain microvascular endothelial cells under hyperglycemic conditions. J Alzheimers Dis 38, 75-83.
[11] Duarte AI, Santos MS, Seiça R, Oliveira CR (2004) Oxidative stress affects synaptosomal gamma-aminobutyric acid and glutamate transport in diabetic rats: the role of insulin. Diabetes 53, 2110-2116.
[12] Moreira PI, Santos MS, Moreno AM, Seiça R, Oliveira CR (2003) Increased vulnerability of brain mitochondria in diabetic (Goto-Kakizaki) rats with aging and amyloid-beta exposure. Diabetes 52, 1449-1456.
[13] Duarte AI, Moreira PI, Oliveira CR (2012) Insulin in central nervous system: more than just a peripheral hormone. J Aging Res 2012, 384017.
[14] Hunter K, Hölscher C (2012) Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis. BMC Neurosci 13, 33.
[15] Frisardi V, Solfrizzi V, Seripa D, Capurso C, Santamato A, Sancarlo D, Vendemiale G, Pilotto A, Panza F (2010) Metabolic-cognitive syndrome: a cross-talk between metabolic syndrome and Alzheimer's disease. Ageing Res Ver 9, 399-417.
[16] Corbett A, Ballard C (2013) Is a potential Alzheimer's therapy already in use for other conditions? Can medications for hypertension, diabetes and acne help with the symptoms? Expert Opin Investig Drugs 22, 941-943.
[17] Lin B, Koibuchi N, Hasegawa Y, Sueta D, Toyama K, Uekawa K, Ma M, Nakagawa T, Kusaka H, Kim-Mitsuyama S (2014) Glycemic control with empagliflozin, a novel selective SGLT2 inhibitor, ameliorates cardiovascular injury and cognitive dysfunction in obese and type 2 diabetic mice. Cardiovasc Diabetol 13, 148.

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