Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums

Diabetes


  • 1.

    et al. Vascular contributions to cognitive impairment and dementia including Alzheimer’s disease. Alzheimers Dement. 11, 710–717 (2015).

  • 2.

    et al. Recommendations of the Alzheimer’s disease-related dementias conference. Neurology 83, 851–860 (2014).

  • 3.

    et al. Complex mechanisms linking neurocognitive dysfunction to insulin resistance and other metabolic dysfunction. F1000Res. 5, 353 (2016).

  • 4.

    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 39, 300–307 (2016).

  • 5.

    , , & New animal models of Alzheimer’s disease that display insulin desensitization in the brain. Rev. Neurosci. 24, 607–615 (2013).

  • 6.

    et al. Diabetes, glucose control, and 9-year cognitive decline among older adults without dementia. Arch. Neurol. 69, 1170–1175 (2012).

  • 7.

    , , , & Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol. 5, 64–74 (2006).

  • 8.

    , , & Changes in cognitive abilities over a 4-year period are unfavorably affected in elderly diabetic subjects: results of the Epidemiology of Vascular Aging Study. Diabetes Care 24, 366–370 (2001).

  • 9.

    , & Prospective study of type 2 diabetes and cognitive decline in women aged 70–81 years. BMJ 328, 548 (2004).

  • 10.

    et al. Relation of diabetes to mild cognitive impairment. Arch. Neurol. 64, 570–575 (2007).

  • 11.

    , , & Diabetes mellitus and the risk of dementia, Alzheimer’s disease and vascular cognitive impairment in the Canadian Study of Health and Aging. Dement. Geriatr. Cogn. Disord. 14, 77–83 (2002).

  • 12.

    et al. Diabetes mellitus and the risk of dementia: the Rotterdam Study. Neurology 53, 1937–1942 (1999).

  • 13.

    et al. Changes in glycemic control are associated with changes in cognition in non-diabetic elderly. J. Alzheimers Dis. 30, 299–309 (2012).

  • 14.

    et al. Insulin metabolism and the risk of Alzheimer disease: the Rotterdam Study. Neurology 75, 1982–1987 (2010).

  • 15.

    et al. Impact of diabetes on cognitive function among older Latinos: a population-based cohort study. J. Clin. Epidemiol. 56, 686–693 (2003).

  • 16.

    et al. Impact of antidiabetic medications on physical and cognitive functioning of older Mexican Americans with diabetes mellitus: a population-based cohort study. Ann. Epidemiol. 13, 369–376 (2003).

  • 17.

    et al. Diabetes as a predictor of change in functional status among older Mexican Americans: a population-based cohort study. Diabetes Care 26, 314–319 (2003).

  • 18.

    et al. Diabetes, impaired fasting glucose, and development of cognitive impairment in older women. Neurology 63, 658–663 (2004).

  • 19.

    , & Diabetes mellitus, dementia, and cognitive function in older persons. J. Nutr. Health Aging 10, 287–291 (2006).

  • 20.

    Regulation of insulin secretion: a matter of phase control and amplitude modulation. Diabetologia 52, 739–751 (2009).

  • 21.

    & Mechanisms of β-cell functional adaptation to changes in workload. Diabetes Obes. Metab. 18 (Suppl. 1), 78–86 (2016).

  • 22.

    Toward a comprehensive neurobiology of IGF-I. Dev. Neurobiol. 70, 384–396 (2010).

  • 23.

    , , & The role of Insulin-Like Growth Factor 1 (IGF-1) in brain development, maturation and neuroplasticity. Neuroscience 325, 89–99 (2016).

  • 24.

    The insulin receptor and its signal transduction network. Endotext (2000).

  • 25.

    et al. Rab10, a target of the AS160 Rab GAP, is required for insulin-stimulated translocation of GLUT4 to the adipocyte plasma membrane. Cell Metab. 5, 293–303 (2007).

  • 26.

    Energy metabolism in the liver. Compr. Physiol. 4, 177–197 (2014).

  • 27.

    , & Selective insulin resistance and the development of cardiovascular diseases in diabetes: the 2015 Edwin Bierman Award lecture. Diabetes 65, 1462–1471 (2016).

  • 28.

    , , & Localization of insulin receptor mRNA in rat brain by in situ hybridization. Endocrinology 127, 3234–3236 (1990).

  • 29.

    & Insulin receptors and signal transduction proteins in the hypothalamo-hypophyseal system: a review on morphological findings and functional implications. Histol. Histopathol. 13, 1215–1224 (1998).

  • 30.

    et al. Localization and characterization of insulin receptors in rat brain and pituitary gland using in vitro autoradiography and computerized densitometry. Endocrinology 121, 1562–1570 (1987).

  • 31.

    et al. Brain insulin receptors and spatial memory. Correlated changes in gene expression, tyrosine phosphorylation, and signaling molecules in the hippocampus of water maze trained rats. J. Biol. Chem. 274, 34893–34902 (1999).

  • 32.

    et al. Cerebrospinal fluid insulin during non-neurological surgery. J. Neural Transm. (Vienna) 117, 1167–1170 (2010).

  • 33.

    et al. Cerebrospinal fluid insulin levels increase during intravenous insulin infusions in man. J. Clin. Endocrinol. Metab. 64, 190–194 (1987).

  • 34.

    The source of cerebral insulin. Eur. J. Pharmacol. 490, 5–12 (2004).

  • 35.

    et al. Saturable transport of insulin from plasma into the central nervous system of dogs in vivo. A mechanism for regulated insulin delivery to the brain. J. Clin. Invest. 92, 1824–1830 (1993).

  • 36.

    , , & Transport of insulin across the blood-brain barrier: saturability at euglycemic doses of insulin. Peptides 18, 1423–1429 (1997).

  • 37.

    , & Human blood-brain barrier insulin receptor. J. Neurochem. 44, 1771–1778 (1985).

  • 38.

    et al. Evidence for entry of plasma insulin into cerebrospinal fluid through an intermediate compartment in dogs. Quantitative aspects and implications for transport. J. Clin. Invest. 88, 1272–1281 (1991).

  • 39.

    , & Insulin in the brain: there and back again. Pharmacol. Ther. 136, 82–93 (2012).

  • 40.

    et al. Evidence for altered transport of insulin across the blood-brain barrier in insulin-resistant humans. Acta Diabetol. 51, 679–681 (2014).

  • 41.

    et al. The brain response to peripheral insulin declines with age: a contribution of the blood-brain barrier? PLOS ONE 10, e0126804 (2015).

  • 42.

    , & Changes in insulin and insulin signaling in Alzheimer’s disease: cause or consequence? J. Exp. Med. 213, 1375–1385 (2016).

  • 43.

    , & Evaluation of rat insulin messenger RNA in pancreatic and extrapancreatic tissues. Diabetologia 28, 343–347 (1985).

  • 44.

    et al. Insulin is released from rat brain neuronal cells in culture. J. Neurochem. 47, 831–836 (1986).

  • 45.

    Periventricular hypothalamic cells in the rat brain contain insulin mRNA. Neuropeptides 8, 93–97 (1986).

  • 46.

    et al. Insulin gene expression and insulin synthesis in mammalian neuronal cells. J. Biol. Chem. 269, 8445–8454 (1994).

  • 47.

    et al. Differential expression of the two nonallelic proinsulin genes in the developing mouse embryo. Proc. Natl Acad. Sci. USA 90, 527–531 (1993).

  • 48.

    et al. Developmental regulation of insulin in the mammalian central nervous system. Brain Res. 582, 27–37 (1992).

  • 49.

    , & Insulin and insulin-like growth factor receptors in the nervous system. Mol. Neurobiol. 3, 71–100 (1989).

  • 50.

    , , , & Analysis of tyrosine hydroxylase and insulin transcripts in human neuroendocrine tissues. Brain Res. Mol. Brain Res. 8, 93–98 (1990).

  • 51.

    , , , & Insulin II gene expression in rat central nervous system. Regul. Pept. 48, 55–63 (1993).

  • 52.

    , , & Insulin and the blood-brain barrier. Curr. Pharm. Des. 9, 795–800 (2003).

  • 53.

    , , , & C-Peptide immunoreactive neurons in human brain. Acta Histochem. 70, 326–330 (1982).

  • 54.

    et al. Brain insulin and insulin receptors in aging and sporadic Alzheimer’s disease. J. Neural Transm. (Vienna) 105, 423–438 (1998).

  • 55.

    et al. 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 (2005).

  • 56.

    et al. Hyperinsulinemia drives diet-induced obesity independently of brain insulin production. Cell Metab. 16, 723–737 (2012).

  • 57.

    , , & Insulin, PKC signaling pathways and synaptic remodeling during memory storage and neuronal repair. Eur. J. Pharmacol. 585, 76–87 (2008).

  • 58.

    , & Insulin signaling in the central nervous system: learning to survive. Prog. Neurobiol. 79, 205–221 (2006).

  • 59.

    et al. Localization and characterization of insulin-like growth factor-i receptors in rat brain and pituitary gland using in vitro autoradiography and computerized densitometry* A distinct distribution from insulin receptors. J. Neuroendocrinol. 1, 369–377 (1989).

  • 60.

    , & Endogenous insulin signaling protects cultured neurons from oxygen-glucose deprivation-induced cell death. Neuroscience 143, 165–173 (2006).

  • 61.

    , & The insulin receptor tyrosine kinase substrate p58/53 and the insulin receptor are components of CNS synapses. J. Neurosci. 19, 7300–7308 (1999).

  • 62.

    , , & ProSAP/Shank postsynaptic density proteins interact with insulin receptor tyrosine kinase substrate IRSp53. J. Neurochem. 83, 1013–1017 (2002).

  • 63.

    & Insulin, synaptic function, and opportunities for neuroprotection. Prog. Mol. Biol. Transl Sci. 98, 133–186 (2011).

  • 64.

    The neuronal insulin receptor in its environment. J. Neurochem. 140, 359–367 (2017).

  • 65.

    & Stop signs in hippocampal insulin signaling: the role of insulin resistance in structural, functional and behavioral deficits. Curr. Opin. Behav. Sci. 9, 47–54 (2016).

  • 66.

    Alzheimer’s disease and insulin resistance: translating basic science into clinical applications. J. Clin. Invest. 123, 531–539 (2013).

  • 67.

    , , , & Insulin modulates hippocampal activity-dependent synaptic plasticity in a N-methyl-D-aspartate receptor and phosphatidyl-inositol-3-kinase-dependent manner. J. Neurochem. 94, 1158–1166 (2005).

  • 68.

    , & Insulin receptor signaling regulates synapse number, dendritic plasticity, and circuit function in vivo. Neuron 58, 708–719 (2008).

  • 69.

    , & Insulin promotes dendritic spine and synapse formation by the PI3K/Akt/mTOR and Rac1 signaling pathways. Neuropharmacology 61, 867–879 (2011).

  • 70.

    et al. LTP inhibits LTD in the hippocampus via regulation of GSK3β. Neuron 53, 703–717 (2007).

  • 71.

    & Insulin inhibits AMPA-induced neuronal damage via stimulation of protein kinase B (Akt). J. Neural Transm. (Vienna) 112, 179–191 (2005).

  • 72.

    , & Glucose transport in primary cultured neurons. J. Neurosci. Res. 22, 397–407 (1989).

  • 73.

    & Insulin regulates neuronal glucose uptake by promoting translocation of glucose transporter GLUT3. Exp. Neurol. 198, 48–53 (2006).

  • 74.

    Glucose transport in brain – effect of inflammation. Endocr. Regul. 48, 35–48 (2014).

  • 75.

    et al. Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J. Clin. Invest. 122, 1316–1338 (2012).

  • 76.

    & Brain glucose transporters: relationship to local energy demand. News Physiol. Sci. 16, 71–76 (2001).

  • 77.

    , & Insulin-sensitive GLUT4 glucose transporters are colocalized with GLUT3-expressing cells and demonstrate a chemically distinct neuron-specific localization in rat brain. J. Neurosci. Res. 57, 693–705 (1999).

  • 78.

    & Glucose transporter expression in the central nervous system: relationship to synaptic function. Eur. J. Pharmacol. 490, 13–24 (2004).

  • 79.

    , , & Insulin-stimulated translocation of GLUT4 to the plasma membrane in rat hippocampus is PI3-kinase dependent. Brain Res. 1296, 35–45 (2009).

  • 80.

    & Novel roles for the insulin-regulated glucose transporter-4 in hippocampally dependent memory. J. Neurosci. 36, 11851–11864 (2016).

  • 81.

    et al. Subcellular localization of glucose transporter 4 in the hypothalamic arcuate nucleus of ob/ob mice under basal conditions. Brain Res. 1049, 34–42 (2005).

  • 82.

    et al. Brain GLUT4 knockout mice have impaired glucose tolerance, decreased insulin sensitivity, and impaired hypoglycemic counterregulation. Diabetes 66, 587–597 (2017).

  • 83.

    , , & Neocortical glial cell numbers in human brains. Neurobiol. Aging 29, 1754–1762 (2008).

  • 84.

    & in The Human Brain in Figures and tables (ed. Blinkow, F. G.) 237–253 (Plenum Press, 1968).

  • 85.

    et al. Astrocytic glycogen influences axon function and survival during glucose deprivation in central white matter. J. Neurosci. 20, 6804–6810 (2000).

  • 86.

    et al. Evidence supporting the existence of an activity-dependent astrocyte-neuron lactate shuttle. Dev. Neurosci. 20, 291–299 (1998).

  • 87.

    Brain glucose transporters: implications for neurologic disease. Neurology 82, 1374–1379 (2014).

  • 88.

    et al. Plasma lactate levels increase during hyperinsulinemic euglycemic clamp and oral glucose tolerance test. J. Diabetes Res. 2015, 102054 (2015).

  • 89.

    , & The binding of insulin to cerebral capillaries and astrocytes of the rat. Neurochem. Res. 7, 489–494 (1982).

  • 90.

    et al. Insulin and IGF1 signalling pathways in human astrocytes in vitro and in vivo; characterisation, subcellular localisation and modulation of the receptors. Mol. Brain 8, 51 (2015).

  • 91.

    , , , & Insulin modulates in vitro secretion of cytokines and cytotoxins by human glial cells. Curr. Alzheimer Res. 12, 684–693 (2015).

  • 92.

    et al. Insulin promotes glycogen storage and cell proliferation in primary human astrocytes. PLoS ONE 6, e21594 (2011).

  • 93.

    , , & Insulin binds to specific receptors and stimulates 2-deoxy-D-glucose uptake in cultured glial cells from rat brain. J. Biol. Chem. 259, 11672–11675 (1984).

  • 94.

    , , & Deficient expression of insulin receptor substrate-1 (IRS-1) fails to block insulin-like growth factor-I (IGF-I) stimulation of brain growth and myelination. Brain Res. Dev. Brain Res. 136, 111–121 (2002).

  • 95.

    et al. Response of human oligodendrocyte progenitors to growth factors and axon signals. J. Neuropathol. Exp. Neurol. 69, 930–944 (2010).

  • 96.

    et al. HIV-1 viral protein R activates NLRP3 inflammasome in microglia: implications for HIV-1 associated neuroinflammation. J. Neuroimmune Pharmacol. 12, 233–248 (2017).

  • 97.

    et al. Distribution of insulin receptor substrate-2 in brain areas involved in energy homeostasis. Brain Res. 1112, 169–178 (2006).

  • 98.

    , & A direct action of insulin on the hypothalamic satiety center. Am. J. Physiol. 219, 938–943 (1970).

  • 99.

    , & Short-term influence of intra-ventromedial hypothalamic administration of insulin on feeding in normal and diabetic rats. Pharmacol. Biochem. Behav. 2, 223–226 (1974).

  • 100.

    & Increased feeding in response to bilateral injection of insulin antibodies in the VMH. Physiol. Behav. 19, 309–313 (1977).

  • 101.

    & The role of insulin as a satiety factor in the central nervous system. Adv. Metab. Disord. 10, 457–468 (1983).

  • 102.

    , , , & Insulin in the brain: a hormonal regulator of energy balance. Endocr. Rev. 13, 387–414 (1992).

  • 103.

    & Effects of insulin administered into cerebrospinal fluid spaces on blood glucose in unanaesthetized and anaesthetized dogs. Indian J. Med. Res. 75, 607–615 (1982).

  • 104.

    , , , & Acute third ventricular administration of insulin decreases food intake in two paradigms. Pharmacol. Biochem. Behav. 72, 423–429 (2002).

  • 105.

    , , & Chronic intracerebroventricular infusion of insulin reduces food intake and body weight of baboons. Nature 282, 503–505 (1979).

  • 106.

    , & Evaluation of the lack of anorectic effect of intracerebroventricular insulin in rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 298, R43–R50 (2010).

  • 107.

    et al. Hypothalamic K(ATP) channels control hepatic glucose production. Nature 434, 1026–1031 (2005).

  • 108.

    , , , & Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats. Nat. Neurosci. 5, 566–572 (2002).

  • 109.

    , , & Hypothalamic insulin signaling is required for inhibition of glucose production. Nat. Med. 8, 1376–1382 (2002).

  • 110.

    et al. Brain insulin controls adipose tissue lipolysis and lipogenesis. Cell Metab. 13, 183–194 (2011).

  • 111.

    et al. Intranasal insulin suppresses systemic but not subcutaneous lipolysis in healthy humans. J. Clin. Endocrinol. Metab. 99, E246–E251 (2014).

  • 112.

    et al. Brain insulin lowers circulating BCAA levels by inducing hepatic BCAA catabolism. Cell Metab. 20, 898–909 (2014).

  • 113.

    et al. Increased susceptibility to metabolic dysregulation in a mouse model of Alzheimer’s disease is associated with impaired hypothalamic insulin signaling and elevated BCAA levels. Alzheimers Dement. 12, 851–861 (2016).

  • 114.

    , , , & Differential sensitivity of men and women to anorexigenic and memory-improving effects of intranasal insulin. J. Clin. Endocrinol. Metab. 93, 1339–1344 (2008).

  • 115.

    , , , & Obese men respond to cognitive but not to catabolic brain insulin signaling. Int. J. Obes. (Lond.) 32, 275–282 (2008).

  • 116.

    et al. Intranasal insulin improves memory in humans. Psychoneuroendocrinology 29, 1326–1334 (2004).

  • 117.

    , , & Central insulin administration improves odor-cued reactivation of spatial memory in young men. J. Clin. Endocrinol. Metab. 100, 212–219 (2015).

  • 118.

    et al. Enhancement of vasoreactivity and cognition by intranasal insulin in type 2 diabetes. Diabetes Care 37, 751–759 (2014).

  • 119.

    et al. Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype. Neurobiol. Aging 27, 451–458 (2006).

  • 120.

    et al. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch. Neurol. 69, 29–38 (2012).

  • 121.

    et al. Long acting intranasal insulin detemir improves cognition for adults with mild cognitive impairment or early-stage alzheimer’s disease dementia. J. Alzheimers Dis. 45, 1269–1270 (2015).

  • 122.

    et al. Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-β in memory-impaired older adults. J. Alzheimers Dis. 13, 323–331 (2008).

  • 123.

    , , & Comparable sensitivity of postmenopausal and young women to the effects of intranasal insulin on food intake and working memory. J. Clin. Endocrinol. Metab. 95, E468–E472 (2010).

  • 124.

    et al. Insulin modulates food-related activity in the central nervous system. J. Clin. Endocrinol. Metab. 95, 748–755 (2010).

  • 125.

    et al. Intranasal insulin enhanced resting-state functional connectivity of hippocampal regions in type 2 diabetes. Diabetes 64, 1025–1034 (2015).

  • 126.

    et al. Intranasal insulin increases regional cerebral blood flow in the insular cortex in men independently of cortisol manipulation. Hum. Brain Mapp. 35, 1944–1956 (2014).

  • 127.

    , , & Central nervous system effects of intranasally administered insulin during euglycemia in men. Diabetes 48, 557–563 (1999).

  • 128.

    et al. Transcortical direct current potential shift reflects immediate signaling of systemic insulin to the human brain. Diabetes 53, 2202–2208 (2004).

  • 129.

    et al. Insulin modulation of magnetoencephalographic resting state dynamics in lean and obese subjects. Front. Syst. Neurosci. 4, 157 (2010).

  • 130.

    et al. The cerebrocortical response to hyperinsulinemia is reduced in overweight humans: a magnetoencephalographic study. Proc. Natl Acad. Sci. USA 103, 12103–12108 (2006).

  • 131.

    et al. Insulin effects on glucose metabolism, memory, and plasma amyloid precursor protein in Alzheimer’s disease differ according to apolipoprotein-E genotype. Ann. NY Acad. Sci. 903, 222–228 (2000).

  • 132.

    & Mini-review: impact of recurrent hypoglycemia on cognitive and brain function. Physiol. Behav. 100, 234–238 (2010).

  • 133.

    & Glucose improves object-location binding in visual-spatial working memory. Psychopharmacol. (Berl.) 233, 529–547 (2016).

  • 134.

    , & Glucose levels and risk of dementia. N. Engl. J. Med. 369, 1863–1864 (2013).

  • 135.

    , & Decreases in rat extracellular hippocampal glucose concentration associated with cognitive demand during a spatial task. Proc. Natl Acad. Sci. USA 97, 2881–2885 (2000).

  • 136.

    & Food for thought: fluctuations in brain extracellular glucose provide insight into the mechanisms of memory modulation. Behav. Cogn. Neurosci. Rev. 1, 264–280 (2002).

  • 137.

    & Insulin Treatment in Psychiatry (Philosophical Library, 1959).

  • 138.

    , , & Depression and type 2 diabetes over the lifespan: a meta-analysis. Diabetes Care 31, 2383–2390 (2008).

  • 139.

    et al. Euglycemic infusion of insulin detemir compared with human insulin appears to increase direct current brain potential response and reduces food intake while inducing similar systemic effects. Diabetes 59, 1101–1107 (2010).

  • 140.

    Insulin resistance as the core defect in type 2 diabetes mellitus. Am. J. Cardiol. 90, 3G–10G (2002).

  • 141.

    et al. A biochemical and functional characterization of diet-induced brain insulin resistance. J. Neurochem. 93, 1568–1578 (2005).

  • 142.

    & Psychologic tests applied in diabetic patients. Arch. Internal Med. 30, 767–777 (1922).

  • 143.

    et al. Decreased cognitive function in aging non-insulin-dependent diabetic patients. Am. J. Med. 77, 1043–1048 (1984).

  • 144.

    , , & Relationship between hyperglycemia and cognitive function in older NIDDM patients. Diabetes Care 13, 16–21 (1990).

  • 145.

    , , , & Type 2 diabetes and cognitive function in community-dwelling elderly women. Diabetes Care 24, 1060–1065 (2001).

  • 146.

    et al. Cognition in the early stage of type 2 diabetes. Diabetes Care 32, 1261–1265 (2009).

  • 147.

    et al. Brain magnetic resonance imaging correlates of impaired cognition in patients with type 2 diabetes. Diabetes 55, 1106–1113 (2006).

  • 148.

    , & Investigation on the relationship between diabetes mellitus type 2 and cognitive impairment. Diabetes Res. Clin. Pract. 82, 305–309 (2008).

  • 149.

    et al. Diabetic retinopathy and cognitive decline in older people with type 2 diabetes: the Edinburgh Type 2 Diabetes Study. Diabetes 59, 2883–2889 (2010).

  • 150.

    et al. Midlife vascular risk factors and late-life mild cognitive impairment: a population-based study. Neurology 56, 1683–1689 (2001).

  • 151.

    et al. The metabolic syndrome, inflammation, and risk of cognitive decline. JAMA 292, 2237–2242 (2004).

  • 152.

    et al. Cerebrovascular and brain morphologic correlates of mild cognitive impairment in the National Heart, Lung, and Blood Institute Twin Study. Arch. Neurol. 58, 643–647 (2001).

  • 153.

    , , & Is type II diabetes associated with an increased risk of cognitive dysfunction? A critical review of published studies. Diabetes Care 20, 438–445 (1997).

  • 154.

    & Type 2 diabetes mellitus, cognitive impairment and dementia. Diabet Med. 16, 93–112 (1999).

  • 155.

    et al. Preliminary evidence for brain complications in obese adolescents with type 2 diabetes mellitus. Diabetologia 53, 2298–2306 (2010).

  • 156.

    , , , & Obesity and metabolic syndrome and functional and structural brain impairments in adolescence. Pediatrics 130, e856–e864 (2012).

  • 157.

    , , , & White matter microstructure and cognitive function in young women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 101, 314–323 (2016).

  • 158.

    et al. Glucose indices are associated with cognitive and structural brain measures in young adults. Neurology 84, 2329–2337 (2015).

  • 159.

    , & Brain imaging in type 2 diabetes. Eur. Neuropsychopharmacol. 24, 1967–1981 (2014).

  • 160.

    et al. Is type 2 diabetes related to leukoaraiosis? an updated review. Acta Neurol. Scand. 132, 147–155 (2015).

  • 161.

    et al. Insulin resistance and Alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes. Arch. Neurol. 68, 51–57 (2011).

  • 162.

    et al. Association of insulin resistance with cerebral glucose uptake in late middle-aged adults at risk for alzheimer disease. JAMA Neurol. 72, 1013–1020 (2015).

  • 163.

    et al. Diabetes and elevated hemoglobin A1c levels are associated with brain hypometabolism but not amyloid accumulation. J. Nucl. Med. 55, 759–764 (2014).

  • 164.

    et al. Increased blood-brain barrier permeability in type II diabetes demonstrated by gadolinium magnetic resonance imaging. J. Neurol. Neurosurg. Psychiatry 74, 70–76 (2003).

  • 165.

    et al. Chronic type 2 diabetes reduces the integrity of the blood-brain barrier by reducing tight junction proteins in the hippocampus. J. Vet. Med. Sci. 78, 957–962 (2016).

  • 166.

    , , & Diabetes mellitus and blood-brain barrier dysfunction: an overview. J. Pharmacovigil. 2, 125 (2014).

  • 167.

    et al. High fat diet produces brain insulin resistance, synaptodendritic abnormalities and altered behavior in mice. Neurobiol. Dis. 67, 79–87 (2014).

  • 168.

    et al. High-fat diet induces hepatic insulin resistance and impairment of synaptic plasticity. PLoSONE 10, e0128274 (2015).

  • 169.

    , , & Mitochondrial abnormalities and synaptic loss underlie memory deficits seen in mouse models of obesity and Alzheimer’s disease. J. Alzheimers Dis. 55, 915–932 (2017).

  • 170.

    et al. Differential central pathology and cognitive impairment in pre-diabetic and diabetic mice. Psychoneuroendocrinology 38, 2462–2475 (2013).

  • 171.

    et al. Attenuation of insulin-evoked responses in brain networks controlling appetite and reward in insulin resistance: the cerebral basis for impaired control of food intake in metabolic syndrome? Diabetes 55, 2986–2992 (2006).

  • 172.

    et al. Variation in the FTO gene locus is associated with cerebrocortical insulin resistance in humans. Diabetologia 50, 2602–2603 (2007).

  • 173.

    , , & Changes in blood glucose and insulin secretion in patients with senile dementia of Alzheimer type. ActaMed. Scand. 213, 387–392 (1983).

  • 174.

    et al. Dementia is associated with insulin resistance in patients with Parkinson’s disease. J. Neurol. Sci. 315, 39–43 (2012).

  • 175.

    , , , & Clinical features of Parkinson disease when onset of diabetes came first: a case-control study. Neurology 78, 1507–1511 (2012).

  • 176.

    et al. Diabetes and risk of Parkinson’s disease. Mov Disord. 28, 257 (2013).

  • 177.

    et al. Prospective cohort study of type 2 diabetes and the risk of Parkinson’s disease. DiabetesCare 31, 2003–2005 (2008).

  • 178.

    , , , & Type 2 diabetes and the risk of Parkinson’s disease. Diabetes Care 30, 842–847 (2007).

  • 179.

    et al. Diabetes is associated with postural instability and gait difficulty in Parkinson disease. Parkinsonism Relat. Disord. 19, 522–526 (2013).

  • 180.

    The relationship between diabetes mellitus and Parkinson’s disease. Int. J. Neurosci. 69, 125–130 (1993).

  • 181.

    et al. Risk of Parkinson disease onset in patients with diabetes: a 9-year population-based cohort study with age and sex stratifications. Diabetes Care 35, 1047–1049 (2012).

  • 182.

    et al. Metformin-inclusive sulfonylurea therapy reduces the risk of Parkinson’s disease occurring with Type 2 diabetes in a Taiwanese population cohort. Parkinsonism Relat. Disord. 18, 753–758 (2012).

  • 183.

    et al. Diabetes and risk of Parkinson’s disease. Diabetes Care 34, 910–915 (2011).

  • 184.

    et al. Cardiovascular risk factors and frontotemporal dementia: a case-control study. Transl Neurodegener. 3, 13 (2014).

  • 185.

    et al. Diabetes, Alzheimer disease, and vascular dementia: a population-based neuropathologic study. Neurology 75, 1195–1202 (2010).

  • 186.

    et al. Diabetes mellitus is a risk factor for vascular dementia, but not for Alzheimer’s disease: a population-based study of the oldest old. Int. Psychogeriatr. 14, 239–248 (2002).

  • 187.

    et al. Vascular risk factors for incident Alzheimer disease and vascular dementia: the Cache County study. Alzheimer Dis. Assoc. Disord. 20, 93–100 (2006).

  • 188.

    et al. Mid-life and late-life vascular risk factors and dementia in Korean men and women. Arch. Gerontol. Geriatr. 52, e117–e122 (2011).

  • 189.

    et al. Glucose tolerance status and risk of dementia in the community: the Hisayama study. Neurology 77, 1126–1134 (2011).

  • 190.

    , , & Honolulu-Asia Aging Study. Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: The Honolulu-Asia Aging Study. Diabetes 51, 1256–1262 (2002).

  • 191.

    et al. The relationship of hypertension in the elderly to AD, vascular dementia, and cognitive function. Neurology 58, 1175–1181 (2002).

  • 192.

    et al. Mid- and late-life diabetes in relation to the risk of dementia: a population-based twin study. Diabetes 58, 71–77 (2009).

  • 193.

    , , & Diabetes mellitus and risk of dementia: a meta-analysis of prospective observational studies. J. Diabetes Investig. 4, 640–650 (2013).

  • 194.

    Therapeutic targets of brain insulin resistance in sporadic Alzheimer’s disease. Front. Biosci. (Elite Ed.) 4, 1582–1605 (2012).

  • 195.

    Diabetes mellitus induces Alzheimer’s disease pathology: histopathological evidence from animal models. Int. J. Mol. Sci. 17, 503 (2016).

  • 196.

    , , & Diet-induced obesity accelerates the onset of terminal phenotypes in alpha-synuclein transgenic mice. J. Neurochem. 131, 848–858 (2014).

  • 197.

    , , , & Brain imaging in patients with diabetes: a systematic review. Diabetes Care 29, 2539–2548 (2006).

  • 198.

    et al. Type 2 diabetes and atrophy of medial temporal lobe structures on brain MRI. Diabetologia 46, 1604–1610 (2003).

  • 199.

    et al. Hippocampal damage and memory impairments as possible early brain complications of type 2 diabetes. Diabetologia 50, 711–719 (2007).

  • 200.

    et al. Impaired insulin sensitivity as indexed by the HOMA score is associated with deficits in verbal fluency and temporal lobe gray matter volume in the elderly. Diabetes Care 35, 488–494 (2012).

  • 201.

    et al. Association of metabolic dysregulation with volumetric brain magnetic resonance imaging and cognitive markers of subclinical brain aging in middle-aged adults: the Framingham Offspring Study. Diabetes Care 34, 1766–1770 (2011).

  • 202.

    et al. Insulin resistance and hippocampal volume in women at risk for Alzheimer’s disease. Neurobiol. Aging 32, 1942–1948 (2011).

  • 203.

    et al. Insulin resistance, brain atrophy, and cognitive performance in late middle-aged adults. Diabetes Care 36, 443–449 (2013).

  • 204.

    et al. Adiposity is inversely associated with hippocampal volume in African Americans and European Americans with diabetes. J. Diabetes Compl. 30, 1506–1512 (2016).

  • 205.

    et al. Memory dysfunction in type 2 diabetes mellitus correlates with reduced hippocampal CA1 and subiculum volumes. Chin. Med. J. (Engl.) 128, 465–471 (2015).

  • 206.

    , , & Neural substrates of verbal memory impairments in adults with type 2 diabetes mellitus. J. Clin. Exp. Neuropsychol. 36, 74–87 (2014).

  • 207.

    , & Type 2 diabetes affects hippocampus volume differentially in men and women. Diabetes Metab. Res. Rev. 28, 76–83 (2012).

  • 208.

    et al. Type 2 diabetes mellitus and biomarkers of neurodegeneration. Neurology 85, 1123–1130 (2015).

  • 209.

    , , & Alzheimer’s Disease Neuroimaging Initiative. Insulin resistance predicts medial temporal hypermetabolism in mild cognitive impairment conversion to Alzheimer disease. Diabetes 64, 1933–1940 (2015).

  • 210.

    et al. Cognitive dysfunctions in middle-aged type 2 diabetic patients and neuroimaging correlations: a cross-sectional study. J. Alzheimers Dis. 42, 1337–1346 (2014).

  • 211.

    et al. The relationship between fasting serum glucose and cerebral glucose metabolism in late-life depression and normal aging. Psychiatry Res. 222, 84–90 (2014).

  • 212.

    et al. Impaired glucose tolerance in midlife and longitudinal changes in brain function during aging. Neurobiol. Aging 34, 2271–2276 (2013).

  • 213.

    et al. Cerebral haemodynamics, cognition and brain volumes in patients with type 2 diabetes. J. Diabetes Compl. 26, 205–209 (2012).

  • 214.

    et al. Resting-state brain functional connectivity is altered in type 2 diabetes. Diabetes 61, 2375–2379 (2012).

  • 215.

    et al. Cerebral perfusion alterations in type 2 diabetes and its relation to insulin resistance and cognitive dysfunction. Brain Imaging Behav. 11, 1248–1257 (2017).

  • 216.

    et al. Insulin resistance is associated with lower arterial blood flow and reduced cortical perfusion in cognitively asymptomatic middle-aged adults. J. Cereb. Blood Flow Metab. (2016).

  • 217.

    et al. Blood pressure is associated with cerebral blood flow alterations in patients with T2DM as revealed by perfusion functional MRI. Med. (Baltimore) 94, e2231 (2015).

  • 218.

    et al. Disrupted resting-state attentional networks in T2DM patients. Sci. Rep. 5, 11148 (2015).

  • 219.

    et al. Insulin resistance-associated interhemispheric functional connectivity alterations in T2DM: a resting-state fMRI study. Biomed. Res. Int. 2015, 719076 (2015).

  • 220.

    et al. Altered baseline brain activity in type 2 diabetes: a resting-state fMRI study. Psychoneuroendocrinology 38, 2493–2501 (2013).

  • 221.

    et al. Insulin resistance predicts brain amyloid deposition in late middle-aged adults. Alzheimers Dement. 11, 504–510 (2015).

  • 222.

    et al. Glucose intolerance, insulin resistance, and pathological features of Alzheimer disease in the Baltimore Longitudinal Study of Aging. JAMA Neurol. 70, 1167–1172 (2013).

  • 223.

    et al. Brain accumulation of amyloid-β protein visualized by positron emission tomography and BF-227 in Alzheimer’s disease patients with or without diabetes mellitus. Geriatr. Gerontol. Int. 13, 215–221 (2013).

  • 224.

    et al. Identification of diabetes-related dementia: longitudinal perfusion SPECT and amyloid PET studies. J. Neurol. Sci. 349, 45–51 (2015).

  • 225.

    et al. Insulin resistance is associated with higher cerebrospinal fluid tau levels in asymptomatic APOε4 Carriers. J. Alzheimers Dis. 46, 525–533 (2015).

  • 226.

    & Diabetics do not have increased Alzheimer-type pathology compared with age-matched control subjects. A retrospective postmortem immunocytochemical and histofluorescent study. Neurology 49, 1306–1311 (1997).

  • 227.

    et al. Insulin in combination with other diabetes medication is associated with less Alzheimer neuropathology. Neurology 71, 750–757 (2008).

  • 228.

    et al. Different patterns of cerebral injury in dementia with or without diabetes. Arch. Neurol. 66, 315–322 (2009).

  • 229.

    et al. Diabetes is related to cerebral infarction but not to AD pathology in older persons. Neurology 67, 1960–1965 (2006).

  • 230.

    et al. Human cerebral neuropathology of Type 2 diabetes mellitus. Biochim. Biophys. Acta 1792, 454–469 (2009).

  • 231.

    et al. Diabetes is associated with cerebrovascular but not Alzheimer’s disease neuropathology. Alzheimers Dement. 12, 882–889 (2016).

  • 232.

    et al. Increased Alzheimer’s disease neuropathology is associated with type 2 diabetes and ApoE ε4 carrier status. Curr. Alzheimer Res. 10, 654–659 (2013).

  • 233.

    et al. Glucose levels during life and neuropathologic findings at autopsy among people never treated for diabetes. Neurobiol. Aging 48, 72–82 (2016).

  • 234.

    Intracranial vascular lesions in patients with diabetes mellitus. J. Neuropathol. Exp. Neurol. 32, 183–196 (1973).

  • 235.

    , , , & β-Amyloid deposition in brains of subjects with diabetes. Neuropathol. Appl. Neurobiol. 35, 60–68 (2009).

  • 236.

    , & Neuropathology of type 2 diabetes: a short review on insulin-related mechanisms. Eur. Neuropsychopharmacol 24, 1961–1966 (2014).

  • 237.

    & Type 2 diabetes as a risk factor for Alzheimer’s disease: the confounders, interactions, and neuropathology associated with this relationship. Epidemiol. Rev. 35, 152–160 (2013).

  • 238.

    et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N. Engl. J. Med. 367, 795–804 (2012).

  • 239.

    , , , & Alzheimer’s Disease Neuroimaging Initiative. Impaired glycemia increases disease progression in mild cognitive impairment. Neurobiol. Aging 35, 585–589 (2014).

  • 240.

    et al. Impaired fasting glucose is associated with increased regional cerebral amyloid. Neurobiol. Aging 44, 138–142 (2016).

  • 241.

    et al. Apolipoprotein E gene polymorphism: effects on plasma lipids and risk of type 2 diabetes and coronary artery disease. Cardiovasc. Diabetol. 11, 36 (2012).

  • 242.

    , & Apolipoprotein E gene polymorphism and risk of type 2 diabetes and cardiovascular disease. Cardiovasc. Diabetol 15, 12 (2016).

  • 243.

    & Recent advances in understanding the genetic architecture of type 2 diabetes. Hum. Mol. Genet. 24, R85–R92 (2015).

  • 244.

    & Genes, genetics, and environment in type 2 diabetes: implication in personalized medicine. DNA Cell Biol. 35, 1–12 (2016).

  • 245.

    , & Genetics of type 2 diabetes: insights into the pathogenesis and its clinical application. Biomed. Res. Int. 2014, 926713 (2014).

  • 246.

    & Genetics of Alzheimer’s disease. Adv. Genet. 87, 245–294 (2014).

  • 247.

    & Alzheimer’s disease risk genes and mechanisms of disease pathogenesis. Biol. Psychiatry 77, 43–51 (2015).

  • 248.

    et al. SORCS1: a novel human type 2 diabetes susceptibility gene suggested by the mouse. Diabetes 56, 1922–1929 (2007).

  • 249.

    et al. Genomic convergence to identify candidate genes for Alzheimer disease on chromosome 10. Hum. Mutat. 30, 463–471 (2009).

  • 250.

    et al. Diabetes-associated SorCS1 regulates Alzheimer’s amyloid-beta metabolism: evidence for involvement of SorL1 and the retromer complex. J. Neurosci. 30, 13110–13115 (2010).

  • 251.

    Glucose intolerance and aging. Diabetes Care 4, 493–501 (1981).

  • 252.

    et al. Age as independent determinant of glucose tolerance. Diabetes 40, 44–51 (1991).

  • 253.

    et al. The natural history of progression from normal glucose tolerance to type 2 diabetes in the Baltimore Longitudinal Study of Aging. Diabetes 52, 1475–1484 (2003).

  • 254.

    et al. Insulin action and age. European Group for the Study of Insulin Resistance (EGIR). Diabetes 45, 947–953 (1996).

  • 255.

    et al. Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer’s disease: link to brain reductions in acetylcholine. J. Alzheimers Dis. 8, 247–268 (2005).

  • 256.

    et al. Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer’s disease indicate possible resistance to IGF-1 and insulin signalling. Neurobiol. Aging 31, 224–243 (2010).

  • 257.

    Is sporadic Alzheimer disease the brain type of non-insulin dependent diabetes mellitus? A challenging hypothesis. J. Neural Transm. (Vienna) 105, 415–422 (1998).

  • 258.

    & Cerebral excess release of neurotransmitter amino acids subsequent to reduced cerebral glucose metabolism in early-onset dementia of Alzheimer type. J. Neural Transm. 75, 227–232 (1989).

  • 259.

    , & Brain insulin-like growth factor and neurotrophin resistance in Parkinson’s disease and dementia with Lewy bodies: potential role of manganese neurotoxicity. J. Alzheimers Dis. 16, 585–599 (2009).

  • 260.

    et al. Role of protein kinase B in Alzheimer’s neurofibrillary pathology. Acta Neuropathol. 105, 381–392 (2003).

  • 261.

    et al. Akt activity in Alzheimer’s disease and other neurodegenerative disorders. Neuroreport 15, 955–959 (2004).

  • 262.

    , , , & Levels of mTOR and its downstream targets 4E-BP1, eEF2, and eEF2 kinase in relationships with tau in Alzheimer’s disease brain. FEBS J. 272, 4211–4220 (2005).

  • 263.

    et al. Activation of Akt/PKB, increased phosphorylation of Akt substrates and loss and altered distribution of Akt and PTEN are features of Alzheimer’s disease pathology. J. Neurochem. 93, 105–117 (2005).

  • 264.

    , & Role of glycogen synthase kinase-3 in Alzheimer’s disease pathogenesis and glycogen synthase kinase-3 inhibitors. Expert Rev. Neurother 10, 703–710 (2010).

  • 265.

    , & The GSK3 hypothesis of Alzheimer’s disease. J. Neurochem. 104, 1433–1439 (2008).

  • 266.

    et al. An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease-associated Abeta oligomers. J. Clin. Invest. 122, 1339–1353 (2012).

  • 267.

    et al. Abnormal serine phosphorylation of insulin receptor substrate 1 is associated with tau pathology in Alzheimer’s disease and tauopathies. Acta Neuropathol. 128, 679–689 (2014).

  • 268.

    et al. Alteration of mTOR signaling occurs early in the progression of Alzheimer disease (AD): analysis of brain from subjects with pre-clinical AD, amnestic mild cognitive impairment and late-stage AD. J. Neurochem. 133, 739–749 (2015).

  • 269.

    et al. Metaflammasome components in the human brain: a role in dementia with alzheimer’s pathology? Brain Pathol. 27, 266–275 (2017).

  • 270.

    et al. Loss of insulin receptor immunoreactivity from the substantia nigra pars compacta neurons in Parkinson’s disease. Acta Neuropathol. 87, 343–348 (1994).

  • 271.

    et al. Insulin receptor mRNA in the substantia nigra in Parkinson’s disease. Neurosci. Lett. 204, 201–204 (1996).

  • 272.

    , , & O’Neill C. Akt signal transduction dysfunction in Parkinson’s disease. Neurosci. Lett. 467, 30–35 (2009).

  • 273.

    et al. Effects of regular and long-acting insulin on cognition and alzheimer’s disease biomarkers: a pilot clinical trial. J. Alzheimers Dis. 57, 1325–1334 (2017).

  • 274.

    & Repurposing diabetes drugs for brain insulin resistance in Alzheimer disease. Diabetes 63, 2253–2261 (2014).

  • 275.

    et al. Metformin in amnestic mild cognitive impairment: results of a pilot randomized placebo controlled clinical trial. J. Alzheimers Dis. 51, 501–514 (2016).

  • 276.

    et al. Effects of the insulin sensitizer metformin in alzheimer disease: pilot data from a randomized placebo-controlled crossover study. Alzheimer Dis. Assoc. Disord. 31, 107–113 (2017).

  • 277.

    , & Peroxisome proliferator-activated receptors (PPARs) as therapeutic target in neurodegenerative disorders. Biochem. Biophys. Res. Commun. 483, 1166–1177 (2017).

  • 278.

    et al. Rosiglitazone does not improve cognition or global function when used as adjunctive therapy to AChE inhibitors in mild-to-moderate Alzheimer’s disease: two phase 3 studies. Curr. Alzheimer Res. 8, 592–606 (2011).

  • 279.

    , & Incretin-based therapy for type 2 diabetes mellitus is promising for treating neurodegenerative diseases. Rev. Neurosci. 27, 689–711 (2016).



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