Therapeutics

Nasal Insulin

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Overview

Name: Nasal Insulin
Synonyms: Detemir, Levemir, Humulin, Novolin, glulisine
Therapy Type: Small Molecule (timeline), Other
Target Type: Amyloid-Related (timeline), Other (timeline)
Condition(s): Alzheimer's Disease, Mild Cognitive Impairment, Parkinson's Disease, Multiple System Atrophy
U.S. FDA Status: Alzheimer's Disease (Phase 2/3), Mild Cognitive Impairment (Phase 2), Parkinson's Disease (Phase 2), Multiple System Atrophy (Phase 2)
Approved for: Diabetes

Background

Insulin is the peptide hormone that is standard treatment for the management of Type 1 diabetes. In a new therapeutic approach, various forms of commercially available insulin are being atomized into a spray and inhaled through the nose. The rationale behind this exploration of insulin for the treatment of cognitive impairment and dementia is twofold. First, brain areas affected in Alzheimer's disease have been shown to express insulin receptors, and insulin levels as well as insulin receptor signaling are thought to be reduced in Alzheimer's (e.g., Chiu et al., 2008; Steen et al., 2005). Second, if effective, delivery of this hormone directly into the brain along olfactory perivascular channels would sidestep the peripheral bloodstream. This would avoid the unwanted effect of increasing systemic insulin levels, which could lead to hypoglycemia or insulin resistance (e.g., Born et al., 2002).

The physiological role of insulin in the brain is incompletely understood, but it has been implicated in synaptic remodeling and glucose utilization. Insulin has also been proposed to protect against Aβ toxicity, and insulin deficits have been linked to tau pathology, neuroinflammation, and other aspects of Alzheimer's pathophysiology (De Felice et al., 2009; El Khoury et al., 2014; Zhao et al., 2009). Insulin resistance, Type 2 diabetes, obesity, and metabolic syndrome are risk factors for Alzheimer's disease (see AlzRisk Diabetes, AlzRisk Obesity).

Intranasal insulin began attracting attention in Alzheimer's research when small human studies reported improved cognition without a change in blood glucose or insulin levels in healthy volunteers (e.g., May 2002 news; Benedict et al., 2004; Benedict et al., 2007).

Findings

A single-center pilot study at the Veterans Affairs Hospital/University of Washington in Seattle reported improved verbal memory retention and attention after a three-week test of 20 international units (IU) daily of intranasal insulin compared with placebo in 24 people with amnestic memory impairment (aMCI) or mild Alzheimer's disease. The insulin was delivered with an electronic atomizer (Reger et al., 2008).

A separate small trial comparing different doses in 33 people with aMCI or early AD reported differential effects by ApoE genotype (Reger et al., 2008).

Intranasal insulin appeared safe in a subsequent four-month course of 20 or 40 IUs of intranasal insulin or placebo given to a larger group of 104 people with aMCI or mild to moderate AD. Called SNIFF-120, this single-center study reported some preservation of cognition in younger participants and some preservation of function. The study reported no change in the CSF biomarkers between the groups, but some signals on subgroup analysis (Craft et al., 2012; Jul 2010 news). Different responses by gender or ApoE genotype were also reported (Claxton et al., 2013).

In September 2013, the Alzheimer's Disease Cooperative Study began enrolling for Study of Nasal Insulin in the Fight Against Forgetfulness (SNIFF), a federally funded study that delivered 20 IU of insulin or placebo after breakfast and dinner to 289 people with either aMCI or early AD. The first 49 participants used the same insulin delivery device as had been used in the previous trial; the remaining 240 used a different one. After one year of treatment, there was no cognitive or functional difference between insulin and placebo groups in the cohort of 240 who used the second delivery device. The smaller group of 48 who used the original device did show slowing of worsening in the ADAS-COG-12 subscale and activities of daily living at one year (Craft et al., 2020). A secondary analysis of MRI data from this smaller group found reduced accumulation of white-matter abnormalities in treated compared to placebo patients after one year (Kellar et al., 2021). Subsequent measurement of CSF markers of inflammation, immune function, and vascular integrity in these participants suggested that the observed clinical benefit correlated with changes consistent with anti-inflammatory properties of insulin (Kellar et al., 2022).

At AD/PD in March 2021, additional trial results were presented. Participants using the original device continued to do better than those on placebo during a six-month open-label period. There was no effect of insulin in the larger cohort using the second device. In a subsequent Phase 2 study to determine how much insulin entered the brain after nasal delivery, 19 people received 40 IU insulin or a placebo using the first device, followed by lumbar puncture. CSF insulin concentrations approximately doubled after 30 minutes. The manufacturer of the second device refused to allow its testing.

In July 2020, a Phase 2 trial of similar design began to compare three different intranasal delivery devices and two doses of insulin, 20 and 40 IU, in 30 people with no or mild cognitive impairment. It will run until October 2023.

In October 2021, a Phase 2 trial started to test nasal insulin alone or in combination with the insulin sensitizer empaglifozin. Taken in pill form, empagliflozin was recently shown to improve the response to nasally delivered insulin in the hypothalamus in people with prediabetes (Kullmann et al., 2022). The single site study at Wake Forest University will enroll 60 participants with elevated brain amyloid and normal cognition, MCI, or early dementia. The four-arm protocol will compare nasal insulin four times daily, one 10 mg empagliflozin pill daily, or both, to placebo. Safety is the primary outcome; secondaries include cognitive measures, CSF Aβ and tau, and brain blood flow. The study will run until 2028.  

This trial will use the Aptar Pharma CPS Intranasal Delivery Device, which is different from devices in previous SNIFF studies. A trial, planned to begin in May 2022, will assess adherence and CSF insulin concentrations in 60 people with AD or MCI who use the device for three weeks. The placebo-controlled study will also measure cognitive, functional, and biomarker outcomes. The estimated end date is May 2026.

The trials of intranasal insulin vary in that some evaluate fast-acting forms of insulin as used in diabetes therapy, while others evaluate longer-acting insulin analogs. For example, two trials conducted at the University of Washington, Seattle, between 2011 and 2013 evaluated insulin detemir, a long-acting insulin analog that differs from human insulin by one amino acid. A three-week study in 60 patients with MCI or AD compared 10 and 20 IUs of detemir twice daily to placebo. The higher dose improved memory in ApoE4 carriers, worsened it in noncarriers, and did not change daily function or executive function (Claxton et al., 2015). A subsequent four-month study compared 20 IUs twice daily of insulin detemir to 20 IUs of regular insulin twice daily in 36 patients. Regular insulin, but not detemir, improved memory compared with placebo, and was associated with preserved brain volume in several regions on MRI (Craft et al., 2017). These trials did not measure exposure or target engagement.

In a small study examining glulisine, a rapid acting form of insulin, nasal delivery of 20 UI twice daily for six months failed to improve cognition, function, or mood compared to placebo in 35 people with MCI or mild probable AD (Rosenbloom et al., 2021). In pilot trials, the same investigators reported no acute improvement in cognition after a single dose of glulisine compared to placebo in nine people with AD, or 12 with Down's syndrome (Rosenbloom et al., 2014; Rosenbloom et al., 2020). From 2015 to 2019, a pilot study of rapid-acting insulin aspart took place at Wake Forest. Twenty-four participants with AD got 20 UI twice daily for 12 weeks, against a primary outcome of change in the ADAS-Cog MCI scale. The trial finished in 2019.

Nasal insulin is also being evaluated for neurologic conditions other than Alzheimer's. In February 2014, a trial started up at the University of Massachusetts. It evaluated the effect of 40 IUs of regular insulin on a visuospatial memory test, the Unified Parkinson's Disease Rating Scale, and other measures compared to placebo in 15 patients with Parkinson's disease. Insulin improved verbal fluency and clinical measures of PD severity compared to placebo. One patient with MSA remained stable on insulin treatment (Novak et al., 2019).

Furthermore, various trials have evaluated nasal insulin for effects on cognitive symptoms in psychiatric conditions such as schizophrenia, bipolar, and major depressive disorder. 

For trials on nasal insulin in Alzheimer's, see clinicaltrials.gov. 

Last Updated: 04 Mar 2022

Comments

    • User Profile Image William Frey II
      HealthPartners Center for Memory and Aging and Professor, Graduate Program in Neuroscience, University of Minnesota
    • Posted:

    Intranasal insulin bypasses the blood-brain barrier, increases brain-cell energy, reduces white-matter hyperintensity, and improves memory in Alzheimer's and healthy adults.

    The noninvasive intranasal insulin treatment has been shown to be a safe and effective treatment for Alzheimer's disease which significantly reduces degeneration of the white matter of the brain and improves memory. In 1989, I discovered that the noninvasive intranasal method bypassed the blood-brain barrier to target therapeutics (including insulin) to the brain to treat neurodegenerative disorders such as Alzheimer's disease and stroke and later expanded the specific use of intranasal insulin to target the brain to treat Alzheimer's disease and Parkinson's disease (U.S. Patents 5,624,898; 6,313,093). Intranasal therapeutics reach the brain directly from the nasal cavity by traveling extracellularly along the olfactory and trigeminal neural pathways (Crowe et al., 2018).

    In 2004, Benedict et al. demonstrated that this intranasal insulin treatment improves memory in healthy adults with no change in the blood levels of insulin or glucose. Over the next several years, German researchers conducted a total of four human clinical trials showing that intranasal insulin improves memory in normal healthy adults. I approached Dr. Suzanne Craft about this intranasal insulin treatment and encouraged her to conduct a clinical trial in Alzheimer's patients. In 2006, Dr. Craft, at the University of Washington, and colleagues (of whom I was one), reported that intranasal insulin improved memory in only 20 minutes after a single intranasal insulin treatment in patients with Alzheimer's disease. In 2008, Dr. Craft and colleagues showed that intranasal insulin (bid) improved memory, attention, and functioning in Alzheimer's disease patients over a 21-day period, and in September of 2011, Dr. Craft and coworkers reported improved memory and general cognition and reduced loss of brain FDG uptake in patients with AD or amnestic mild cognitive impairment treated in a four-month clinical trial with no change in the blood levels of insulin or glucose. Intranasal insulin reduced the loss of glucose uptake and utilization as measured by FDG PET imaging in the bilateral frontal, right temporal, bilateral occipital and right precuneus, and cuneus regions of the brain. Dr. Craft has been the driving force behind many clinical trials of intranasal insulin for Alzheimer's disease.

    It is not surprising that intranasal insulin is an effective treatment for AD since it has been known for many years that glucose uptake and utilization is dramatically decreased in patients with AD based in part on the early PET work of Dr. Mony de Leon at NYU. Intranasal insulin increases brain-cell energy (ATP & Phosphocreatine) in brain cells in humans as demonstrated with 31-P-MRI. Glucose is the primary source of energy for brain cells, and the brain cells of AD patients are starved for energy. Alzheimer's disease has been shown to involve an insulin and IGF-I signaling deficiency in the brain by Eric Steen, Suzanne de la Monte, and colleagues in 2005. Dr. De la Monte has referred to Alzheimer's as Type 3 Diabetes. We also know that Type 2 diabetes doubles the risk for developing Alzheimer's disease. Intranasal insulin may possibly reduce the risk of individuals with diabetes from developing Alzheimer's disease and help to prevent or delay the onset of the disease.

    Intranasal insulin is far more than simply a treatment for AD symptoms. Recently Kellar et al. (2021) reported that Intranasal Insulin Reduces White Matter Hyperintensity Progression in Association with Improvements in Cognition and CSF Biomarker Profiles in MCI and AD. Also, when intranasal insulin reaches the brain, it also stimulates the formation of insulin-degrading enzyme (IDE) which is capable of degrading Aβ, one of the principal abnormal proteins known to accumulate in the brains of AD patients. Insulin has also been reported to enhance Aβ clearance from the brain (Vandal et al., 2014). Further, the activity of glycogen-synthase kinase-3-β, the enzyme that phosphorylates tau to create AD neurofibrillary tangles, has been reported to be downregulated in response to insulin. Also, insulin receptor signaling increases synaptic density, and loss of synapses is key to the neuropathology of AD. Dr. Fernanda De Felice and colleagues have demonstrated that insulin protects both insulin receptors and synapses from Aβ oligomers and prevents the overall negative impact of Aβ on neurons (Freiherr et al., 2013; Lourenco et al., 2013). The insulin-signaling deficit precedes Aβ-42 accumulation in a transgenic mouse model, and intranasal insulin was also reported to increase regional cerebral blood flow in the insular cortex in humans (Schilling et al., 2014). Additionally, intranasal insulin is anti-inflammatory.

    Most recently, researchers at Harvard and the University of Massachusetts reported that our intranasal insulin is safe in Parkinson's and MSA patients and may provide clinically relevant functional improvement (Novak et al., 2019).

    References:

    Crowe TP, Greenlee MH, Kanthasamy AG, Hsu WH. Mechanism of intranasal drug delivery directly to the brain. Life Sci. 2018 Feb 15;195:44-52. Epub 2017 Dec 22 PubMed.

    Kellar D, Lockhart SN, Aisen P, Raman R, Rissman RA, Brewer J, Craft S. Intranasal Insulin Reduces White Matter Hyperintensity Progression in Association with Improvements in Cognition and CSF Biomarker Profiles in Mild Cognitive Impairment and Alzheimer's Disease. J Prev Alzheimers Dis. 2021;8(3):240-248. PubMed.

    Vandal M, White PJ, Tremblay C, St-Amour I, Chevrier G, Emond V, Lefrançois D, Virgili J, Planel E, Giguere Y, Marette A, Calon F. Insulin reverses the high-fat diet-induced increase in brain Aβ and improves memory in an animal model of Alzheimer disease. Diabetes. 2014 Dec;63(12):4291-301. Epub 2014 Jul 9 PubMed.

    Freiherr J, Hallschmid M, Frey WH, Brünner YF, Chapman CD, Hölscher C, Craft S, De Felice FG, Benedict C. Intranasal insulin as a treatment for Alzheimer's disease: a review of basic research and clinical evidence. CNS Drugs. 2013 Jul;27(7):505-14. PubMed.

    Lourenco MV, Clarke JR, Frozza RL, Bomfim TR, Forny-Germano L, Batista AF, Sathler LB, Brito-Moreira J, Amaral OB, Silva CA, Freitas-Correa L, Espírito-Santo S, Campello-Costa P, Houzel JC, Klein WL, Holscher C, Carvalheira JB, Silva AM, Velloso LA, Munoz DP, Ferreira ST, De Felice FG. TNF-α mediates PKR-dependent memory impairment and brain IRS-1 inhibition induced by Alzheimer's β-amyloid oligomers in mice and monkeys. Cell Metab. 2013 Dec 3;18(6):831-43. PubMed.

    Schilling TM, Ferreira de Sá DS, Westerhausen R, Strelzyk F, Larra MF, Hallschmid M, Savaskan E, Oitzl MS, Busch HP, Naumann E, Schächinger H. Intranasal insulin increases regional cerebral blood flow in the insular cortex in men independently of cortisol manipulation. Hum Brain Mapp. 2014 May;35(5):1944-56. Epub 2013 Aug 1 PubMed.

    Novak P, Pimentel Maldonado DA, Novak V. Safety and preliminary efficacy of intranasal insulin for cognitive impairment in Parkinson disease and multiple system atrophy: A double-blinded placebo-controlled pilot study. PLoS One. 2019;14(4):e0214364. Epub 2019 Apr 25 PubMed.

    View all comments by William Frey II

  2. Are there any mass spectrometry or other studies that show the distribution of intranasal insulin in the brain?

    View all comments by Mary Newport

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References

News Citations

  1. Honolulu: Intranasal Insulin Trial Claims Promise in MCI, AD
  2. Sniff This: Therapeutic Peptides Through the Nose?

Therapeutics Citations

  1. Empagliflozin

Paper Citations

  1. Reger MA, Watson GS, Green PS, Wilkinson CW, Baker LD, Cholerton B, Fishel MA, Plymate SR, Breitner JC, DeGroodt W, Mehta P, Craft S. Intranasal insulin improves cognition and modulates beta-amyloid in early AD. Neurology. 2008 Feb 5;70(6):440-8. PubMed.
  2. Reger MA, Watson GS, Green PS, Baker LD, Cholerton B, Fishel MA, Plymate SR, Cherrier MM, Schellenberg GD, Frey WH, Craft S. Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired older adults. J Alzheimers Dis. 2008 Apr;13(3):323-31. PubMed.
  3. Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, Arbuckle M, Callaghan M, Tsai E, Plymate SR, Green PS, Leverenz J, Cross D, Gerton B. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol. 2012 Jan;69(1):29-38. PubMed.
  4. Claxton A, Baker LD, Wilkinson CW, Trittschuh EH, Chapman D, Watson GS, Cholerton B, Plymate SR, Arbuckle M, Craft S. Sex and ApoE Genotype Differences in Treatment Response to Two Doses of Intranasal Insulin in Adults with Mild Cognitive Impairment or Alzheimer's Disease. J Alzheimers Dis. 2013 Jan 1;35(4):789-97. PubMed.
  5. Craft S, Raman R, Chow TW, Rafii MS, Sun CK, Rissman RA, Donohue MC, Brewer JB, Jenkins C, Harless K, Gessert D, Aisen PS. 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 Sep 1;77(9):1099-1109. PubMed.
  6. Kellar D, Lockhart SN, Aisen P, Raman R, Rissman RA, Brewer J, Craft S. Intranasal Insulin Reduces White Matter Hyperintensity Progression in Association with Improvements in Cognition and CSF Biomarker Profiles in Mild Cognitive Impairment and Alzheimer's Disease. J Prev Alzheimers Dis. 2021;8(3):240-248. PubMed.
  7. Kellar D, Register T, Lockhart SN, Aisen P, Raman R, Rissman RA, Brewer J, Craft S. Intranasal insulin modulates cerebrospinal fluid markers of neuroinflammation in mild cognitive impairment and Alzheimer's disease: a randomized trial. Sci Rep. 2022 Jan 25;12(1):1346. PubMed.
  8. Kullmann S, Hummel J, Wagner R, Dannecker C, Vosseler A, Fritsche L, Veit R, Kantartzis K, Machann J, Birkenfeld AL, Stefan N, Häring HU, Peter A, Preissl H, Fritsche A, Heni M. Empagliflozin Improves Insulin Sensitivity of the Hypothalamus in Humans With Prediabetes: A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Trial. Diabetes Care. 2022 Feb 1;45(2):398-406. PubMed.
  9. Claxton A, Baker LD, Hanson A, Trittschuh EH, Cholerton B, Morgan A, Callaghan M, Arbuckle M, Behl C, Craft S. Long-acting intranasal insulin detemir improves cognition for adults with mild cognitive impairment or early-stage Alzheimer's disease dementia. J Alzheimers Dis. 2015 Jan 1;44(3):897-906. PubMed.
  10. Craft S, Claxton A, Baker LD, Hanson AJ, Cholerton B, Trittschuh EH, Dahl D, Caulder E, Neth B, Montine TJ, Jung Y, Maldjian J, Whitlow C, Friedman S. Effects of Regular and Long-Acting Insulin on Cognition and Alzheimer's Disease Biomarkers: A Pilot Clinical Trial. J Alzheimers Dis. 2017;57(4):1325-1334. PubMed.
  11. Rosenbloom M, Barclay TR, Kashyap B, Hage L, O'Keefe LR, Svitak A, Pyle M, Frey W, Hanson LR. A Phase II, Single-Center, Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Therapeutic Efficacy of Intranasal Glulisine in Amnestic Mild Cognitive Impairment and Probable Mild Alzheimer's Disease. Drugs Aging. 2021 May;38(5):407-415. Epub 2021 Mar 15 PubMed.
  12. Rosenbloom MH, Barclay TR, Pyle M, Owens BL, Cagan AB, Anderson CP, Frey WH 2nd, Hanson LR. A single-dose pilot trial of intranasal rapid-acting insulin in apolipoprotein E4 carriers with mild-moderate Alzheimer's disease. CNS Drugs. 2014 Dec;28(12):1185-9. PubMed.
  13. Rosenbloom M, Barclay T, Johnsen J, Erickson L, Svitak A, Pyle M, Frey W, Hanson LR. Double-Blind Placebo-Controlled Pilot Investigation of the Safety of a Single Dose of Rapid-Acting Intranasal Insulin in Down Syndrome. Drugs R D. 2020 Mar;20(1):11-15. PubMed.
  14. Novak P, Pimentel Maldonado DA, Novak V. Safety and preliminary efficacy of intranasal insulin for cognitive impairment in Parkinson disease and multiple system atrophy: A double-blinded placebo-controlled pilot study. PLoS One. 2019;14(4):e0214364. Epub 2019 Apr 25 PubMed.
  15. Chiu SL, Chen CM, Cline HT. Insulin receptor signaling regulates synapse number, dendritic plasticity, and circuit function in vivo. Neuron. 2008 Jun 12;58(5):708-19. PubMed.
  16. Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, Xu XJ, Wands JR, de la Monte SM. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease--is this type 3 diabetes?. J Alzheimers Dis. 2005 Feb;7(1):63-80. PubMed.
  17. Born J, Lange T, Kern W, McGregor GP, Bickel U, Fehm HL. Sniffing neuropeptides: a transnasal approach to the human brain. Nat Neurosci. 2002 Jun;5(6):514-6. PubMed.
  18. De Felice FG, Vieira MN, Bomfim TR, Decker H, Velasco PT, Lambert MP, Viola KL, Zhao WQ, Ferreira ST, Klein WL. Protection of synapses against Alzheimer's-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers. Proc Natl Acad Sci U S A. 2009 Feb 10;106(6):1971-6. PubMed.
  19. El Khoury NB, Gratuze M, Papon MA, Bretteville A, Planel E. Insulin dysfunction and Tau pathology. Front Cell Neurosci. 2014;8:22. Epub 2014 Feb 11 PubMed.
  20. Zhao WQ, Townsend M. Insulin resistance and amyloidogenesis as common molecular foundation for type 2 diabetes and Alzheimer's disease. Biochim Biophys Acta. 2009 May;1792(5):482-96. PubMed.
  21. Benedict C, Hallschmid M, Hatke A, Schultes B, Fehm HL, Born J, Kern W. Intranasal insulin improves memory in humans. Psychoneuroendocrinology. 2004 Nov;29(10):1326-34. PubMed.
  22. Benedict C, Hallschmid M, Schmitz K, Schultes B, Ratter F, Fehm HL, Born J, Kern W. Intranasal insulin improves memory in humans: superiority of insulin aspart. Neuropsychopharmacology. 2007 Jan;32(1):239-43. PubMed.

External Citations

  1. Phase 2 trial
  2. three-week study
  3. four-month study
  4. pilot study
  5. clinicaltrials.gov
  6. AlzRisk Diabetes
  7. AlzRisk Obesity

Further Reading

Papers

  1. Dhuria SV, Hanson LR, Frey WH. Intranasal delivery to the central nervous system: mechanisms and experimental considerations. J Pharm Sci. 2010 Apr;99(4):1654-73. PubMed.
  2. Freiherr J, Hallschmid M, Frey WH, Brünner YF, Chapman CD, Hölscher C, Craft S, De Felice FG, Benedict C. Intranasal insulin as a treatment for Alzheimer's disease: a review of basic research and clinical evidence. CNS Drugs. 2013 Jul;27(7):505-14. PubMed.
  3. Zemva J, Schubert M. The Role of Neuronal Insulin/ IGF-1 Signaling for the Pathogenesis of Alzheimer's Disease: Possible Therapeutic Implications. CNS Neurol Disord Drug Targets. 2013 Sep 18; PubMed.
  4. Yang Y, Ma D, Wang Y, Jiang T, Hu S, Zhang M, Yu X, Gong CX. Intranasal Insulin Ameliorates Tau Hyperphosphorylation in a Rat Model of Type 2 Diabetes. J Alzheimers Dis. 2012 Aug 30; PubMed.
  5. de la Monte SM. Contributions of brain insulin resistance and deficiency in amyloid-related neurodegeneration in Alzheimer's disease. Drugs. 2012 Jan 1;72(1):49-66. PubMed.
  6. Spielman LJ, Little JP, Klegeris A. Inflammation and insulin/IGF-1 resistance as the possible link between obesity and neurodegeneration. J Neuroimmunol. 2014 Aug 15;273(1-2):8-21. Epub 2014 Jun 12 PubMed.