Name: Nasal Insulin
Synonyms: Detemir, Levemir, Humulin, Novolin
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
Insulin is the peptide hormone that is standard treatment for the management of Type 1 diabetes. In a new therapeutic approach, various forms of commerically 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 story; Benedict et al., 2004).
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 to 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 story). 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 is to deliver 20 IU of insulin or placebo after breakfast and dinner to 240 people with either aMCI or early AD. This study is set to run until early 2017.
The trials of intranasal insulin vary in that some test 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 in 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 insulin detemir twice daily to placebo. A subsequent four-month study then compared 20 IUs twice daily of insulin detemir to 20 IUs of regular insulin twice daily in 90 patients. Both trials looked for effects on a memory composite and six different secondary outcomes; results are not yet published.
For more trials on nasal insulin in Alzheimer's, see clinicaltrials.gov.
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 will evaluate the effect of 40 IUs of regular insulin on a visuospatial memory test, the Unified Parkinson's Disease Rating Scale, and other measures in 22 patients with Parkinson's disease and 22 patients with multiple system atrophy.
Furthermore, various trials have evaluated nasal insulin for effects on cognitive symptoms in psychiatric conditions such as schizophrenia, bipolar, and major depressive disorder.
- Honolulu: Intranasal Insulin Trial Claims Promise in MCI, AD
- Sniff This: Therapeutic Peptides Through the Nose?
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Peptide Brace Against AD—Insulin, Neuropeptide Y Tame Aβ Toxicity
- Paris: Diabetes, Insulin, and Alzheimer Disease
- Madrid: Highs and Lows of The Insulin Connection
- San Diego: A New Tack on Insulin-Based Therapies?
- Diabetes-Insulin Roundup: Dementia Connection Grows Stronger, Part 2
- New York: The Nose, Your Magic Portal?
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.