Cognitive-Vitality-ADDF-Intranasal-Insulin-ratings

Intranasal Insulin

  • Drugs
  • Updated October 7, 2019

Insulin is a hormone that regulates blood glucose levels and is a prescription drug used to treat type 2 diabetes. Type 2 diabetes and Alzheimer’s share certain characteristics including impaired insulin signaling and insulin resistance; these issues are also seen in brain cells of Alzheimer’s patients. Intranasal insulin is a method to increase brain insulin levels by administering insulin with a spray device through the nasal cavity. Short-term clinical studies suggest that intranasal insulin may improve some aspects of cognitive functions, though results varied depending on different factors such as sex and genetics. Intranasal insulin is generally safe but can cause burning in the nasal cavity and increase the risk for nasal infections.

Evidence

Many small studies suggest that intranasal insulin may improve cognition in healthy adults and people with mild cognitive impairment, though large long-term clinical trials have not been conducted.

Our search identified:

  • 7 randomized controlled trials in healthy adults
  • 8 randomized controlled trials in patients with mild cognitive impairment or Alzheimer’s disease
  • Multiple biomarkers studies of insulin resistance in patients with Alzheimer’s disease
  • Multiple preclinical studies

Potential Benefit

Insulin resistance is a state where cells in the body have an impaired ability to respond to insulin. Metabolic conditions associated with insulin resistance, such as diabetes, are well-known risk factors for mild cognitive impairment and Alzheimer’s [1].  No studies have examined whether intranasal insulin can prevent Alzheimer’s disease. However, intranasal insulin may improve memory in some healthy individuals.

In some short-term studies, intranasal insulin improved aspects of memory performance in healthy women but not healthy men. There were no improvements in non-memory cognitive tasks, such as attention [2; 3; 4]. On the other hand, intranasal insulin over eight weeks improved some aspects of memory performance (such as improvements in delayed, but not immediate, word recall) in both healthy men and women. There were no improvements in non-memory cognitive tasks [2; 5; 6; 7].

APOE4 carriers: Preliminary results suggest that regular intranasal insulin may improve memory in APOE4 negative Alzheimer’s patients while long-acting insulin, insulin detemir, may improve memory in APOE4 positive Alzheimer’s patients [8; 9]. For more information on what the APOE4 gene allele means for your health, read our APOE4 information page.

For Dementia Patients

Multiple studies show abnormal insulin signaling in brain tissue of patients with Alzheimer’s disease [10; 11; 12; 13]. Furthermore, insulin signaling may be even more impaired in patients with both type 2 diabetes and Alzheimer’s disease [14], though insulin signaling was also impaired in brain tissue from patients with Alzheimer’s disease and no history of diabetes [12].

Studies on the acute effects of intranasal insulin in patients with mild cognitive impairment and Alzheimer’s disease suggest that it may improve some aspects of memory in APOE4 negative patients and has no effect (or may be detrimental) to APOE4 positive patients [15; 16; 17]. Other studies report regular, but not long-acting, intranasal insulin improved memory in patients with Alzheimer’s when given for longer periods of time [18; 19]. On the other hand, a 21-day treatment with long-acting intranasal insulin improved memory in APOE4 positive patients but made memory worse in APOE4 negative patients [8]. This suggests that different types of intranasal insulin may have different effects depending on the APOE4 carrier status of the patient.

One study in 104 individuals with Alzheimer’s showed that regular intranasal insulin over four months improved cognitive performance compared to placebo [9]. However, these beneficial effects were not replicated in a larger study where intranasal insulin failed to improved cognition. Although these study results are not yet published in a peer-reviewed journal, the intranasal delivery device used in this trial frequently malfunctioned and had to be changed mid-way through the trial.

Safety

Too much insulin in the blood may lead to dangerously reduced blood glucose levels. One advantage of intranasal insulin is that, unlike injected insulin, little enters the blood stream. However, symptoms of hypoglycemia, such as confusion, feeling lightheaded, and feeling shaky, should be monitored. The most common side effect with intranasal insulin is a slight burning in the nasal cavity and a risk for nasal infections [20]. However, no large trials have tested long-term intranasal insulin use. Although little insulin leaves the brain after intranasal insulin, it could potentially interact with other glucose lowering medications.

NOTE: This is not a comprehensive safety evaluation or complete list of potentially harmful drug interactions. It is important to discuss safety issues with your physician before taking any new supplement or medication.

How to Use

The doses and types of insulin used in intranasal insulin clinical trials have varied. In healthy adults, 40 international units (IU) of regular insulin was used four times per day. In patients with mild cognitive impairment or Alzheimer’s disease, 10 IU or 20 IU of regular insulin or insulin detemir was used twice per day. Insulin is given with an intranasal delivery device.

Learn More

Learn more about the ongoing intranasal insulin trials at clinicaltrials.gov.

References

  1. Biessels GJ, Despa F (2018) Cognitive decline and dementia in diabetes mellitus: mechanisms and clinical implications. Nat Rev Endocrinol 14, 591-604.
  2. Benedict C, Hallschmid M, Schmitz K et al. (2007) Intranasal insulin improves memory in humans: superiority of insulin aspart. Neuropsychopharmacology 32, 239-243.
  3. Benedict C, Kern W, Schultes B et al. (2008) Differential sensitivity of men and women to anorexigenic and memory-improving effects of intranasal insulin. J Clin Endocrinol Metab 93, 1339-1344.
  4. Krug R, Benedict C, Born J et al. (2010) Comparable sensitivity of postmenopausal and young women to the effects of intranasal insulin on food intake and working memory. J Clin Endocrinol Metab 95, E468-472.
  5. Benedict C, Hallschmid M, Hatke A et al. (2004) Intranasal insulin improves memory in humans. Psychoneuroendocrinology 29, 1326-1334.
  6. Hallschmid M, Benedict C, Schultes B et al. (2008) Obese men respond to cognitive but not to catabolic brain insulin signaling. Int J Obes (Lond) 32, 275-282.
  7. Ritze Y, Kern W, Ebner EM et al. (2018) Metabolic and Cognitive Outcomes of Subchronic Once-Daily Intranasal Insulin Administration in Healthy Men. Front Endocrinol (Lausanne) 9, 663.
  8. Claxton A, Baker LD, Hanson A et al. (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.
  9. Craft S, Baker LD, Montine TJ et al. (2012) Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol 69, 29-38.
  10. Steen E, Terry BM, Rivera EJ et al. (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.
  11. Moloney AM, Griffin RJ, Timmons S et al. (2010) 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.
  12. Talbot K, Wang HY, Kazi H et al. (2012) 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.
  13. Kapogiannis D, Boxer A, Schwartz JB et al. (2015) Dysfunctionally phosphorylated type 1 insulin receptor substrate in neural-derived blood exosomes of preclinical Alzheimer's disease. FASEB J 29, 589-596.
  14. Liu Y, Liu F, Grundke-Iqbal I et al. (2011) Deficient brain insulin signalling pathway in Alzheimer's disease and diabetes. J Pathol 225, 54-62.
  15. Reger MA, Watson GS, Frey WH, 2nd et al. (2006) Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype. Neurobiol Aging 27, 451-458.
  16. Reger MA, Watson GS, Green PS et al. (2008) Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired older adults. J Alzheimers Dis 13, 323-331.
  17. Rosenbloom MH, Barclay TR, Pyle M et al. (2014) A single-dose pilot trial of intranasal rapid-acting insulin in apolipoprotein E4 carriers with mild-moderate Alzheimer's disease. CNS Drugs 28, 1185-1189.
  18. Reger MA, Watson GS, Green PS et al. (2008) Intranasal insulin improves cognition and modulates beta-amyloid in early AD. Neurology 70, 440-448.
  19. Craft S, Claxton A, Baker LD et al. (2017) Effects of Regular and Long-Acting Insulin on Cognition and Alzheimer's Disease Biomarkers: A Pilot Clinical Trial. J Alzheimers Dis 57, 1325-1334.
  20. Schmid V, Kullmann S, Gfrorer W et al. (2018) Safety of intranasal human insulin: A review. Diabetes Obes Metab 20, 1563-1577.