Proposed Treatments for Alzheimer’s Disease Linked to Type 2 Diabetes

As mentioned previously in the page “Disease Mechanism: A Biochemical View of How Alzheimer’s Disease and Type 2 Diabetes are Linked”, it has been recently discovered that insulin affected the solubility and toxicity of amyloid-β and its aggregates. This finding has opened the door to the possibility of using insulin as a treatment for patients who suffer from Alzheimer’s disease and type 2 diabetes. In recent years, intranasal insulin therapy for cognitive impairment and neurodegeneration has gone through some clinical trials and is thought to hold a lot of potential as a treatment for type 2 diabetes linked Alzheimer’s Disease.

Intranasal delivery of insulin is possible via direct neuroanatomical connections between the olfactory nerves and brain. This mode of administering insulin is superior to other forms in that it does not require any structural modification (de la Monte, 2013). Insulin can easily cross through the blood brain barrier, which gives it wide access to the central nervous system. In general, intranasal therapy allows for easy delivery of neuroprotective agents via an easy noninvasive procedure. Other methods for targeting insulin have been intravenous insulin infusion, intranasal insulin administration, and insulin sensitizers. These methods have given various results improving cognitive function (Morris, J. & Burns, J., 2012). Using lyophilized nasal insert formulations have been shown to extend nasal residence, which allows prolonged delivery. Also, using polysaccharide nanoparticles and hybrid polysaccharide/oligosaccharide nanoparticles as carriers for macromolecules has been shown to extend nasal residence. Insulin-loaded chitosan (CS) and cyclodextrin (CD) derivative-based nanoparticles have been shown to reduce plasma glucose levels (Morris, J. & Burns, J., 2012). This is helpful to avoid any repeated use of nasal spray solutions in the future. Although this method seems promising, there have been concerns raised.

 

Figure 1. Intranasal therapy as a way to deliver insulin to the CNS (Selameh et al., 2015)

Intranasal delivery of insulin has shown that the molecule is not easily absorbed through the nasal mucosa because of its large size, hydrophilic form, and low permeability across membranes (de la Monte, 2013). Nanoparticles instead of macromolecules have been tested, but research has not yet reached completion. Another approach involves the addition of tetradecyl-beta-D-maltoside (TDM). This molecule has been shown experimentally to improve recovery of the nasal permeability barrier after repeatedly administering peptides via intranasal methods.

Another challenge concerning the repeated use of intranasal delivery of insulin and other drugs is the increase of time-dependent reductions in nasal permeability. This is a form of nasal transport resistance, which is brought by a change in nasal form due to loss of cell-to-cell junctions. Due to this issue, strategies are needed to help with the transportation of various compounds across the nasal mucosa, which will maintain the positive effects of intranasal therapy for long term use. To accomplish this, researchers examined the cyclopentadecalactone (CPE-215), a compound that improves the absorption of molecules going through the mucous membranes, for intranasal insulin delivery (Nasulin, CPEX Pharmaceuticals)(de la Monte, 2013). In a clinical trial, the researchers observed that a nasal spray that contained recombinant human insulin with CPE-215 could effectively lower blood glucose in diabetics(de la Monte, 2013)(Morris, J. & Burns, J., 2012).

 

 

4 Replies to “Proposed Treatments for Alzheimer’s Disease Linked to Type 2 Diabetes

  1. A complete or substantial loss of olfactory ability is often a symptom of Alzheimer’s and other neurodegenerative diseases. Would the mechanisms of this decreased acuity have any effect insulin delivery?

    1. Hello Greg,
      It’s true that a substantial loss of the olfactory is a symptom of Alzheimer’s disease. This symptom is presented later in the progression of the disease. Intranasal delivery of insulin is intended for those who are still in the early stages of the disease as it would help combat some cognitive impairment that is present. Presenting this treatment option early on will be much more effective since not all olfactory abilities are lost.
      Thank you for reading and engaging my work.

  2. Hi Aisha. I really appreciated how you talked about the problems with intranasal delivery of insulin. In class, we talked about how the presence of insulin can help prevent amyloid-β aggregates, but of course, clinically administering the treatment proves to be difficult. I am wondering if there is any literature that discusses the doses of insulin that are used for intranasal delivery. Would too much of an insulin concentration cause insulin aggregates?

    1. Hi Melanie,
      There is some literature (de la Monte, 2013)(Morris, J. & Burns, J., 2012) (Reger et al., 2008) that suggests doses of 10, 20, or 40 IU per day are safe so that insulin aggregates will not form. Anything above 100 IU per day heightens the risk of insulin aggregates being formed, which will be detrimental. Besides dose, as I have mentioned above, long term use of intranasal delivery of insulin can be harmful since it can lead to an increase of time-dependent reductions in nasal permeability.

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