Alzheimer’s Disease and Insulin Resistance




Insulin vials and syringe

For years, researchers have noted a connection between conditions of impaired insulin use and regulation, such as obesity and type 2 diabetes, and Alzheimer’s Disease (AD), but the mechanism of association has not been well-defined. Now, researchers report that proteins that influence the development and progression of AD are suppressed by insulin, encouraging new treatment strategies for AD.

Rates of AD are nearly twice as high among patients with obesity or type 2 diabetes compared to a general population. Decades of research have indicated that this is likely due to a combination of factors: vascular dementia, impaired insulin metabolism and signaling pathways, and dysfunctional glucose transport to the brain. Several studies have supported a causal link between insulin resistance or impaired insulin response, even early in life, with the development of AD.

Insulin and insulin receptors and transporters are densely located in areas of the brain that support memory function. Normal insulin regulation is essential for healthy cognitive functioning, and impaired insulin regulation leads to cognitive and memory deficits seen in AD. Also, insulin regulates proteins involved in the pathophysiology of AD; insulin regulates amyloid precursor protein (APP), which is associated with the formation of the hallmark plaques in the brains of AD patients, and insulin moderates the metabolism of the protein tau, the building block of neurofibrillary tangles, another distinctive finding in AD. The plaques and tangles lead to neurodegeneration and loss of cognitive function in AD.

To uncover the actual mechanism by which insulin influences the pathogenesis of AD, researchers administered a low-dose insulin infusion (two units per hour) for four hours to ten obese patients with type 2 diabetes. On two other days, the same patients received a four-hour infusion of either normal saline or dextrose without insulin. Blood samples were obtained at 0, 2, 4, and 6 hours. The patients were receiving antidiabetic medications, but none were taking insulin as part of their diabetes treatment.

The one-time infusion of insulin suppressed the expression of APP, as well as presenilin-1 (PS1), presenilin-2 (PS2), and glycogen synthase kinase-3-beta (GSK-3-beta). PS1 and PS2 convert APP into beta-amyloid, which forms the plaques in AD brains. GSK-3-beta activates tau, which forms the tangles in AD brains. The results were published a recent issue of Journal of Clinical Endocrinology and Metabolism.

The new study is small, and the long-term effects of a low-dose insulin infusion on AD-related proteins are not known. Also, it is unclear if the findings are applicable to non-obese or non-diabetic patients. The next challenge is to administer insulin directly to the brain, possibly intranasally, to avoid the hypoglycemic effects of insulin.

The exact cause of AD is unknown, though a familial connection is evident, and genetic mutations related to PS1 and PS2 have been noted in early-onset AD. Treatments to slow the progression of AD are limited, and no cure is yet available. The new insulin research offers exciting information, as it paves the way for new therapeutic strategies. Targeting insulin resistance may prevent, or at least slow, the onset of AD.

References

Biessels GJ, Kappelle LJ, & Utrecht Diabetic Encephalopathy Study Group (2005). Increased risk of Alzheimer’s disease in Type II diabetes: insulin resistance of the brain or insulin-induced amyloid pathology? Biochemical Society transactions, 33 (Pt 5), 1041-4 PMID: 16246041

Dandona P, Mohamed I, Ghanim H, Ling Sia C, Dhindsa S, Dandona S, Makdissi A, & Chaudhuri A (2011). Insulin Suppresses the Expression of Amyloid Precursor Protein, Presenilins, and Glycogen Synthase Kinase-3{beta} in Peripheral Blood Mononuclear Cells. The Journal of clinical endocrinology and metabolism PMID: 21411544

Maccioni RB, Muñoz JP, & Barbeito L (2001). The molecular bases of Alzheimer’s disease and other neurodegenerative disorders. Archives of medical research, 32 (5), 367-81 PMID: 11578751

Naderali EK, Ratcliffe SH, & Dale MC (2009). Obesity and Alzheimer’s disease: a link between body weight and cognitive function in old age. American journal of Alzheimer’s disease and other dementias, 24 (6), 445-9 PMID: 19801534

Rönnemaa E, Zethelius B, Sundelöf J, Sundström J, Degerman-Gunnarsson M, Berne C, Lannfelt L, & Kilander L (2008). Impaired insulin secretion increases the risk of Alzheimer disease. Neurology, 71 (14), 1065-71 PMID: 18401020

Suh YH, & Checler F (2002). Amyloid precursor protein, presenilins, and alpha-synuclein: molecular pathogenesis and pharmacological applications in Alzheimer’s disease. Pharmacological reviews, 54 (3), 469-525 PMID: 12223532

Watson GS, & Craft S (2003). The role of insulin resistance in the pathogenesis of Alzheimer’s disease: implications for treatment. CNS drugs, 17 (1), 27-45 PMID: 12467491

  • http://www.talkwelisten.com/ Mark

    I’m sure there are many causes for AD in general. It seems that trauma in many fashions can be a cause. We’ve heard about how repeated concussions can cause dementia. It’s likely that other forms of injury such as deprivation of oxygen or nutrients can be a factor. We can try to prevent it and hopefully lessen the severity, but people are going to develop AD and we need to learn to deal with it as best we can be caring for those who develop it and those who care for them as well. The research is quite interesting and hopefully we will continue to learn, discuss and discover.

  • Anna

    Wow, cool research. I wonder if they’ll eventually trace this back to some kind of polyadenylation error as has been happening with so many neural disorders recently.

Jennifer Gibson, PharmD

Jennifer Gibson, PharmD, is a practicing clinical pharmacist and medical writer/editor with experience in researching and preparing scientific publications, developing public relations materials, creating educational resources and presentations, and editing technical manuscripts. She is the owner of Excalibur Scientific, LLC.
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