By Ralph Sanchez, L.Ac.,CNS,D.Hom
Insulin fulfills an indispensable role in your body’s utilization of blood sugar (glucose). In type 2 diabetes and Metabolic Syndrome, insulin’s function of glucose uptake into the body’s cells is impaired due to a resistance to insulin that develops over time. This insulin resistance pattern which defines the disease process of the above mentioned disorders, is now seen as a link to the degenerative spiral that occurs in Alzheimer’s disease (AD) over and above the role of insulin in glucose metabolism in the brain. Insulin resistance and its role in inflammation, and impaired insulin function in the brain are now understood to be underlying pieces of the Alzheimer’s puzzle.
The brain’s consumption of glucose is critical to fueling the high-energy machinery of its cells (neurons). This uptake of glucose into brain cells was formerly thought to transpire without the aid of insulin. However, it is now established that insulin’s function for neuron uptake of glucose is an important component of brain glucose metabolism. (1) If the uptake of glucose into the neurons is diminished, energy metabolism is hindered with significant consequences to the brain’s capacity to generate the connections vital to memory and learning. (2) Studies utilizing brain scans demonstrate the decreased brain metabolism of glucose in normal individuals that eventually go on to develop cognitive impairment or dementia. (3) Furthermore, there is now evidence that demonstrates insulin and it’s receptors in the brain as key elements to memory formation and learning beyond its function for glucose uptake. (4)
Insulin binds to receptors at the synapse, a key communication locus between neurons in the brain. Synaptic junctures between neurons is where the cell-to-cell brain circuitry is facilitated. Insulin is now known to serve as a vital element for synapse maintenance (structure and function) and subsequently for the strength of connections between neurons. (5) This insulin/synaptic axis and the formation of new circuitry in the brain, is a key contributor to “brain plasticity”. Brain plasticity refers to the brain’s malleability-its capacity for adaptive change. It is the brain’s ability to integrate change associated with learning, organize that experience and form new connections (synaptic density)* between brain cells that supports and enables that process. These processes occur throughout a person’s lifetime…as a young brain grows and develops, or as it recovers from brain trauma. The brain forms new connections and it “rewires” itself to integrate new information, as in a learning process, or it “rewires” itself to replace damaged pathways lost in a stroke. If insulin’s function in the brain is disrupted, synapse function and density is diminished and the neural pathways that optimize and reflect learning and memory formation are hindered. Decreased synaptic density and brain plasticity is a central feature of AD and disrupted insulin function at the synapse is largely to blame. So what causes insulin function in the brain to go awry and eventually contribute to adverse changes in brain function associated with AD? It has been largely postulated that amyloid plaque and neurofibrillary tangles, and you can pick your poison, were the primary and underlying processes that explained the loss of cognitive function associated with AD. Now we have more illuminating evidence that the cognitive impairment typical of AD begins prior to plaques and tangles accumulating. Amyloid-Beta Derived Diffusible Ligands (ADDLs) and their interaction with insulin
Insulin resistance and the associated inflammation that typifies type 2 diabetes/Metabolic Syndrome, is linked to increased beta- amyloid protein** (BAP) production and deposition in the brain. (7) The build up of BAP and the subsequent accumulation of amyloid plaques, has been theorized to be the central (please read my article on Plaques and Tangles) process associated with the degeneration in AD. However, more recent studies have demonstrated that a probable precursor to insoluble amyloid plaques, ADDLs, are thought to be more toxic than the amyloid plaques they eventually form, and largely responsible for the cognitive deficits that occur in AD. (10) In AD, insoluble plaque formation is preceded by the production of Amyloid-Beta Derived Diffusible Ligands (ADDLs). ADDLs are small, soluble aggregated proteins, which are gaining acceptance as the primary mediators of the neurodegeneration associated with AD before the aggregation and deposition of insoluble amyloid plaque.
One of the damaging effects of ADDL formation in the brain is its impact on insulin levels and function. In part, ADDLs do their damage by binding at the synapse and triggering the loss of insulin and synapse function. ADDLs are thought to prevent insulin receptors from accumulating at the synapse and effectively making them unable to respond to insulin and thus insulin resistant. (11) This loss of insulin function in AD is described by several researchers as a brain specific “type 3 diabetes”. The insulin/ADDL pivot in AD is certainly a component that represents another important piece in the AD puzzle.
Elevated insulin patterns that underlies Type 2 diabetes and Metabolic Syndrome, is linked to inflammatory processes. (6) This pro-inflammatory milieu associated with many other disorders as well, has the potential to spur inflammation in the brain and increase the risk for AD. (7) Abdominal fat stores and obesity that are hallmark signs of type 2 diabetes/Metabolic Syndrome also contribute to the inflammatory cascade and raises the risk for AD and dementia. One large study conducted by Kaiser-Permanente in Northern California concluded that belly fat at middle age could almost triple the risk of dementia later in life. (8)
Apart from the pro-inflammatory effects of elevated insulin levels in AD, elevated insulin poses another problem. Insulin in the brain is degraded by insulin degrading enzyme (IDE). IDE also degrades toxic amyloid plaque. Insulin has a very similar molecular structure to amyloid plaque and thus might compete for the benefits of IDE. (9) Elevated insulin levels are implicated in the brain cells’ failure to clear beta-amyloid. Compounding the insulin/beta-amyloid competition for IDE is the finding that indicates lower IDE levels in patients with AD. The takeaway? Excess insulin can increase the risk of AD by stimulating pro-inflammatory molecules in the brain, and by impeding the clearance of beta-amyloid.
To summarize, insulin levels and function in the brain are key elements in memory, learning and brain plasticity. Research shows that levels of brain insulin and its related receptors are lower in individuals with Alzheimer’s disease. Underlying this insulin/AD axis is the impact of ADDLs and their binding with insulin receptors at a crucial locus of memory and learning facilitation-the synapse. This disrupted insulin interaction (signaling) with receptors leads to the loss of synapse function vital to the connectivity between brain cells and a healthy brain that can learn and retain information.
Insulin is in part responsible for the uptake of glucose into the neuron. The human brain needs a great deal of glucose for energy metabolism and individuals who have a greater genetic risk (ApoE4) for AD have lower rates of glucose metabolism. Insulin resistance that underlies type 2 diabetes/Metabolic Syndrome contributes to decreased brain insulin levels (12), and elevated insulin in the body (periphery) contributes to inflammatory molecules in the brain. Indeed, elevated insulin in the body can have direct and deleterious consequences on brain integrity. However, as an emerging theory and explanation of the cascade of neurodegeneration that characterizes AD, the role of insulin function in the brain and how its dysregulation directly contributes to the cognitive impairment that defines AD, is now becoming a neuroendocrine model of AD that seems destined to replace the amyloid theory of AD.
As compelling as the role of insulin dysfunction and its link to a type 3 diabetes of the brain is in AD, it is important to bear in mind that the core elements that contribute to AD remain the same. Genetics, nutrition, lifestyle, toxins, inflammation, oxidative stress, mitochondrial dysfunction and hormonal factors like insulin, and estrogen, are all inextricably woven together in the fabric of the AD brain. There is not a single isolated entity in that fabric that we can hang our hat on and pronounce it as the holy grail of the AD cure. The insulin/synapse axis and its role in brain plasticity gives a more upstream and plausible model of AD that illustrates the cognitive decline inherent in AD before actual neurodegeneration occurs. (13) However, AD is a multifactorial disease process and it is my utmost conviction that only the careful evaluation of each person’s risk factors before they manifest into this disease, will ultimately reduce the growing health crisis that AD is becoming.
* Synapse density: percentage of synapses per cubic millimeter of tissue
** beta-amyloid protein is also referred to as amyloid beta or ABeta is produced from amyloid precursor protein and is the principal component of amyloid plaque found in Alzheimer’s as well as other neurological diseases.
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2. Zhao WQ, Alkon DL.
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7. Mark A. Fishel, G. Stennis Watson, Thomas J. Montine et al.
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9. Alafuzoff I, Aho L, Helisalmi S, Mannermaa A, Soininen H. beta-Amyloid deposition in brains of subjects with diabetes.
10. Catalano Susan M, Dodson Elizabeth C, Henze Darrell A. et al. The Role of Amyloid-Beta Derived Diffusible Ligands (ADDLs) in Alzheimer’s Disease. Current Topics in Medicinal Chemistry, Volume 6, Number 6, March 2006 , pp. 597-608(12)
11. Wei-Qin Zhao, Fernanda G. De Felice, Sara Fernandez, et al.
12. Craft, Suzanne PhD. Insulin Resistance Syndrome and Alzheimer Disease: Pathophysiologic Mechanisms and Therapeutic Implications.
13. Dennis J. Selkoe. Alzheimer’s Disease Is a Synaptic Failure