Alzheimer’s = Type-3 Diabetes: Cerebral insulin resistance causes Alzheimer’s disease
Our brain is one of the largest glucose consumers in our body. Not all areas of the brain need the hormone insulin to take up glucose and thus operate insulin-independently. However, this is different in the neurons of the hippocampus, the brain region responsible for our memory consolidation and one of the first to be affected by Alzheimer’s and dementia: here – as researchers have recently discovered – insulin is needed to provide the neurons with sufficient glucose supply during times of increased energy demand (1).
Thus, it’s not surprising that when insulin resistance is present, for example during developing or established type-2 diabetes, the brain can also suffer from a glucose deficiency. This impaired glucose utilization and the associated energy crisis in the brain have also been visualized in imaging techniques, the so-called PET scan, in Alzheimer’s patients (2).
Today, it is well accepted that Alzheimer’s disease can be a consequence of this undersupply of the brain and that it is closely related to type-2 diabetes. Diabetics, for example, have about twice the risk of developing Alzheimer’s disease as non-diabetics (3). The reduction of energy production in the hippocampus is considered a very early event in the course of Alzheimer’s disease and precedes the manifestation of symptoms by years to decades. In this context, the physician Suzanne de le Monte defined the term ‘type-3 diabetes‘ in 2008 for this cerebral (affecting the cerebrum) form of insulin resistance: according to this, Alzheimer’s dementia represents a form of diabetes that overlaps with type-2 diabetes mellitus, but can also be present in isolated cases in the brain. That is, there are also Alzheimer’s patients with cerebral energy deficit who do not have type-2 diabetes (4). This should not be confused with type-3c diabetes, called pancreatogenic diabetes. This form of diabetes results from diseases or injuries of the pancreas that, among other things, impair insulin secretion.
Furthermore, studies also show a close correlation between cerebral glucose deficiency (measured by PET scan) and reduced cognitive abilities in Alzheimer’s patients. We now know that the brain’s starvation state leads in the long term to the breakdown of its specific functions and the death of brain cells, which is particularly noticeable in the impairment of memory. But how does this cerebral undersupply occur?
Unlike muscle and fat tissue, the brain was long considered an insulin-independent organ. But since nearly all brain cells are equipped with insulin receptors and the brain itself is also capable of producing its own insulin, it quickly becomes clear that the brain is dependent on insulin to function: Insulin has numerous important functions in addition to glucose uptake, including promoting synapse formation and neuronal development, and thus plays a key role in our cognitive function (5).
When insulin resistance is present in the body, only a reduces amount of insulin from the systemic circulation reaches the brain through the blood-brain barrier. Also, the brain’s own insulin synthesis may be decreased in response to insulin resistance in the body. In this way, insulin deficiency occurs in the brain, which develops into cerebral insulin resistance as Alzheimer’s disease progresses (6).
A lack of insulin can have devastating consequences due to the multifunctionality of this hormone. It leads – in addition to energy deficiency – to loss of synaptic plasticity, amyloid-ß and neurofibrillary deposition, acetylcholine deficiency, oxidative stress, mitochondrial dysfunction, and brain inflammation, neuroinflammation, all of which are essential building blocks in Alzheimer’s pathology.
The link between diabetes mellitus and Alzheimer’s disease has been known for a long time. It is also now known that the impairment of glucose metabolism in the hippocampus leads to energy insufficiency due to a disability of the insulin signaling cascade. Insulin has critical regulatory functions in the central nervous system in addition to glucose uptake. The cerebral insulin resistance that occurs in Alzheimer’s disease is characterized by insulin deficiency and can have devastating consequences, leading slowly but surely to cognitive decline. Thus, it is becoming increasingly clear that Alzheimer’s dementia represents a complex neuro-endocrine disorder that is similar to, but also distinct from, diabetes type-2 and is therefore correctly called type 3 diabetes. Because these disorders occur long before the symptoms typical of Alzheimer’s disease, early recognition and treatment of insulin resistance is critical in the prevention and treatment of Alzheimer’s disease.
And please don’t forget that there are very simple lifestyle measures that help prevent insulin resistance. The top 3 are: Regular exercise, avoidance of refined sugars especially so-called HFCS (high fructose corn syrup) – a mixture of 50% fructose and 50% glucose used as a cheap sweetener in industrial products such as lifestyle drinks – and generally a diet that is in line with the MIND diet or at least a Mediterranean diet.
Did the newsfeed catch your interest, and would you like to know even more about the link between diabetes and Alzheimer’s disease?
To help you dive even deeper into this exciting topic, we at ‘Knowledge stopps Dementia’ have provided you with a detailed update on the connection between these diseases based on the latest scientific data. Please have a look at (Cerebral insulin resistance) and learn how important a healthy and consistent blood glucose management is in the prevention and therapy of Alzheimer’s disease.
- EC McNay, J Pearson-Leary (2020) GluT4: A central player in hippocampal memory and brain insulin resistance. Exp Neurol 323/113076: 1-9. DOI 10.1016/j.expneurol.2019.113076.
- L Mosconi (2005) Brain glucose metabolism in the early and specific diagnosis of Alzheimer’s disease. European Journal of Nuclear Medicine and Molecular Imaging 32: pp 486–510. DOI 10.1007/s00259-005-1762-7.
- A Ott, RP Stolk, A Hofman, F van Harskamp, DE Grobbee & MMB Breteler (1996) Association of diabetes mellitus and dementia: The Rotterdam Study. Diabetologia 39: pp 1392–1397. DOI 10.1007/s001250050588.
- SM de la Monte, JR Wands (2008) Alzheimer’s disease is type 3 diabetes-evidence reviewed. Diabetes Sci Technol 2(6): pp 1101-13. DOI: 10.1177/193229680800200619.
- JCC Shieh, PT Huang, YF Lin (2020) Alzheimer’s Disease and Diabetes: Insulin Signaling as the Bridge Linking Two Pathologies. Molecular Neurobiology 57:1966–1977 DOI: 10.1007/s12035-019-01858-5
- E Steen, BM Terry, EJ Rivera, JL Cannon, TR Neely, R Tavares, XJ Xu, JR Wands JR, SM de la Monte SM (2005) Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease–is this type 3 diabetes? Journal of Alzheimer’s Disease 7(1): pp 63-80. DOI: 10.3233/jad-2005-7107.