I was stimulated to read this paper by:
- The recent publication in The Lancet of Dementia prevention, intervention, and care.
- Georgia Ede, MD’s (@GeorgiaEdeMD) talk at Low Carb San Diego (Adventures at Low Carb San Diego ) which was triggered by the above
- General interest in knowing if there’s a better way to do something for human health (it’s a family doctor thing, actually a doctor thing in general 🙂 )
@GeorgiaEdeMD @Gill_Livingston Interested in your take on https://t.co/TkpVXIUFEu & role of insulin resistance. I see it mentioned in passing – more to the story / helpful references? Thanks for your work!
At Low Carb San Diego, I first heard the term “Type III Diabetes,” which, it turns out is new to the 21st Century, but not to this decade, as this paper was published in 2008 and references use of the term as early as 2005. The term is intriguing and opens the mind to a potential mechanism for dementia progression, and maybe prevention.
Concept of Cognitive Reserve
The dementia review, which appears very complete (and with a very respected team of experts, some of whom I have the pleasure to know), covers the determinants of dementia using the best data available.
It also introduces (to me) the concept of “cognitive reserve,” because it has been shown that people who do not have dementia while they are alive have damaged brains when they are examined in death.
Interestingly to me, this single concept is similar to insulin resistance, because it’s known that a person can have normal glucose control (or “glucose control reserve”) at the same time their insulin system is struggling….
In the review, diet/nutrition approaches for prevention treatment are briefly discussed, as well as the potential relationship to insulin resistance in the brain, but “Diabetes Type III” is not mentioned specifically & this paper isn’t referenced.
With that in mind, and after asking Georgia and the study author on Twitter for comment on this, I decided to review this paper, written by a team at Brown University, to get grounded:
Cognitive impairment is associated with disorders in brain glucose metabolism
- People with diabetes or related metabolic syndromes are at much higher risk for mild cognitive impairment (MCI) and alzheimers’ dementia (AD)
- However, diabetes is not a requirement for either
- It is therefore not accurate to say that MCI and AD are effects of type 2 diabetes
- Instead, the changes in insulin action and glucose metabolism in the brain (markedly reduced insulin and receptor activity) associated with MCI and AD are similar to what happens in other organs but happen independently.
What this means is that insulin resistance, i.e., impaired ability to respond to insulin stimulation, can vary among target organs and be present in just one or two organs and not in others, a phenomenon that could explain the lack of complete overlap between T2DM and AD.
Since the abnormalities identified in the brain were quite similar to the effects of T1DM or T2DM (though none of the patients had either of these diseases), including abnormalities in IGFs, which are important for islet cell function, we proposed the concept that AD may represent a brain-specic form of diabetes mellitus and coined the term “type 3 diabetes.”
In the brain, insulin is a growth/energy hormone, that when disrupted, can accelerate cell death
Therefore, brain insulin and IGF deficiency and resistance could account for the cytoskeletal collapse, neurite retraction, synaptic disconnection, loss of neuronal plasticity, and deciencies in acetylcholine production, all of which correlate with cognitive decline and dementia in AD. Altogether, the studies utilizing postmortem human brain tissue provide solid evidence that AD is associated with fundamental abnormalities in insulin/IGF signaling mechanisms that are highly correlated with development and progression of structural, molecular, and biochemical lesions that correlate with dementia.
Neurochemistry is super complex & I am not the best explainer (see links below), what I read, though, is that insulin supports cell life in the brain, and when withdrawn, cells undergo more stress that isn’t repaired and trigger inflammation and creation of harmful proteins.
In the less palatable side of the research world, when animals have their brain (but not pancreas) insulin capacities destroyed using a specific toxin, their brains degenerate while the rest of their bodies do not show the effects of diabetes. When the animals are also given a drug that turns up insulin receptors in the brain (but still has insulin manufacturing capacity destroyed), they do not suffer the same deficits.
What this has to do with diet
If people with dementia cannot use the glucose that’s being delivered to their brain properly because of insulin resistance, then this may provide clues to prevention by preventing insulin resistance.
There’s further research that in these states, the brain is still able to use ketone bodies to make up for energy deficits, however/and it would probably better if people don’t arrive to these states in the first place.
Looking again at the Lancet review, it’s noted that these four risk factors are called out independently in the potential prevention of dementia:
- High blood pressure
- Physical activity
Which are all diet mediated. And, the kind of diet that prevents these things is the kind of diet that prevents insulin resistance – they are all connected.
2. Wish more attention had been paid to insulin resistance as a powerful driving force behind many of the (secondary) risk factors mentioned in the paper, such as hypertension, obesity, and DM.
Does a lower insulin (high fat, low carbohydrate) diet work to prevent dementia?
The Lancet review doesn’t make a clear recommendation based on the evidence availble. It also doesn’t make a recommendation based on other risk factors, like hearing loss, either:
The mechanism underlying cognitive decline associated with peripheral hearing loss is not yet clear; nor is it established whether correction, such as hearing aids, can prevent or delay the onset of dementia.
That doesn’t mean that fixing these risk factors doesn’t help. My answer is, I am still learning. I recommend the additional articles below, which include a more comprehensive body of research review than just this one paper.
4. My reading of the literature convinces me that insulin resistance is a strong, primary causal factor in most garden-variety cases of Alzheimer's disease, and therefore potential to prevent w lifestyle is YUGE:) https://t.co/y8fHLug1su
I also think it’s worth considering the that if a carbohydrate-restricted diet is better for metabolic health overall, this might fall into the category of “what if the evidence isn’t there and you created a better you anyway.”
(see: Just Read: Dietary carbohydrate restriction as the first approach in diabetes management: critical review and evidence base., Just Read: Saturated fat does not clog the arteries: coronary heart disease is a chronic inflammatory condition, the risk of which can be effectively reduced from healthy lifestyle interventions )
The desire to know rather than a desire to disrupt
Back to the interest in wanting to know what’s better for health.
What I find the physicians in this field have in common is that they want to know what’s best for health, even at the cost of challenging their own long-held beliefs (Just Read: Diet: Less a Debate, More an Interest to Know What a Healthy Diet Is).
I mentioned in one of my first posts on the topic how I strove to adhere to the low fat diet mandated for humans when I began my medical career, even though our own pathology textbook curiously listed “high carbohydrate diets” as a risk factor for heart disease. I didn’t follow-up then, but I’m following up now, and I thank other physicians for doing the same.
Georgia Ede, MD (@GeorgiaEdeMD) is a board-certified psychiatrist and expert in nutrition approaches to brain health, as well as expertise in explaining the complexity of brain science to a wide audience:
- Ketogenic Diets for Psychiatric Disorders: A New 2017 Review | Psychology Today
- Preventing Alzheimer’s Disease Is Easier Than You Think | Psychology Today
- Your Brain on Plants: Micronutrients and Mental Health – Diagnosis:Diet
Additional papers reviewed
Thanks also to Georgia for referring me to several of these peer-reviewed pieces
- Bostock ECS, Kirkby KC, Taylor BVM. The Current Status of the Ketogenic Diet in Psychiatry. Front Psychiatry. 2017;8:43. doi:10.3389/fpsyt.2017.00043.
- de la Monte SM, Wands JR. Alzheimer’s Disease is Type 3 Diabetes—Evidence Reviewed. J Diabetes Sci Technol [Internet]. Diabetes Technology Society; 2008 Nov [cited 2018 Jan 1];2(6):1101–13.
- Hertz L, Chen Y, Waagepetersen HS. Effects of ketone bodies in Alzheimer’s disease in relation to neural hypometabolism, β-amyloid toxicity, and astrocyte function. J Neurochem [Internet]. 2015 Jul 1 [cited 2018 Jan 1];134(1):7–20.
And the pieces from The Lancet
- Livingston G, Sommerlad A, Orgeta V, Costafreda SG, Huntley J, Ames D, et al. Dementia prevention, intervention, and care. Lancet [Internet]. 2017 Dec [cited 2017 Dec 29];390(10113):2673–734.
- Larson EB. Prevention of Late-Life Dementia: No Magic Bullet. Ann Intern Med [Internet]. 2017 Dec 19 [cited 2017 Dec 29]; Available from: http://annals.org/article.aspx?doi=10.7326/M17-3026