Difference between revisions of "Insulin Resistance"

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(added study showing even "normal" A1c, if higher is related to CVD)
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'''TOFI'''  – Thin Outside, Fat Inside. These are people who have a limited ability to store fat. They look thin, have acceptable Body Mass Index (BMI) level, but since they have limited capacity to store fat they can be horribly insulin resistant or T2 diabetic.  It’s been hypothesized that everyone has a '''Personal Fat Threshold''' (PFT).  When that PFT is exceeded, the development of T2D is likely. ([https://www.ncbi.nlm.nih.gov/pubmed/25515001 Taylor R, Holman RR, 2015]) Conversely, there’s also a small percentage of obese people who, through a process called '''hyperplasia''', just develop additional adipocytes (fat cells), thereby not reaching a PFT or developing insulin resistance or T2D.  
'''TOFI'''  – Thin Outside, Fat Inside. These are people who have a limited ability to store fat. They look thin, have acceptable Body Mass Index (BMI) level, but since they have limited capacity to store fat they can be horribly insulin resistant or T2 diabetic.  It’s been hypothesized that everyone has a '''Personal Fat Threshold''' (PFT).  When that PFT is exceeded, the development of T2D is likely. ([https://www.ncbi.nlm.nih.gov/pubmed/25515001 Taylor R, Holman RR, 2015]) Conversely, there’s also a small percentage of obese people who, through a process called '''hyperplasia''', just develop additional adipocytes (fat cells), thereby not reaching a PFT or developing insulin resistance or T2D.  
   
   
'''Hemoglobin A1c''' – More commonly referred to as '''HbA1c''' or just '''A1c'''.  This is a blood test which measures the average level of blood sugar (glucose) over the past 2 to 3 months. See [[Fasting insulin less than 5; HgbA1c less than 5.6]]
'''Hemoglobin A1c''' – More commonly referred to as '''HbA1c''' or just '''A1c'''.  This is a blood test which measures the average level of blood sugar (glucose) over the past 2 to 3 months. In addition to factoring in Fasting Plasma Glucose (FPG) and an Oral Glucose Tolerance Test (OGTT), the [http://www.diabetes.org/diabetes-basics/diagnosis/ American Diabetes Association] says
* A1c less than 5.7% is normal
* A1c 5.7 to 6.4 is prediabetes
* A1c 6.5 or higher is diabetes
However, there are studies that have determined HbA1c levels that are considered "normal," but on the higher end of normal, are associated with increased risk for cardiovascular disease and brain shrinkage (studies cited below). Dr Bredesen's Protocol recommends an A1c of less than 5.6, see [[Fasting insulin less than 5; HgbA1c less than 5.6]]


'''HOMA-IR''' – Short for Homeostatic Model Assessment of Insulin Resistance, commonly referred to in medical literature.  This is a method used to quantify insulin resistance and beta-cell function.  It is calculated by taking the fasting glucose times fasting insulin divided by 405. (FG x FI/405) Desired range: 1.0 or lower. Over 2.5 is insulin resistance.   
'''HOMA-IR''' – Short for Homeostatic Model Assessment of Insulin Resistance, commonly referred to in medical literature.  This is a method used to quantify insulin resistance and beta-cell function.  It is calculated by taking the fasting glucose times fasting insulin divided by 405. (FG x FI/405) Desired range: 1.0 or lower. Over 2.5 is insulin resistance.   

Revision as of 08:57, 21 May 2018

Introduction

Insulin is a hormone. Normally, insulin is released by beta cells in the pancreas in response to high blood sugar in the bloodstream, and reduces glucose (blood sugar) levels by carrying the glucose into the body's cells where it can be used. When there's excess glucose, insulin converts this excess to fat. In a daily diet with high amounts of sugary and refined carbohydrate foods, the cells will become "resistant" to insulin effects, that is, they stop absorbing glucose. The body responds to the higher blood glucose by producing even higher levels of insulin to help more glucose enter the cells. As long as the beta cells are able to produce enough insulin to overcome the insulin resistance, blood glucose levels stay in the healthy range. Over time, the beta cells can fail to keep up with the body's increased need for insulin. Without enough insulin, excess glucose builds up in the bloodstream, leading to diabetes, prediabetes, and other serious health disorders and the condition of insulin resistance occurs, with its high levels of fasting blood glucose. See this description of insulin resistance for more.

Insulin resistance is at the root of many health concerns, particularly those diseases to which ApoE4s are susceptible. A person can be insulin resistant without being Type 2 Diabetic, but Type 2 Diabetes by definition includes insulin resistance. There are many factors which can play in to insulin resistance, but a person is particularly vulnerable to developing insulin resistance if they are sedentary and eat a poor diet.

Insulin Resistance leads to chronic disease

In our primer we emphasize:

Lowering insulin resistance. Many researchers and doctors, and many on our forum including myself, think this is the most important thing you can do to hopefully prevent AD. In addition, it is critical for prevention of cardiovascular disease. This latter statement is not controversial at all.

As many health issues have common roots originating from insulin resistance, this advice is good for all genetic populations, but especially for ApoE4s given the association with Alzheimer’s, cardiovascular disease, and lowered longevity.

Why it is important for ApoE4s

  • We know that E4 carriers typically have a higher levels of amyloid beta, up to 2.7 times higher than E3 carriers. (Tadafumi Hashimoto, et al., 2012). The body normally uses insulin-degrading enzyme to degrade insulin so blood sugar doesn't go too low. But, it is also used to degrade amyloid beta. With continuing high levels of blood glucose and insulin, insulin competes with amyloid beta for IDE. (Qiu WQ1, Folstein MF, 2006) Producing higher levels of amyloid with less degradation is not a good combination.
  • E3/E4 and E4/E4s have a higher risk of coronary heart disease than other genotypes. (Min Xu, et al., 2016) Because insulin resistance, as measured by HOMA-IR, appears to be independently associated with greater risk of cardiovascular or all-cause mortality in non-diabetic adults, it is one risk factor we can control. (Zhang X., et al., 2017)

Strategies to Lower Insulin Resistance

Avoid added sugar

Do not replace sugar with artificial sweeteners, because they are equally bad for you (see Gut Microbiome below). Unfortunately, avoiding sugar is easier said than done because sugars are everywhere in processed food, so a surprisingly large amount may be ingested without realization.

Sugar is not always labeled as such. Other names include sucrose, glucose, fructose, maltose, dextrose, molasses, hydrolyzed starch, honey, invert sugar, cane sugar, glucose-fructose, high fructose corn syrup, brown sugar, corn sweetener, rice/ corn/ cane/ maple/ malt/ golden/ palm syrup, agave nectar, and evaporated cane juice. These aliases conceal the presence of large amounts of added sugars.

Another popular trick is to use several different sources of sugar on the food label. This prevents sugar from being listed as the first ingredient. For example, the ingredient list of a food product list may contain 3 different sugars: sugar, brown sugar, and corn syrup. But because the sugars are listed as 3 ingredients, the first ingredient on the list is now something else, disguising just how much total sugar is in a product, which if you were to add all the sugars up would be the first ingredient.

Sauces can be very high in hidden sugar: barbeque, plum, honey garlic, hoisin, sweet and sour and other dipping sauces. Spaghetti sauce may contain as much as 10-15 grams of sugar (3-4) teaspoons. Sugar is added to spaghetti and some other sauces to counter the tartness of ingredients such as tomatoes, and therefore something may not even taste sweet, but have a fair amount of sugar in it. Commercial salad dressings and condiments such as ketchup and relish often contain lots of sugar.

Bottom line: if it comes in a package, it likely contains added sugar. Stay away as much as possible.

Limit starchy carbohydrates

Limit foods like breads, rice, pasta, grains, even whole grains and brown rice, as well as starchy vegetables like potato and sweet potato. This doesn't mean eliminating carbohydrates in total; there are carbohydrates which offer health benefits, such as fiber. Low carb dieters count “net carbs” which takes total carbohydrates and subtracts the grams of fiber because low carb dieters don’t count fiber carbohydrates as carbs. Also, when it comes to resistant starches, if they are consumed in moderation, they have health benefits, About resistant starch Among the health benefits of resistant starches is that they aid the Gut Microbiome (see below). Also see Dr Gundry's Protocol.

Limit fruit

This includes some fruits that we think are vegetables, such as tomatoes, cucumbers, zucchini, and peppers. Fruits contain fructose which contributes to fat storage but can be deceiving if tracking blood sugar levels. Unlike glucose, which can be metabolized throughout the body, fructose is metabolized almost completely in the liver. Fructose does not raise insulin as quickly as glucose does: see Fructolysis When insulin is released in the body, the hormone leptin is also released. Leptin is known as the “satiety hormone" ; it suppresses hunger. So while fruits hold certain healthful qualities, they do not release leptin; therefore, fruit does not make a person feel full, which may lead to overeating. Also, cancer cells prefer to ferment fructose rather than glucose: see Cancer and Fructose Moreover, fructose is hard on the kidneys (Michael S. Gersch, et al., 2007). Humans only used to eat fruit when it was in season, and that was generally before winter, so the fruit helped “fatten” them up before lean times. Thus, some believe that the human body is not “designed” to eat grocery store available fruit year round. So eat fruit judiciously.

Exercise

This makes the cells more sensitive to the insulin, plus many other benefits for ApoE4s, such as increasing BDNF, reducing stress, maintaining brain volume. See Exercise - Types, Lengths, and Benefits

Eat good fats

Fats are low glycemic which is helpful if trying to increase insulin sensitivity. This is partial rationale as to why some who post in the ApoE4.info forums advocate a Low Carb, High Fat (LCHF) diet. But fats have other concerns, so regardless of diet, low carb, high carb, whatever, any fats that are consumed should be good, healthy fats. A Mediterranean Diet is a common recommendation for ApoE4s because it is rich in MUFAs (Monounsaturated Fatty Acids) such as olive oils which are good fats. See Fats, Omega -3(ω-3) & -6(ω-6), DHA and More, Good Fats and Dr Gundry's Protocol.

As discussed in the ApoE4 wiki article about fats, Omega-6s (vegetable, corn, safflower oils, etc) are very common and typically over-consumed in the western diet, and they have been found to correlate to a higher incidence of disease. Omega-6 fatty acids from vegetable oils have also been found to interfere with the health benefits of omega-3 fats. PUFAs (Polyunsaturated Fatty Acids) have a tendency to oxidize leading to lipid peroxides, and “lipid peroxidation is thought to be one important mechanism involved in the pathogenesis of inflammation, cancer, and atherosclerosis" (Jan Eritsland, 2000).

Incorporate fasting/intermittent fasting

By following the above advice of reducing sugars and refined carbohydrates, you will reduce the insulin spikes, but you might not reduce fasting insulin. Fasting insulin is a number that indicates the minimum constant level of insulin that is always circulating in your blood regardless of whether you’re eating or not. About fifty percent of the insulin released by the body each day is released at this constant background level, regardless of how fat or how thin you are. However, on average, skinny people have a lower constant background level, i.e. a lower floor, but it is still about HALF of the insulin they produce each day. The higher your fasting insulin level, the more background insulin you have all day long. This is why some people find losing weight almost impossible even on a low carb diet, because their body holds high levels of insulin.

Both skinny and fat people spike insulin after eating, but because the 50% insulin condition is much higher in the fat person, their insulin jumps to a level higher than the thin person’s, even when they eat the same food. A way to lower this high fasting insulin “floor” is to periodically hold insulin as low as possible so this low insulin will begin to burn up that extra body fat. In other words, add an element of timing to a low glycemic diet by fasting/intermittent fasting. This means not eating for a period of time, even a short period such as 16 to 24 hours, which if incorporated with the time spent sleeping can mean something as simple as skipping breakfast. Fasting is very effective at lowering insulin. For more information see Fasting and the 50% insulin problem/.

Also, Dr Jason Fung has been referred to numerous times within the ApoE4.info forums. As a nephrologist (kidney doctor) he is an expert on treating people with Type 2 Diabetes. According to the National Kidney Foundation, 10 to 40 percent of those with Type 2 diabetes will eventually suffer from kidney failure Kidney Foundation on Diabetes). He advocates fasting/intermittent fasting for addressing insulin resistance and has a website full of easy to understand videos and articles on these subjects. See Dr Jason Fung.

Other References:

Valter D. Longo, Satchidananda Panda, 2016. Fasting, Circadian Rhythms, and Time-Restricted Feeding in Healthy Lifespan

Don’t overdo the protein

To reduce sugar intake, sometimes people replace carbs with protein. The body does need some protein, but if a person eats more than needed, the body converts the excess to blood sugar, which drives up the insulin and the excess gets stored as fat.

How much protein? It depends

“…the Recommended Dietary Allowance of protein for a healthy adult with minimal physical activity is currently 0.8 g protein per kg body weight (BW) per day. To meet the functional needs such as promoting skeletal-muscle protein accretion and physical strength, dietary intake of 1.0, 1.3, and 1.6 g protein per kg BW per day is recommended for individuals with minimal, moderate, and intense physical activity, respectively.” (Wu G, 2016)

Most people do not understand that serving size does not match the total amount of protein. For example, 3 ounces of fish (85 g) only has about 17 grams of protein. But, protein is found in all foods, and if nuts and seeds are part of the food mix, it’s easy to over eat the RDA in protein if the serving sizes of meat, chicken or fish are too large. See this overview.

Protein requirements also differ by age. Research shows that severe protein restriction causes weight loss in old, but not young, mice, and low protein intake is associated with protection from mortality in 65 and younger, but not 66 and older, individuals. (Valter D. Longo, Satchidananda Panda, 2016)

Address Gut Microbiome

The intestines are filled with gut bacteria which if imbalanced or decimated can affect a wide spectrum of mental, cognitive, and physical issues in the body. There are “good bugs” and “bad bugs.” The challenge is to encourage the good bugs and minimize the bad bugs. Obese individuals, who tend to suffer from insulin resistance, present different proportions of bugs compared with lean individuals. Modern medical drugs (antibiotics, common pain killers (NSAIDS) inadvertently destroy/imbalance the gut biome. Artificial sweeteners appear to change the population of intestinal bacteria. Studies have found they kill gut flora and make mice more glucose intolerant. Prebiotics and probiotics help to repopulate the gut, but this can take time, from months to years depending on the initial state.

The gut biome is a comprehensive subject with ramifications beyond just insulin resistance. Sticking to the subject of insulin resistance, here are some references:

Andrea M. Caricilli and Mario J. A. Saad, 2013. The Role of Gut Microbiota on Insulin Resistance
Gut Bacteria are partly to blame for insulin resistance, article by Better Body Chemistry
The Gut Microbiome: New-Treatments-for-Diabetes, article by Diabetes Daily
Artificial Sweeteners may change our Gut Bacteria in Dangerous Ways, 2015 article by Scientific American
How Artificial Sweeteners Wreak Havoc on Your Gut, 2016 article by Chris Kresser
Suez J., et al., 2015. Non-caloric artificial sweeteners and the microbiome: findings and challenges
Mohamed B. Abou-Donia, et al., 2008. Splenda Alters Gut Microflora and Increases Intestinal P-Glycoprotein and Cytochrome P-450 in Male Rats

A guide to associated terms

Blood Sugar - the amount of glucose present in the blood. Glucose is the body’s primary source of energy. The body works to keep blood glucose regulated to a near constant level (metabolic homeostasis). Foods that greatly interrupt this homeostasis by rapidly increasing blood sugar are called high glycemic. Foods that are high glycemic tend to be those containing sugar and carbohydrates, especially simple carbohydrates, although excess protein will also raise blood sugar levels (gluconeogenesis). See Blood Sugar

Source: Dr. Georgia Ede’s Presentation to Low Carb USA San Diego, Aug 4, 2017 on “Preventing Alzheimer’s Is Easier Than You Think” Slide #6

Insulin – A hormone made by the pancreas that allows the body to use or to store glucose. When stored, it becomes fat. Fat is stored in fat cells, called adipocytes. Insulin works to keep the blood sugar steady, neither too high (hyperglycemia) or too low (hypoglycemia).

Type 2 Diabetes -- A metabolic disorder characterized by high blood sugar, insulin resistance, and low insulin. It is also referred to as T2D or Type 2 Diabetes mellitus. In T2D, the pancreas doesn’t produce sufficient insulin because either the insulin resistance is too high or the ability of the pancreas to produce a compensating amount of insulin (compensatory hyperinsulinemia) reaches a point where it drops. Unlike Type 1 Diabetes, T2D is largely preventable (often associated with obesity) and even reversible: see Reversing T2D start guide. T2D is preceded by pre-diabetes.

Pre-Diabetes – A period of many years when the blood sugar level is higher than normal but not yet high enough to be type 2 diabetes. Without diet and/or lifestyle intervention, pre-diabetes will become T2 diabetes. During this long phase, the blood glucose levels slowly rise and insulin resistance similarly rises, but the body produces enough insulin to overcome this resistance, so blood glucose remains relatively normal.

Insulin Resistance – When the body’s cells fail to respond normally to insulin, they become “resistant” to the insulin hormone, leading to high blood sugar. In turn, the beta cells of the pancreas increase their production of insulin, contributing to a high blood insulin level. A person can be insulin resistant without having T2D. With insulin resistance, the fat cells expand to a point where they can’t get any bigger (adipocyte hypertrophy), they don’t get enough oxygen, they create inflammation, and the fatty acids look for other storage places, so they go into the abdominal cavity (visceral fat), other organs (liver, pancreas, kidneys), and muscle. See Dr Gundry's Protocol

Source: Dr Ted Naiman’s Presentation to Low Carb Breckenridge, Feb 25, 2017 on “Insulin Resistance” slide #24, http://denversdietdoctor.com/ted-naiman-hyperinsulinemia/

Insulin Sensitivity – When the body responds quickly to the effects of insulin and requires smaller amounts of insulin to lower blood glucose levels. Generally speaking, having good sensitivity to insulin is a sign of good health.

Non-Alcoholic Fatty Liver Disease (NAFLD) – Also referred to as Non-Alcoholic Steatohepatitis (NASH) after the condition progresses. This condition occurs when a liver accumulates fat (not due to alcohol) which leads to abnormalities in liver function. In NAFLD there is little or no inflammation or liver cell damage. In NASH there is inflammation and liver cell damage in addition to fat in the liver. Both occur under conditions of persistent high insulin. A fatty liver can precede Type 2 diabetes. If the liver becomes fat it becomes insulin resistant, so it’s not regulated by insulin appropriately. Thus, throughout the night the liver secretes more and more glucose. When people with fatty liver wake up in the morning they will have high glucose even though they haven’t eaten for 8-10 hours. When the liver tries to decompress itself from fat, it makes triglycerides through de novo lipogenesis. A person with high triglycerides, low HDL, and small dense LDLs is likely to have fatty liver even if they are a lean/normal weight person. (Højland Ipsen D, et al., 2016)

TOFI – Thin Outside, Fat Inside. These are people who have a limited ability to store fat. They look thin, have acceptable Body Mass Index (BMI) level, but since they have limited capacity to store fat they can be horribly insulin resistant or T2 diabetic. It’s been hypothesized that everyone has a Personal Fat Threshold (PFT). When that PFT is exceeded, the development of T2D is likely. (Taylor R, Holman RR, 2015) Conversely, there’s also a small percentage of obese people who, through a process called hyperplasia, just develop additional adipocytes (fat cells), thereby not reaching a PFT or developing insulin resistance or T2D.

Hemoglobin A1c – More commonly referred to as HbA1c or just A1c. This is a blood test which measures the average level of blood sugar (glucose) over the past 2 to 3 months. In addition to factoring in Fasting Plasma Glucose (FPG) and an Oral Glucose Tolerance Test (OGTT), the American Diabetes Association says

  • A1c less than 5.7% is normal
  • A1c 5.7 to 6.4 is prediabetes
  • A1c 6.5 or higher is diabetes

However, there are studies that have determined HbA1c levels that are considered "normal," but on the higher end of normal, are associated with increased risk for cardiovascular disease and brain shrinkage (studies cited below). Dr Bredesen's Protocol recommends an A1c of less than 5.6, see Fasting insulin less than 5; HgbA1c less than 5.6

HOMA-IR – Short for Homeostatic Model Assessment of Insulin Resistance, commonly referred to in medical literature. This is a method used to quantify insulin resistance and beta-cell function. It is calculated by taking the fasting glucose times fasting insulin divided by 405. (FG x FI/405) Desired range: 1.0 or lower. Over 2.5 is insulin resistance.

Type 1 Diabetes – (also known as Juvenile Diabetes, or insulin-dependent diabetes) This occurs when the body doesn’t produce enough insulin because its immune system is destroying the beta cells in the pancreas which is where insulin is made. The cause of Type 1 Diabetes is unknown.

Type 3 Diabetes – Not a medically recognized type of diabetes but an informal term for Alzheimer’s.

Oral Glucose Tolerance Test (OGTT) --. Common test used to diagnose diabetes and prediabetes by measuring the body's ability to use glucose. It involves fasting overnight, then the fasting blood sugar level is measured, followed by consuming a sugary liquid drink and testing blood sugar levels periodically for the next two hours. This test has been debated within the ApoE4 forums for its comprehensiveness, deferring to Dr Joseph Kraft’s test better accuracy in determining diabetes and prediabetes.

Dr Joseph Kraft – Referred to numerous times within the ApoE4 forums. Dr. Kraft’s test is similar to the oral glucose tolerance test (OGTT), but runs longer and adds insulin measurements. He found that 80% of those who had normal glucose responses had abnormal insulin responses. In other words, subjects who would be classified as “normal” under Fasting Glucose Tests, thereby not even progressing to an OGTT test, are not “normal” in their insulin response. For more info search see Dr Joseph Kraft or read his book "Diabetes Epidemic & You." Dr Catherine Crofts has also been referred to within the forums. She did her PhD work using Dr. Kraft's data. Discussions on both of these individuals can be found by using the advanced search function ApoE4.info Advanced Search Function..

A deeper dive into the science

Insulin Resistance's Link to Alzheimer’s disease

The term Type 3 Diabetes has remained popular since the 2008 article, Alzheimer's Disease is Type 3 Diabetes-Evidence Reviewed (Suzanne M. de la Monte, Jack R. Wands, 2008). The study concluded that, “the term “type 3 diabetes” accurately reflects the fact that AD represents a form of diabetes that selectively involves the brain and has molecular and biochemical features that overlap with both type 1 diabetes mellitus and T2DM.”

Source: Dr. Georgia Ede’s Presentation to Low Carb USA San Diego, Aug 4, 2017 on “Preventing Alzheimer’s Is Easier Than You Think” Slide #18

Since 2008, there has been much additional research, and the link between between Alzheimer’s disease (AD) and insulin resistance is even stronger. Some studies and their quotes:

"This article attempted to disentangle the complex mechanisms underlying brain IR, highlight proven or plausible links to A and tau pathologies in AD, as well as provide information about promising recent EV-based biomarkers, in vivo glucose MRS measures, and gene array neuroinformatics techniques. The convergence of such diverse sources of evidence makes it all but certain that brain IR plays a major role in AD pathogenesis linking the two main types of pathology" [bold font added for emphasis]
  • Insulin resistance and reduced brain glucose metabolism in the aetiology of Alzheimer’s disease (Amy L. Berger, 2016)
“Significant epidemiological and clinical evidence has emerged that suggests Alzheimer’s disease (AD) can be added to the list of chronic illnesses that are primarily caused by modern diets and lifestyles at odds with human physiology. High intakes of refined carbohydrates, insufficient physical activity, suboptimal sleep quantity and quality, and other factors that may contribute to insulin resistance combine to create a perfect storm of glycation and oxidative stress in the brain. Specific neurons lose the ability to metabolise and harness energy from glucose, ultimately resulting in neuronal degeneration and death. Simultaneously, chronic peripheral hyperinsulinaemia prevents ketogenesis, thus depriving struggling neurons of a highly efficient alternative fuel substrate.”
“However, a diagnosis of T2D is not required for eventual progression to AD, because T2D does not cause AD. Rather, they may be thought of as ‘physiological cousins’ – conditions that result from the same underlying metabolic disturbances, but which have different outward manifestations in the body. One may be a diagnosed T2 diabetic and not develop AD, and many AD patients are not diagnosed diabetics.”
“There is a significant link between Alzheimer’s disease and impaired fuel metabolism in the brain, with disturbed cerebral glucose metabolism being an invariant pathophysiological feature of AD.23 The defining metabolic signature of AD is a decrease in the cerebral metabolic rate of glucose (CMRglu). This may be the primary underlying cause of neuronal degeneration and death: at its heart, AD is an energy crisis in the brain. It is the death of neurons via starvation, as they have lost the capacity to effectively harvest energy from glucose.”
“It is certain, however, that brain insulin dynamics play a role in neurotransmission, cognition, and the regulation of hormones that control feeding behaviour and reproductive function.32”
“One potential aggravating factor for the ApoE4 genotype is that ApoE4 homozygotes produce 50% less hippocampal IDE compared to healthy controls, as well as AD patients who are not carriers of the ε4 allele.36”
  • Unraveling Alzheimer's: Making Sense of the Relationship between Diabetes and Alzheimer's Disease (Schilling MA, 2016)
“Numerous studies have documented a strong association between diabetes and Alzheimer's disease (AD). The nature of the relationship, however, has remained a puzzle, in part because of seemingly incongruent findings.…However, careful integration of multiple strands of research, with attention to the methods used in different studies, makes it possible to disentangle the research on AD. This integration suggests that there is an important relationship between insulin, IDE, [Insulin Degrading Enzyme] and AD that yields multiple pathways to AD depending on the where deficiency or excess in the cycle occurs. I review evidence for each of these pathways here.”
“Importantly, Cook et al. found that AD patients with the ApoE4 allele had a 50% reduction in expression of IDE compared to AD patients without the ApoE4 allele, suggesting that the ApoE4 allele may play a role in IDE deficiency leading to AD [95].”
“In our prospective study, diabetes was associated with significantly increased risk of Alzheimer's disease and vascular dementia”
  • Effects of Glucose and Insulin on Secretion of Amyloid-β by Human Adipose Tissue Cells (Tharp WG, et al., 2016)
“Aβ was made by adipose tissue cells in vitro at concentrations similar to in vivo measure¬ments. Regulation of Aβ production by glucose and insulin and effects of Aβ on the insulin receptor path-way suggest similar cellular mechanisms may exist between neuronal dysfunction in Alzheimer disease and adipose dysfunction in type 2 diabetes.
This research shows significant decrease in brain volume or brain shrinkage in individuals whose blood sugars are at the high end of what is considered normal/acceptable glucose levels
CONCLUSIONS: "High plasma glucose levels within the normal range (<6.1 mmol/L) were associated with greater atrophy of structures relevant to aging and neurodegenerative processes, the hippocampus and amygdala. These findings suggest that even in the subclinical range and in the absence of diabetes, monitoring and management of plasma glucose levels could have an impact on cerebral health. If replicated, this finding may contribute to a reevaluation of the concept of normal blood glucose levels and the definition of diabetes."
6.1 mmol/L = 110 mg/dl
6.1 mmol/L or 110 mg/dl = HbA1c of between 5.4 and 5.5

Insulin Resistance's Link to Cardiovascular Disease

"In summary, insulin resistance and/or hyperinsulinemia promote fatty liver — a combination that in turn drives high blood insulin and associated mechanistic pathways that shuttle lipids (fats) into your vascular walls, which is a hallmark of atherosclerosis. It also leads to high blood glucose, particularly post-prandial blood glucose, and this too has mechanistic pathways that promote atherosclerosis.
"High blood pressure is another side effect of insulin resistance that drives atherosclerosis by placing stress on your arteries. As noted by Cummins, most idiopathic hypertension (high blood pressure with no known cause) is now thought to be caused by hyperinsulinemia.
Hyperinsulinemia/insulin resistance promotes inflammation, causing your visceral fat to release inflammatory cytokines and systemic signaling molecules. Over time, your visceral fat becomes increasingly resistant as well, causing the systemic signaling to falter. Taken as a whole, this cascade of events drives atherogenic dyslipidemia, characterized by the now familiar culprits: high LDL, oxidized LDL and triglycerides, and low HDL."
  • Diversity of apolipoprotein E genetic polymorphism significance on cardiovascular risk is determined by the presence of metabolic syndrome among hypertensive patients (Teixeira AA, et al, 2014)
"CONCLUSIONS: The results presented demonstrate that the association between ApoE gene and CVD may be modulated by the presence of MetS, [Metabolic Syndrome] with an increased CV burden observed among E4 allele carriers with the syndrome. On the opposite way, E4 allele carriers without visceral obesity had lesser prevalence of CVD."
  • Haemoglobin A1c even within non-diabetic level is a predictor of cardiovascular disease in a general Japanese population: the Hisayama Study (Fumie Ikeda, et al. 2013)
"Conclusions: Our findings suggest that elevated HbA1c levels are an independent risk factor for CVD, especially CHD and ischaemic stroke, and that the addition of HbA1c to the model with traditional risk factors significantly improves the predictive ability of CVD."
"Four large prospective studies (25–28) have shown that hyperinsulinemia is a predictor of coronary artery disease (CAD), with a few prospective reports not demonstrating such a relationship. The greatest association of hyperinsulinemia with CAD has been found in Finland in a population with a very high frequency of CAD (25). Results of a prospective investigation of 2103 men from Quebec (29) clearly showed that high fasting insulin concentrations are an independent predictor of CAD. This important study used an insulin assay without cross-reactivity with proinsulin, thus avoiding that confounding influence. Several recent studies (30–33) have shown a relationship between carotid wall atherosclerotic lesions, angina, and insulin levels/resistance. One report (34) suggested that insulin levels predicted blood pressure elevations in children. Other data (35) suggest that a high ratio of estrogen to testosterone combined with hyperinsulinemia predisposes to premature coronary heart dis¬ease and related mortality in men. Collectively, these observations suggest that CV interactions of altered sex hormone profiles and high levels of insulin may aggravate hypertension and increase the risk of CV mortality in both men and women"
insulin resistance represents a major underlying abnormality driving cardiovascular disease, the major cause of morbidity and mortality in much of the world.
Figure 1. Source: Insulin resistance and cardiovascular disease, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC380256/pdf/JCI0010762.pdf
Figure 1: a simplified model relating insulin resistance to dyslipidemia and cardiovascular disease. Insulin resistance at the adipocyte results in increased release of fatty acids into the circulation. A similar accumulation of fatty acids could arise from defects in fatty acid transporters or intracellular binding proteins. Increased FFA flux to the liver stimulates the assembly and secretion of VLDL resulting in hypertriglyceridemia. In addition, VLDL stimulates the exchange of cholesteryl esters from both HDL and LDL for VLDL TG. ApoA-I can dissociate from TG-enriched HDL. This free apoA-I is cleared rapidly from plasma, in part by excretion through the kidney, thus reducing the availability of HDL for reverse cholesterol transport. TG-enriched LDL can undergo lipolysis and become smaller and more dense. Low levels of HDL and the presence of small dense LDL are each independent risk factors for cardiovascular disease. IR, insulin resistance; CE, cholesteryl ester; SD, small dense.

Insulin Resistance's Link to Longevity

"HOMA-IR, a marker of insulin resistance, was independently associated with increased all-cause mortality in nondiabetic adults after adjusting for measures of obesity, including BMI and waist-to-hip ratio, and other common predictors of mortality that might also be associated with insulin resistance."
  • Insulin resistance in non-diabetic subjects is associated with increased incidence of myocardial infarction and death (B. Hedblad, et al., 2002)
"Conclusions Insulin resistance, as assessed by the HOMA method, was in this cohort of middle-aged non-diabetic subjects associated with an increased incidence of myocardial infarction and death. This risk remained when smoking, low physical activity and factors included in the insulin resistance syndrome were taken into account in a stepwise regression model."
"Conclusions— These findings provide the first tangible nexus of telomere biology with insulin resistance and adiposity in humans."
FYI, “Telomere length shortens with age. Progressive shortening of telomeres leads to senescence, apoptosis, or oncogenic transformation of somatic cells, affecting the health and lifespan of an individual. Shorter telomeres have been associated with increased incidence of diseases and poor survival." Masood A. Shammas, 2011)
"Conclusion: Even though there were some justifiable discrepancies, significant association was seen between cancer and HOMA-IR in this Malaysian population. These results are in line with previous studies which check for association in select cancers."