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Here is YOUR 30 Day Package 60 Meal Replacements 90 Metabolism/Energy Boosters Great results are 1 click away http://www.transformwithbrian.com/getstarted.html 
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You will lose more weight if you eat three 70-calorie eggs instead of a candy bar, even if the calorie count is the same. The eggs will regulate insulin and not cause your blood sugar to spike. The extra protein will also help keep you feel full longer. The candy bar will do the exact opposite and can cause you to pack on the pounds. It’s not just calories in and calories out, it’s the kind of calories you put in and how your body processes them that helps you reach your weight-loss goals..  When you are sure what to do what do you do? Well, ya just do it! Some of y'all may not know I've dropped 129 pounds, I can assure you I'm no genetic marvel I just found an easy and inexpensive way to get the job done. No Yo-Yo here, 6.5 years later I am STILL getting better daily. I can show anyone how to do the same thing or even better. Dont do it for me, do it for you and your family Do it so YOU feel awesome Do it so YOU see your kids and grandkids grow up Do it so YOU love what's looking at you in the mirror Do it so YOU have tons of energy There is a sense of accomplishment that comes from building your body that you just can't get anywhere else. You cant buy or borrow it, the only way to get it is to WORK FOR IT. You can continue to watch or make a decision to be as healthy as possible. Ready to get started? Check out our Get Started tab or go here Transfomwithbrian.com/GetStarted  Losing weight has been great, keeping off 129 pounds has been better Gym Quickstarts
Weightloss and and Nutrition Quickstarts Private and group fitcamps Tons of things on the way STORY AT-A-GLANCE Research data show 90 percent of sea salt sold worldwide contains plastic microparticles, leading researchers to believe most people consume nearly 2,000 particles a year in their sea salt Your body requires a specific sodium-to-potassium ratio to normalize your blood pressure. Low salt intake may result in an increased risk of heart disease and osteoporosis, and low magnesium levels accompanied by a long list of other potential health risks Important since ancient times, salt has been used as currency and was one trigger in the French Revolution. Today, salt is mined from deep in the earth or extracted from saltwater sources Your best option to salt your whole foods is Himalayan sea salt, created long before the environment was polluted by plastics and chemical toxins Your body requires a specific sodium-to-potassium ratio to normalize your blood pressure that does not rely on your total sodium intake. In other words, your body uses the sodium you eat to help maintain the balance, and excretes the sodium you don't need. Research has demonstrated potassium helps to relax the walls of your arteries and lower your blood pressure.1 In one study,2 researchers found women without high blood pressure who consumed the most potassium had a 21 percent reduced risk of stroke and were also 12 percent less likely to die during the study than those who consumed the least. Another study3 evaluating salt intake in older adults found an increase was not associated with higher mortality over 10 years, or an increased incidence of cardiovascular disease or heart failure. However, as the bad reputation of salt is slowly reversing and more are turning to using a perceived healthier choice, sea salt, environmental damage has now reached your dinner table. In a study analyzing 39 salt brands from 21 countries, including the U.S. and China, researchers found more than 90 percent contain microplastics. Sea Salt May Not Be Your Healthiest Salt OptionThe extent to which plastic microparticles have spread throughout the world had been unclear. This new study4 evaluating salt brands sampled worldwide is the first on this scale to analyze the geographical spread of microplastic in sea salt and the correlation to where plastic pollution is found in the environment.5 Only three brands originating from Taiwan, China and France did not contain microplastic particles. While the density of microplastics found in the analyzed samples were dramatically different, data showed those from Asian brands continue to be especially high. The highest quantities were found in Indonesia, which ranks as suffering the second-worst level of plastic pollution in the world.6 The findings highlight concerns raised earlier7 when researchers found nearly 90 percent of popular bottled water brands contained microplastics. Mikyoung Kim, campaigner at Greenpeace East Asia said:8 "Recent studies have found plastics in seafood, wildlife, tap water and now in salt. It's clear that there is no escape from this plastics crisis, especially as it continues to leak into our waterways and oceans. We need to stop plastic pollution at its source. For the health of people and our environment, it's incredibly important that corporations reduce their reliance on throwaway plastics immediately." Researchers in the featured study estimate the average adult consumes nearly 2,000 microplastic beads each year from salt. A separate study9 planned to assess the risks microplastic have on the environment and concluded, despite a review of 320 existing studies, that there are major knowledge gaps in the scientific understanding of the impact of microplastics. Historical References Demonstrate the Importance of SaltSalt was one of the greatest treasures in the ancient world, often used as currency.10 In fact, the high value of salt prompted an ancient Roman proverb, which says people who do their job well are "well worth their salt," or "worth their weight in salt." Even after the Roman Empire domination ended, salt remained an important item in trade and ancient economies. One of the most traveled salt routes was from Morocco across the Sahara Desert to Timbuktu. Ships carrying salt traveled from Egypt to Greece across the Mediterranean and the Aegean Sea. The great wealth of Venice was attributed to common salt and not exotic spices.11 Moving into the Middle Ages, the purity of salt moved toward the superstitious. If salt was spilled it was a premonition of doom. After spilling, the spiller had to cast a pinch of salt over his left shoulder as this was thought to be where evil spirits tended to congregate.12 As late as the 18th century, the rank of a guest at a banquet was gauged by where they were seated in relationship to the salt cellar at the table. Taxes on the mineral help dissolve the French governments as they were forced to buy all their salt from royal depots. The tax was so high it eventually helped spark the French Revolution.13 As late as the 1930s Mahatma Gandhi led a pilgrimage of followers to the seaside as a protest against high British taxes on salt in India.14 Throughout the past centuries salt has played a unique and powerful role in health, politics and commerce. Low Salt Intake May Threaten Your HealthThis long history of reliance on salt took a wrong turn when Western medicine began demonizing the mineral, relating it to high blood pressure. Historically, people consumed 10 times more than we do today, as it was the primary preservative before the invention of refrigerators. The correlation with blood pressure was popularized by the Dietary Approaches to Stop Hypertension (DASH) study, during which lowering intake resulted in improvements in blood pressure. However, the diet not only lowers salt recommendations, but also advocates eating substantially less processed foods and sugars,15 which have a far greater impact on your blood pressure measurements. According to James DiNicolantonio, Pharm.D., and author of "The Salt Fix: Why the Experts Got It All Wrong — and How Eating More Might Save Your Life," your blood pressure may go down with a reduction in salt, but your ratio of total cholesterol to high-density lipoprotein, a much better predictor of heart disease, worsens. Triglyceride levels and insulin resistance also increase. This means that, overall, your heart disease risk increases rather than decreases, even though your blood pressure readings appear to be better. When your body does not have enough salt it starts pulling sodium from your bones, stripping magnesium and calcium to maintain a normal sodium level.16 This results in a reduction in sodium excretion in sweat, substituting magnesium and calcium instead. Low sodium also elevates aldosterone, a sodium-retaining hormone, which in turn reduces magnesium by shuttling it out through your urine. As a result, low sodium intake may damage your bone and heart health, as magnesium is a vital mineral for biological function. Today, most processed foods are loaded with added sugar, processed salt and harmful industrially processed oils while containing virtually no healthy saturated fats or natural, unprocessed salt. So, while most sea salt may contain plastic microbeads, eliminating salt from your nutritional intake is not the answer. How Salt Is ManufacturedBefore discussing your best salt option, it's helpful to understand the three basic methods used to process salt. Manufacturers may use solar evaporation, vacuum evaporation or rock salt mining.17 The solar method is the oldest means of producing salt. Practically, it may be used only in warm climates where the evaporation rate exceeds the precipitation rate for an extended period of time. Using solar evaporation, large quantities of natural salt water are transported to shallow ponds where the water is allowed to evaporate, leaving crystals of sodium and other natural minerals.18 Rock salt mining is the second oldest method of producing salt, accessing underground veins of salt. Large machines move through cave-like passageways. Salt appears in veins or may be found in domes. Most domes in North America are located between Alabama and Texas. In some cases the salt is mined through hydraulic mining or solution mining during which water is pumped below the surface to dissolve salt deposits and then pumped out.19 The fluid is then added to commercial vacuum pans and undergoes vacuum evaporation, incorporating steam heat in a large commercial evaporator. This method yields fine-textured, high-purity salt.20 Salt Myths Impacting Your Long-Term HealthStudies have consistently failed to support the premise that high amounts of salt increase your thirst and contribute to high blood pressure and heart disease. Actually, the converse is true. Here's a summary of findings that may surprise you:
A team of researchers from Heriot-Watt University29 placed petri dishes with sticky dust traps next to plates at dinner time and were able to capture up to 14 pieces of plastic at the end of each meal from household dust. According to this study, the average person swallows an estimated 68,415 plastic fibers each year just from the dust landing on their plates during meals. Researchers at the State University of New York30 tested 259 bottles of 11 popular bottled water brands — including Aquafina, Nestle Pure Life, Evian, Dasani and San Pelligerino — finding, on average, 325 pieces of microplastic per liter. Research31 published in Science of the Total Environment found that the annual release of plastics to the land is estimated to be four to 23 times greater than what is released in the oceans. This data means you are likely consuming tens of thousands of plastic microparticles every year from salt, food, dust and water. The end result of this plastic exposure has yet to be scientifically analyzed and reported. However, as most plastic particles contain known endocrine disrupting chemicals and other toxins, it only makes sense to reduce your exposure as much as possible. In response to these and other findings, the World Health Organization has vowed to launch a safety review to assess the potential short- and long-term health risks of consuming microplastic in water.32 What Is Your Best Salt Option?Your body needs sodium and chloride ions in salt crystals, but is unable to produce either. This means you must get it from your food. However, all salt is not created equally. Refined table salt is nearly all sodium chloride with some additional man-made chemicals. Unprocessed salt, such as my particular favorite, pink Himalayan salt, has a different balance of sodium and chloride with added natural minerals your body also requires,33 which contributes to the pink color of the salt. The crystals have matured untouched by pollutants over thousands of years. Himalayan salt is mined from salt beds created long before plastic and other toxic chemicals were manufactured. When the ocean beds were lifted, as the Himalayan Mountains were formed, these salt beds rose from the sea and were later protected by lava and covered in snow and ice for thousands of years. Compared to the salt mined from oceans laden with persistent organic pollutants and microparticles of plastic, Himalayan salt is by far your best option when you want to reduce your toxic load. Himalayan salt also contains at least 80 naturally occurring trace elements in their natural mineral form, contributing to health benefits.34 What remains after typical salt is "chemically cleaned" is sodium chloride — an unnatural chemical form of salt requiring additional energy from your body to metabolize, creating a burden on your elimination system.35 This form of salt is in almost every preserved product that you eat. Therefore, when you add more typical table salt to your already salted food, your body receives more sodium chloride than it can easily use. Reduce Your Toxic Load Making Simple Everyday ChoicesYou have an impact on your environment and your health with each choice you make. By making the commitment to reduce or eliminate your use of plastic containers and disposable products packaged in plastic, you make an impact on your health, reducing your exposure to bisphenol-A and other chemicals that leach into your food and water, and on your environment. Glass is a healthy, reusable and recyclable option to use at home. If you are purchasing a product that isn't whole food, seek out those packaged in glass and not plastic and commit to recycling that glass. You can discover more steps you may take at home to reduce your toxic load in my previous article, "7 Ways to Cancer-Proof Your Home."  How much waste (poop) is in the human body at any given time? Much more than you probably think. Depending on your height, age, and diet you could be carrying anywhere from 5 to 20 pounds of poop in your intestines. It’s not a pretty picture. The stinking waste that piles up in your intestines can seriously harm your digestive health. According to Harvard Medical School [1], symptoms of poor digestive health include:
236,000 Americans die of digestive-related disease every year. And another 1.9 million are disabled. Poor digestive health is much more than a problem in America. It’s a nationwide epidemic. You need to understand WHY millions of Americans are carrying 20 pounds (or more) of feces around in their digestive system. And what YOU can do to protect your health… Why You Might Have 20 Pounds Of Poop Trapped In Your BodyDo you eat the Standard American Diet of heavily processed foods? Then it’s practically guaranteed you’re lugging around unwanted pounds of poop. Processed foods are made from refined ingredients and added substances like salt, sugar, high fructose corn syrup and artificial colors and preservatives. Some of the most common processed foods include soda, microwavable meals, cereal, lunch meat, fast food, bread, chips, crackers, cookies and candy. A lot of these foods are marketed to you as healthy. And as a result we eat a TON of processed food in America. A 2016 study published in the journal BMJ Open found that the average American gets 57.9% of their daily calories from ‘ultra-processed foods’. [3]  These ultra-processed foods are the worst of the worst: Pepsi and Coke. Greasy burgers and fries. Pizza. Fried chicken. Sugary drinks from your neighborhood Starbucks. They’re loaded with artificial ingredients. Hard-to-pronounce chemical agents like pyridoxine hydrochloride, sucralose, and dipotassium phosphate. They’re low in fiber. So they sit in your gut for days. Weeks. And can lead to severe constipation. These ultra-processed foods aren’t found in nature. They’re cooked up in labs run by mega-rich food companies. And they slam the brakes on your body’s natural ability to digest and eliminate waste. And we’re gorging on these foods in America! No wonder the average American has 20 pounds of poop trapped in their intestines! Your body cannot properly digest and eliminate these ultra-processed “Frankenfoods”. As a result they get lodged in the lining of your intestinal tract in the form of old, rotten feces and mucus. And when your intestines are crammed with putrid feces your belly bloats like a balloon. You feel fatigued. Tired all the time. You seem to catch every little bug that goes around church or the office. And your health is seriously compromised. Unless you do something about it… The Silent Problem Inside Of You  The intestines are a long tube running from the stomach to the anus and includes the small intestines, large intestines (colon), and rectum. Your body absorbs most of its nutrients in the intestines. The small intestine is about 20 feet long and about an inch in diameter. It’s responsible for absorbing nutrients from the things you eat and drink. The large intestine, or colon, is about as long as you are tall. And it’s roughly as big around as your wrist. The colon absorbs water from waste. This creates feces. For every foot of colon the body can store between 5 and 10 pounds of feces. So if you’re just over five foot tall you could easily have 25 pounds of poop stuck in your colon. And that estimate is on the conservative side! “The intestines can store a vast amount of partially digested, putrefying matter,” says natural health expert, Richard Anderson, N.D., N.M.D. “Some intestines, when autopsied, have weighed up to 40 pounds and were distended to a diameter of 12 inches with only a pencil-thin channel through which the feces could move. “That 40 pounds was due to caked layers of encrusted mucus, mixed with fecal matter, bizarrely resembling hardened blackish-green truck tire rubber or an old piece of dried rawhide.” Doctors refer to this poisonous waste as “mucoid plaque”. I considered including a picture of it in this article. But, frankly, the images are too graphic. And I want to make sure not to scare you off. Because you can’t afford to miss out on the exciting health news I want to share with you… 4 Amazing Benefits Of Good Digestive HealthWhen you flush trapped poop out of your intestines, your digestive health improves. And when your digestive health improves, you gain better head-to-toe health. You surge with more energy. You fight off cold and flu. You have a much easier time burning fat and shedding pounds. You experience these health benefits (and more) because your digestive system is responsible for: 1. Vitamin, Mineral and Nutrient Absorption  All of your vitamin, mineral and nutrient absorption takes place in the intestines. If your gut is burdened with 20 pounds of toxic waste, you can’t absorb the nutrients you need from the foods you eat. And this will leave you tired, run down, and at risk for illness. And that’s not all… Research suggests that poor gut health could be a major contributing factor to obesity. [4] If you’re trying to lose weight it’s essential that you purge rotten feces from your colon. This will quickly lead to weight loss and a flatter stomach. And, it will improve your digestive health which makes ongoing weight loss easier and more effective. 2. Metabolism  Do you struggle with slow or no metabolism? Do you find it difficult to lose weight? Have you tried diet and exercise in the past but still can’t seem to get rid of unwanted pounds? Blame it on your gut. Scientists are now convinced that the good bacteria that live in your gut impact your metabolism and your body’s ability to lose weight. [5] These good bacteria, known as “probiotics”, need to live in a clean, healthy environment. Not a toxic swamp filled with pounds of decaying, undigested food. Flush the trapped poop out of your digestive system. And your good bacteria will fire up your metabolism and restore your body’s natural fat burning abilities. 3. Protection Against Illness and Disease  New research suggests that as much as 80% of your body’s immune cells are located in your digestive system! [6] You don’t need me to tell you that poop is crawling with nasty bugs, bacteria and pathogens. If you’ve got 20 pounds of poop sitting in your gut do you think you’ll look and feel healthy? Not a chance. Do you find yourself getting sick more often than usual? Do you suffer from allergies? Do you feel like your health is slowly going downhill? These are all signs that your digestive health has been compromised. And you need to act fast to flush the toxic poop that’s poisoning you from the inside out. I’ll show you how to do that in just a second… 4. Emotional Well-Being  We all want to feel happy and live life to the fullest.
Purging your digestive system of harmful waste will make you feel like a million bucks! That’s because 90% of the body’s serotonin is made in the digestive system. [7] Serotonin is a neurotransmitter known as the “happy hormone”. It influences how happy and relaxed you feel. If your digestive system is toxic and unhealthy, you’re not going to get adequate levels of serotonin. And insufficient serotonin levels have been linked to mood swings, stress and depression. Purge the nasty waste from your digestive system. You’ll be amazed at how much happier it makes you feel! The benefits of a healthy digestive system are amazing. But if you’ve got 20 pounds of toxic poop lodged in your colon, you’re not able to enjoy these health benefits the way you deserve. You’re missing out… 70,000,000 Americans Suffer, NeedlesslyRemember: the National Institutes of Health estimates that 70 million Americans experience poor digestive health. And some experts believe that number could be closer to 100 million. 100 MILLION… Good men and women. Who are being cheated out of the fun and vibrant health they deserve. All because the so-called “healthy” foods they eat are anything but healthy. The mega-rich food companies load our plates with their ultra-processed junk and promise, “Dig in! It’s good for you!” But so many of these foods rot in our gut for days. Weeks. Even longer. These foods fester and decompose in our colon. Until we’re burdened with 20 pounds of toxic poop trapped in our bodies. Harming our digestive health. And forcing us to suffer from constipation, gas, bloating, weight gain, heartburn, Irritable Bowel Syndrome, acne, fatigue, depression and a host of other health issues. Don’t let trapped poop rob you of your precious health! Flush Toxic Poop From Your Body Quickly…Painlessly… Permanently! Could you be one of the millions of Americans with 5 pounds, 10 pounds, 20 pounds — or more — of rotting poop lodged in your colon, poisoning you from the inside out, and stealing away the precious gift of health? Take our short Gut Health Quiz and find out:
. You simply can’t afford to ignore the WARNING SIGNS your body is giving you right now. Discover how to rid yourself of the trapped poop that’s making you sick… how to restore your digestive system to good health… how to quickly (and easily) lose your fat, bloated belly… and the #1 thing you MUST DO if you’re serious about experiencing the radiant health you desire and deserve! GET YOUR DIGESTIVE Reset System Here The digestive system plays an important role in helping your body function at its best, as it extracts and absorbs nutrients from food for the body to use for energy, growth and cell repair. Support healthy gastrointestinal function* with this 3-in-1 program, which includes Herbal Aloe Concentrate, 21-Day Herbal Balancing Program and Simply Probiotic.  Most of us recognize keto diet as beneficial for busting the high weight digits that peak out from the weight machine. However, there’s more to a keto diet than that. The ketone, or in simple words, fats used as energy may help benefit several health concerns. Not to mention, research has been enthusiastic about the positive benefits of ketone on your brain. Although the long-term effects are still not known. Quickly recalling, a ketogenic diet is based on a significant amount of good fats, moderate protein content, and a small portion of carbohydrates. Such a high-fat and low-carb diet poses several health benefits. These include reduced blood sugar levels, lower cholesterol, and triglycerides markers, lower blood sugars, and reduced risks of diabetes type II and metabolic syndrome. On the foundation of these health benefits and others, the ketogenic diet is helpful in several health conditions. Let’s discuss some of the major ones below: 1. May help improve your eyesight Low-carb and ketogenic diets are highly applauded for their weight loss results. However, recent research goes on to say that such diet plans may be beneficial for your eyesight as well. These may help maintain vision in glaucoma patients. The study indicates that a high fat and low carb diet protects your retinal cells from degeneration. Although this needs more research to validate, experts opine that a low-carb or keto diet is helpful in maintaining vision among glaucoma patients. 2. May help manage the symptoms of Alzheimer’s disease Although there is no known cure for Alzheimer’s disease, a leading mental ailment that affects about 5.5 million elderly individuals in the US, it is always possible to manage symptoms of the disease. 3. May prevent traumatic brain injury from worsening Mounting evidence says that very high blood sugar levels may sit at the center of severe head trauma. Moreover, investigations show that high blood sugar levels can elevate head injuries. It also impairs the repair of traumatic brain injury. Animal studies have concluded that a ketogenic diet can help prevent the trauma condition from worsening, so such a diet plan is helpful in this regard too. 4. May lower the odds of developing metabolic syndrome Metabolic syndrome also goes by the name of prediabetes and is recognized as insulin resistance. Patients with this health condition are at an increased risk of diabetes, heart disease, and other serious concerns. However, a keto diet helps in regulating your blood sugar levels and blood pressure. It also brings down cholesterol markers. All this helps to cut the risks of metabolic syndrome significantly. In a 12-week study of patients with metabolic syndrome, it was learned that the participants lost their body fat by 14% and decline triglycerides by 50%. 5. Helps with Parkinson’s disease Parkinson’s disease (PD) correlates with a decline in one’s dopamine levels. Such a lack of this molecule culminates in tremors, impaired posture, stiffness, and more. A keto diet can help an individual suffering from PD due to their protective effects on the nervous system and the brain. A small study also had a keto diet that showed 43%improvement in the symptoms of their disease. 6. May assist in ADHD management ADHD is another health concern for which a keto diet is helpful. It may assist by helping manage the ADHD symptoms called epileptiform discharges that overlap with epilepsy. By helping manage this symptom, the diet plan can help improve a patient’s condition. Need help starting your Keto Journey? Lets talk  Abstract Alzheimer's disease (AD) has characteristic histopathological, molecular, and biochemical abnormalities, including cell loss; abundant neurofibrillary tangles; dystrophic neurites; amyloid precursor protein, amyloid-β (APP-Aβ) deposits; increased activation of prodeath genes and signaling pathways; impaired energy metabolism; mitochondrial dysfunction; chronic oxidative stress; and DNA damage. Gaining a better understanding of AD pathogenesis will require a framework that mechanistically interlinks all these phenomena. Currently, there is a rapid growth in the literature pointing toward insulin deficiency and insulin resistance as mediators of AD-type neurodegeneration, but this surge of new information is riddled with conflicting and unresolved concepts regarding the potential contributions of type 2 diabetes mellitus (T2DM), metabolic syndrome, and obesity to AD pathogenesis. Herein, we review the evidence that (1) T2DM causes brain insulin resistance, oxidative stress, and cognitive impairment, but its aggregate effects fall far short of mimicking AD; (2) extensive disturbances in brain insulin and insulin-like growth factor (IGF) signaling mechanisms represent early and progressive abnormalities and could account for the majority of molecular, biochemical, and histopathological lesions in AD; (3) experimental brain diabetes produced by intracerebral administration of streptozotocin shares many features with AD, including cognitive impairment and disturbances in acetylcholine homeostasis; and (4) experimental brain diabetes is treatable with insulin sensitizer agents, i.e., drugs currently used to treat T2DM. We conclude 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. Keywords: Alzheimer's disease, central nervous system, diabetes, insulin gene expression, insulin signaling Introduction Alzheimer's disease (AD) can only be diagnosed with certainty by postmortem demonstration of abundant neurofibrillary tangles and neuritic plaques with accompanying accumulation of amyloid precursor protein, amyloid-β (APP-Aβ) deposits in plaques and vessel walls in selected regions of the brain. Dementia-associated structural lesions are caused by neuronal cytoskeletal collapse and accumulation of hyperphosphorylated and polyubiquitinated microtubule-associated proteins, such as tau, resulting in the formation of neurofibrillary tangles, dystrophic neuritis, and neuropil threads.1–3 Progressive loss of fibers and cells and disconnection of synaptic circuitry mediate the cerebral atrophy that worsens over time. The biochemical, molecular, and cellular abnormalities that precede or accompany AD neurodegeneration, including increased activation of prodeath genes and signaling pathways, impaired energy metabolism, mitochondrial dysfunction, chronic oxidative stress, and DNA damage, are virtually stereotypical,4–11 yet they lack a clear etiology. For nearly three decades of relatively intense research on AD, the inability to interlink this constellation of abnormalities under a single primary pathogenic mechanism resulted in the emergence and propagation of various heavily debated theories, each of which focused on how one particular component of AD could trigger a cascade that contributes to the development of all other known abnormalities. However, reevaluation of the older literature revealed that impairments in cerebral glucose utilization and energy metabolism represent very early abnormalities that precede or accompany the initial stages of cognitive impairment12–14 and led us to the concept that impaired insulin signaling has an important role in the pathogenesis of AD and the proposal that AD represents “type 3 diabetes.”5 Characteristic features of diabetes mellitus syndromes include impairments in insulin actions and signaling that result in chronic hyperglycemia, irrespective of subtype, etiology, pathogenesis, or insulin availability. Type 1 diabetes mellitus (T1DM) is caused by destruction (usually autoimmune) of pancreatic islet beta cells and attendant insulin deficiency. Type 2 diabetes mellitus (T2DM), the most common form, is caused by insulin resistance in peripheral tissues and is most frequently associated with aging, a family history of diabetes, obesity, and failure to exercise. Individuals with T2DM have hyperglycemia and hyperinsulinemia. Insulin resistance in T2DM is partly mediated by reduced insulin receptor expression, insulin receptor tyrosine kinase activity, insulin receptor substrate (IRS) type 1 expression, and/or phosphatidyl-inositol-3 (PI3) kinase activation in skeletal muscle and adipocytes.15 Gestational diabetes is pregnancy associated and caused by insulin deficiency and hyperglycemia. Nonalcoholic steatohepatitis (NASH), or metabolic syndrome, is associated with hepatic insulin resistance but overlaps with T2DM.16–18 Type 3 diabetes mellitus (T3DM, discussed later) corresponds to a chronic insulin resistance plus insulin deficiency state that is largely confined to the brain but, like NASH, can overlap with T2DM. We have proposed that T3DM represents a major pathogenic mechanism of AD neurodegeneration.5,10 Interest in clarifying the roles of T2DM, insulin resistance, and hyperinsulinemia in relation to cognitive impairment, AD-associated neuronal cytoskeletal lesions, or APP-Aβ deposits in the brain began around 2000,4,8,14,19–24 but since around 2005, this field literally exploded with new information and a new concept, i.e., that primary brain insulin resistance and insulin deficiency mediate cognitive impairment and AD.5,10,25–29 This idea was fueled by evidence that tau gene expression and phosphorylation are regulated through insulin and insulin-like growth factor (IGF) signaling cascades.23,24 In addition, research performed in our laboratory demonstrated that many key aspects of the central nervous system (CNS) degeneration that occur in AD can be effectuated by impaired insulin signaling.30–33 By way of review, insulin and IGF-1 mediate their effects by activating complex intracellular signaling pathways starting with ligand binding to cell surface receptors, followed by autophosphorylation and activation of the intrinsic receptor tyrosine kinases.34–36 Insulin/IGF-1 receptor tyrosine kinases phosphorylate IRS molecules,34,37–39 which transmit signals downstream by activating the extracellular signal-related kinase/mitogen-activated protein kinase (ERK/MAPK) and PI3 kinase/Akt pathways, and inhibit glycogen synthase kinase 3β (GSK-3β). Major biological responses to signaling through IRS molecules include increased cell growth; survival, energy metabolism, and cholinergic gene expression; and inhibition of oxidative stress and apoptosis.39–46 These very same signaling pathways are activated in various cell types, tissues, and target organs that express insulin and IGF receptors and therefore are practically universal. Moreover, these pathways are phylogenetically conserved and have critical roles in regulating development, growth, survival, senescence, carcinogenesis, and neurodegeneration. Potential Roles of Obesity and Type 2 Diabetes Mellitus in Alzheimer's Disease PathogenesisThere is an ongoing debate about the degree to which T2DM and, more recently, T1DM contribute to AD pathogenesis. This concept has been fueled by the rising prevalence rates of obesity, T2DM, and AD over the past several decades. Moreover, an interrelationship among these entities is suggested by (1) increased risk of developing mild cognitive impairment (MCI), dementia, or AD in individuals with T2DM47,48 or obesity/dyslipidemic disorders;49 (2) progressive brain insulin resistance and insulin deficiency in AD;5,10,26,27 (3) cognitive impairment in experimental animal models of T2DM and/or obesity;50,51 (4) AD-type neurodegeneration and cognitive impairment in experimentally induced brain insulin resistance and insulin deficiency;29,52–55 (5) improved cognitive performance in experimental models and humans with AD or MCI after treatment with insulin sensitizer agents or intranasal insulin;28,56–62 and (6) shared molecular, biochemical, and mechanistic abnormalities in T2DM and AD.47,63–67 The urgency of this problem is spotlighted by the estimated 24 million people in the world with dementia and the expectation that, if current trends continue,68 prevalence rates of AD are likely to double every 20 years in the future. While aging is clearly the strongest risk factor for AD, emerging data suggest that T2DM and dyslipidemic states can contribute substantially to the pathogenesis of AD either directly or as cofactors.68 Epidemiologic studies provide convincing evidence for a significant association between T2DM and MCI or dementia and furthermore suggest that T2DM is a significant risk factor for developing AD.47,69–73However, those findings are not without controversy,74 and in a longitudinal survey, investigators found that although borderline diabetics had a significantly increased risk for future development of diabetes, dementia, or AD, the risk effects were independent rather than linked.75 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. Correspondingly, the finding that obesity (body mass index [BMI] > 30) without T2DM produces a three-fold increase in risk for subsequently developing AD whereas overweight, but nonobese, subjects (BMI 25–30) experience a two-fold increase in risk for AD76 calls into question the specific effects of obesity and T2DM versus a yet unknown associated factor in relation to AD pathogenesis. Mechanistically, the increased risk of dementia in T2DM and obesity could be linked to chronic hyperglycemia, peripheral insulin resistance, oxidative stress, accumulation of advanced glycation end products, increased production of pro-inflammatory cytokines, and/orcerebral microvascular disease.73 The potential role of cerebral microvascular disease as a complicating, initiating, or accelerating component of AD has been recognized for years.77 However, a magnetic resonance imaging study demonstrated that older adults with T2DM have a moderately increased risk for developing lacunes and hippocampal atrophy and that the severity of those lesions increases with the duration and progression of T2DM.78 Another study showed that T2DM and impaired fasting glucose occur significantly more frequently in AD than in non-AD controls.79 However, since diffuse and neuritic plaques were similarly abundant in T2DM and control brains, and since neurofibrillary tangles, one of the hallmarks and correlates of dementia in AD, were not increased in T2DM,79 the results suggest that T2DM can enhance progression but may not be sufficient to cause AD. Therefore, what remains unclear is the net contribution of T2DM or obesity to the pathogenesis of AD-type neurodegeneration. To address this question, we utilized an established experimental model of chronic high-fat diet (HFD) feeding of C57BL/6 mice to examine the degree to which obesity/T2DM was sufficient to produce histopathological, molecular, and/or biochemical brain abnormalities of AD-type neurodegeneration, i.e., T3DM. High-fat diet feeding for 16 weeks doubled mean body weight, caused T2DM, and marginally reduced mean brain weight.80 Those effects were associated with significantly increased levels of tau, IGF-1 receptor, IRS-1, IRS-4, ubiquitin, glial fibrillary acidic protein (GFAP), and 4-hydroxynonenal and decreased expression of β actin. Importantly, HFD feeding also caused brain insulin resistance manifested by reduced top-level (Bmax) insulin receptor binding and modestly increased brain insulin gene expression. However, HFD fed mouse brains did not exhibit AD histopathology or increases in APP-Aβ or phospho-tau, nor were there impairments in IGF signaling, which typically occurs in AD.10 In essence, although the chronic obesity with T2DM model exhibited mild brain atrophy with insulin resistance, oxidative stress, and cytoskeleton degradation, the effects were modest compared with AD5,10 and other more robust experimental models of T3DM,28,29 and most of the molecular, biochemical, and histopathological features that typify AD were not present. Therefore, T2DM and obesity may contribute to, i.e., serve as cofactors of AD but by themselves are probably not sufficient to cause AD. Moreover, the findings in the T2DM/obesity model indicate the unlikelihood that brain insulin resistance is sufficient to cause AD and that additional significant abnormalities, such as ongoing DNA damage and mitochondrial dysfunction, are required. Alzheimer's Disease is Type 3 Diabetes: Evidence from Human StudiesThis hypothesis was directly investigated by first examining postmortem cases of advanced AD and determining if the neurodegeneration was associated with significant abnormalities in the expression of genes encoding insulin, IGF-1, and IGF-2 peptides, their receptors, and downstream signaling mechanisms.5 In that study, we demonstrated advanced AD to be associated with strikingly reduced levels of insulin and IGF-1 polypeptide and receptor genes in the brain (Figure 1). In addition, all the signaling pathways that mediate insulin and IGF-1-stimulated neuronal survival, tau expression, energy metabolism, and mitochondrial function were perturbed in AD. This study carries additional significance because it established that, like all other pancreatic and intestinal polypeptide genes, the insulin gene was also expressed in the adult human brain. Moreover, the results taught us that endogenous brain deficiencies in insulin, IGF-1, IGF-2, and their corresponding receptors, in the absence of T2DM or obesity, could be linked to the most common form of dementia-associated neurodegeneration in the Western hemisphere. 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,81–83 which are important for islet cell function,84,85 we proposed the concept that AD may represent a brain-specific form of diabetes mellitus and coined the term “type 3 diabetes.”
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AuthorIve Lost 118 pounds, I feel great and love helping others. Archives
February 2019
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