This is Year Two in my series of the progression of my Alzheimer's disease since it was first diagnosed in December 2017.
Year One was titled I am waiting for when I forget I have Alzheimer's
I am writing Year Three presently. The Pursuit of Happiness with Alzheimer's.
The global pandemic of obesity and overweight now affects between 2.8 and 3.5 billion of the world population and shows no signs of abatement. Treatment for what is now recognized as a chronic disease includes pharmacotherapy, considered an essential component of comprehensive therapy. New drug discovery is robust, but the pace of the US Food and Drug Administration approval for obesity drugs has been glacial, and only a handful of approved drugs are available for treating obesity. In the last 20 years, the US Food and Drug Administration has approved 208 drugs for cancer, 118 for cardiovascular diseases, 168 for neurological diseases, and 223 endocrinologic drugs, but only 6 for obesity, 2 of which have been taken off market. Currently, there are only 9 drugs approved by the FDA for obesity treatment. US physicians have turned to off-label drug use in their effort to care for increasing numbers of patients with excess adiposity. Phentermine is the most commonly used drug for treating obesity. Although approved only for short-term use, US physicians have used it successfully for long-term since its initial approval in 1959. This drug, used off-label for long-term, has proven to be safe and effective, far safer than the disease it is used to treat. Phentermine and diethylpropion, an equally safe but somewhat less effective drug, are both generic and therefore inexpensive. These drugs have been maligned inappropriately because their two-dimensional structure diagrams resemble amphetamine and also because of unproven presumptions about their potential adverse effects. In the face of an increasing epidemic, worldwide obese and overweight patients deserve effective treatment that prescribing these drugs could provide, if rehabilitated and used more frequently. US physicians will likely continue to use any drug proven useful off-label for this illness until such time as more effective drugs are approved.
"There are two distinguished types of food intake regulation:
a) the short-term (satiety signals, SS) occurring at the beginning and end of a single meal; it also includes the length between meals and
b) the long-term regulation (adiposity signal, AS) that is influenced by such factors as body fat deposition."
"Hormones like leptin and insulin, both secreted into the blood, reflect the stored body fat. These hormones can pass the BBB and stimulate specific receptors. Hypothalamic areas are richly supplied by axons from ARC, which has greater concentrations of leptin and insulin receptors than any other hypothalamic site (Valassi et al., 2008).
The ARC exerts opposing actions on food intake responding not only to leptin and insulin, but also to gut hormones (the most studied are ghrelin and, recently, PYY). The neurophysiological pathways suggest that feeding is regulated by a feedback loop, where the hypothalamus provides the long-term regulatory input to the NTS, which acts as a setpoint (Williams et al., 2001).
It has recently been proposed that the ARC is required for the coordination of homeostatic circadian systems including temperature and activity."
Many molecules produced by the GIT exert hunger or satiety effects on the brain."
Cholecystokinin (CCK) Three other related hormones are
1- pancreatic polypeptide (PP),
2- amylin, and
3- peptide YY (PYY).
AmylinPeptide YY (PYY)
glucagon-like peptide 1 (GLP-1)
"The gut-brain link is important not only for the hormones produced by the gut, but also for the long-term body weight regulation."
"It is important to note that during physiological ketosis (fast or very low calorie ketogenic diets) ketonemia reaches maximum levels of 7–8 mmol/L with no change in blood pH, while in uncontrolled diabetic ketoacidosis blood concentration of KBs can exceed 20 mmol/L with a consequent lowering of blood pH (Robinson and Williamson, 1980; Cahill, 2006) (Table (Table11).
We can say that no species, including humans,
could have survived for millions of years without the ability to withstand brief periods of hunger or starvation (Amen-Ra, 2006).
These periods of fasting are themselves ketogenic (McCue, 2010) during which the concentrations of insulin and glucose decrease
while that of glucagon increases in the attempt to maintain normal blood glucose levels.
When the body passes from a condition of food abundance to one of deprivation (or else via VLCKD simulated deprivation), there is, with a slight delay, an increase in the concentration of free FAs as well as KB in the blood.
Thus, from this point of view KD could be compared to caloric restriction for fasting. "
Effects of ketosis on hunger and satiety
"Although convincing, the bulk of evidence in relation to the inhibitory effects of ketosis on appetite is still anecdotal.
Preliminary scientific reports seem to support this phenomenon, and the evidence shows that KD is more effective, at least in the short/medium-term, on fat loss (Paoli, 2014).
It was demonstrated that diet-induced weight loss leads to changes in energy expenditure and in appetite-regulating hormones that facilitate weight regain and the return to initial energy homeostasis (Sumithran et al., 2011).
This response to alteration of energy balance nullifies the success of many dietary approaches.
It is well-known that the long-term success of a nutritional approach is defined by the amount of weight regain and is the main problem regarding the so-called weight cycling or “yo-yo” effect (Jeffery, 1996).
A recent study by our group has demonstrated that a brief ketogenic period, if followed by a longer period of correct Mediterranean diet could avoid this yo-yo effect (Paoli et al., 2013)."
INSERT:Brian Edwards note: this long term study was only 12 months long.
"Recently, Sumithran et al. demonstrated that there is a long-term persistence of changes in some peripheral hormones involved in food control (Sumithran et al., 2011). In this study, they found a significant difference in mean levels of many food intake-related hormones 1 year after the cessation of weight loss via the hypocaloric diet. There was a long lasting decrease of anorexigenic compounds: 1-leptin, 2-PYY, 3-cholecystokinin, 4- insulin, and 5- pancreatic peptide and an 6-increase of the orexigenic molecule ghrelin. Moreover, they found that hunger remained elevated 1 year after diet cessation. In a successive study the same group investigated hunger-related hormones after 8 weeks of KD, demonstrating that during ketosis the increase of ghrelin (a strong stimulator of appetite) was suppressed (Sumithran et al., 2013). These results are consistent with those of Ratliff et al (Ratliff et al., 2009), who found no significant change in fasting plasma ghrelin after 12 weeks of VLCD."
Excerpt seven "The global picture is complicated by the contradictory role of ketosis on anorexigenic and orexigenic signals (summarized in Figure Figure4).4).
Ketones (mainly BHB) can act both orexigenically or anorexigenically."
INSERT my comment: Insulin acts peripherally anabolic, and centrally catabolic. Leptin and Insulin act on the same pathways centrally. (i.e on inhibiting Ghrelin)
The main message of this book is that The Sponge Syndrome will cause weight regain despite Atkins diet and exercise because the low leptin levels tell your brain you are starving. Subsequently multiple compensatory hormonal pathways are utilized to make a reduced obese patient re-gain weight even at relatively low calorie intakes.
I believe by my personal experience of having Chronic Obesity, the only way to maintain weight loss for greater than 10 years with satiety is with the addition of multiple diet medications.
Satiety on a restricted caloric diet is crucial to maintain that diet for the long term.
Major challenges to treatment of chronic obesity:
1- Diet Medication high cost
2- Must stay on diet medication for rest of life.
3- Must stay on restrictive diet for rest of life.
People are offered bariatric surgery rather than trying a LCHF diet with nutritional ketosis.
Physicians must learn about diet medications and use them as a first drug. If on Insulin with Diabetes Type 2 for example switch to Metformin, Victoza or Invokana.
Don’t ever tell a reduced obese patient, they regained weight because they didn’t exercise enough (60 to 90 minutes/day) or stick to a starvation diet (1500 cal/day). This may be in the guidelines but it did not work over 10 years in the LOOK AHEAD trial despite the best institutional support in the treatment group.
Ask your Doctor if he had read Gina Kolata NYT article on The Biggest Loser. They regained even though they did everything right.
It is all about never losing your fat cells. When adipocytes
are shrunken in the reduced obese, they are low in Leptin and tell your brain you are starving. MiRNA from the numerous fat cells then send same message (starvation) to most of the body in the form of episomes in the blood stream.
Remember 70% of your resting metabolism is from the liver, brain and kidney. When these organs are tuned down in metabolism no amount of exercise can overcome it. More exercise makes a patient more hungry.
The only way to fight the Sponge Syndrome is with multiple diet medications.
Finally, find a physician certified in the American Board of Obesity Medicine who has a good bioelectric impedance weight scale so you can follow your muscle mass. It will be discouraging to see the 5-10% loss of muscle mass as you lose weight.
First Body Composition Report before starting Qysmia at Stormont Obesity Clinic 6-23-15 244.8 lbs 46.1 lbs muscle mass
12-11-15 222.1 lbs 41.8 lbs muscle mass
4-11-18 204.3 lbs Muscle Mass 38.4 lbs.
5-11-18 vs 5-3-18 at 210 lbs after wt lifting
I think it is more important to lose as much weight as possible in the first 6 to 9 month window. Then at the plateau, start the low weight high repetition (24 reps, 3 sets, 4 times a week) exercises on very high protein diet (2.4 mg/d protein per kg of lean body weight).
With more exercise is more hunger. This is why you will need the diet medications more than ever.
Insulin is probably one of the main reasons people gain their weight back from the plateau of weight loss.
Let me go through the physiology.
Insulin peripherally is anabolic.
It promotes constructive metabolism. Insulin will store fat in adipose and glycogen in muscle and liver.
Insulin centrally is catabolic. (like Leptin) Insulin breaks down molecules to release energy..
Low Leptin increases food intake and suppresses energy expenditure.
"Leptin is an important signal for starvation."
High Leptin reduces food intake by inhibiting NPY/AgRP neurons and stimulating the alpha-MSH neurons. (Except in the Obese who become Leptin resistant. Only lean individuals appear to be regulating body weight.)
Centrally,Leptin and Insulin share same feeding inhibitory and thermogenic pathways.
However, in Obese, Insulin triggers steroidogenic factor 1 (SF-1) expressing neurons of the VMH, resulting in inhibition of POMC neurons, which promotes food intake and perpetuates obesity.
Let me repeat.
1-In lean individuals who have never been obese, leptin and insulin prevent them from becoming obese.
Centrally high levels of leptin and insulin reduce food intake and suppress energy expenditure through same pathway. Centrally both insulin and leptin are catabolic.
A lean individual eats a large meal. High insulin from pancreas peripherally stores fat and adipose and centrally increases thermogenesis to burn excess calories to maintain weight.
2-A “genetically obese prone” individual with early insulin resistance and early leptin resistance does all this less effectively.
Storing more fat, burning less energy and allowing more food intake on the slippery slope of always more appetite and more fat with more leptin and insulin resistance.
With tremendous will power an obese person follows the 3500 calorie rule and is able to lose weight for 6-9 months until the plateau is reached.
At this point the thermodynamic laws of physics fail and the biological laws of survival take over.
Your body thinks you are starving. The plethora of retained fat cells in the reduced obese tell the brain this early warning.
The numerous fat cells did not disappear, they are shrunken. The subsequent low leptin level in the face of so many fat cells signals the body that starvation is occurring by sending out MiRNA’s to many cells all over the body.
This is the Sponge Syndrome.
So many fat cells remain in the reduced obese, so little leptin. Insulin probably high, but there is resistance to it’s glucose lowering effect. MiRNA’s(episomes) are sent from the billions of fat cells to all the body via blood stream.
Priority number one for the body is no longer to heat the body in order to restore the prior size of the fat cells(get back to prior high level of Leptin).
Thermogenesis is reduced in the plateau as the determined dieter goes to 800 calories a day or increases to three hours of walking a day.
The physics of the 3500 rule calorie fails.
This is where the dieter learns that most of calories burned during 24 hours are from theresting metabolism. Up to 70% of calories may be burned by the brain, liver, kidneys, heart, lungs, endocrine organs. Muscles themselves become food at this point, not the tool for a weight lifter to lose weight.
Thermogenesis is reduced by Leptin and Insulin and I suspect MiRNA (by sending the message of starvation to the many cells of the body)
The dieter can do nothing about this.
Maybe the new diet pills and gastric bypass help?
The only hormone that stimulates appetite?
Leptin inhibits Ghrelin but not in obese.
Insulin inhibits Ghrelin centrally but not in obese.
The reduced obese with the billions of excess shrunken fat cells and subsequent low leptin level have high Ghrelin levels making us thinking of nothing but our next meal.
The sub-starvation state. This miserable psychological condition is what most diet guidelines are telling us we must stay in to maintain our weight loss and they are wrong. It is not sustainable.
The high insulin levels will take any food we eat and use the food for fat storage. It might take years but at any moment of mild excess food intake above 1,000 calories, those extras calories don’t go to build muscle or make heat it is used instead to store fat(increase Leptin level). Survival of famine is the body’s main objective. It’s in our DNA.
The sponge of excess fat cells with the help of insulin will convert food to fat at low levels of calorie intake to slowly get the leptin level back to a safe level for survival. MiRNA also play a key role yet to be totally determined.
This is why you can’t maintain your weight loss.
This is why your plateau usually is not even close to your optimum BMI.
Your body uses your leptin level to determine your risk of starvation.
Your reduced obese body has the same number of fat cells as your former maximum obese self and all those excess shrunken fat cells secrete an excess of MiRNA.
The reduced obese body uses the excess adipocytes that is has as a survival mechanism to rapidly re-gain fat and they never go away.
If you surgically remove them, they grow back some place else.
Brain cells die. Fat cells replace themselves as they are more important for survival.
Obese individuals are Leptin resistant and often insulin resistant.
Thus Leptin and Insulin acts differently in the obese state.
They also act differently in the reduced obese state which is why people cannot maintain their weight loss despite low calorie diet and exercise.
What is the truth about the failure of the reduced obese to maintain weight loss?
“The answer is that there is a convergence of evidence from multiple lines of inquiry—”
Part of the anorexic pathway:
Ileal Brake controls rate at which food moves through the gut. It is a form of gut traffic control.
Locaserin acitvates POMC neurons in brain.
Alpha MSH release
Part of the feeding stimulatory pathway
Ghrelin opposes Leptin effect in hypothalamus. Leptin inhibits ghrelin action.
Ghrelin activates NPY/AgRP neuron
Ghrelin stimulate NPY release and AgRP release increase orexigenic pathway.
The above is a short summary that is based in science and on my Obesity Boards.
Medications were designed to affect these pathways. The brain makes compensations with one medicine, thus multiple medicines needed to affect many of the different pathways that cause weight regain.