In the last blog, The Insomnia Epidemic, I spoke about how our natural sleep patterns differ from the “cultural norm” of one 6-8 hour block at night and suggested that this causes many folks sleep problems.
Sleep experts believe that our 24/7 culture has created such pervasive sleep deprivation that abnormal sleepiness is the norm. Unfortunately, there is no adapting to getting less sleep than we need. What happens is we adjust to a sleep-deprived state in which our judgement, memory, reaction time, and many other functions are impaired. Studies also document how our subjective assessment of performance with sleep deprivation is way off. We consistently think we’re doing fine, until we really can’t function. The experts say that if you feel drowsy during the day, even when bored, you haven’t had enough sleep. Similarly, falling asleep within 5 minutes of lying down in bed suggests severe sleep deprivation. So there’s no question, the public is hungry for more (or better) sleep. And a smorgasbord of medications are on offer everywhere you look, in magazines, on television, and on the internet.

According to Medco Health Solutions, a prescription drug benefit program manager, the number of adults ages 20 - 44 using sleeping pills doubled from 2000 to 2004. Children apparently have not been spared. Usage increased 85% in 10-19 year olds during the same period. And the trend has continued. In 2008 the sale of prescription sleep aids totaled $3 billion. The number of prescriptions written for sleep meds exceeded 59 million in 2009, an increase of approximately 4 million scrips from the previous year. In 2010 the pharmaceutical industry took in $5 billion from the sale of sleep medications.

How do we explain this astronomical rise in sleep medication usage? There are only a few possibilities. It’s hard to imagine that this population’s sleep deteriorated so dramatically in these 4 years it accounts for this trend. Some might suggest that the sleep impaired were always out there but hadn’t been diagnosed and treated until the recent focus on insomnia. While this may have some truth, it hardly explains the rate of increased usage of these meds. After all, insomnia is not a sexually transmitted disease. There is not a stigma attached to sleep disorders that would make it difficult for patients to report their concerns. Has the cultural environment changed significantly? Has this time period witnessed big changes in our use of mobil devices, lap tops, etc.? Did we become even more 24/7 since the turn of the century? Yes, to some extent we have.

But I believe it’s none of the above. So what happened?

The combined effect of changes in three areas, medicine, advertising, and our psyche, created the perfect climate for these medications. Let’s take them one at a time.

Medicine:
Over the past two decades the practice of medicine has been transformed (some would say ruined). The average patient visit is 10 minutes. There is no time to discuss the patient’s home life, work situation, social or financial stressors. There is no continuity of care. Patients bounce around to specialists without anyone overseeing the whole person. So if people complain of difficulty sleeping, there will not be an exploration of what’s going on in their life. That takes way too much time. Physicians continue to want to help. They want to respond to the patient’s complaint. In this context, the prescription is the best they’ve got.
In addition, physicians diminishing control of the field of medicine (now run by government and insurers) and decreased remuneration has made them more susceptible to dubious practices such as responding to patient requests for specific medications.
These forces have catalyzed the “medicalization” of sleep, a process where a formerly normal behavior is reframed as a medical problem. In fact, analysis of data over a 15 year period shows the new generation nonbenzodiazepine sleep med prescriptions grew 21 times more rapidly than did sleeplessness complaints and 5 times more rapidly than did insomnia diagnoses. The inappropriate use of medical solutions to treat problems of living fits neatly into the changes in the American psyche that I discuss below.

Advertising:
In the early 1980’s the pharmaceutical industry began marketing prescription drugs directly to the public. The FDA questioned this practice and imposed a moratorium in 1983, but lifted it in 1985. Not surprisingly, there is a striking correlation between the amount of money spent on advertising for a drug and that drug’s sales. The 4 million sleep scrip increase from 2008 to 2009 coincided with a direct-to-consumer 2008 ad budget of $500 million for Ambien CR and Lunesta, the most prescribed sleep meds that year.

Our Psyche:
The funny thing about sleep medications is they don’t change your sleep very much. If you look at efficacy studies you realize that people are not sleeping much better on these sleep medications that are selling like hot cakes. The studies show that on average, subjects fall asleep about 12 minutes faster and increase their total sleep time by about 15 minutes compared to placebo. And yet these very same subjects report that they slept well. So what gives?

Well, it so happens that a side effect of these medications is something called anterograde amnesia, a state in which you cannot form new memories. In other words, you don’t remember how you slept. (In fact you may not remember all sorts of things that went on during the night, like driving around, sending emails, or eating more than you thought humanly possible. But that’s another story.) These agents also have an anti-anxiety effect. Not only might this help you fall asleep, but it also minimizes the impact of not doing so.

One Lunesta advert has a mellifluous women’s voice cooing sympathetically “Does you restless mind keep you from sleeping?” That is a bullseye. The American mind has reason to be restless. A decade ago, 9/11 presented the greatest shock in this country’s history. What initially seemed to have the potential to unite the population and create common purpose quickly deteriorated. The country became polarized into red and blue, antagonistic camps speaking different tongues, accusing the other of being unpatriotic, unamerican. For the past 10 years we have engaged in the “War on Terror”, an amorphous conflict without boundaries, a means for assessing how we’re doing, or consensus. We do not feel safer.
Iraq and Afghanistan have not been transformed, but we have. Our belief in American ability and fair play has been compromised. Historically, national traumas have provided a fulcrum from which we have forced positive changes. None of the past decade’s national nightmares, Hurricane Katrina, mortgage defaults, stock bubbles, a collapsing economy, or unemployment have been able to provide the stimulus for a gathering of transformative momentum.

Why are sleep medications so popular? Because in the quiet darkness of our bedrooms with nothing to distract us, the mind struggles to empty itself of haunting anxieties. To swallow these pills is to change our state of consciousness. We forget. Then we sleep.

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More than 30% of adult Americans, about 40 million people, complain of difficulty sleeping. For most of these individuals,
treatment begins with medication. This tells us two things. Sleep is a big problem and a big business. These two aspects of the ecology of sleep create a complicated calculus in an already enormously complex field. But I think it is possible to keep the two issues separate and tell a few good stories in parallel. It must be said that the cultural influences on the medical community in deciding what constitutes normal and disordered sleep are profound. While all medical conditions are culturally bound, the fact that sleep is a universal behavior (that takes many forms and can be willfully modified) in addition to a biological one, makes its conceptualization particularly susceptible to the vagaries of a given era’s customs and beliefs.

So how does one of the most basic biological functions become so disordered? After all, what could be more natural than sleep?

The first thing you notice when digging into what we know about sleep is how little we understand. The function of sleep, a state that occupies one third of our lives, remains unclear. Why is sleep necessary for our survival? Why do we dream? Sure we have made some connections by observing what happens to people who are sleep-deprived or perform shift work. Clearly physical and cognitive function take a hit. Medical interns working on the night shift are twice as likely as others to misinterpret hospital test records that could endanger their patients. The Exxon Valdez oil spill and the Three Mile Island and Chernobyl nuclear power plant accidents were attributed in large part to the consequences of compromised night shift workers. We know memory and learning is impaired. Protein synthesis that produces the building blocks needed for cell growth and repair is markedly diminished. But theses are crude observations, not understanding.

The second thing you realize, and this boggles the mind, is that almost everything we do know about human sleep has been learned in the last fifty years. Unfortunately, like the first beliefs in any discipline, many of the early theories about our sleep were wrong. Until recently, humans were thought to be different from all other animals in having sleep that is consolidated into one continuous nocturnal episode. This notion of uniquely human sleep held sway until the early 1990’s when Thomas Wehr, a sleep researcher at NIMH inadvertently stumbled on something that changed everything, or should have.

Wehr selected healthy untroubled sleepers who were accustomed to 16-17 hour days and 7-8 hours of sleep, a routine that many of us live by or envy because we get less sleep. He exposed them to ten hours of light and fourteen hours of dark per day and watched what happened to their sleep. This ratio of light to dark (10:14) mimics the natural light of a typical winter day in a temperate climate. Initially they slept for 11 hours per night, suggesting a chronic sleep deficit, and then settled into an average of 8.9 hours each night. By the fourth week Wehr saw something that wasn’t supposed to happen in humans. They all developed a sleep pattern characterized by two sleep sessions. Subjects tended to lie awake for one to two hours and then fall quickly asleep. After about 4 hours of solid sleep, they would awaken and spend one to two hours in a state of quiet wakefulness before a second four hour sleep period.

This bimodal sleep has been observed in many other animals. One such creature turns out to be pre-industrial man. Only recently have anthropologists and historians scrutinized the sleep of other cultures, earlier centuries and prehistoric humans. In the remarkably informative “At Day’s Close, Night in Times Past”, Roger Ekirch unveils nocturnal life in the pre-industrial west. Drawing from a broad range of sources he found a trove of evidence documenting our history of bimodal sleep. Until the late 1700s, and the widespread use of artificial light, people retired to bed soon after sun down and entered what was called “first sleep.” They would awaken three or four hours later and enjoy a couple hours of quiet. During this time they often prayed, chatted about dreams and had sex. A French physician described this time between sleeps as a particularly good opportunity for sexual intimacy when couples “do it better” and have “more enjoyment”. The middle night interactions seem to have been essential for social cohesion. This was followed by “second sleep” that again lasted 3-4 hours and ended with sunrise.

In fact a study of contemporary cultures across the globe reveals a wide spectrum of sleep habits. Some anthropologists now speak of three sleep cultures: monophasic cultures (the West where one consolidated sleep period dominates), siesta cultures (where one afternoon nap is added in the afternoon, the word siesta meaning the 6th hour) and polyphasic cultures (China, Japan, India where multiple naps throughout the day of varying lengths are the norm).

Researchers have replicated and expanded on Wehr’s work. Several studies have taken subjects to deep underground bunkers free of any artificial light in order to observe our internal clock’s rhythm. Again, they observe this biphasic pattern. Subjects sleep in two four hour solid blocks separated by a couple hours of meditative quiet during which there is a remarkable surge of prolactin, unseen in modern humans. The participants report feeling so awake during the day that it is as if they experience true wakefulness for the first time.

So we find ourselves in a somewhat perverse situation. We have not evolved to naturally drift rapidly into one continuous nocturnal snooze. But according to the medical community and the pharmaceutical industry, if we don’t do this, we suffer from a sleep disorder that merits medicating. However, if you ask any sleep expert how some people seem to fall asleep quickly and sleep continuously for seven or eight hours they’ll say that such a sleep pattern is characteristic of chronic sleep deprivation.

We evolved in an environment of alternating light and darkness and developed internal clocks to manage in such conditions. Every known organism with two or more cells has an internal clock. In this regard we are not unique. It is our use of artificial light to extend our day and defy our natural rhythms that distinguishes humans. We have just begun to understand the consequences of this Promethean sin. Sleep deprivation has been linked to obesity, hypertension, insulin resistance, cardiac disease, compromised immune function and depression. In the same way that food products/supplements are replacing normal eating with dire health effects, sleep continues to be condensed by the 24/7 culture. The recent rapid growth of a new category of medications that promote wakefulness makes one wonder if sleep will soon be optional or ultimately obsolete.

So what are you supposed to do if you?

The constraints of work schedules and family responsibilites make radical changes in sleep-wake timing difficult. Here’s some guidelines:

Abandon the idea of going to bed for 6-8 hours of sleep at night (unless this works for you).
Get a feel for what your sleep cycle looks like. If you wake up before you need to, get up. This is probably a natural cycle end. You will make up for lost nighttime sleep with a nap(s).
Napping Guidelines:
· Timing: Afternoon (3-5 PM) Proven to provide more sleep efficiency, more slow wave sleep, and less time to fall asleep
· Duration: Optimally 10 – 20 minutes. People experience greater cognitive impairment due to sluggishness after a nap of 30 or more minutes than that due to sleep deprivation.
· The full benefits of naps comes with habitual napping. Stick with it!

4. If possible, when you feel like reaching for that afternoon caffeine fix, take a nap.

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The only source of sweet for 99.9% of human existence has been glucose and fructose. Not surprisingly we developed a physiology where feeding behavior is largely controlled by the ebb and flow of blood levels of these sugars and their metabolites which reflect our energy status. In other words, a part of the brain watches our gas tank and sends messages accordingly, directing us toward or away from the kitchen. The obesity epidemic strongly suggests that we have lost this signal.

The sources of sweet started to change after World War II. The combination of a sugar shortage and a changing esthetic that favored a thin figure encouraged women to try a sugar substitute. Saccharin (Sweet N’ Low), the oldest nonnutritive sweetener was discovered in 1879 at Johns Hopkins during experimentation with coal tar derivatives. Saccharin had been used to replace sugar in soda marketed to diabetics until after the war when soda bottle labels were changed from “for use only in people who must limit sugar intake” to “for use in people who desire to limit sugar intake.” Saccharin, which is 300 times sweeter than sucrose (table sugar, a disaccharide composed of 50% glucose and 50% fructose) was followed by cyclamate in 1937. Concern over cyclamate’s capacity to cause cancer took it off the market in 1969. Similar concerns resulted in the FDA’s plan to pull saccharin in 1977, but consumer protest reversed the decision. A warning label accompanied all saccharine products until 2000 when subsequent studies demonstrated that it is not carcinogenic. These investigations essentially silenced concerns over the safety of artificial sweeteners. Cyclamate continues to be available in 50 countries including Canada.

The next generation of sugar substitutes gave us aspartame (NutraSweet, Equal, 200 times sweeter than sucrose), sucralose (Splenda, 600 times sweeter than sucrose), and Neotame, the sweetest, weighing in at 7,000 times the sweetness of sucrose. These sweeteners have been well received. Between 1999 and 2004 6,000 food products containing these agents went to market. According to foodfacts.com, an ingredient search engine, there are now no fewer than 3,648 foods containing these chemicals in the U.S.. A sizable majority of americans consume artificial sweeteners, usually believing that they are making the healthy choice. In fact diet soda drinkers diets contain more whole grains and low-fat dairy, and less processed meat and refined sugar, than the general population. The idea that diet soda is a health food has accelerated with the recent “low-carb” diet fad.

Unfortunately, what was supposed to provide the perfect solution to caloric overload and weight gain by eliminating the need for sugar failed miserably. In fact, many large epidemiological studies have demonstrated a positive correlation between artificial sweeteners and weight gain. How could this happen? Ironically, exactly what seemed to make nonnutritive sweeteners ideal, the capacity to provide unlimited sweetness with zero caloric load, opened the door to overeating on a scale our species has never witnessed.

Human taste provides sensations of sweet, sour, salty, bitter, savory and possibly fat and metallic. While the identification and tracking of food relied upon the visual and olfactory systems, animals developed the capacity for taste in order to recognize potential nutrients and poisons. A keen sense of taste was enormously adaptive because it provided a guide to what was full of energy/calories (sweet), a source of electrolytes (salty), rich in protein (savory) and a potential toxin (bitter).

Because life ceases without an energy source, our capacity to discern small differences in sweetness and our preference for the sweeter, is innate, not learned. We come into the world fully loaded with a genius for choosing the sweeter option, the product of about two and half million years of evolution. Newborns will invariably prefer a sweetened nipple. Numerous experiments have documented infants’ pleasure response to sweetened water including a slowed heart beat, relaxed face, hedonic brain pattern and endorphin release. Infants also learn to associate thicker fluids with greater sweetness because the viscosity and caloric density of human breast milk vary together.

Experiments in a variety of animals including humans have repeatedly demonstrated that artificial sweeteners increase hunger and total energy intake while sugar seems to trigger a mechanism that keeps energy consumption fairly constant. Functional MRI studies, where they take pictures of the brain while someone ingests something and see what areas are active, indicate that the food reward system responds differently to sugar versus artificial sweetener. This reward system is not only what drives appetite, but also when turned off, allows us to push away from the table before loosening our belts.

When man tampered with nature and uncoupled the sensory signal (sweetness) from caloric load, a pairing that we adjusted to for over 100,000 generation, our capacity to know when we had enough was eradicated. Failure to activate the full food reward response fuels increased consumption.

There is another unanticipated side-effect of these sugar impostors. In 2005 Americans ate 24 pounds of sugar substitutes per person, double the 1980 rates. Surprisingly, sugar consumption increased by 25% between 1980 and 2005. Our sweet receptors evolved in environments with so little sugar they seem to have no shut off point. By exposure to compounds that are hundreds to thousands of times sweeter than sugar, our taste for sweetness is being up-regulated. This has translated into consuming more sugar while using sugar substitutes.

Once again what seemed like a no-brainer proved to be a disaster because of a disregard for our evolutionary history. It is not unreasonable to suggest that sugar substitutes have significantly contributed to the obesity and type 2 diabetes epidemics. Completely change something as basic as the fuel we’ve survived on since the beginning? What could possibly go wrong?

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The following article exemplifies the importance of following trends in bloodtest results rather than waiting until values have entered the “abnormal range”, something I have been stressing at Pantheon Medicine for years. This issue now affects all adult American’s blood sugar levels which, when elevated but still within the “normal” non-diabetic range, are a prognostic indicator for cardiovascular disease and progression to Type 2 Diabetes (T2DM). The US is witnessing an epidemic of these two diseases, caused not only by our lifestyles (diet/exercise) but also because of an antiquated view of when the disease process begins and therefore when intervention is initiated. Here is some background on the evolution of our conceptualization of blood sugar levels and an important new finding that connects these levels to pathological changes associated with aging.

The current definition of diabetes was based on studies that demonstrated the incidence of retinopathy and nephropathy at specific glucose concentrations. The definition was not tied to the risk for
CVD. Over the past 20 years there has been a growing body of evidence showing that the risk for both cardiovascular events and atherosclerosis extends below the microvascular disease threshold.
This awareness has contributed to the development of a lowered range for Impaired Fasting Glucose. The association between progressive increases in blood sugar level and increases in cardiovascular risk is similar to the relationships between cholesterol and blood pressure levels and cardiovascular risk. The “normal” ranges for BP and cholesterol have also been revised. These findings reinforce the idea that pathophysiological processes are initiated long before standard clinical and laboratory testing become postitive.

The finding that after an oral dose of glucose the resulting blood level has a linear relationship with cardiovascular disease in the non-diabetic range (normal range), and that postprandial (after eating) hyperglycemia is particularly damaging and occurs long before the fasting blood glucose level rises is particularly important. This is why one should monitor the oral glucose tolerance test (OGTT). CVD risk has been observed to increase more steeply for increasing fasting blood sugar level than for OGTT glucose level. It is of note that some studies have suggested that the glycosylated hemoglobin level (HgbA1c) may be predictive of CVD across the whole range of values and may have a higher predictive value for mortality than other CVD risk factors. In addition, women appear to have a greater CVD risk associated with hyperglycemia than men in these populations.

Small et al have now published a paper (Annals of Neurology 2008; 64: 698-706) suggesting that a similar process is at play in cognitive decline associated with aging. They demonstrate that a major systemic cause of cognitive aging is damage to a specific area in the brain’s hippocampus (the dentate gyrus, an area involved in memory). Aging does not cause diffuse brain dysfunction but rather targets the frontal lobes and the hippocampus. This hippocampal pathology is due to an increase in blood glucose levels in the absence of disease, such as diabetes.

I believe this research will contribute to the growing concern about the consequences of blood glucose levels in the high end of the normal range and support the contention that there may be a need for
following glucose tolerance test results as people enter middle age.

It also suggests that more aggressive measures are needed to therapeutically address “normal aging” in this area. Cognitive studies have shown that normal age-related hippocampal dysfunction
begins during the fourth decade of life, well before the onset of age-related diseases. Interestingly, among all hippocampal subregions, physical exercise causes a differential improvement in dentate gyrus function.

I spoke with Dr. Small to ask if he had any ideas about what lab results within the normal range should trigger more aggressive intervention. He was reluctant to give any numbers but agreed that a
glucose tolerance test was the best way to assess this situation, and that any trend of decreased insulin sensitivity should translate into more aggressive treatment. He is a great believer in the capacity of
exercise to increase insulin sensitivity and specifically ameliorate hippocampal function.

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It is very difficult to know how to choose a surgeon. Often people select one based on the recommendation of a friend or a referring physician without knowing anything about the surgeon’s record. The following pinpoints specific information that should be researched before making such a decision.

In the September issue of Annals of Surgery, a group from the University of Michigan examined operative mortality in approximately 461,000 patients undergoing 1 of 8 procedures between 1998 and 1999. They assessed relationships between surgeon age (<=40 years, 41–50 years, 51–60 years, and >60 years) and operative mortality (in-hospital or within 30 days), adjusting for patient characteristics, surgeon procedure volume, and hospital attributes.

Compared with surgeons aged 41 to 50 years, surgeons over 60 years had higher mortality rates with pancreatectomy (adjusted odds ratio [OR], 1.67; 95% confidence interval [CI], 1.12–2.49), coronary artery bypass grafting (OR, 1.17; 95% CI, 1.05–1.29), and carotid endarterectomy (OR, 1.21; 95% CI, 1.04–1.40). The effect of surgeon age was largely restricted to those surgeons with low procedure volumes and was unrelated to mortality for esophagectomy, cystectomy, lung resection, aortic valve replacement, or aortic aneurysm repair.

Conclusion:
There are two important points that this work highlights:
1. Of the 8 procedures monitored, only 3 had outcomes significantly affected by surgeon age. Generally the surgeon procedure volume was the more important variable.

2. It is essential to determine the surgeon procedure volume not only over his career, but over the year prior to your potential surgery date because often surgeons approach retirement by gradually tapering off their operative volumes. Therefore the "best" practitioners of a given procedure, if winding down, may have performed more of the specific surgery over their career, but not more than another surgeon with a lower career total, over the past year.

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The following piece explains the connection between the role of energy intake, sirtuins, PPARs, exercise, thiazolidinediones and insulin sensitivity. I think you will find them interesting. They suggest possible strategies for metabolic syndrome management and illustrate the complexity of  caloric restriction effects which clearly involve many pathways.

Sirt1 and PPARgamma
Guarente, in 2004 (Nature Vol. 429, 17 June), attempted to demonstrate a molecular pathway that connects caloric restriction and life extension. He proposed that Sirt1 is the regulatory gene that monitors cellular metabolism and triggers fat mobilization in white adipose tissue (WAT) in response to caloric restriction. (WAT stores energy when food intake exceeds energy expenditure, whereas brown adipose tissue (BAT)* has the ability to dissipate energy through thermogenesis. De novo adipocyte differentiation can be initiated throughout the lifespan of mammals by recruiting fibroblastic precursors, a process in which peroxisome proliferators-activated receptor gamma (PPARg, a lipid activated nuclear hormone receptor with the highest expression in adipose tissue but also found in pancreatic beta cells, vascular endothelium, and macrophages) is a master regulator. Committed precursor cells synthesize specific lipid metabolites that bind to PPARg, promoting terminal differentiation. Guarente suggests that Sirt1 triggers fat mobilization by repressing PPARg, which would otherwise promote adipogenesis and fat retention.

*BAT expresses the uncoupling protein1 (UCP-1) that can dissipate energy through adaptive thermogenesis. Retinoblastoma protein (pRB) is known to be a central regulator of the mammalian cell cycle and cellular differentiation. Hansen et al. (PNAS March 23,2004, Vol. 101, no. 12) showed that cells with genetic ablation of the Rb gene in the adipose state displayed a gene expression pattern closely resembling that of BAT, including expression of UCP-1. These adipocytes developed
many more mitochondria than wild-type adipocytes, like brown adipocytes. Cells lacking pRB can not undergo adipose conversion, but are rescued by administration of a PPARg ligand. Hansen suggests that pRB acts as a molecular switch controling white vs. brown adipogenesis. This could be an interesting pharmacological target.

Thiazolidinediones and Insulin Sensitivity
Thiazolidinediones are selective ligands of the nuclear PPARg. PPARg is necessary for normal adipocyte differentiation and proliferation as well as fatty acid uptake and storage. It is hypothesized that thiazolidinediones sensitize insulin either directly ("fatty acid steal" ) or indirectly, through altered adipokine release, modulating insulin sensitivity outside adipose tissue. According to the 'fatty acid steal" hypothesis, thiazolidinediones promote fatty acid uptake and storage in adipose tissue. This  increases adipose tissue mass and spares other insulin-sensitive tissues such as skeletal muscle, liver and pancreatic beta cells, from the destructive effects of high concentrations of free fatty acids. One of the indirect effects of thiazolidinediones in adipose tissue is the increase of adiponectin secretion, which in turn increases insulin sensitivity.

Sirt1 and Peroxisome proliferators-activated receptor-gamma
co-activator 1alpha (PGC1alpha) In 2005, Rodgers et al. (Nature Vol. 434, 3 March), illustrated how Sirt1 operates in glucose homeostasis as a modulator of PGC-1alpha, a key regulator of glucose production in the liver. His work demonstrated that Sirt1 increased in the liver of fasted mice secondary to changes in glucose (decreases) and/or pyruvate (increases). This was the first time PGC-1alpha and Sirt1 were shown to function together to promote adaptation to caloric restriction by regulating the genetic programs of gluconeogenesis and glycolysis.

PGC1alpha, Skeletal Muscle and Exercise
PGC-1alpha is very low in WAT, but has been shown to stimulate mitochondrial biogenesis and regulate genes involved in oxidative phosphorylation in skeletal muscle. Studies suggest that decreased skeletal muscle PGC1alpha activity is associated with impaired mitochondrial function and the development of insulin resistance in humans. Muoio et al. in 2005 (Jl of Bio Chem Vol. 280, No.39 pp.33588-33598) presented data demonstrating that high fat diet induced insulin resistance in rodents occurs in association with decreased muscle PGC1alpha expression and impaired mitochondrial performance. Exercise, which increases PGC1alpha activity, reversed this lipid-induced glucose intolerance. A growing literature links decreased PGC1alpha activity, and accompanying reductions in the expression of genes involved in oxidative phosphorylation, to the etiology of type 2 diabetes in humans. Muoio demonstrated that the capacity of muscle mitochondria to fully oxidize a large dose of fatty acid is correlated with PGC1alpha levels.

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These two articles (see attached) address the relevance of elevated nondiabetic blood glucose levels as a prognostic indicator for cardiovascular disease and progression to T2DM. Below I summarize the articles and provide a background for their significance.

Conclusion:
-  Blood glucose is a risk marker for CVD in healthy nondiabetic people independent of other metabolic syndrome variables. Postchallenge blood glucose levels have a linear relationship with CVD in the nondiabetic range while there may be a threshold effect for a fasting blood glucose level of approximately 100mg/dl.

-  Nichols et al. found 8.1% of subjects with an initial fasting blood glucose of 100-109 mg/dl and 24.3% of subjects with an initial fasting blood glucose of 110-125 mg/dl developed diabetes (P,0.0001). The 100-109 mg/dl group progressed to diabetes within a mean of 41.4 months and the 110-125 mg/dl progressed to diabetes within a mean of 29.0 months.

I recommend monitoring your OGTT annually, and the fasting blood glucose and glycosylated hemoglobin quarterly.

Background:
The current definition of diabetes was based on studies that demonstrated the incidence of retinopathy and nephropathy at specific glucose concentrations. The definition was not tied to the risk for CVD. Over the past 20 years there has been a growing body of evidence showing that the risk for both cardiovascular events and atherosclerosis extends below the microvascular disease threshold. This awareness has contributed to the development of a lowered range for Impaired Fasting Glucose. The association between progressive increases in blood sugar level and increases in cardiovascular risk is similar to the relationships between cholesterol and blood pressure levels and cardiovascular risk. The “normal” ranges for BP and cholesterol have also been revised. These findings reinforce the idea that pathophysiological processes are initiated long before standard clinical and laboratory testing become postitive.

The finding that postchallenge blood glucose levels have a linear relationship with CVD is particularly important. Postprandial hyperglycemia is particularly damaging and occurs long before the fasting glucose level rises. This is why it makes sense for us to monitor your OGTT. The CVD risk was observed to increase more steeply for increasing fasting blood sugar level than for OGTT glucose level. It is of note that some studies have suggested that glycosylated hemoglobin level may be predictive of CVD across the whole range of values and may have a higher predictive value for mortality than other CVD risk factors. In addition, women appear to have a greater CVD risk associated with hyperglycemia than men in these populations.

Summary:
Progression From Newly Acquired Impaired Fasting Glucose to T2Diabetes
-  estimated progression from incident IFG to DM under old and new IFG criteria
-  5,452 HMO members with no history of DM, with at least 2 elevated FBGs (100-125) preceded by a normal FBG, monitored between 1994 and 2003
-  8.1% of subjects with an initial fasting blood glucose of 100-109 mg/dl and 24.3% of subjects with an initial fasting blood glucose of 110-125 mg/dl developed diabetes (P,0.0001). The 100-109 mg/dl group progressed to diabetes within a mean of 41.4 months and the 110-125 mg/dl progressed to diabetes within a mean of 29.0 months.
-  Steeper rate of increasing FBG, higher BMI, BP, and triglycerides, and lower HDLchol predicted diabetes development.
-  Higher BMI and lower HDL were most highly significant nonglucose predictors of hyperglycemic progression.
-  Limitations: readings taken at irregular intervals, lack of precise data on point of crossing IFG threshold, 19% drop out, unable to assess known predictors of DM in subjects.

Is Nondiabetic Hyperglycemia a Risk Factor for CVD
-  meta analysis of 38 prospective studies with CVD or mortality as endpoint and blood glucose levels measured. RR reported comparing groups of nondiabetic people with CIs or P values
-  Group with highest postchallenge blood glucose (midpoint range: 150-194mg/dl) had a 27% greater risk for CVD compared to group with lowest level (midpoint range: 69-107mg/dl).
-  Adjustment for CVD risk factors attenuated but did not abolish relationship(RR 1.19 vs 1.27)
- Women demonstrated greater CVD risk secondary to hyperglycemia

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In recent years, the focus of anticancer drug development has shifted dramatically from conventional cytotoxic drugs (drugs that kill cells) that directly affect processes such as DNA synthesis to targeted agents that modulate proteins such as kinases whose activities are more specifically associated with cancerous cells. The following are some examples.

Avastin (bevacizumab) is an intravenous molecular targeted agent that binds and inhibits vascular endothelial growth factor (VEGF), decreasing microvascular growth and metastatic progression. Avastin has been approved for the treatment of colorectal and non-small cell lung cancer.

Rapamycin is an immunosuppressive agent that inhibits T-lymphocyte activation and proliferation, as well as antibody production. It usually is used to prevent the body from rejecting organ and bone marrow transplants. It binds a protein which results in the inhibition of the activation of a key regulatory kinase. This blocks the reproduction of the targeted cell. Rapamycin can be used to treat certain lung cancers.

Sprycel (dasatinib) is a novel oral multi-targeted inhibitor of two kinases that has been used with imatinib-resistant cancers. Imatinib (Gleevac) was the first approved drug to directly turn off the signal of a protein known to cause cancer. Sprycel has been used to treat resistant chronic myeloid leukemia and other cancers.

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The following summarizes a recent article in Nature on calorie restriction, Resveratrol and longevity.

Resveratrol reduced the risk of death from the high-calorie (HC) diet by 31%, to a point where it was not significantly different from the standard diet (SD) group

Reseveratrol-fed HC mice steadily improved their motor skills as they aged, to the point where they were indistinguishable from the SD group

The high-calorie, reseveratrol-fed (HCR) group had significantly lower levels of markers that predict the onset of diabetes, including insulin, glucose and IGF-1, paralleling the SD group

An oral glucose tolerance test indicated that the insulin sensitivity of the resveratrol-treated mice was considerably higher than controls

Possible mechanism: phosphorylation of AMPK, a metabolic regulator that promotes insulin sensitivity and fatty acid oxidation, as well as two downstream indicators of activity, phosphorylation of acetyl-coA carboxylase at Ser79 and decreased expression of fatty acid synthase

Compared with the HC group, the HCR group had reduced size and weight of livers without altered plasma lipid levels

Compared with the HC group, the HCR group had reduced plasma amylase, which can indicate pancreatic damage

Compared with the HC group, the HCR group had considerably more hepatic mitochondria

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In a recent issue of Circulation, Lam et al. describe a new risk factor for Metabolic Syndrome that may prove useful for monitoring programs.

Summary:
-  495 nondiabetic adults from the Hong Kong Cardiovascular Risk factor Prevalence Study
-  Subjects followed prospectively for up to 5 years
-  High serum Adipocyte-Fatty Acid Binding Protein (A-FABP) levels at baseline were associated with Metabolic Syndrome (odds ratio 4.0; 95% CI, adjusted for BMI, insulin resistance, CRP, and adiponectin, P=0.005)
-  Baseline A-FABP and insulin resistance were the only independent predictors for Metabolic Syndrome during the 5-year follow-up (A-FABP odds ratio 4.7; 95% CI, adjusted for BMI).
-  Weaknesses of study: small population with Metabolic Syndrome, ethnically homogeneous study population genetically and environmentally

Background:
-  A-FABP is expressed in adipocytes and macrophage
-  Mouse data have shown:
- A-FABP deficiency protects against the development of dyslipidemia, hyperglycemia, insulin resistance, and fatty liver in the context of both genetic and dietary obesity
- Ablation of the A-FABP gene in Apolipoprotein E-deficient mice dramatically reduces atherosclerosis and increases survival while on a high-fat diet.
-  Human Studies (Nurse’s Health Study and Health Professionals Follow-Up Study)
- Subjects with a genetic variant of the A-FABP gene that decreases expression had a reduced risk for hypertriglyceridemia, T2DM, and coronary artery disease.
- Lam et al. in a cross-sectional study (Diabetologia 2006; 49: 1806-1815) found that circulating A-FABP levels correlate with specific components of the Metabolic Syndrome (central adiposity, increased triglyceride levels, decreased HDL levels, fasting glucose, insulin resistance and blood pressure. A-FABP levels increased with the presence of increasing numbers of Metabolic Syndrome components.

Proposed Pathophysiology:
-  Proatherogenic action of A-FABP acts directly through macrophage effect on cholesterol trafficking and activation of inflammatory pathways, independent of lipid metabolism and insulin sensitivity.
-  A-FABP suppresses PPARgamma activity and cholesterol efflux facilitating foam cell formation.
-  Adverse effect on lipid metabolism and insulin resistance may be secondary to A-FABP’s capacity to affect intracellular and systemic fatty acid transport and composition.

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