Print Page | Contact Us | Sign In | Join ACAM
ACAM Integrative Medicine Blog
Blog Home All Blogs

Cutting Out the Sugar

Posted By Carol Hunter, Monday, December 7, 2015

When I was growing up, there was no better lunch than a grilled cheese sandwich coupled with a bowl of Campbell’s Tomato Soup. Today, that meal continues to provide much comfort for me. Although, now the cheese is processed from cashew nuts and the soup is homemade. For the moment, back to tomatoes, as there was such a bumper crop this summer. I am busy preparing various tomato dishes. My recipe this month is so simple, I am almost embarrassed to offer it, but it’s too delicious and nutritious to neglect: my homemade tomato soup, minus the sugar.

What I have begun to realize is that just about all prepared foods, even the ones made with organic ingredients, contain “organic cane sugar.” That might sound good, but it’s not. We are deluged with too much sugar in our diets today. Maybe Americans are so programmed to the taste of sugar, we have trouble getting along without it. Unfortunately, the taste for it begins in childhood with the cereals and many other products containing sugar. As early as I can remember, those around me were pouring sugar on grapefruit, cereal, oatmeal, and other foods. I think there is a place for sugar, let’s say, in a piece of chocolate or some type of dessert, but do we need it in breakfast foods, lunch meats, and dinner entrees?

A realization I had when I first started drinking almond and coconut milk was that it was too sweet. First, I bought the Silk Almond Milk Light which provides 40 calories per serving. When I tasted it, I could tell immediately that it contained sugar. Then, I noticed that the original Unsweetened Silk Almond Milk contains 30 calories per serving with no sugar.  Now if you are a consumer, you might just think, as I had, that the Light version would be healthier than the original. Not! In addition, I had bought Raw Meal by Garden of Life along with Raw Protein by Garden of Life in chocolate (my fav) and was planning to whip up my liquid breakfast with some Silk Almond Chocolate Milk at 100 calories per serving. Yes, it contains cane sugar ( 17 grams/serving), but for meal substitution, perhaps that’s not too worrisome. My argument is not one of calories although that matters down the road. My point is about taste and how we Americans are programmed from an early age to love sugar.

When you’ve been literally blasted by sugar your entire life, what happens when you try to eliminate it from your diet? Nothing earth shaking if you are getting enough fiber, thank goodness. The worst of it is that you miss that sugary taste and that might be what drives you back to your old habits. Yes, at first, the taste seems bland or even unpalatable.  But if you persist, you will soon find yourself preferring the non-sugar version! Keep at it, and keep away from the inside grocery aisles, because the majority of   prepared food contains sugar.

Even frozen organic foods contain sugar. I had some Amy’s frozen dinners, because there are days when work leaves me depleted, and I simply need some sustenance without cooking it myself. I really like Amy’s vegetarian products, so I bought the Thai Red Curry frozen dinner. It would have been wonderful if not for one thing: it was sugary and sweet. When I am eating my entree, I don’t want it to taste sweet.

When we indict individuals about their weight gain, diabetes, and unhealthy lifestyles, we had better examine the food manufacturing in our country. Not many live on a farm anymore and are able to grow their own fresh fruits and vegetables. We depend on large manufacturers to give us the nutrition we need. Sugar is a common ingredient, and unless we protest, it will not change.  We do not need to be consuming the current amounts of sugar that are routine ingredients in most, but not all, packaged foods.  My disclaimer is that I do not mean to pick on Silk and Amy brands. They simply serve as examples of many other health oriented products. I will continue to buy them myself, and especially like the Silk Original Unsweetened Almond Milk and Amy’s soups and chili.

Last month, I talked about making the switch from the omnivore to the herbivore diet. Here are my conclusions, at least at this time. I have made many changes. I had stopped eating meat, cheese, dairy, and other meat based foods, such as eggs, for a period of several weeks when I had an intense craving for meat. Since it was my birthday, I had a rib eye steak on the grill and it was great. Since then, I have not had any meat and don’t miss it, but I know down the road, I will.  Here is how I envision the dietary habits of our cavepeople, which teach us the following: most of the diet was plant based—greens, nuts, berries. What drove those people to hunt? Was it a basic biological drive to avert anemia? Killing an animal for food was not foolproof, and my guess is it did not happen often. So my educated guess is that prehistoric man was an omnivore, primarily eating plant based foods but eating animals on a sporadic basis. Why would I think that? We do have canine like incisors, designed to tear flesh. So a healthy diet always seems to come back to common sense. The mainstay should be plant based interspaced by an occasional meat based treat, like a small bite of real cheddar cheese!

 Attached Thumbnails:

Tags:  diabetes  foods  nutrition  organic  soup  sugar  tomatoes 

Share |
PermalinkComments (0)

Type 2 Diabetes: A Toxic Epidemic

Posted By Isaac Eliaz, MD, MS, LAc - reprinted with permission, Monday, September 7, 2015
Updated: Friday, September 4, 2015
The epidemic of type 2 diabetes and metabolic syndrome, which is striking Western nations and the United States in particular, has elicited somewhat of a muted reaction. “Diabesity” may affect as many as 100 million Americans and nearly a billion people around the world, but compare the public health response to previous epidemics—polio for example. It doesn’t come close. Perhaps this is because it’s a silent, insidious epidemic, developing over years with debilitating symptoms that seriously impact a person’s quality of life.

Yes, we have taken some measures, such as urging people at risk to improve their diet and exercise habits. This approach places the emphasis on the lifestyle choices of the individual, but new research, along with the skyrocketing rates of diabetes, suggests that we’re missing some key pieces of the puzzle.

As a nation, we adhere religiously to the notion of calories in and calories out. Eat less, exercise more and everything will be fine. This is not entirely wrong—but it’s clearly an oversimplification. We cannot pretend that metabolism functions in isolation,sequestered from environmental influences
and the delicate balance of our biological systems.

So it’s not a question of following the same strategies—except more vigorously. We need to look beyond the well-worn tropes that have dominated our approach to these conditions. Fortunately, there’s a growing body of research to help us better understand the complex factors behind metabolic
syndrome and type 2 diabetes. Two factors emerging as key culprits: environmental toxins and poor quality sleep.

The Toxic Load
While what we eat, and how much, certainly affect our weight and susceptibility to diabetes and metabolic syndrome, this oversimplified equation ignores the body’s ability to process these calories. Again, there is a growing body of evidence that overexposure to
environmental toxins can impair our intricate metabolic mechanisms.

Numerous studies demonstrate that many of the chemical compounds pervasive today have an adverse impact on metabolism.
• A study published in The Lancet found a correlation between persistent organic pollutants (POPs) in blood and insulin resistance.1
• Another study described the different ways toxins provoke insulin resistance, such as mitochondrial injury, oxidative stress, inflammation and debilitated thyroid metabolism.2
• Research published in JAMA showed BPA, found in plastics, canned foods and even cash register receipts, increases risk of diabetes.3
• Toxins have been shown to interfere with an entire class of nuclear receptors (called PPARs), causing insulin resistance and other harm.4
• Another study found that weight gain and fat storage in rats exposed to chemical toxins was completely independent of calories and exercise.5

There are dozens of studies with similar findings, and they paint a toxic picture: environmental pollutants appear to scramble our metabolic signals, impairing glucose management and weight control mechanisms.Clearly, genes and genetic expression play a role as well, but as so many have suggested, “Genetics loads the gun, environment pulls the trigger.”

While it’s upsetting to see that common chemicals are having such a profound impact on metabolism—and other areas of health—the fact that research is elucidating some of these complex mechanisms means we may be zeroing in on effective therapeutic targets.

Given the quantity of toxins we face in our everyday lives, detoxification plays an important role in maintaining long-term health on a number of levels. The practice of detox is an ancient one, popularized in recent years with a myriad of products, services and wellness retreats aimed at reducing toxic body burden and restoring vitality.

Aside from the hype, as well as the discrediting of detox by much of conventional medicine, there are a number of foods, ingredients and supplements, which are shown to reduce levels of toxins in the body. But it’s important to do it right so as not to overwhelm your system or deplete essential nutrients. I rarely recommend extreme measures such as rapid detox programs, fasting or colonics. Rather, an emphasis on nutrient-dense whole foods and select botanicals and nutrients offers a gentle yet effective route to eliminating toxins from the body over time. Our bodies are designed
with an elaborate system of detoxification mechanism, incorporating many organ systems and biochemical pathways including the skin, lungs, liver and kidneys. The daily intake of dietary phytochemicals found in common foods, herbs, and nutrients provides ongoing support for the optimal functioning of our inherent detox capacities.

Cruciferous vegetables, such as broccoli, cabbage, kale and bok choy are well-known detoxifiers, and also help promote healthy hormone metabolism. Other effective detoxifiers include green tea, garlic, milk thistle, dandelion leaf and root, onions and turmeric. One clinical study showed that broccoli sprouts helped the body detoxify a number of airborne pollutants, particularly benzene. A half cup a day enhanced excretion of benzene, acrolein and other toxins.

There are also a variety of vitamins, minerals and other nutrients that support detoxification, such as L-methylfolate, zinc, selenium, N-acetyl-cysteine, glutathione and vitamin C. Alginates, derived from kelp, are also effective detoxifiers shown to remove heavy metals, radioactive isotopes and pesticides from the digestive tract. Alginates also support healthy glucose metabolism.

Another clinically proven detoxifier is modified citrus pectin (MCP). Made from the pith of orange peels, MCP has a well deserved reputation for safely binding and removing toxins such as lead, mercury, arsenic and others, while not affecting essential minerals. MCP also binds and blocks galectin-3, an inflammatory protein that’s been linked to cancer, fibrosis, heart disease and other conditions.

Sleep and Metabolism
In addition to overexposure to toxins, there’s another potential culprit in the diabetes and metabolic syndrome epidemic— lack of sleep. Like industrial pollutants, sleep deprivation has become a common feature of modern life. It’s well known that poor sleep can lead to a host of health problems,
including problems with immunity, cellular health, digestion and cognitive well being— including the ability to flush toxins from the brain. Now we can add metabolism to the list.

This is not really news. There have been studies as far back as 1969 showing that sleep deprivation, even for just a few days, decreases insulin sensitivity and increases glucose levels.
• One study found that people who slept only four hours each night for six nights reduced their glucose tolerance by 40 percent,prematurely aging their metabolism. The issue reversed after normal sleep was restored.6
• Another study found similar results even with less severe sleep deprivation—5.5 hours per night over 14 nights.7
• Other studies have shown that loss of sleep contributes to increases in certain growth hormones, associated with increased glucose and cortisol.8-10
• Lack of sleep has also been shown to increase the release of inflammatory cytokines, which can also increase insulin resistance, as well as causing other problems.11

The Sleep Solution
The first step toward fixing sleep deprivation is recognizing the problem. This may mean convincing patients that the competitive advantages they may gain from sleeping less are more than offset by the damage they are
doing to their health.

Routine plays a critical role in good sleep, and also helps balance circadian rhythms, which in turn can benefit metabolic function. It’s best to go to bed at the same time each night and embrace relaxation routines before bedtime. That means avoiding televisions, smart phones and computers at least two hours before bed, as well as other electronic devices that emit blue light since this disrupts melatonin production. Melatonin naturally increases in a dark environment, so make sure your bedroom is free of glowing electronics, and external light sources such as streetlights.

There are many herbs and nutrients that can also support relaxation and good sleep. One extract emerging as a multi-purpose ingredient is honokiol, derived from magnolia bark. Honokiol supports restful sleep and healthy mood, is a powerful antioxidant, and has been shown to support metabolism, cellular function, neurological health and offer other important benefits.

There are a number of other natural ingredients that support sleep, including lemon balm and passionflower extracts and the amino acid L-tryptophan. I also recommend calcium and magnesium. A small amount of supplemental melatonin can also promote relaxation and more restful sleep, and offer powerful protective benefits.

Metabolic Support
In addition to detoxification and better sleep, we can also support healthy metabolism more directly. There are a number of botanicals that help balance glucose, improve insulin function and support overall metabolic function. I recommend gymnema leaf, fenugreek, holy basil, as well as berberine-containing botanicals such as extracts of Indian kino bark and golden thread rhizome. Minerals, such as zinc and chromium, the amino acid taurine, as well as the organosulfur compound alpha lipoic acid, also work to benefit metabolic function.

Like so many other chronic health conditions, metabolic syndrome and type 2 diabetes are rooted in complex biological interactions requiring precise balance. By taking a comprehensive, holistic approach, we can help our patients address the multiple underlying causes of the diabesity epidemic while improving other key areas of health in the process.

1 Jones OA, Maguire ML, Griffin n JL. Environmental pollution and diabetes: a neglected association. Lancet. 2008;371(9609):287-288.

2 Hyman M. Systems biology, toxins, obesity, and functional medicine. Altern Ther Health Med. 2007;13(2):S134-S139.

3 Lang IA, Galloway TS, Scarlett A, et al.Association of urinary bisphenol A concentration with medical disorders and laboratory abnormalities in adults. JAMA. 2008;300(11):1303-1310.

4 Griffi n JL, Scott J, Nicholson JK. The influence of pharmacogenetics on fatty liver disease in the wistar and kyoto rats: a combined transcriptomic and metabonomic study. J Proteome Res. 2007;6(1):54-61.

5 Chen JQ, Brown TR, Russo J. Regulation of energy metabolism pathways by estrogens and estrogenic chemicals and potential implications in obesity associated with increased exposure to endocrine disruptors. Biochim Biophys Acta. 2009;1793(7):1128-1143.

6 Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine function. Lancet 1999; 354:1435–1439.

7 Nedeltcheva AV, Kessler L, Imperial J, Penev PD. Exposure to recurrent sleep restriction in the setting of high caloric intake and physical inactivity results in increased insulin resistance and reduced glucose tolerance. J Clin Endocrinol Metab 2009; 94:3242–3250.

8 Spiegel K, Leproult R, Colecchia EF, et al. Adaptation of the 24-h growth hormone profile to a state of sleep debt. Am J Physiol Regul Integr Comp Physiol 2000; 279:R874–R883.

9 Van Cauter E, Polonsky KS, Scheen AJ. Roles of circadian rhythmicity and sleep in human glucose regulation. Endocr Rev 1997; 18:716– 738.

10 Vgontzas AN, Papanicolaou DA, Bixler EO, et al. Circadian interleukin- 6 secretion and quantity and depth of sleep. J Clin Endocrinol Metab 1999; 84:2603–2607.

11 Vgontzas AN, Zoumakis E, Bixler EO, et al. Adverse effects of modest sleep restriction on sleepiness, performance, and inflammatory cytokines. J Clin Endocrinol Metab 2004; 89:2119–2126.

Tags:  diabetes  epidemic  Isaac Eliaz  Naturopathic Physicians  toxic  type 2 

Share |
PermalinkComments (0)

Case Study on Link Between Sleep & Diabetes

Posted By Carol Touma, MD and Silvana Pannain, MD, Friday, August 5, 2011
Updated: Tuesday, February 4, 2014
Published in the Cleveland Clinic Journal of Medicine.

by Carol Touma, MD and Silvana Pannain, MD


Several lines of evidence indicate that chronic lack of sleep may contribute to the risk of type 2 diabetes mellitus. Adequate sleep and good sleep hygiene should be included among the goals of a healthy lifestyle, especially for patients with diabetes. We urge clinicians to recommend at least 7 hours of uninterrupted sleep per night as part of a healthy lifestyle.

Key Points

  • Sleep loss and sleep disturbances have become very common in our society, and so have obesity and type 2 diabetes.
  • In epidemiologic studies, people who reported sleeping less were at higher risk of diabetes or disordered glucose metabolism.
  • In laboratory studies, short-term sleep deprivation caused measurable changes in glucose metabolism, hormone levels, autonomic nervous system activity, and other variables, which are plausible mechanisms by which loss of sleep could contribute to diabetes.
  • Obstructive sleep apnea is very common in people with diabetes and may be directly linked to diabetes risk and worse diabetes control. Diabetic patients should be systematically assessed for obstructive sleep apnea, and patients with known obstructive sleep apnea should be screened for diabetes.

ADULTS ARE SLEEPING LESS AND LESS in our society. Yet sleep is no longer thought of as strictly a restorative process for the body. The importance of sleep for metabolic function and specifically glucose homeostasis is now widely accepted, as many studies have shown a correlation between sleep deprivation or poor sleep quality and an increased risk of diabetes.

Obesity and aging are both associated with worse sleep. As the prevalence of obesity and diabetes increases, and as the number of elderly people increases, it is imperative to target sleep in the overall treatment of our patients.

In the pages that follow, we examine the evidence of a link between sleep loss (both short sleep duration and poor-quality sleep) and the risk of diabetes. (For evidence linking short sleep duration and the related problem of obesity, we invite the reader to refer to previous publications on the topic.)


The prevalence of obesity and, consequently, of type 2 diabetes mellitus has increased alarmingly worldwide and particularly in the United States in the past few decades. Such a rapid increase cannot be explained simply by an alteration in the genetic pool; it is more likely due to environmental, socioeconomic, behavioral, and demographic factors and the interaction between genetics and these factors. Besides traditional lifestyle factors such as high-calorie diets and sedentary habits, other, nontraditional behavioral and environmental factors could be contributing to the epidemic of obesity and diabetes.

At the same time, people are sleeping less, and sleep disorders are on the rise. According to recent polls from the US Centers for Disease Control and Prevention, approximately 29% of US adults report sleeping less than 7 hours per night, and 50 to 70 million have chronic sleep and wakefulness disorders.

The sleep curtailment of our times probably is partly self-imposed, as the pace and the opportunities of modern society place more demands on time for work and leisure activities and leave less time for sleep.

The quality of sleep has also declined as the population has aged and as the prevalence of obesity and its related sleep disorders has increased. Furthermore, patients with type 2 diabetes tend to sleep less, and to sleep poorly. Poor sleep quality generally results in overall sleep loss.




The human body regulates blood levels of glucose within a narrow range.

Glucose tolerance refers to the ability to maintain euglycemia by disposing of exogenous glucose via insulin-mediated and non–insulin-mediated mechanisms. Normal glucose tolerance depends on the ability of the pancreatic beta cells to produce insulin. As insulin sensitivity declines, insulin secretion increases to maintain normal glucose levels. Diabetes becomes manifest when the pancreatic beta cells fail to compensate for the decreased insulin sensitivity.

Glucose tolerance varies in a circadian rhythm, including during the different stages of sleep.


Sleep has often been thought of as a "restorative” process for the mind and the body; however, many studies have shown that it also directly affects many metabolic and hormonal processes.

Sleep has five stages: rapid eye movement (REM) sleep and stages 1, 2, 3, and 4 of non-REM sleep. The deeper stages of non-REM sleep, ie, stages 3 and 4, are also known as slow-wave sleep and are thought to be the most restorative.

Additionally, the onset of slow-wave sleep is temporally associated with transient metabolic, hormonal, and neurophysiologic changes, all of which can affect glucose homeostasis. The brain uses less glucose, the pituitary gland releases more growth hormone and less corticotropin, the sympathetic nervous system is less active, and conversely, vagal tone is increased.

As a result, in the first part of the night, when slow-wave sleep predominates, glucose metabolism is slower. These effects are reversed in the second part of the night, when REM sleep, stage 1, and awakening are more likely.

In view of these important changes in glucose metabolism during sleep, it is not surprising that getting less sleep or poorer sleep on a regular basis could affect overall glucose homeostasis.


Laboratory and epidemiologic evidence supports an association between short sleep duration (< 7 hours per night) and the risk of diabetes, and also between poor sleep quality and the risk of diabetes. We will explore putative mechanisms for these relationships.

Laboratory studies of short sleep duration and glucose metabolism

Studies in small numbers of healthy volunteers who underwent experimental sleep restriction or disruption have revealed mechanisms by which sleep loss might increase the risk of diabetes.

Kuhn et al performed the very first laboratory study of the effect of sleep deprivation on metabolism. Published in 1969, it showed that total sleep deprivation led to a marked increase in glucose levels.

A caution in extrapolating such results to real-life conditions is that total sleep deprivation is uncommon in humans and is inevitably followed by sleep recovery, with normalization of glucose metabolism. However, people in modern society are experiencing recurrent partial sleep deprivation, and its effect on glucose metabolism may be different.

Spiegel et al, in landmark laboratory studies of partial sleep deprivation in healthy, lean adults, found that restricting sleep to 4 hours per night for 6 nights resulted in a 40% decrease in glucose tolerance, to levels similar to those seen in older adults with impaired glucose tolerance. This metabolic change was paralleled by an increase in the activity of the sympathetic nervous system, and both of these effects reversed with sleep recovery.

A criticism of these initial studies is that they restricted sleep to 4 hours, a restriction more severe than that seen in real life.

Nedeltcheva et al more recently examined the effects of less-severe sleep curtailment (5.5 hours per night for 14 nights) in sedentary middle-aged men and women. This degree of bedtime restriction led to a decrease in glucose tolerance due to decreased insulin sensitivity in the absence of adequate beta cell compensation.

Such recurrent bedtime restriction is closer to the short sleep duration experienced by many people in everyday life, and in people at risk it may facilitate the development of insulin resistance, reduced glucose tolerance, and ultimately diabetes. Indeed, epidemiologic studies suggest that people who sleep less than 6 hours per night are at higher risk of type 2 diabetes.

Epidemiologic studies of short sleep duration and glucose metabolism

Multiple cross-sectional epidemiologic studies have suggested an association between short sleep duration and diabetes, and several prospective epidemiologic studies have suggested that short sleep actually plays a causative role in diabetes.

The landmark observations of Spiegel et al led to a number of epidemiologic studies examining the relationships between sleep duration and sleep disturbances and diabetes risk.

The Sleep Heart Study was a large, cross-sectional, community-based study of the cardiovascular consequences of sleep-disordered breathing. The authors assessed the relationship between reported sleep duration and impaired glucose tolerance or type 2 diabetes in more than 1,400 men and women who had no history of insomnia. After adjustment for age, sex, race, body habitus, and apnea-hypopnea index, the prevalence of impaired glucose tolerance and type 2 diabetes was higher in those who reported sleeping 6 hours or less per night—or 9 hours or more per night (more below about the possible effect of too much sleep on the risk of diabetes).

The major limitations of the study were that it was cross-sectional in design, sleep duration was self-reported, the reasons for sleep curtailment were unknown, and possible confounding variables as physical activity, diet, and socioeconomic status were not measured.

Knutson et al, in our medical center, examined the association between self-reported sleep duration and sleep quality on the one hand and hemoglobin A1c levels on the other in 161 black patients with type 2 diabetes. In patients without diabetic complications, glycemic control correlated with perceived sleep debt (calculated as the difference between self-reported actual and preferred weekday sleep duration); the authors calculated that a perceived sleep debt of 3 hours per night predicted a hemoglobin A1cvalue 1.1 absolute percentage points higher than the median value. The analyses controlled for age, sex, body mass index, insulin use, and the presence of major complications; it excluded patients whose sleep was frequently disrupted by pain. The effect size was comparable to (but opposite) that of oral antidiabetic drugs. However, the direction of causality cannot be confirmed from this association, as it is possible that poor glycemic control in diabetic patients could impair their ability to achieve sufficient sleep.

To date, several major prospective studies have looked at the association between short sleep duration and sleep problems and the risk of developing type 2 diabetes in adults.

The Nurses Health Study followed 70,000 nondiabetic women for 10 years. Compared with nurses who slept 7 to 8 hours per 24 hours, those who slept 5 hours or less had a relative risk of diabetes of 1.34 even after controlling for many covariables, such as body mass index, shift work, hypertension, exercise, and depression.

The first National Health and Nutrition Examination Survey (NHANES I) examined the effect of sleep duration on the risk of incident diabetes in roughly 9,000 men and women over a period of 8 to 10 years. The statistical model included body mass index and hypertension and adjusted for physical activity, depression, alcohol consumption, ethnicity, education, marital status, and age. Findings: those who slept 5 hours or less per night were significantly more likely to develop type 2 diabetes than were those who slept 7 hours per night (odds ratio 1.57, 95% confidence interval [CI] 1.11–2.22), and so were those who slept 9 or more hours per night (odds ratio 1.57, 95% CI 1.10–2.24).

Kawakami et al followed 2,649 Japanese men for 8 years. Those who had difficulty going to sleep and staying asleep, which are both likely to result in shorter sleep duration, had higher age-adjusted risks of developing type 2 diabetes, with hazard ratios of 2.98 and 2.23, respectively.

Björkelund et al followed 6,599 nondiabetic Swedish men for an average of 15 years. Self-reported difficulty sleeping predicted the development of diabetes with an odds ratio of 1.52 even after controlling for age, body mass index at screening, changes in body mass index at follow-up, baseline glucose level, follow-up time, physical activity, family history of type 2 diabetes, smoking, social class, and alcohol intake.

Interestingly, the authors found that the resting heart rate was higher at baseline in the men who later developed diabetes. This finding could be interpreted as reflecting greater sympathetic nervous system activity, a putative mediator of the metabolic dysfunction associated with both short sleep duration and obstructive sleep apnea.

Meisinger et al, in a study of more than 8,000 nondiabetic German men and women 25 to 74 years old, found a hazard ratio of developing diabetes of 1.60 (95% CI 1.05–2.45) in men and 1.98 (95% CI 1.20–3.29) in women who reported difficulty staying asleep, who thus would have shortened sleep duration. This effect was independent of other risk factors for diabetes.

Yaggi et al, in a prospective study of 1,139 US men, also found a U-shaped relationship between sleep duration and the incidence of diabetes, with higher rates in people who slept less than 5 or more than 8 hours per night.

Cappuccio et al performed a meta-analysis of all the prospective studies published to date. Their review included 10 prospective studies, with 107,756 participants followed for a median of 9.5 years. Sleep duration and sleep disturbances were self-reported in all the studies. They calculated that the risk of developing diabetes was 28% higher with short sleep duration (≤ 5 or < 6 hours in the different studies), 48% higher with long sleep duration (> 8 hours), 57% higher with difficulty going to sleep, and 84% higher with difficulty staying asleep.

Limitations of these studies. A consideration when trying to interpret the relationship between length of sleep and the incidence of diabetes is that sleep duration in these studies was self-reported, not measured. If a patient reports sleeping more than 8 hours per night, it could mean that he or she is not truly getting so much sleep, but rather is spending more time in bed trying to sleep.

Another possibility is that the higher incidence of type 2 diabetes in people who slept longer is due to undiagnosed obstructive sleep apnea, which is associated with daytime sleepiness and possibly longer sleep time to compensate for inefficient sleep.

Finally, depressive symptoms, unemployment, a low level of physical activity, and undiagnosed health conditions have all been associated with long sleep duration and could affect the relationship with diabetes risk.

In summary, epidemiologic studies from different geographic locations have consistently indicated that short sleep or poor sleep may increase the risk of developing type 2 diabetes mellitus and suggest that such an association spans different countries, cultures, and ethnic groups.

Therefore, there is a need for additional prospective epidemiologic studies that use objective measures of sleep. Furthermore, studies need to determine whether the cause of sleep restriction (eg, insomnia vs lifestyle choice) affects this relationship. Randomized, controlled, interventional studies would also be useful to determine whether lengthening sleep duration affects the development of impaired glucose tolerance or type 2 diabetes mellitus.

Putative mechanisms linking short sleep duration and the risk of diabetes

The effects of sleep loss on glucose metabolism are likely multifactorial, involving several interacting pathways.

Decreased brain glucose utilization has been shown on positron emission tomography in sleep-deprived subjects.

Hormonal dysregulation. Sleep deprivation is associated with disturbances in the secretion of the counterregulatory hormones growth hormone and cortisol.

Young, healthy volunteers who were allowed to sleep only 4 hours per night for 6 nights showed a change in their patterns of growth hormone release, from a normal single pulse to a biphasic pattern. They were exposed to a higher overall amount of growth hormone in the sleep-deprived condition, which could contribute to higher glucose levels.

Also, evening cortisol levels were significantly higher in young, healthy men who were allowed to sleep only 4 hours per night for 6 nights, as well as in young, healthy women who were allowed to sleep only 3 hours for 1 night. A cross-sectional analysis that included 2,751 men and women also demonstrated that short sleep duration and sleep disturbances are independently associated with more cortisol secretion in the evening.Elevated evening cortisol levels can lead to morning insulin resistance.

Inflammation. Levels of inflammatory cytokines, inflammation, or both increase as sleep duration decreases, which in turn can also increase insulin resistance.

Sympathetic nervous system activity. Patients who have been sleep-deprived have been shown to have higher sympathetic nervous system activity, lower parasympathetic activity, or both. The sympathetic nervous system inhibits insulin release while the parasympathetic system stimulates it, so these changes both increase glucose levels.Moreover, overactivity of the sympathetic nervous system results in insulin resistance.

Excess weight is a well-established risk factor for type 2 diabetes mellitus, and several epidemiologic studies have suggested that sleep loss may increase the risk of becoming overweight or obese, which would ultimately increase the risk of type 2 diabetes.

A primary mechanism linking sleep deprivation and weight gain is likely to be hyperactivity of the orexin system. Orexigenic neurons play a central role in wakefulness, but, as suggested by the name, they also promote feeding. Studies in animals have indicated that the orexin system is overactive during sleep deprivation, and this could be in part mediated by the increase in sympathetic activity.

Increased sympathetic activity also affects the levels of peripheral appetite hormones, inhibiting leptin release and stimulating ghrelin release. Lower leptin levels and higher ghrelin levels act in concert to further activate orexin neurons, resulting in increased food intake.

One could also argue that less time sleeping also allows more opportunity to eat.

Reduced energy expenditure. Sleep loss and its associated sleepiness and fatigue may result in reduced energy expenditure, partly due to less exercise but also due to less nonexercise activity thermogenesis. To date, reduced energy expenditure is an unexplored pathway that could link short sleep, the risk of obesity, and ultimately diabetes. In many overweight and obese people, this cascade of negative events is likely to be accelerated by sleep-disordered breathing, a reported independent risk factor for insulin resistance.


Slow-wave sleep and diabetes

Slow-wave sleep, the most restorative sleep, is associated with metabolic, hormonal, and neurophysiologic changes that affect glucose homeostasis. Its disturbance may have deleterious effects on glucose tolerance.

Shallow slow-wave sleep occurs in elderly people and in obese people, even in the absence of obstructive sleep apnea. Both groups are also at higher risk of diabetes. One wonders if the decreased slow-wave sleep could in part contribute to the risk of diabetes in these groups.

A few studies specifically tested the effect of experimental suppression of slow-wave sleep on glucose homeostasis.

Tasali et al evaluated nine young, lean, nondiabetic men and women after 2 consecutive nights of undisturbed sleep and after 3 consecutive nights of suppressed slow-wave sleep without a change in total sleep duration or in REM sleep duration. Slow-wave sleep was disturbed by "delivering acoustic stimuli of various frequencies and intensities” whenever the subjects started to go into stage 3 or stage 4 sleep. This decreased the amount of slow-wave sleep by nearly 90%, which is comparable to the degree of sleep fragmentation seen in moderate to severe obstructive sleep apnea. After 3 nights of slow-wave sleep suppression, insulin sensitivity decreased by 25%, without a compensatory increase in insulin release, which resulted in a reduction in glucose tolerance of 23%, a value seen in older adults with impaired glucose tolerance.

Stamatakis et al confirmed these findings in a similar study of 11 healthy, normal volunteers whose sleep was fragmented for 2 nights across all stages of sleep using auditory and mechanical stimuli. Insulin sensitivity significantly decreased, as did glucose effectiveness (ability of glucose to dispose itself independently of an insulin response) after the 2 nights of disturbed sleep quality.

These results support the hypothesis that poor sleep quality with short durations of slow-wave sleep, as seen with aging and obesity, could contribute to the higher risk of type 2 diabetes in these populations. These data also suggest that more studies are needed to look at the relationship between amount and quality of slow-wave sleep and diabetes risk.

Obstructive sleep apnea and diabetes

The most robust evidence that not only short sleep duration but also poor sleep quality affects diabetes risk comes from studies of metabolic function in patients with obstructive sleep apnea, an increasingly common condition.

Obstructive sleep apnea is characterized by recurrent episodes of partial or complete upper airway obstruction with intermittent hypoxia and microarousals, resulting in low amounts of slow-wave sleep and overall decreased sleep quality.

Obstructive sleep apnea is common in patients with type 2 diabetes, and several clinical and epidemiologic studies suggest that, untreated, it may worsen diabetes risk or control.

The Sleep AHEAD (Action for Health in Diabetes) study revealed, in cross-sectional data, that more than 84% of obese patients with type 2 diabetes had obstructive sleep apnea (with an apnea-hypopnea index ≥ 5).

Aronsohn et al, in a study conducted in our laboratory in 60 patients with type 2 diabetes, found that 46 (77%) of them had obstructive sleep apnea. Furthermore, the worse the obstructive sleep apnea, the worse the glucose control. After controlling for age, sex, race, body mass index, number of diabetes medications, level of exercise, years of diabetes, and total sleep time, compared with patients without obstructive sleep apnea, the adjusted mean hemoglobin A1c was increased in a linear trend by (in absolute percentage points):

  • 1.49% in patients with mild obstructive sleep apnea (P = .0028)

  • 1.93% in patients with moderate obstructive sleep apnea (P = .0033)

  • 3.69% in patients with severe obstructive sleep apnea (P < .0001).

Other epidemiologic studies. A growing number of epidemiologic studies, in various geographic regions, have suggested an independent link between obstructive sleep apnea and risk of type 2 diabetes. Most of the studies have been cross-sectional, and while most had positive findings, a criticism is that the methodology varied among the studies, both in how obstructive sleep apnea was assessed (snoring vs polysomnography) and in the metabolic assessment (oral glucose tolerance test, homeostatic model assessment, hemoglobin A1c, medical history, physician examination, or patient report).

So far, 14 population studies (TABLE 1) have assessed obstructive sleep apnea with polysomnography, but only two of them were prospective. Of the cross-sectional studies, all but the earliest study, which also was the smallest, found an association between the increased severity of obstructive sleep apnea and alterations in glucose metabolism consistent with an increased risk of diabetes. The one retrospective study and the first published prospective study did not find an independent relationship between the severity of obstructive sleep apnea at baseline and the incidence of diabetes. Of note, the duration of follow-up in the prospective study was only 4 years, which may not be sufficient.

Table 1

Studies linking obstructive sleep apnea to altered glucose metabolism and diabetes

Author & Year No. of Patients Findings

Cross-Sectional Studies

Stoohs et al,62 1996 50 Increase in insulin resistance in obstructive sleep apnea (OSA) was entirely dependent on body mass index.

Elmasry et al,66 2001 116 Prevalence of severe OSA in people with diabetes was 36% vs. 14% in those without diabetes (P < .05)

Punjabi et al,55, 2002 150 Quartiles of OSA severity (apnea-hypopnea index [AHI] 5-40) had dose effect on 2-hour glucose and insulin levels.

IP et al,452002 270 One unit increase in AHI increased fasting insulin or homeostasis model

Reichmuth et al,64 2005 1,382 Odds ratio of diabetes with AHI > 15 vs. < 5 was 2.30 (95% confidence interval [CI] 1.28-4.11

Lam et al,67 2006 255 AHI greater than or equal to 5 (vs < 5) increased the odds of fasting glucose greater than or equal to 110 mg/dL, with an odds ratio of 2.74 (95% CI 1.16-6.49)

Okada et al,68 2006 207 12% of subjects with sleep-disordered breathing had hemoglobin A1c > 5.8%, vs. only 4% of those without sleep-disordered breathing (P < .05)

Sulit et al,69 2006 394 Subjects with oxygen saturation < 90% greater than or equal to 2% of time had odds ratio of 2.33 (95% CI 1.38-3.94) of impaired glucose tolerance.

Seicean et al,70 2008 2,588 Respiratory disturbance index greater than or equal to 10 events/hour was associated with odds ratio of 1.3 (95% CI 1.1-1.6) for impaired fasting glucose, 1.2 (1.0-1.4) for impaired glucose tolerance, 1.4 (1.1-2.7) for both impaired fasting glucose and impaired glucose tolerance, and 1.7 (1.1-2.7) for occult type 2 diabetes mellitus.

Punjabi et al,71 2009 118 26.7% reduction in insulin sensitivity with mild sleep-disordered breathing, 36.5% with moderate, and 43.7% with severe.

Steiropoulos et al,72 2009 56 Fasting glucose and hemoglobin A1c were not correlated with AHI or average oxygen saturation (P = .008).

Aronsohn et al,5 2010 60 Mean hemoglobin A1c significantly increased by 1.49% with mild OSA, 1.93% with moderate OSA, and 3.69% with severe OSA.

Prospective Studies

Reichmuth et al,64 2005 987 No change in odds ratio of type 2 diabetes with higher AHI when adjusted for waist girth.

Botros et al,65 2009 544 For every quartile of severity of OSA, there was a significant 43% increased incidence of type 2 diabetes.

Retrospective Study

Mahmood et al,63 2009 1,088 OSA was not independently associated with type 2 diabetes.

A more recent prospective study of 544 nondiabetic patients showed that the risk of developing type 2 diabetes over an average of 2.7 years of follow-up was a function of the severity of obstructive sleep apnea expressed in quartiles: for each increased quartile of severity there was a 43% increase in the incidence of diabetes. Additionally, in patients with moderate to severe sleep apnea, regular use of continuous positive airway pressure (CPAP) was associated with an attenuated risk.

Two prospective studies (not included in TABLE 1) used snoring as a marker of obstructive sleep apnea; at 10 years of follow-up, snoring was associated with a higher risk of developing diabetes in both men and women.

Does CPAP improve glucose metabolism? Other studies have specifically examined the effects of CPAP treatment on glucose metabolism, in both diabetic and nondiabetic populations. Accumulating evidence suggests that metabolic abnormalities can be partially corrected by CPAP treatment, which supports the concept of a causal link between obstructive sleep apnea and altered glucose control. This topic is beyond the scope of this review; please see previously published literature for further information. Whether treating obstructive sleep apnea may delay the development or reduce the severity of type 2 diabetes is another important unanswered question.

Is obstructive sleep apnea a cause or consequence of diabetes? It may be a novel risk factor for type 2 diabetes, and its association with altered glucose metabolism is well supported by a large set of cross-sectional studies, but there are still insufficient longitudinal studies to indicate a direction of causality.

If obstructive sleep apnea is the cause, what is the mechanism? There are likely many. High levels of sympathetic nervous system activity, intermittent hypoxia, sleep fragmentation, and sleep loss in obstructive sleep apnea may all lead to dysregulation of the hypothalamic-pituitary axis, endothelial dysfunction, and alterations in cytokine and adipokine release and are all potential mechanisms of abnormal glucose metabolism in this population.


Taken together, the current evidence suggests that strategies to improve the duration and the quality of sleep should be considered as a potential intervention to prevent or delay the development of type 2 diabetes mellitus in at-risk populations. While further studies are needed to better elucidate the mechanisms of the relationship between sleep loss and diabetes risk and to determine if extending sleep and treating obstructive sleep apnea decreases the risk of diabetes, we urge clinicians to recommend at least 7 hours of uninterrupted sleep per night as a goal in maintaining a healthy lifestyle. Additionally, clinicians should systematically evaluate the risk of obstructive sleep apnea in their patients who have type 2 diabetes mellitus and the metabolic syndrome, and conversely, should assess for diabetes in patients with known obstructive sleep apnea.


    1. Pannain S,
    2. Van Cauter E
    . Sleep loss, obesity and diabetes: prevalence, association and emerging evidence for causation. Obesity Metab 2008; 4:28–41.
    1. Van Cauter E,
    2. Knutson KL
    . Sleep and the epidemic of obesity in children and adults. Eur J Endocrinol 2008; 159(suppl 1):S59–S66.
    1. US Centers for Disease Control and Prevention (CDC)
    . Perceived insufficient rest or sleep among adults—United States, 2008. MMWR Morb Mortal Wkly Rep 2009;58:1175–1179.
    1. Knutson KL,
    2. Ryden AM,
    3. Mander BA,
    4. Van Cauter E
    . Role of sleep duration and quality in the risk and severity of type 2 diabetes mellitus. Arch Intern Med 2006;166:1768–1774.
    1. Aronsohn RS,
    2. Whitmore H,
    3. Van Cauter E,
    4. Tasali E
    . Impact of untreated obstructive sleep apnea on glucose control in type 2 diabetes. Am J Respir Crit Care Med 2010; 181:507–513.
    1. Broussard J,
    2. Knutson KL
    . Sleep and metabolic risk and disease. In: CappuccioFP, Miller MA, Lockley SW, editors. Sleep, Health and Society: From Aetiology to Public Health. Cary, NC: Oxford University Press; 2010:111–140.
    1. Zoccoli G,
    2. Walker AM,
    3. Lenzi P,
    4. Franzini C
    . The cerebral circulation during sleep: regulation mechanisms and functional implications. Sleep Med Rev 2002;6:443–455.
    1. Pannain S,
    2. Van Cauter E
    . Modulation of endocrine function by sleepwake homeostasis and circadian rhythmicity. Sleep Med Clin 2007; 2:147–159.
    1. Somers VK,
    2. Dyken ME,
    3. Mark AL,
    4. Abboud FM
    . Sympathetic-nerve activity during sleep in normal subjects. N Engl J Med 1993; 328:303–307.
    1. Kuhn E,
    2. Brodan V,
    3. Brodanová M,
    4. Rysánek K
    . Metabolic reflection of sleep deprivation. Act Nerv Super (Praha) 1969; 11:165–174.
    1. Spiegel K,
    2. Leproult R,
    3. Van Cauter E
    . Impact of sleep debt on metabolic and endocrine function. Lancet 1999; 354:1435–1439.
    1. Nedeltcheva AV,
    2. Kessler L,
    3. Imperial J,
    4. Penev PD
    . Exposure to recurrent sleep restriction in the setting of high caloric intake and physical inactivity results in increased insulin resistance and reduced glucose tolerance. J Clin Endocrinol Metab2009; 94:3242–3250.
    1. Zizi F,
    2. Jean-Louis G,
    3. Brown CD,
    4. Ogedegbe G,
    5. Boutin-Foster C,
    6. McFarlane SI
    . Sleep duration and the risk of diabetes mellitus: epidemiologic evidence and pathophysiologic insights. Curr Diab Rep 2010; 10:43–47.

    1. Gottlieb DJ,
    2. Punjabi NM,
    3. Newman AB,
    4. et al.
    Association of sleep time with diabetes mellitus and impaired glucose tolerance. Arch Intern Med 2005; 165:863–867.
    1. Ayas NT,
    2. White DP,
    3. Al-Delaimy WK,
    4. et al.
    A prospective study of selfreported sleep duration and incident diabetes in women. Diabetes Care 2003;26:380–384.

    1. Gangwisch JE,
    2. Heymsfield SB,
    3. Boden-Albala B,
    4. et al.
    Sleep duration as a risk factor for diabetes incidence in a large U.S. sample. Sleep 2007; 30:1667–1673.
    1. Kawakami N,
    2. Takatsuka N,
    3. Shimizu H
    . Sleep disturbance and onset of type 2 diabetes. Diabetes Care 2004; 27:282–283.
    1. Björkelund C,
    2. Bondyr-Carlsson D,
    3. Lapidus L,
    4. et al.
    Sleep disturbances in midlife unrelated to 32-year diabetes incidence: the prospective population study of women in Gothenburg. Diabetes Care 2005; 28:2739–2744.
    1. Nilsson PM,
    2. Rööst M,
    3. Engström G,
    4. Hedblad B,
    5. Berglund G
    . Incidence of diabetes in middle-aged men is related to sleep disturbances. Diabetes Care 2004;27:2464–2469.
    1. Spiegel K,
    2. Tasali E,
    3. Penev P,
    4. Van Cauter E
    . Brief communication: sleep curtailment in healthy young men is associated with decreased leptin levels, elevated ghrelin levels, and increased hunger and appetite. Ann Intern Med 2004; 141:846–850.
    1. Punjabi NM,
    2. Polotsky VY
    . Disorders of glucose metabolism in sleep apnea. J Appl Physiol 2005; 99:1998–2007.
    1. Meisinger C,
    2. Heier M,
    3. Loewel H,
    4. MONICA/KORA Augsburg Cohort Study
    .Sleep disturbance as a predictor of type 2 diabetes mellitus in men and women from the general population. Diabetologia 2005; 48:235–241.
    1. Yaggi HK,
    2. Araujo AB,
    3. McKinlay JB
    . Sleep duration as a risk factor for the development of type 2 diabetes. Diabetes Care 2006; 29:657–661.
    1. Cappuccio FP,
    2. D’Elia L,
    3. Strazzullo P,
    4. Miller MA
    . Quantity and quality of sleep and incidence of type 2 diabetes: a systematic review and meta-analysis. Diabetes Care 2010; 33:414–420.
    1. Thomas M,
    2. Sing H,
    3. Belenky G,
    4. et al.
    Neural basis of alertness and cognitive performance impairments during sleepiness. I. Effects of 24 h of sleep deprivation on waking human regional brain activity. J Sleep Res 2000; 9:335–352.
    1. Spiegel K,
    2. Leproult R,
    3. Colecchia EF,
    4. et al.
    Adaptation of the 24-h growth hormone profile to a state of sleep debt. Am J Physiol Regul Integr Comp Physiol 2000;279:R874–R883.
    1. Omisade A,
    2. Buxton OM,
    3. Rusak B
    . Impact of acute sleep restriction on cortisol and leptin levels in young women. Physiol Behav 2010; 99:651–656.
    1. Kumari M,
    2. Badrick E,
    3. Ferrie J,
    4. Perski A,
    5. Marmot M,
    6. Chandola T
    . Selfreported sleep duration and sleep disturbance are independently associated with cortisol secretion in the Whitehall II study. J Clin Endocrinol Metab 2009; 94:4801–4809.
    1. Van Cauter E,
    2. Polonsky KS,
    3. Scheen AJ
    . Roles of circadian rhythmicity and sleep in human glucose regulation. Endocr Rev 1997; 18:716–738.
    1. Vgontzas AN,
    2. Papanicolaou DA,
    3. Bixler EO,
    4. et al.
    Circadian interleukin-6 secretion and quantity and depth of sleep. J Clin Endocrinol Metab 1999; 84:2603–2607.
  1. 31.
    1. Vgontzas AN,
    2. Zoumakis E,
    3. Bixler EO,
    4. et al.
    Adverse effects of modest sleep restriction on sleepiness, performance, and inflammatory cytokines. J Clin Endocrinol Metab 2004; 89:2119–2126.
    1. Spiegel K,
    2. Leproult R,
    3. L’hermite-Balériaux M,
    4. Copinschi G,
    5. Penev PD,
    6. Van Cauter E
    . Leptin levels are dependent on sleep duration: relationships with sympathovagal balance, carbohydrate regulation, cortisol, and thyrotropin. J Clin Endocrinol Metab 2004; 89:5762–5771.
    1. Teff KL
    . Visceral nerves: vagal and sympathetic innervation. JPEN J Parenter Enteral Nutr 2008; 32:569–571.
    1. Esler M,
    2. Rumantir M,
    3. Wiesner G,
    4. Kaye D,
    5. Hastings J,
    6. Lambert G
    .Sympathetic nervous system and insulin resistance: from obesity to diabetes. Am J Hypertens 2001; 14:304S–309S.
    1. Cappuccio F,
    2. Miller MA
    . The epidemiology of sleep and cardiovascular risk and disease. In: Cappuccio FP, Miller MA, Lockley SW, editors. Sleep, Health and Society: From Aetiology to Public Health. Cary, NC: Oxford University Press;2010:111–140.

    1. Sakurai T
    . Roles of orexin/hypocretin in regulation of sleep/wakefulness and energy homeostasis. Sleep Med Rev 2005; 9:231–241.
    1. Wu MF,
    2. John J,
    3. Maidment N,
    4. Lam HA,
    5. Siegel JM
    . Hypocretin release in normal and narcoleptic dogs after food and sleep deprivation, eating, and movement. Am J Physiol Regul Integr Comp Physiol 2002; 283:R1079–R1086.
    1. Estabrooke IV,
    2. McCarthy MT,
    3. Ko E,
    4. et al.
    Fos expression in orexin neurons varies with behavioral state. J Neurosci 2001; 21:1656–1662.
    1. Zeitzer JM,
    2. Buckmaster CL,
    3. Lyons DM,
    4. Mignot E
    . Increasing length of wakefulness and modulation of hypocretin-1 in the wake-consolidated squirrel monkey. Am J Physiol Regul Integr Comp Physiol 2007; 293:R1736–R1742.
  2. Rayner DV,
    1. Trayhurn P
    . Regulation of leptin production: sympathetic nervous system interactions. J Mol Med 2001; 79:8–20.
    1. van der Lely AJ,
    2. Tschöp M,
    3. Heiman ML,
    4. Ghigo E
    . Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin. Endocr Rev 2004;25:426–457.
    1. Samson WK,
    2. Taylor MM,
    3. Ferguson AV
    . Non-sleep effects of hypocretin/orexin. Sleep Med Rev 2005; 9:243–252.
    1. Willie JT,
    2. Chemelli RM,
    3. Sinton CM,
    4. Yanagisawa M
    . To eat or to sleep? Orexin in the regulation of feeding and wakefulness. Annu Rev Neurosci 2001;24:429–458.
    1. Qin LQ,
    2. Li J,
    3. Wang Y,
    4. Wang J,
    5. Xu JY,
    6. Kaneko T
    . The effects of nocturnal life on endocrine circadian patterns in healthy adults. Life Sci 2003; 73:2467–2475.
    1. Ip MS,
    2. Lam B,
    3. Ng MM,
    4. Lam WK,
    5. Tsang KW,
    6. Lam KS
    . Obstructive sleep apnea is independently associated with insulin resistance. Am J Respir Crit Care Med2002; 165:670–676.
    1. Punjabi NM,
    2. Shahar E,
    3. Redline S,
    4. Gottlieb DJ,
    5. Givelber R,
    6. Resnick HE,
    7. Sleep Heart Health Study Investigators
    . Sleep-disordered breathing, glucose intolerance, and insulin resistance: the Sleep Heart Health Study. Am J Epidemiol 2004;160:521–530.
    1. Van Cauter E,
    2. Leproult R,
    3. Plat L
    . Age-related changes in slow wave sleep and REM sleep and relationship with growth hormone and cortisol levels in healthy men. JAMA 2000; 284:861–868.
    1. Resta O,
    2. Foschino Barbaro MP,
    3. Bonfitto P,
    4. et al.
    Low sleep quality and daytime sleepiness in obese patients without obstructive sleep apnoea syndrome. J Intern Med 2003; 253:536–543.
    1. Vgontzas AN,
    2. Tan TL,
    3. Bixler EO,
    4. Martin LF,
    5. Shubert D,
    6. Kales A
    . Sleep apnea and sleep disruption in obese patients. Arch Intern Med 1994; 154:1705–1711.
    1. Mokdad AH,
    2. Ford ES,
    3. Bowman BA,
    4. et al.
    Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA 2003; 289:76–79.

    1. Tasali E,
    2. Leproult R,
    3. Ehrmann DA,
    4. Van Cauter E
    . Slow-wave sleep and the risk of type 2 diabetes in humans. Proc Natl Acad Sci U S A 2008; 105:1044–1049.
    1. Prigeon RL,
    2. Kahn SE,
    3. Porte D Jr.
    . Changes in insulin sensitivity, glucose effectiveness, and B-cell function in regularly exercising subjects. Metabolism 1995;44:1259–1263.
    1. Stamatakis KA,
    2. Punjabi NM
    . Effects of sleep fragmentation on glucose metabolism in normal subjects. Chest 2010; 137:95–101.
    1. Caples SM,
    2. Gami AS,
    3. Somers VK
    . Obstructive sleep apnea. Ann Intern Med2005; 142:187–197.
    1. Punjabi NM,
    2. Sorkin JD,
    3. Katzel LI,
    4. Goldberg AP,
    5. Schwartz AR,
    6. Smith PL
    .Sleep-disordered breathing and insulin resistance in middle-aged and overweight men. Am J Respir Crit Care Med 2002; 165:677–682.
    1. Tassone F,
    2. Lanfranco F,
    3. Gianotti L,
    4. et al.
    Obstructive sleep apnoea syndrome impairs insulin sensitivity independently of anthropometric variables. Clin Endocrinol (Oxf) 2003; 59:374–379.

    1. Coughlin SR,
    2. Mawdsley L,
    3. Mugarza JA,
    4. Calverley PM,
    5. Wilding JP
    . Obstructive sleep apnoea is independently associated with an increased prevalence of metabolic syndrome. Eur Heart J 2004; 25:735–741.

    1. Svatikova A,
    2. Wolk R,
    3. Gami AS,
    4. Pohanka M,
    5. Somers VK
    . Interactions between obstructive sleep apnea and the metabolic syndrome. Curr Diab Rep 2005; 5:53–58.

    1. Budhiraja R,
    2. Quan SF
    . Sleep-disordered breathing and cardiovascular health. Curr Opin Pulm Med 2005; 11:501–506.
    1. Foster GD,
    2. Sanders MH,
    3. Millman R,
    4. et al.,
    5. Sleep AHEAD Research Group
    .Obstructive sleep apnea among obese patients with type 2 diabetes. Diabetes Care2009; 32:1017–1019.
    1. Tasali E,
    2. Mokhlesi B,
    3. Van Cauter E
    . Obstructive sleep apnea and type 2 diabetes: interacting epidemics. Chest 2008; 133:496–506.

    1. Stoohs RA,
    2. Facchini F,
    3. Guilleminault C
    . Insulin resistance and sleep-disordered breathing in healthy humans. Am J Respir Crit Care Med 1996; 154:170–174.
    1. Mahmood K,
    2. Akhter N,
    3. Eldeirawi K,
    4. et al.
    Prevalence of type 2 diabetes in patients with obstructive sleep apnea in a multi-ethnic sample. J Clin Sleep Med 2009;5:215–221.
    1. Reichmuth KJ,
    2. Austin D,
    3. Skatrud JB,
    4. Young T
    . Association of sleep apnea and type II diabetes: a population-based study. Am J Respir Crit Care Med 2005;172:1590–1595.
    1. Botros N,
    2. Concato J,
    3. Mohsenin V,
    4. Selim B,
    5. Doctor K,
    6. Yaggi HK
    . Obstructive sleep apnea as a risk factor for type 2 diabetes. Am J Med 2009; 122:1122–1127.
    1. Elmasry A,
    2. Lindberg E,
    3. Berne C,
    4. et al.
    Sleep-disordered breathing and glucose metabolism in hypertensive men: a population-based study. J Intern Med 2001;249:153–161.
    1. Lam JC,
    2. Lam B,
    3. Lam CL,
    4. et al.
    Obstructive sleep apnea and the metabolic syndrome in community-based Chinese adults in Hong Kong. Respir Med 2006;100:980–987.
    1. Okada M,
    2. Takamizawa A,
    3. Tsushima K,
    4. Urushihata K,
    5. Fujimoto K,
    6. Kubo K
    .Relationship between sleep-disordered breathing and lifestyle-related illnesses in subjects who have undergone health-screening. Intern Med 2006; 45:891–896.
    1. Sulit L,
    2. Storfer-Isser A,
    3. Kirchner HL,
    4. Redline S
    . Differences in polysomnography predictors for hypertension and impaired glucose tolerance. Sleep 2006; 29:777–783.
    1. Seicean S,
    2. Kirchner HL,
    3. Gottlieb DJ,
    4. et al.
    Sleep-disordered breathing and impaired glucose metabolism in normal-weight and overweight/obese individuals: the Sleep Heart Health Study. Diabetes Care 2008; 31:1001–1006.
    1. Punjabi NM,
    2. Beamer BA
    . Alterations in glucose disposal in sleep-disordered breathing. Am J Respir Crit Care Med 2009; 179:235–240.
    1. Steiropoulos P,
    2. Papanas N,
    3. Nena E,
    4. et al.
    Markers of glycemic control and insulin resistance in non-diabetic patients with obstructive sleep apnea hypopnea syndrome: does adherence to CPAP treatment improve glycemic control? Sleep Med2009; 10:887–891.
    1. Al-Delaimy WK,
    2. Manson JE,
    3. Willett WC,
    4. Stampfer MJ,
    5. Hu FB
    . Snoring as a risk factor for type II diabetes mellitus: a prospective study. Am J Epidemiol 2002;155:387–393.
    1. Elmasry A,
    2. Janson C,
    3. Lindberg E,
    4. Gislason T,
    5. Tageldin MA,
    6. Boman G
    . The role of habitual snoring and obesity in the development of diabetes: a 10-year follow-up study in a male population. J Intern Med 2000; 248:13–20.
    1. Steiropoulos P,
    2. Papanas N,
    3. Nena E,
    4. Maltezos E,
    5. Bouros D
    . Continuous positive airway pressure treatment in patients with sleep apnoea: does it really improve glucose metabolism? Curr Diabetes Rev 2010; 6:156–166.

Cleve Clin J Med. 2011 Aug;78(8):549-58. Does lack of sleep cause diabetes? Touma, C. Pannain, S.

Tags:  diabetes  sleep 

Share |
PermalinkComments (0)

Magnesium Helps to Heal Type II Diabetes

Posted By Administration, Tuesday, March 22, 2011
Updated: Friday, April 18, 2014


by Gina Nick, NMD, PhD

A new research study published in Clinical Nutrition looked at magnesium intake and levels in patients diagnosed with Type II Diabetes.  The researchers found that those with Diabetes had lower levels of magnesium in their body and there was a direct correlation between magnesium status and insulin control.  Magnesium is used by the body in over 325 enzyme reactions and in the case of Diabetes, healthy insulin function is dependent upon magnesium! Try to keep your magnesium intake at a minimum of 500 mg per day and if you are not getting enough from food (a common occurrence), then consider supplementing with a high quality mineral supplement with magnesium.  Some of the highest sources of magnesium in foods are dark green leafy vegetables, kelp, wheat bran, wheat germ and organic raw cashews.

Tags:  diabetes  magnesium 

Share |
PermalinkComments (0)

The Relationship Between Alzheimer's Disease and Diabetes: Type 3 Diabetes?

Posted By Administration, Friday, April 9, 2010
Updated: Friday, April 18, 2014


Published in Alternative Medicine Review, Volume 14, Number 4 2009

by Zina Kroner, DO





In recent years, Alzheimer’s disease (AD) has been considered to be, in part, a neuroendocrine disorder, even referred to by some as type 3 diabetes. Insulin functions by controlling neurotransmitter release processes at the synapses and activating signaling pathways associated with learning and long-term memory. Novel research demonstrates that impaired insulin signaling may be implicated in AD. Post-mortem brain studies show that insulin expression is inversely proportional to the Braak stage of AD progression. It was also demonstrated that neurotoxins, coined amyloid beta-derived diffusible ligands (ADDLs), disrupt signal transduction at synapses, making the cell insulin resistant. ADDLs reduce plasticity of the synapse, potentiate synapse loss, contribute to oxidative damage, and cause AD-type tau hyperphosphorylation. Diabetes and AD have signs of increased oxidative stress in common, including advanced glycation end products (AGEs), when compared to normal subjects. Diabetic patients appear to have an increased risk for AD because AGEs accumulate in neurofibrillary tangles and amyloid plaques in AD brains. This research should encourage a more proactive approach to early diagnosis of diabetes and nutritional counseling for AD patients. (Altern Med Rev 2009;14(4):373-379) 


The epidemic of insulin resistance/prediabetes and type 2 diabetes may be associated with the emergence of higher rates of Alzheimer’s disease (AD). New research delineates a direct correlation between sugar imbalance and AD. AD is associated with consistent pathological findings, including neurofibrillary tangles, amyloid-beta deposits, and signs of oxidative stress. No common link among the proposed pathological processes has been identified. Novel evidence demonstrates that impaired insulin signaling may significantly contribute to the pathogenesis of AD, contributing to the idea that it is actually a neuroendocrine disease. Neurotoxins called amyloid beta-derived diffusible ligands (ADDLs) have been implicated as a cause of impaired insulin signaling. Advanced glycation end products (AGEs) are found in higher concentration in both hyperglycemia and AD, contributing to oxidative stress and cell damage. These AGEs are known to be further modified to reactive advanced glycation end products, (RAGEs), which can generate oxidative injury. 

Understanding the mechanism of action of this neuroendocrine disorder, termed type 3 diabetes by some, may shed light on new tools for diagnosing and treating AD and for the need for early intervention in obese patients with insulin resistance. 

The Clinical Link: Diabetes and AD 

The research linking diabetes and AD has its roots in the groundbreaking Rotterdam study. Of 6,370 elderly subjects studied for 2.1 years, 126 developed dementia; 89 of these were specifically diagnosed with AD. Type 2 diabetes doubled the risk of a patient having dementia and patients on insulin had four times the risk.As rates of insulin resistance and diabetes in the senior population are both increasing, this landmark study, conducted almost a decade ago, has been getting more attention in recent years since further studies have solidified the connection between diabetes and AD.

Since type 2 diabetes is reaching epidemic proportions and is under-diagnosed, and AD may be associated with hyperglycemia, more attention should be drawn to early diagnosis of diabetes. The Gertner Institute for Epidemiology and Health Policy Research in Israel, in a recently published 25-year, cross-sectional study of 623 adults, demonstrated that approximately 13 percent of the studied population had undiagnosed type 2 diabetes. This study reinforces the importance of early diagnosis of type 2 diabetes by identifying patients with risk factors, including hypertension, hypertriglyceridemia, and a large waist circumference (males: ≥40 inches [102 cm], females: ≥35 inches [88 cm]) – factors seen in metabolic syndrome. These results encourage early detection via screening methods targeting those with traits of metabolic syndrome in otherwise healthy adults.

Another study demonstrating the high prevalence of diabetes showed almost one-third of elderly patients in a sample of 7,267 subjects had diabetes, and three-fourths had impaired fasting glucose (glucose lev- els >99 but <126) or diabetes.

Elevated body mass index (BMI), adiposity, impaired fasting glucose, and diabetes increase the risk of AD substantially. The latest study, utilizing data on 2,322 participants in the Baltimore Longitudinal Study of Aging, shows the incidence of AD increased in men who gained weight between the ages of 30 and 45 and in women with a BMI >30 at ages 30, 40, and 45.7 This suggests more emphasis should be placed on early weight-loss strategies for preventing AD. 

A 2008 Swedish study showed a statistically significant increase in the risk of developing AD in men who develop type 2 diabetes in midlife. The researchers followed 2,269 men for 32 years and found that those with low insulin production at age 50 were 150-percent more likely to develop AD than those with adequate insulin production. This association was greatest in patients who did not have the apolipoprotein E4 (ApoE4) genetic predisposition to AD (which renders individuals less efficient at breaking down beta-amyloid plaques), thereby making diabetes a possible independent risk factor for AD. This study illustrates the importance of maintaining healthy blood glucose control in middle-aged men as a possible means of preventing AD later in life. 

A recent investigation suggests that AD is associated with metabolic syndrome. After studying 50 patients diagnosed with AD and comparing them to 75 cognitively normal controls, the AD patients had a greater waist circumference, higher triglyceride and glucose levels, and lower high-density lipoprotein cholesterol. Patients with metabolic syndrome are diagnosed with AD at a younger age than AD patients without metabolic syndrome.

Type 3 Diabetes: Is It Actually a Unique Condition? 

The term type 3 diabetes was coined in 2005 by Suzanne de la Monte, MD, MPH, Associate Professor of Pathology and Medicine and neuropathologist at Brown Medical School. Her team, examining postmortem brain tissue of AD patients, found that AD may be a neuroendocrine disease associated with insulin signaling. The team termed it type 3 diabetes because it harbors elements of both types 1 and 2 diabetes, since there is both a decrease in the production of insulin and a resistance to insulin receptors.

The team analyzed 45 postmortem brains of patients of varying Braak stages of AD neurodegeneration and found that insulin expression was inversely proportional to the Braak stage, with an 80-percent decrease in the number of insulin receptors in AD patients compared to normal subjects. In addition, the ability of insulin to bind to the receptors was compromised. There was a reduced level of mRNA corresponding to insulin, insulin-like growth factor-1 (IGF-1) and -2 polypeptides, and their receptors. The research team also noted a reduction in the tau protein, which is regulated by insulin and IGF-1. This phenomenon ultimately could lead to neuronal cell death and AD exacerbation.  

The postmortem studies inspired a rat study in which intracerebral injection of streptozotocin resulted in a chemical depletion of insulin and an alteration of IGF-signaling mechanisms together with oxidative injury. The combination of alterations resulted in neurodegeneration, including reduction in brain size and other neurological changes seen in AD.

AD is characterized by a reduction in the utilization of glucose, and treatment with insulin has been associated with improved memory. Insulin, important in memory processing, crosses the blood-brain barrier and is even produced in brain tissue itself. AD patients have less insulin and fewer insulin receptors than non-AD patients, and correction of insulin levels improves cognition. Insulin binds to insulin receptors in the brain, most of which are located in the cerebral cortex, olfactory bulb, hippocampus, cerebellum, and hypothalamus. Since there are more insulin receptors in the cognitionpertinent areas of the brain, it is logical to consider the association between insulin and cognition.

Several studies utilizing intranasal, intravenous, and intracerebral administration of insulin demonstrate improved cognition. A study utilizing intranasal insulin showed that its administration enhanced verbal recall in normoglycemic adults with early AD or cognitive impairment. In the study, 25 participants were randomly assigned to receive either placebo (n=12) or 20 IU intranasal insulin (n=13) twice daily. After 21 days of treatment, changes in cognition were measured. The fasting plasma glucose and insulin levels were unchanged with treatment. However, when compared with the placebo treated subjects, the insulin-treated subjects retained more verbal information and displayed superior attention and functional status. 

A study utilizing intravenous (IV) insulin assessed cognitive performance in 22 adults with AD and 15 normal adults receiving five consecutively higher IV doses of insulin resulting in five plasma insulin levels (10, 25, 35, 85, and 135 microU/mL), while plasma glucose levels of ~100 mg/dL were maintained. Cognitive performance was measured after 120 minutes of infusion. AD patients who were ApoE4-positive were found to have improved memory at lower insulin levels of 25 microU/mL, compared to their ApoE4-negative counterparts, who required a higher blood insulin level of 35 and 85 microU/mL before an improvement in memory was noted. Interestingly, normal adults also showed improved memory at insulin levels of 25 and 85 microU/mL. This shows that AD patients who are ApoE4-negative may not be as sensitive to insulin.  

A study utilizing intracerebroventricular insulin showed that its administration enhanced memory formation in rodents undergoing a step-through passive avoidance task These studies suggest that insulin may have a role in enhancement of cognition and memory. The other implication is that patients with the ApoE4 genetic predisposition to AD may not reap the benefits of improvement in AD by glycemic control. 

Based on a recent epidemiological study, individuals who are ApoE4-positive are not more likely to be insulin resistant than those who are ApoE4-negative. Therefore, insulin resistance and being positive for the ApoE4 allele are independent risk factors for AD; having both may pose an additive risk. 

Pathophysiological Connections between Insulin and AD 

AD is characterized by both low insulin levels and insulin resistance within the central nervous system (CNS), as opposed to type 2 diabetes, which is characterized by high insulin levels and insulin resistance outside of the CNS. Insulin resistance and hyperinsulinemia cause a reduction in brain insulin. Several mechanisms might explain why insulin mediates memory facilitation. As noted, insulin receptors are found in areas of the brain responsible for cognition. Insulin activates signaling pathways associated with learning and long-term memory. According to de la Monte, insulin helps to regulate processes such as neuronal survival, energy metabolism, and plasticity. These processes are required for learning and memory.  Peripheral insulin resistance, therefore, affects cognition.

In addition to regulating blood sugar levels, insulin functions as a growth factor for all cells, including neurons in the brain. Thus, insulin resistance or lack of insulin, in addition to adversely affecting blood sugar levels, contributes to degenerative processes in the brain.

When insulin levels reach an exceedingly high level, the beta-amyloid peptide, the hallmark of AD that accumulates in senile plaques, is modulated. Exaggerated elevation of plasma insulin levels causes amyloid peptide levels in the cerebrospinal fluid to increase, resulting in memory insult.

Amyloid beta-Derived Diffusible Ligands 

A group of researchers at Northwestern University studied why brains of AD patients are both low in, and resistant to, insulin. According to William Klein, PhD, who led the research, amyloid beta-derived diffusible ligands may be responsible for the phenomenon. ADDLs are oligomers similar in morphology and size to prions that have been linked to neurodegenerative disease. ADDLs may contribute to lowered insulin levels and insulin resistance in AD brains. Because the ADDLs are so small, they are more diffusible and therefore more harmful than amyloid. 

In healthy brains, insulin binds to a receptor at a synapse, resulting ultimately in memory formation. Klein’s team found that ADDLs disrupt this mechanism of communication by binding to the synapse and changing its shape, thereby causing dysfunction. Because the shape of the synapse is altered, insulin cannot effectively bind, disrupting signal transduction and resulting in insulin resistance. ADDLs have been shown to reduce the plasticity of the synapse, potentiate synapse loss, cause oxidative damage, and result in AD-type tau hyperphosphorylation, mechanisms linked to AD. Since ADDLs have been shown to affect neuronal insulin receptor signaling, it has been suggested that insulin resistance in the AD brain is a response to  ADDLs, inducing a neurological form of diabetes.  Neurons with no ADDLs show an adequate number of insulin receptors. 

Measuring ADDL levels may potentially be a novel tool for diagnosing AD. In 2005, the ultrasensitive bio-barcode assay was used to measure ADDL concentration in cerebrospinal fluid. Of 30 subjects, ADDL concentrations were found to be higher in those diagnosed with AD compared to non-AD patients. This test is not readily available and less invasive testing is underway. An ADDL vaccine is being studied and ADDL-blocking drugs are being considered by Klein et al.

Insulin and the Cholinergic Hypothesis 

The cholinergic hypothesis that suggests AD is caused by an inadequate production of acetylcholine may also have links to blood sugar abnormalities and insulin resistance. The researchers at Brown point out that insulin also participates significantly in neurological function by stimulating the expression of choline acetyltransferase (ChAT), the enzyme responsible for acetylcholine synthesis. Therefore, suboptimal insulin levels as well as poor insulin receptor sensitivity can ultimately contribute to a decrease in acetylcholine, which further elucidates a possible bio-chemical link between diabetes and AD.

AGEs and Oxidation – Common Thread between Diabetes and AD 

Another mechanism linking diabetes with AD is that both diseases, as mentioned previously, are associated with increased oxidative stress and production of AGEs. Although the association between vascular dementia and AGEs is well established, new research points to a link between AGEs and AD. AGEs are formed by a sequence of events originally identified in 1912 as the end-products of the Maillard reaction, during which reducing sugars can react with the amino groups of proteins to produce cross-linked complexes and unstable compounds. 

AGEs have been found in retinal vessels, peripheral nerves, kidneys, and the CNS of diabetics. AGEs couple with free radicals and create oxidative damage, which in turn leads to cellular injury. Diabetic patients could have an increased risk of AD via AGE production. Oxidative stress on its own also causes AGEs, creating a vicious cycle.

AGEs are also known to modify plaques and neurofibrillary tangles, both implicated in AD. AGEs have been identified in neurofibrillary tangles (consisting of tau protein) and senile plaques (consisting of beta-amyloid protein). Since type 2 diabetes accelerates the production of AGEs, it may be another causative factor in the development of AD. It has been proposed that a potential biomarker for early detection of AD may be measurement of toxic AGEs in the serum or cerebrospinal fluid.


Understanding that AD has its foundation in neuroendocrinology is persuasive evidence that there should be greater emphasis on early diagnosis of metabolic syndrome, insulin resistance, and type 2 diabetes. Referring to AD as type 3 diabetes has its foundation in the fact that the CNS in AD is characterized by a paucity of insulin and resistance of the insulin receptors. This results in cognitive dysfunction, since insulin is crucial for neurological signaling processes to occur. Insulin also participates in neurological function by stimulating the expression of ChAT, the enzyme responsible for acetylcholine synthesis; acetylcholine is in turn a necessary neurotransmitter for cognition. AGEs, found in greater amounts in diabetic patients compared to controls with normal glucose regulation, have also been found in high concentration in AD brains. 

The links between hyperglycemic states and AD can allow for better future diagnostic strategies. Since ADDLs may contribute to lowered insulin levels and insulin resistance in AD brains, the future of diagnosis may entail the measurement of ADDLs. Measurement of AGEs has also been proposed. 

Treatment strategies utilizing this information require more research. The knowledge that there is a reduction of the sensitivity to insulin in AD patients who are not ApoE4-positive suggests that optimization of blood sugar levels may have therapeutic benefits. Insulin-sensitizing agents may potentially be used in the setting of early AD. 


1. Rönnemaa E, Zethelius B, Sundelöf J, et al. Impaired insulin secretion increases the risk of Alzheimer disease. Neurology 2008;71:1065-1071. 

2. Steen E, Terry BM, Rivera EJ, et al. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease – is this type 3 diabetes? J Alzheimers Dis 2005;7:63-80. 

3. Viola KL, Velasco PT, Klein WL. Why Alzheimer’s is a disease of memory: the attack on synapses by A beta oligomers (ADDLs). J Nutr Health Aging 2008;12:51S-57S. 

4. Ott A, Stolk RP, van Harskamp F, et al. Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology 1999;53:1937-1942. 

5. Dankner R, Geulayov G, Olmer L, Kaplan G. Undetected type 2 diabetes in older adults. Age Ageing 2009;38:56-62. Psychoneuroendocrinology 2003;28:809-822. 

6. Cowie CC, Rust KF, Ford ES, et al. Full accounting of diabetes and pre-diabetes in the U.S. population in 1988-1994 and 2005-2006. Diabetes Care 2009;32:287-294. 

7. Beydoun MA, Lhotsky A, Wang Y, et al. Association of adiposity status and changes in early to mid- adulthood with incidence of Alzheimer’s disease. Am J Epidemiol 2008;168:1179-1189. 

8. Razay G, Vreugdenhil A, Wilcock G. The metabolic syndrome and Alzheimer disease. Arch Neurol 2007;64:93-96. 

9. Vilalta-Franch J, López-Pousa S, Garre-Olmo J, et al. Metabolic syndrome in Alzheimer’s disease: clinical and developmental influences. Rev Neurol 2008;46:13-17. 

10. Rivera EJ, Goldin A, Fulmer N, et al. Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer’s disease: link to brain reductions in acetylcholine. J Alzheimers Dis 2005;8:247-268. 

11. de la Monte SM, Tong M, Lester-Coll N, et al. Therapeutic rescue of neurodegeneration in experimental type 3 diabetes: relevance to Alzheimer’s disease. J Alzheimers Dis 2006;10:89-109. 

12. Lester-Coll N, Rivera EJ, Soscia SJ, et al. Intracerebral streptozotocin model of type 3 diabetes: relevance to sporadic Alzheimer’s disease. J Alzheimers Dis 2006;9:13-33. 

13. Craft S, Watson GS. Insulin and neurodegenerative disease: shared and specific mechanisms. Lancet Neurol 2004;3:169-178. 

14. Reger MA, Watson GS, Green PS, et al. Intranasal insulin improves cognition and modulates beta- amyloid in early AD. Neurology 2008;70:440-448. 

15. Craft S, Asthana S, Cook DG, et al. Insulin dose-response effects on memory and plasma amyloid precursor protein in Alzheimer’s disease: interactions with apolipoprotein E genotype. Psychoneuroendocrinology 2003;28:809-822. 

16. Park CR, Seeley RJ, Craft S, Woods SC. Intracerebroventricular insulin enhances memory in a passive-avoidance task. Physiol Behav 2000;68:509- 514. 

17. Peila R, Rodriguez BL, Launer LJ, et al. Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: The Honolulu-Asia Aging Study. Diabetes 2002;51:1256-1262. 

18. Zhao WQ, Alkon DL. Role of insulin and insulin receptor in learning and memory. Mol Cell Endocrinol 2001;177:125-134. 

19. Bingham EM, Hopkins D, Smith D, et al. The role of insulin in human brain glucose metabolism: an 18fluoro-deoxyglucose positron emission tomography study. Diabetes 2002;51:3384-3390. 

20. de la Monte SM. Insulin resistance and Alzheimers’s disease. BMB Rep 2009;42:475-481. 

21. Li L, Holscher C. Common pathological processes in Alzheimer disease and type 2 diabetes: a review. Brain Res Rev 2007;56:384-402.

22. Westerman MA, Cooper-Blacketer D, Mariash A, et al. The relationship between Abeta and memory in the Tg2576 mouse model of Alzheimer’s disease. J Neurosci 2002;22:1858-1867. 

23. De Felice FG, Wu D, Lambert MP, et al. Alzheimer’s disease-type neuronal tau hyperphosphorylation induced by A beta oligomers. Neurobiol Aging 2008;29:1334-1347. 

24. Zhao WQ, De Felice FG, Fernandez S, et al. Amyloid beta oligomers induce impairment of neuronal insulin receptors. FASEB J 2008;22:246-260. 

25. Gong Y, Chang L, Viola KL, et al. Alzheimer’s disease-affected brain: presence of oligomeric A beta ligands (ADDLs) suggests a molecular basis for reversible memory loss. Proc Natl Acad Sci U S A 2003;100:10417-10422. 

26. Georganopoulou DG, Chang L, Nam JM, et al. Nanoparticle-based detection in cerebral spinal fluid of a soluble pathogenic biomarker for Alzheimer’s disease. Proc Natl Acad Sci U S A 2005;102:2273- 2276. 

27. [Accessed October 19, 2009] 

28. Rivera EJ, Goldin A, Fulmer N, et al. Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer’s disease: link to brain reductions in acetylcholine. J Alzheimers Dis 2005;8:247-268. 

29. Yamagishi S, Ueda S, Okuda S. Food-derived advanced glycation end products (AGEs): a novel therapeutic target for various disorders. Curr Pharm Des 2007;13:2832-2836. 

30. Pasquier F, Boulogne A, Leys D, Fontaine P. Diabetes mellitus and dementia. Diabetes Metab 2006;32:403- 414. 

31. Sato T, Shimogaito N, Wu X, et al. Toxic advanced glycation end products (TAGE) theory in Alzheimer’s disease. Am J Alzheimers Dis Other Demen 2006;21:197-208. 

32. Valente T, Gella A, Fernàndez-Busquets X, et al. Immunohistochemical analysis of human brain suggests pathological synergism of Alzheimer’s disease and diabetes mellitus. Neurobiol Dis 2009;Sep 22 [Epub ahead of print] 

33. Zhu X, Su B, Wang X, et al. Causes of oxidative stress in Alzheimer disease. Cell Mol Life Sci 2007;64:2202-2210. 

34. Takeuchi M, Yamagishi S. Possible involvement of advanced glycation end-products (AGEs) in the pathogenesis of Alzheimer’s disease. Curr Pharm Des 2008;14:973-978. 

35. Takeuchi M, Sato T, Takino J, et al. Diagnostic utility of serum or cerebrospinal fluid levels of toxic advanced glycation end-products (TAGE) in early detection of Alzheimer’s disease. Med Hypotheses 2007;69:1358-1366. 


Tags:  alzheimer's  diabetes 

Share |
PermalinkComments (0)
Connect With Us

380 Ice Center Lane, Suite C

Bozeman, MT 59718

Our mission

The American College for Advancement in Medicine (ACAM) is a not-for-profit organization dedicated to educating physicians and other health care professionals on the safe and effective application of integrative medicine.