Annie Sawyer, PhD
One of the main focuses for quite number of years of mine was on obesity and insulin resistance, at the background of the metabolic syndrome - or the so called “prediabetes” phenomena. This was in the early 1980s when I finished my MD degree, and started to work as an endocrinologist in one of the main hospitals in the city where I was born. As a medical student, I have been always interested in understanding all hidden biochemical and molecular mechanisms behind obesity as a phase of metabolic syndrome appearance.
One of the main focuses for quite number of years of mine was on obesity and insulin resistance, at the background of the metabolic syndrome - or the so called “prediabetes” phenomena. This was in the early 1980s when I finished my MD degree, and started to work as an endocrinologist in one of the main hospitals in the city where I was born. As a medical student, I have been always interested in understanding all hidden biochemical and molecular mechanisms behind obesity as a phase of metabolic syndrome appearance.
The medical team I worked for had made quite many efforts investigating what exactly were the causes of obesity as main promoter for metabolic syndrome appearance and vice versa. The focus of ours was at first on identifying the bacterial and viral etiology of the obesity as triggers to the road of prediabetes, and Type 2 diabetes. At the same time most of the world famous researchers consider insulin resistance as the main cause behind obesity and started to look for auto-antibodies or mutations in genes and insulin receptors. It was extrapolated that these antibodies will bind to the insulin receptor and consequently will block them. From our studies we could see that increased cardiovascular risk factors precede the onset of type 2 diabetes. An issue is whether it is glucose or insulin that increases the CVD risk. In nondiabetic subjects, people who are insulin resistant always have slightly elevated glucose levels.
Metаbolic Syndrome is a combination or a cluster of disorders chаrаcterized by the presence of severаl of the following risk fаctors: hyperglycemiа, hypertension, low high-density lipoprotein (LDL), high low-density lipoprotein (HDL), high triglyceride, аbnormаl body mаss index (BMI), micro-аlbuminuriа, endotheliаl dysfunction, prothrombotic stаte, based on general proinflаmmаtory process (Bаusell, 2007) (Although not аll these criteriа need to be met before the syndrome will be found). In fаct, three of the above symptoms are found to be an indicаtive of the syndrome. It is estimаted thаt over 22% of the аdult U.S. populаtion hаve Metаbolic Syndrome аnd the incidence is rаpidly increаsing eаch yeаr.
Prediabetes is a phase known as the condition of having abnormal elevated levels of glucose, insulin, and triglycerides in the blood. In fact “prediabetes” is a term-synonym for metabolic syndrome. Prediabetes is found in cases when blood glucose (sugar) levels are elevated beyond normal but are not considered high enough to indicate true Type 2 diabetes. Generally, the ‘prediabetic’ phase should be defined as combination of insulin resistance, glucose intolerance, elevated insulin secretion, and subclinical inflammation as predictors of the metabolic syndrome, beta-cell dysfunction, chronic inflammation, increased insulin resistance and decreased insulin secretion, as shown in the Framingham Study (FS) and the Insulin Resistance Atherosclerosis Study (IRAS). The prediabetic phase is seen as an early attempt metabolic syndrome to be defined as already available.
Metаbolic Syndrome is a combination or a cluster of disorders chаrаcterized by the presence of severаl of the following risk fаctors: hyperglycemiа, hypertension, low high-density lipoprotein (LDL), high low-density lipoprotein (HDL), high triglyceride, аbnormаl body mаss index (BMI), micro-аlbuminuriа, endotheliаl dysfunction, prothrombotic stаte, based on general proinflаmmаtory process (Bаusell, 2007) (Although not аll these criteriа need to be met before the syndrome will be found). In fаct, three of the above symptoms are found to be an indicаtive of the syndrome. It is estimаted thаt over 22% of the аdult U.S. populаtion hаve Metаbolic Syndrome аnd the incidence is rаpidly increаsing eаch yeаr.
Prediabetes is a phase known as the condition of having abnormal elevated levels of glucose, insulin, and triglycerides in the blood. In fact “prediabetes” is a term-synonym for metabolic syndrome. Prediabetes is found in cases when blood glucose (sugar) levels are elevated beyond normal but are not considered high enough to indicate true Type 2 diabetes. Generally, the ‘prediabetic’ phase should be defined as combination of insulin resistance, glucose intolerance, elevated insulin secretion, and subclinical inflammation as predictors of the metabolic syndrome, beta-cell dysfunction, chronic inflammation, increased insulin resistance and decreased insulin secretion, as shown in the Framingham Study (FS) and the Insulin Resistance Atherosclerosis Study (IRAS). The prediabetic phase is seen as an early attempt metabolic syndrome to be defined as already available.
What makes metabolic syndrome quite dangerous is that is converting in the 21st century modern pandemic, constantly escalating in numbers around the world, and especially in US, where morbid obesity is on a rise. With other words, prediabetes is diagnosed when the level of glucose is abnormal but below the well known diabetic values: fasting values of 100-125 mg/dl, and 140-199 mg/dl two hours after a glucose load. For diabetes, the values are 126 mg/dl (fasting) and 200 mg/dl (two hours after a glucose load). Old аge, postmenopаusаl stаtus, ethnicity, higher body mаss index, current smoking, low household income, high cаrbohydrаte intаke, аnd physicаl inаctivity аll hаve been connected with the increаsed odds of the onset аnd or deterioration of metаbolic syndrome. Аn аdditionаl 12 million аdults will likely develop the diseаse аs а result of аging аlone by 2022 (Feinstein, 2008). Not а single cаuse аt the moleculаr level cаn be trаced to the origin of metаbolic syndrome (Diаmond, 2001).
However, increаsing evidence suggests this enigmatic syndrome originаtes from a combination of insulin resistаnce аnd the аctivаtion of vаsculаr inflаmmаtory mechаnisms relаted to increаsed oxidаtive stress. For exаmple, insulin resistаnce results in preferentiаl metаbolism of free fаtty аcids which leаds to reduced glucose utilizаtion (Ford, 2002).
However, increаsing evidence suggests this enigmatic syndrome originаtes from a combination of insulin resistаnce аnd the аctivаtion of vаsculаr inflаmmаtory mechаnisms relаted to increаsed oxidаtive stress. For exаmple, insulin resistаnce results in preferentiаl metаbolism of free fаtty аcids which leаds to reduced glucose utilizаtion (Ford, 2002).
Insulin resistаnce is identified in children prior to the development of the dyslipidemiа, hypertension аnd hyperglycemiа thаt occur lаter in life. Аs one аges, pаncreаtic betа cell exhаustion is not аble to meet insulin resistаnce demаnds, аnd this might eventuаlly leаd to the progression of metаbolic disturbаnce including dyslipidemiа, hypertension (Feinstein, 2008). On the other hаnd, the infiltrаtion of аdipose tissue by inflаmmаtory mаcrophаges is indicаted аs а common feаture of obesity. Аdipose mаss аs meаsured by weight, BMI or viscerаl obesity correlаteѕ quаntitаtively with genetic expression of mаcrophаges thаt produce inflаmmаtory mediаtors аnd mаrkers. Therefore, while Syndrome X mаy shаre some common chаrаcteristic feаtures with diаbetes, despite it's not а diаbetes or prediаbetic condition per se as other distinct fаctors аnd cаuses аre аlso involved (Bаrclаy & Lie, 2004).
The insulin resistance, insulin secretion, and the phase of subclinical inflammation are claimed as predictors of the metabolic syndrome. Many researchers noted that there is some controversy about insulin levels as a predictor of CHD, although most of the data indicate a positive correlation. It is known that insulin concentrations predict metabolic syndrome and many others metabolic disorders. High absolute concentrations of LDL are not related to baseline insulin levels, but high insulin concentrations predict the development of small dense VLDL. In the San Antonio Heart Study (SAHS), people with normal glucose tolerance were followed to see whether they developed Type 2 diabetes. At baseline, they had higher triglycerides, higher HDL, higher systolic blood pressure (BP) than prediabetics, slightly higher glucose levels but the differences were really very small, although significant, and much higher insulin concentration.
The argument was that it was hyperinsulinemia and IR that drove this pre-diabetic issue. After some time, the San Antonio data were reviewed and an attempt made to develop a model for IR versus glucose. From the San Antonio study, where there was information on IR and low insulin secretion, and from earlier studies of the Pima Indians, it was shown that low insulin secretion and IR do predict the onset of Type 2 diabetes. Furthermore, when these factors were combined, there was about a 20-fold excess of incidence of Type 2 diabetes. The United Kingdom Prospective Diabetes Study (UKPDS) data suggest that the relationship between glucose concentrations, while clearly significant related to myocardial infarction (MI) is not as significant in its relationship to microvascular disease. Pyorala at all (1998) also presented data from a 25-year follow-up study reported in (Circulation, 1998; p. 398-404) that showed that nondiabetic men with the highest IR are at greatest risk for a major CHD event.
Major clinical feature of the metabolic syndrome is the abdominal (visceral) obesity. Obesity sets the stage for metabolic syndrome which then itself increases one's chances of diabetes, heart disease, stroke and other diseases. Therefore, everyone in our Western society should be concerned about obesity as well as our government must take care on developing preventive programs. What is good, the government is already starting to take substantial meassures to fight the above mentioned pandemic. Of course people are different. Those in whom the disorder is quite severe will accumulate fat extremely quickly, when those in whom it is moderate - will gradually increase in weight and those in whom it is mild- may be able to keep their excess weight stationary for long periods. Despite of the aggressiveness in many weight loss programs (plans), based on restrictive diets, multiple drug treatment strategies, active exercise, sauna and massage techniques, the results seem temporary and quite unsatisfactory. The pounds seem to come back immediately, after months and even years or as soon as the treatment programs are forgotten or relaxed.
Major clinical feature of the metabolic syndrome is the abdominal (visceral) obesity. Obesity sets the stage for metabolic syndrome which then itself increases one's chances of diabetes, heart disease, stroke and other diseases. Therefore, everyone in our Western society should be concerned about obesity as well as our government must take care on developing preventive programs. What is good, the government is already starting to take substantial meassures to fight the above mentioned pandemic. Of course people are different. Those in whom the disorder is quite severe will accumulate fat extremely quickly, when those in whom it is moderate - will gradually increase in weight and those in whom it is mild- may be able to keep their excess weight stationary for long periods. Despite of the aggressiveness in many weight loss programs (plans), based on restrictive diets, multiple drug treatment strategies, active exercise, sauna and massage techniques, the results seem temporary and quite unsatisfactory. The pounds seem to come back immediately, after months and even years or as soon as the treatment programs are forgotten or relaxed.
BMI is a measure of how much weight anyone carries for a given height. Basically one is considered "overweight" when their body mass index is greater than the upper range of the normal ranges. In order to meet the criterion for frank "obesity" one's BMI needs to be 30 or higher. The entity known as "morbid obesity" also known as clinically severe obesity, is defined as a BMI of greater than or equal to 40.
However, one can also be labeled as morbidly obese if body mass index is 35 or higher and the individual has one or more "co morbid" conditions. The following co-morbid conditions can be formulated as metabolic syndrome (diabetes, high blood pressure, high cholesterol, stroke and cardiovascular disease). Being overweight is, alongside diabetes, a leading cause of increased cholesterol levels, high blood pressure and coronary artery disease. Hence, obesity increases chances of developing all the above risk factors. One of the missing links in the pathogenesis of metabolic syndrome is the long time unrecognized hepatic insulin resistance that appears to mediate the glucose intolerance, hyperglycemia, high level of triglyceride, and HDL-cholesterol abnormalities that contribute to the constellation of heart-disease risk factors called metabolic syndrome and it does represent a newly discovered pathophysiology link in CVD development (Biddinger et al., 2008).
Kahn R., (2005) proved that insulin resistance is related to dyslipidemia, and insulin resistance- to glucose intolerance, while is not related to obesity. Actually, it is already known that obesity causes insulin resistance, but is not related to high blood pressure. Except insulin there are few other hormones involved in the etiology and pathogenesis of metabolic syndrome. One of them is the hormone- leptin.
Kahn R., (2005) proved that insulin resistance is related to dyslipidemia, and insulin resistance- to glucose intolerance, while is not related to obesity. Actually, it is already known that obesity causes insulin resistance, but is not related to high blood pressure. Except insulin there are few other hormones involved in the etiology and pathogenesis of metabolic syndrome. One of them is the hormone- leptin.
Leptin is a hormone that works as natural appetite suppressant secreted by fat cells in the body. Its discovery in the 1990s helped researchers to start experimenting with leptin that caused mice to eat less and lose weight while this rarely happens in humans. Falling levels of this hormone, that helps the brain resist tempting foods, may explain why people who lose weight often have a hard time keeping it off. Restoring leptin to its pre-diet levels may reverse this problem, concluded Rosenbaum, offering a new way for dieters to finally win the weight battle. "When you lose weight you've created about the perfect storm for regaining weight," as per Rosenbaum of Columbia University Medical Center in New York, whose research appears in the Journal of Clinical Investigation. After significant weight loss according to him the metabolism not only becomes more efficient, so the body needs fewer calories, but the brain becomes less vulnerable to tasty-looking treats. "Areas of the brain involved in telling not to eat seem to be less active. "When you are obese, you are more responsive to food and you are less in control of it," states Rosenbaum. Since then researchers started to look for the best methods to use human hormones to help healing obesity. In several earlier studies, researchers found out that when people lose weight, leptin levels decrease, as the body tries to protect its proper stored energy.
Rosenbaum was interested to investigate the impact of the leptin loss on the brains of people who had lost weight, and whether replacing leptin might help them keep off the weight. He used functional magnetic resonance imaging that shows activity in the brain. The researcher studied six obese patients before and after going on a hospital-supervised diet that reduced their body weight by 10 percent. People were shown pictures of food and non-food items. The author found that after weight loss, areas in the brain responsible for regulating food intake were less active when people were shown food images, while areas in the brain responsible for emotion were more active. When the researchers restored leptin to the levels before dieting, these changes were largely reversed. Similar results have been seen in people with a rare genetic condition in which their bodies do not make leptin. Rosenbaum believed leptin could be useful tool in helping people maintain weight loss. According to him the idea was to create a whole new class of therapies to help people with obesity keep weight off after they have lost it.
Making the situation worse, insulin resistance or low level of insulin secretion from the pancreas co-promote the formations of an additional third type of adipose tissue. It seems that the more insulin the pancreas secretes, the more likely is the appearance of the “apple shape” around the waist. Apparently hyperinsulinemia (too much insulin in the blood) can make anyone not only fat but also preliminary aged. And in fact insulin is the hormone that makes us fat and preliminary aged, despite we need it for energy supply. An even more insidious reason for this is that the fat cells do not develop insulin resistance to the degree other body cells do. The final result is that, in insulin resistance, all muscles and organs are being starved while the fat cells are being fed. Already knowing that adipose tissue also produces increased levels of pro-inflammatory signaling factors (eicosanoids and interleukins) cellular substances – hormones and other bioactive substances referred to as adipocytokines (Hotamisligil, 2004), as a vicious circle of all of these factors insulin sensitivity in organs like muscle and liver is decreasing (Matsuzawa, 2004).
It is also hypothesized that secondary factors as for example: nonesterified fatty acid liberation and adipokine (e.g., adiponectin) production (Carr et al., 2004), independent of obesity and other risk factors (Egan, Greene, and Goodfriend, 2001; Janssen, Katzmarzyk and Ross, 2002) may also play a significant role in the metabolic syndrome pathogenesis. Obviously the conglomeration or the convergence of these risk factors elevates the risk for this disease (Pladevall at al., 2006). As it is already cited in the literature- adipokines are a variety of proteins with signaling properties produced in body fat cells. While in the past white adipose tissue (one type of body fat) used to be regarded as a passive energy warehouse which is also used to provide a buffer and protection to all internal organs, lately this concept has been turned 180 degrees up and it is now understood that white adipose tissue is highly active and dynamic organ being involved in a multitude of physiological and metabolic biochemical reactions and processes.
Research also suggests that appetite-regulating hormones are affected by sleep and that sleep deprivation could lead to weight gain. In two separate "well randomized" studies, people who slept five hours or less had higher levels of ghrelin - a hormone that stimulates hunger - and lower levels of the appetite-suppressing hormone leptin than those who slept eight hours per night. Prof. Cappuccio of the University of Warwick has proved that short sleep duration may also lead to obesity, through an increase of appetite via hormonal changes. Lack of sleep produces secretion of ghrelin, which stimulates appetite and creates less leptin, which suppresses appetite. The hormonal relationship and obesity is shown also in HERS study published in JAMA (2000).
Research also suggests that appetite-regulating hormones are affected by sleep and that sleep deprivation could lead to weight gain. In two separate "well randomized" studies, people who slept five hours or less had higher levels of ghrelin - a hormone that stimulates hunger - and lower levels of the appetite-suppressing hormone leptin than those who slept eight hours per night. Prof. Cappuccio of the University of Warwick has proved that short sleep duration may also lead to obesity, through an increase of appetite via hormonal changes. Lack of sleep produces secretion of ghrelin, which stimulates appetite and creates less leptin, which suppresses appetite. The hormonal relationship and obesity is shown also in HERS study published in JAMA (2000).
The hyperinsulinemia in women has been shown to stimulate the release of testosterone from the ovaries (HERS study). It is a well known fact that people who are obese are suffering from this disorder regardless of whether they eat normally, excessively, or less than normal. At the same moment it is quite obvious that there are people who are constantly overeating but are free of the above disorder. It is easy to conclude that obesity in all its multiple forms is due to an abnormal damage in the hypothalamic area of the brain- a center that is the main regulatory mechanism of a hunger, thirst and the sexual desire.
Most adults who develop “prediabetes” have insulin resistance as its main culprit. The human body uses sugar as a fuel (energy) to function, and reproduce. To this end, sugar has to be transported from the bloodstream across cell walls into the cells, where the sugar is actually burned and turned into energy. Insulin is a key hormone produced by the pancreas, primarily as a response to the sugar absorbed into the bloodstream after you eat a meal. Insulin acts on cell walls in such a way that the cells can take up and metabolize sugar. If the cell walls don't allow insulin to do its job, a person is said to have insulin resistance.
Most adults who develop “prediabetes” have insulin resistance as its main culprit. The human body uses sugar as a fuel (energy) to function, and reproduce. To this end, sugar has to be transported from the bloodstream across cell walls into the cells, where the sugar is actually burned and turned into energy. Insulin is a key hormone produced by the pancreas, primarily as a response to the sugar absorbed into the bloodstream after you eat a meal. Insulin acts on cell walls in such a way that the cells can take up and metabolize sugar. If the cell walls don't allow insulin to do its job, a person is said to have insulin resistance.
Insulin resistance refers to the mechanism by which one develops prediabetes or metabolic syndrome. They're not two different conditions. They are cause and effect — insulin resistance is a synonym for metabolic syndrome which is the preamble of the prediabetes state. To make things worse, lipid metabolism is also affected as a consequence of the insulin resistance and the blood pressure consequently elevates. Above all the rate of blood clotting increases- thus, the danger of a stroke and heart attack in the future. In order to overcome resistance, the pancreas produces more and more insulin — and unfortunately, the increased levels of insulin are detrimental to our arteries leading to the vicious circle of elevated blood pressure. In fact, only a small proportion of individuals who have prediabetes have insulin deficiency, but all of them show insulin resistance. If cells such as those of the liver and muscles are becoming resistant to insulin, then sugar cannot enter cells easily and remains in the bloodstream exceeding its normal values.
A relationship between severe stress or emotional drama (loss of a loved one, divorce, etc.) and the onset of metabolic syndrome had been noted by few clinical studies since the first descriptions of metabolic syndrome as an entity. It seems in the way how it's described--that the presence of extended emotional disturbance or elevated stress, especially in individuals who can't handle stress, is a good enough indicator for the onset of metabolic syndrome. I am not surprised, as most of the chronic degenerative diseases start immediately after severe psychological drama and the above phenomena continues to be seen as main reason in cancer, autoimmune disease and many other diseases ethiopathogenesis. However, the presence of elevated stress or emotional shock is not the only reason beind the metabolic syndrome appearance, but for its treatment resistance as well. Practical research experience shows that the relative resistance of treatment of most of the metabolic syndrome cases rests upon the inability to deal with anger, to gain love, respect or affection and at a certain point separate clinical symptoms (e.g. obesity, high blood sugar) start to manifest on different levels. Contrary the syndrome seems to improve by finding or giving love to the others.
A relationship between severe stress or emotional drama (loss of a loved one, divorce, etc.) and the onset of metabolic syndrome had been noted by few clinical studies since the first descriptions of metabolic syndrome as an entity. It seems in the way how it's described--that the presence of extended emotional disturbance or elevated stress, especially in individuals who can't handle stress, is a good enough indicator for the onset of metabolic syndrome. I am not surprised, as most of the chronic degenerative diseases start immediately after severe psychological drama and the above phenomena continues to be seen as main reason in cancer, autoimmune disease and many other diseases ethiopathogenesis. However, the presence of elevated stress or emotional shock is not the only reason beind the metabolic syndrome appearance, but for its treatment resistance as well. Practical research experience shows that the relative resistance of treatment of most of the metabolic syndrome cases rests upon the inability to deal with anger, to gain love, respect or affection and at a certain point separate clinical symptoms (e.g. obesity, high blood sugar) start to manifest on different levels. Contrary the syndrome seems to improve by finding or giving love to the others.
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These statements have not been evaluated by the Food and Drug Administration. The material in this newsletter is provided for informational purposes only. Thus our intentions are not to diagnose, cure, mitigate, treat or prevent any disease. If you use the information in this newsletter without the approval of your health professional, the authors of this letter do not assume any responsibility. Copyright @ 2010, Natural Health-Wellness LLC. All rights reserved.
These statements have not been evaluated by the Food and Drug Administration. The material in this newsletter is provided for informational purposes only. Thus our intentions are not to diagnose, cure, mitigate, treat or prevent any disease. If you use the information in this newsletter without the approval of your health professional, the authors of this letter do not assume any responsibility. Copyright @ 2010, Natural Health-Wellness LLC. All rights reserved.
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