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Crisis: The Cardio-Metabolic Syndrome of Insulin Resistance Epidemic

The twin epidemic of obesity and Type 2 diabetes mellitus have spawned a public health crisis. In the United States 1.5 million of new cases of diabetes occur every year. The projected micro vascular and macro vascular complications include: cardiovascular disease, nephropathy , amputations, and blindness, which are likely to become the major cause of preventable disease and premature death in the millennium .
The latest estimate from the Center for Disease Control indicates that in 2010 approximately 26 million American adults had diabetes and 79 million had pre diabetes. African-Americans and other ethnic groups continue to suffer higher rates of diabetes than whites. Currently, it was estimated that diabetes affects 8% of Americans and among persons older than 60 years the prevalence exceeded 25%, with an annual cost of $ 194 billion in 2010. Therefore, almost one out of three Americans has diabetes or prediabetes.
Worldwide diabetes affects 285 million adults and Type 2 diabetes accounts for 90- 95 % of all cases. The emergence of obesity in children and adolescents in the last two decades has been demonstrated clearly by the national health and nutrition survey (NHANES) . The most significant rise in the prevalence of obesity occurred In the children of African-Americans and Hispanic descent. Along with the obesity epidemic, a second phenomenon observed in the last decade is the increased rate of Type 2 diabetes in children and adolescents. In some pediatric diabetes centers across the United States, as many as one in every four patients with newly-diagnosed diabetes had Type 2 diabetes.
One must remember that 20 years ago, children with Type 2 diabetes were rare, representing less than 2% of diabetes cases in childhood. Thus, the increase in obesity and Type 2 diabetes in youth can be considered twin epidemics and are occurring worldwide. And the important question is whether we intend to treat pediatric obesity with an ever-increasing array of powerful adult drugs such as beta – blockers and diuretics for hypertension, aspirin for coagulopathy, insulin sensitizers for the metabolic syndrome, and, of course, insulin for diabetes.
Once that door has been opened, the pharmaceutical industry will happily walk through it. Instead of fewer advertisements for junk food, we will be destined to see new commercials promoting the use of cholesterol-lowering and antiobesity medications in children. According to the NHANES survey in 2006, 16.3% of children and adolescents 2-19 years of age are obese. Obesity is defined as a body mass index >25kg/m2. (Fig 1.) A normal BMI ( Body Mass Index) is 18 -24. 9 kg slash m2 ( weight in kg. divided by body surface in sq. meters) . A BMI >25 and > 30 kg /m2 is associated with 5 -10 fold and 30- fold increases in risk of developing Type 2 diabetes, respectively. With each 5 kg increase in body weight there is a 40% increase in developing diabetes.
Of course, obesity is not only associated with diabetes but also with hypertension and hyperlipidemia. It is the so-called malignant family of cardiovascular disorders. Type 2 diabetes is a multifactorial disease Involving genetic and environmental factors. The driving force of Type 2 diabetes is insulin resistance. The main cause of insulin resistance is obesity , and the mechanism by which obesity leads to insulin resistance is due to increased fatty acid flux from the visceral fat depot to insulin sensitive tissues. These fatty acids compete with glucose as substrate for utilization.
The fatty acid release causes ectopic lipid deposition in insulin sensitive tissues such as muscle, liver, and heart affecting the insulin receptor signaling cascade and also causing steatosis, which can lead to nonalcoholic steatohepatitis (fatty liver) progressing to fibrosis and cirrhosis of the liver, pancreatic failure with Type 2 diabetes, and dilated cardiomyopathy.
Secretion of hormones by the adipocytes( fat cells), namely adiponectin,TNF- A (tumor necrosis factor), interleukin-6 , resisting all of which are causing insulin resistance except the adiponectin, which is an insulin sensitizer and prevents diabetes in individuals with decreased intrabdominal visceral fat.( Fig 2.) In summary, the common pathway of altered glucose metabolism involves obesity leading to insulin resistance and later on to Type 2 diabetes.
The natural history of Type 2 diabetes directly reflects the interrelationships among the three defects of Type 2 diabetes: insulin resistance, increased hepatic glucose output, and pancreatic beta cell deficiency. The primary and earliest pathogenic lesion is insulin resistance with the B -cell able to compensate for a variable length of time by secreting supra physiologic amounts of insulin. Insulin resistance, compensatory hyper insulin emia, and post prandial (post meal) hyperglycemia characterize impaired glucose tolerance (IGT).
{46631}During that stage, which can last for years to decades, most of the macro vascular complications develop, namely: cardiovascular disease, cerebrovascular disease, strokes, and peripheral vascular disease with amputations. It is then that insulin sensitizers and insulin therapy may have their greatest impact on the disease. If untreated over time, the pancreas fails and relative insulin deficiency occurs with a fasting hyper glycemia and full-blown Type 2 diabetes develops. It has been estimated that these newly- diagnosed diabetic subjects at this time had only 50% left of their B-cell pancreatic function. Once Type 2 diabetes develops, the micro vascular complications follow, such as diabetic retinopathy with blindness ,nephropathy with end stage renal failure, and dialysis and painful peripheral diabetic neuropathy and/or autonomic neuropathy with arrhythmias and sudden death, if untreated.
Current criteria for the diagnosis of diabetes are: A1c (HbA1c) ->6.5 % (it Is considered the gold standard). Fasting plasma glucose >126 mg /dl. Two-hour plasma glucose >_200 mg /dl. after an oral glucose tolerance test. A random glucose level of _>200mg /dl. Prevention and or delay of Type 2 diabetes includes : weight loss of 7% of body weight and increase of physical activity to at least 150 min per week of moderate activity, such as walking. Follow-up counseling with a specialist. Metformin therapy may be considered in those with prediabetes or an A1c of 5.7 -6.4 and those with prior gestational diabetes. Testosterone deficiency has been found in more than 50% of men with Type 2 diabetes, and vitamin D deficiency has been associated with development of diabetes. Obesity, particularly abdominal obesity, is associated with resistance to the effects of insulin on peripheral glucose and fatty acid utilization often leading to Type 2 diabetes. Insulin resistance, the associated hyperinsulinemia and hyperglycemia, and adipocyte cytokines may also lead to vascular endothelial dysfunction, an abnormal lipid profile, hypertension, and vascular inflammation, all of which will increase the risk for cardiovascular disease. The presence of those metabolic risk factors characterize the existence of the metabolic syndrome, insulin resistance syndrome, or syndrome X . Most of the time, the insulin resistant individual maintains a normal blood sugar level.
The obvious question is how it is possible individuals who are so insulin sensitive versus others who are so insulin resistant to have the same normal OGTT (oral glucose tolerance test )?
If insulin resistant individuals could not secrete large amounts of insulin, they will become diabetic and that’s what Type two diabetes basically is. Its resistance to insulin action and the pancreas cannot compensate for this defect by secreting large amounts of insulin. Unfortunately even compensating by secreting large amounts of insulin, insulin-resistant individuals are at risk of developing a series of abnormalities, due primarily to the abnormality in insulin action, and that abnormality is insulin resistance, which is partially environmental.
The more obese a person, the more insulin resistant. The more sedentary, the more insulin resistant you are …and it is partially genetic. Insulin resistant persons, no matter how much is genetic or how much environmental, are going to try to secrete large amounts of insulin in order to maintain normal glucose homeostasis. An insulin resistant individual, then, does not become diabetic as long is the pancreas secretes large amounts of insulin to compensate and maintain a normal glucose homeostasis.
The insulin resistant individual, however, pays a price for this compensatory hyperinsulinemia by being glucose intolerant, having higher triglyceride levels, lower HDL (good cholesterol) higher blood pressure, high uric acid, and all of these variables will increase risk for CHD (coronary heart disease).
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Those are the clusters of abnormalities associated with syndrome X. In the morning when we wake up, we survive because our livers are making endogenous triglyceride-rich VLDL, containing lipoproteins as they come out from the liver they are acted upon by lipoprotein lipase, which hydrolyzes the triglycerides (TG) and releases tree fatty acids, which are used as a major source of energy by both skeletal muscle and cardiac muscle even before we eat breakfast.
When we eat the newly absorbed-dietary fat, it is packaged in the intestinal cell as another triglyceride-rich lipoprotein. The chylomicron again is broken down to FFA (free fatty acids), but in this instance the FFA are used primarily to replete the adipose tissue-stored FFA. These pathways are important for a variety of reasons. First of all, those particles are highly atherogenic and provide significant amounts of cholesterol ester to the arterial wall and become the source of the earliest lesion of atherosclerosis. Second, human beings have a very, very insufficient way of clearing these particles. Third, insulin resistance and hyperinsulinemia increase VLDL (Triglyceride ) concentration. Fourth, regardless of the TG concentration, individuals that are insulin resistant have difficulty in clearing those particles from their plasma (blood). Fifth, the insulin-resistant non diabetic hyperinsulinemic individual has some defects in lipoprotein lipase activity. So, there is this horrible situation of making more TG due to insulin resistance ,and because of that there are problems clearing those particles. Add to that a defect in LP lipase activity and a disaster which is an epidemic of CHD (coronary heart disease) ensues in people from Western cultures.
To summarize, what we are faced with in 2012 is a greatly-expanded version of the metabolic syndrome or syndrome X. (Fig 3.) Insulin resistance is still up there, and obesity makes it worse. Sedentary activity makes it worse and recently it has been shown that smokers have higher TG and lower HDL (good cholesterol) , more insulin resistance, higher insulin levels. Therefore, smoking seems to accentuate the appearance of syndrome X. We still have genetic influences, but we are still equally naive as to what they are at the gene level.
{46632}At any rate, folks with that defect will try to secrete more insulin, and if they cannot do it they will get diabetes. If they can do it, we now know that they will be glucose intolerant, have higher triglyceride, lower HDL, high uric acid, higher PAI-1, increased postprandial(post-meals), and lipemia , all of which will make it much more likely to have coronary heart disease.
In other words, the bottom line is that being insulin resistant is good for nobody. Those lucky enough to secrete lots of insulin, will not get diabetes, but will not be lucky enough to avoid coronary heart disease and syndrome X. More or less, then: stay slim, run a lot, and choose good parents.

Frixos O. Goussis, MD – Endocrinology, Diabetes, Metabolism – is an assistant professor of medicine and Senior Attending Physician at St. Francis Hospital, Heart Center Roslyn and Great Neck, NY.

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