A patient primer. (Revised January 2006)
So I (or my child) has insulin resistance syndrome, is that bad?
Sometimes also called the “metabolic syndrome” or syndrome X, you are but one member of a national epidemic of insulin resistance syndrome that is fast spreading through Western Countries and much of the non-Western world as well. While most persons affected by insulin resistance syndrome (IRS) are overweight and most very obese persons have insulin resistance, persons who are not over-weight can become insulin resistant too. Certain ethnic groups are more prone to IRS than others because of their genes and ethnicity related life-styles. Whereas the basic predisposition appears to be strongly genetic, environmental factors notably an “unhealthy-high carbohydrate, high animal fat” diet and lack of exercise are also keys to its development. The bad news about IRS is that it may result in a number of bodily problems (lipid problems, high blood pressure, sex hormone imbalance and type-2 diabetes) that may culminate in widespread blood vessel disease (atherosclerosis). The good news is that with commitment to changes in life style and effective medications, the condition can be controlled, preventing specific long term problems such as infertility, impotence, polycystic ovaries, heart disease, liver disease, gout, stroke and peripheral vascular disease of the legs and feet. There are also strong suggestions that IRS increases the risk for certain cancers and Alzheimer’s disease too.
OK, then what is insulin resistance syndrome?
This common condition results from the body being unable to respond normally to the pancreatic insulin it makes. Insulin is a hormone that is secreted into the blood stream after eating, in an amount that is generally proportional to the amount of carbohydrate consumed. Muscles, fat and liver are three of the main organs that are insulin sensitive and affected by rises in insulin levels. In muscles, insulin directs influx of glucose from the blood for energy. In the liver, insulin inhibits the breakdown and export of fats, the main energy fuel for muscles in between meals. In adipose tissues, insulin inhibits breakdown of fat to high energy fatty acids. In persons with IRS, high levels of blood insulin initially build up to overcome the insulin resistance, and this in turn becomes associated with obesity and often a pigmented thickening of the skin about the neck, the arm-pits, abdominal skin folds and groin areas called acanthosis nigricans and/or an excessive formation of skin tags usually about the neck, eyes and arm pits. Inside the body however, the insulin resistance/high insulin levels may cause more serious problems.
So why do I (my child) have insulin resistance?
There are several known causes of the problem. In some persons with IRS, there is a defective signaling to the brain that they have adequate fat stores and/or have had enough to eat after a substantial meal. Recent studies have identified an increasing number of hormonal and metabolic signals involved. Overeating behavior can lead to onset of obesity from early life and IRS in turn. In others, there is a primary problem affecting sensitivity to insulin, leading to IRS. In such cases, obesity may become a complication of IRS rather than the cause. Specifically, some rare families have inherited defects in the insulin receptors on the surface of the insulin responsive cells in the body. Others can develop an antibody that attacks the insulin receptors and blocks them from responding normally to the insulin that the body produces. The latter persons commonly develop other immunological diseases such as systemic lupus erythematosis (SLE). Other unusual persons with IRS lack fat cells in their bodies. This condition is called lipodystrophy and results in a muscular like appearance since there is a lack of fat covering the muscles. Others may have genetic disorders whereby hormonal signaling from body fat stores (leptin) is unable to suppress appetite. Such a defect can lie in the fat cells or in the receptors of the brain that receive suppressed appetite or “satiety” signals. Rarely, there is an inability to make the neurotransmitter substances that suppress appetite or receive such signals within the appetite center of the brain-the hypothalamus. One of the more common types of these disorders involves a receptor named melanocortin receptor-4 (MCR-4) which BioSeek screens for when obesity begins at an early age and appears to have a strong familial occurrence. A rare form results from the lack of proopiomelanocorticotrophin or POMC which results in unusall pigmented or red hair along with early severe obesity and adrenal gland insufficiency. Others persons have defects inside the insulin responsive cells of the body that impair the insulin signal from doing its job. In all probability, there are many more genetic disorders that need to be discovered than these which can lead to IRS, however once IRS has developed, it needs to be managed.
However when all of the above causes if IRS are considered together, they account for just a few percent of the IRS problems that presents to clinics like BioSeek. For most persons affected by IRS, it seems likely that the condition is strongly inherited, affecting as many as half the family members in every generation. This is called a dominant mode of inheritance, where as many as half the children of an affected parent may have the disease too. However, despite huge research efforts, the responsible genes remain largely unknown. Whereas you or your child is likely to have such a gene defect too, the mere inheritance of the gene is often insufficient by itself to cause IRS. There are predisposing environmental factors at work too. These important factors are lack of physical exercise and eating more calories than necessary for your body’s energy needs, especially in the form of carbohydrates and animal fats. Persons with IRS are unusually prone to lay down fat stores from foods that they eat, especially from simple carbohydrates. Patients are often “carbohydrate addicted”, but eat much lower amounts of calories when simple carbohydrates are restricted but proteins and fats are not. In one study in adults, fat only restriction did not lead to less calorie consumption while a low carbohydrate diet lead to a reduction of 1000 calories daily and weight loss. This is the Clinic’s experience exactly. Poor physical activity and over-eating leads to obesity, which worsens insulin resistance (especially just before the time of puberty or during the pubertal years) hastening the development of the full blown IRS.
Some racial groups are unusually prone to IRS, and in them such problems as type-2 diabetes mellitus (T2DM) and high blood pressure (hypertension) have become epidemic. Western (American) Indians are such a group, with some tribes having the highest incidence of T2DM in the world. Other very IRS prone racial groups are persons from the Indian subcontinent (Asian Indians), of African descents, from the Caribbean where genes from both of the latter racial groups are prevalent, from Arabia, from China and from Polynesia. Hispanic populations prevalent in the New York area are unusually prone to IRS also. The reasons for this appear to lie in the ability of the insulin resistance genes to create a survival advantage in times of want and starvation (“metabolically thifty genes”), but which lead to obesity in times of plenty. Thus, in some racial groups who have been repeatedly exposed to starvation over generations, such genes have accumulated in frequency over long periods of time since those with such genes would be overly present in those that did survive times of deprivation. However, in a more affluent cultural setting, where food availability is not a problem, obesity abounds in such persons. Thus nomadic peoples of Africa, North America and Arabia for example had a low incidence of T2DM in their native habitats, but develop a high incidence of obesity and diabetes once they became urbanized and take up a Western life style. The BioSeek Clinics calls this “the civilization syndrome” where economic advance is having a devastating effect of these IRS prone populations. However all racial groups are afflicted by insulin resistance in varying proportions.
What problems are caused by of the insulin resistance syndrome?
- A principal problem is obesity. Obesity as measured by the body mass index (BMI). BMI is the weight in kilograms (Kg) divided by the square of the height in meters. BMIs over 27 in adults indicate obesity.
- Children with IRS are often tall and outgrow their parents. This is due to excessive levels of bioactive insulin like growth factors (IGFs).
- Acanthosis nigricans is a troublesome hyperpigmentation, that can give an appearance like an unwashed neck, but it is only a cosmetic problem which will not wash off. It is a hallmark of underlying insulin resistance however. Similarily, some patients develop excessive numbers of skin tags.
- Dyslipidemia is disturbed lipids or fats in the blood. A fat containing molecule produced in the liver named very low density lipoprotein (VLDL) is involved, and blood levels of triglycerides are elevated (>140mgs/dl) and high density lipoprotein (HDL) or “good” cholesterol levels are low (<40mgs/dl). This profile is associated with premature atherosclerosis if left untreated. Triglyceride accumulation in the liver can lead to fatty liver disease with inflammation (steatohepatitis) and gall bladder disease. Elevations of bad cholesterol (LDL) are not raised because of IRS but some patients may coincidentally have elevated LDL because of another genetic disorder. If present the Clinic treats it vigorously since the risk of arterial disease is greatly increased.
- Hyperadrenalism: Cortisol and weak male hormones (androgens) are often secreted prematurely (premature pubarche) in childhood or excessively when red and later pale “stretch” marks or striae appear on the skin of the lower abdomen shoulders and hips. This often occurs around 8 years of age but can be earlier or later by a year or two.
- Polycystic ovarian syndrome (PCOS) is common in females with IRS. The ovaries overproduce male hormones (androgens) resulting in increased male pattern hair, acne, reduced menstrual periods and infertility. The affected ovaries can develop cystic changes that can be seen by ultra-sound examinations. The androgen binding proteins (sex hormone binding protein or SHBG) in the blood are often low, meaning that androgen hormones are free to affect the body, leading to excessive facial hair, acne, male pattern balding and suppressed or irregular menstrual periods.
- Allergies: Asthma is unusually common with IRS while eczema is increased but less often.
- Hypertension or high blood pressure can be a complicating problem, especially in persons of African descent. One problem appears to be a predisposition for salt and thus water retention by the kidneys. The Clinic will advise those so affected to restrict their salt intake.
- T2DM is a common complication as the patient ages, and results from the pancreatic insulin secreting b cells failing to keep up with the demands of excessive insulin secretion needed to overcome insulin resistance.This problem may have its’ own underlying genetics, and a major but common gene has been recently identified from researchers in Iceland.
- Atherosclerosis is the most serious complication, and can be accelerated by dyslipidemia, high blood pressure, and T2DM. In the long term, this is a principal reason why IRS must be aggressively treated to prevent such problems.
- Tendency to thromboses or clotting within a blood vessel aggravates the risks of atherosclerosis.
- Fatty liver or hepatic steatosis is a common problem that can lead to cirrhosis. Gall stones and attacks of pancreatitis (a life threatening inflammation of the pancreas) may occur also when triglyceride levels rise excessively.
- Gout appears to occur at an increased frequency in adults.
- Nephropathy appears to result in some patients and worsened by diabetes. This is tested for in the Clinic by small amounts of protein (microalbumin) leaking into the urine.
Wow, this is a lot of trouble for me or my child. What can I do about it?
The answer happily is a great deal. The remedy lies with diet, exercise and medications to control it and prevent progression of the syndrome into the above complications. Once insulin resistance has developed, you have a problem that needs to be managed for life. This requires nothing less than a permanent life style change. Let’s take these treatments one at a time.
- Exercise is the key: Exercise is needed to be taken for long enough each day to benefit you. Your muscles are the most insulin sensitive organs, and insulin resistance reduces flow of energy from glucose from the blood flowing into them. However, glucose can pass into muscle cells and be used as energy when exercising without insulin being involved. The type of exercise needed is swimming or walking for 30-40 minutes daily most days of the week. If you want to exercise in sports, jazz dancing, skiing or mountain climbing, that is fine too, but you need to do it often. Short bursts of strenuous exercise are not too helpful. The BioSeek Clinics can provide pedometers so that the number of steps taken in a week can be counted up to those prescribed by your therapist. Most adults need 20,000 steps weekly to keep in shape.
- Diet is also vital: Persons with insulin resistance put on weight more easily than others. This may not seem fair to you, but this is the hand you were dealt when you were born. The first goal is to stop gaining weight through dieting. In general, diets high in carbohydrates are most likely to put weight on you. The offending foods are refined sugars and foods made from them, quantities of fruit juice, breads, rice, potatoes, and pastas. Step one will be to examine the typical weeks’ food intake and make a plan how to reduce the carbohydrates and animal fats from it. Avoid sugar, fruit juice, rice, potato chips and fries and pizza. Get used to reading the labels on manufactured foods. You will get some surprises when you do this. Some foods and drinks are not a problem for you. Diet drinks (diet sodas, diet Snapple, Crystal Light, water), most vegetables, popcorn, fish, chicken, cheese, low fat milk and lean meats need not be restricted, albeit if you have high blood triglycerides, animal fats will have to be very restricted too. In those adults who are deemed to be at risk of heart disease, reductions in saturated fats and reduction in trans-fats need to be made, often combined with daily enteric aspirin (81mgs) since blood clotting within arteries (thromboses) are associated with IRS.
- Medications are available that can help: There are several drugs that attack the underlying insulin resistance. Metformin (Glucophage) is one of these, which reduces excessive conversion of proteins and fats into new glucose by the liver. It may improve insulin actions in fatty tissues and muscles as well. It is the leading member of the class of drugs called biguanides. Some people (about 40%) develop initial intestinal upsets initially after taking metformin. The Clinic therefore advises taking it with meals, and only once daily for some days/weeks initially and then to build up the number of doses taken in a day to the full dose. In elderly patients and those with heart or kidney disease, the drug has been reported to cause a dangerous elevation of lactic acid from the muscles, but this association is currently thought to be rare or possibly non-existent. A more recent class of drugs called the PPAR-g agonists or thioglitazones has come available to lower insulin resistance. These drugs work on muscle and fatty tissues by reducing insulin resistance induced from fatty acids released from fats cells. However in higher doses, weight gains and fluid retention are problem side effects. New drugs of this type are appearing currently. In larger doses of the PPAR agonists, patients sometimes complain of fluid retention. They do not induce weight loss either and in moderate doses tend to create weight gains. Combination therapy with metformin and one of the PPAR-gs works unusually well at lower individual doses when there are thus less side effects.
- These drugs will reduce the density of acanthosis nigricans of the skin, assist you in weight loss, reduce ovarian androgen hormones often leading to resumption of normal menstrual periods, even permitting pregnancy, and they tend to reduce elevated blood lipids. For those who remain with elevated blood triglyceride levels > 150mgs/dl after an overnight fast, another drug of the fibrate class should be taken. We recommend gemfribrozil (Lopid) or fenofibrate (tricor) in divided doses.
- Oral contraceptive pills (OCPs) may help those afflicted by PCOS: In insulin resistance syndrome, the ovaries can over-secrete male hormones. Hormones like these are carried in the blood bound to certain proteins. One is sex hormone binding protein (SHBP). In IRS, the SHBP levels are very often low, leaving more hormones like testosterone is an unbound or “active” state. These two problems can result in missed menstrual periods, in unwanted facial or body hair, in loss of scalp hair in a male like pattern and in acne problems. OCPs can raise the levels of SHBP and improve these clinical problems. However they increase the risk of thromboses or clotting within blood vessels too.
- We usually prescribe insulin sensitizers like metformin first, but if problems with missed periods and unwanted hair persist, may prescribe a low dose estrogen OCP in addition.
- The drugs of choice for high blood pressure or hypertension are the angiotenin converting enzyme (ACE) inhibitors and angiotensin blockers (ARBs). ACE inhibitors can rarely lead to angio-neurotic edema often presenting as swellings about the face and neck. They can also lead to a dose dependent chronic dry cough especially in the older patients. The ACE inhibitor enalopril (Vasotec) is generally used by the Clinic. In cases when enalopril produces coughing side effects, an ARB like Cozaar may be prescribed. In very high degrees of hypertension, the two drugs may both be prescribed together, often with a thiazide diuretic (hydrochlorthiazie or HCTZ), since persons with IRS are poor at excreting excess salt into their urine.
Medications that provoke obesity if not IRS: Since many patients with IRS are affected by asthma, their IRS can be dramatically worsened by steroids such as prednisone. Further, increasing numbers of our population are taking “second generation anti-psychotic medications and most of them can provoke weight gains, IRS and type-2 diabetes in susceptible persons. The list includes clozaine (Cloraril), respiradone (Resperdal), olanzapine (Zyprexa), quennapine (Seroquel), ziprasidone (Geodon) and aripiprazole (Ability).
New medications for obesity:
A drug that suppresses appetite and the urge to smoke has recently been developed. In Europe the agent is named Rimonobant while it is to be named Acomplia when released in the US. It is not a stimulant and appears safe, albeit nausea may follow its initial use. For obese diabetics who cannot lose weight with diet, exercise and metformin, a new agent has been approved in late 2005 named exenatide (Byetta). The agent stimulates insulin secretion and lowers blood glucose levels. As an important bonus, weight loss is usual which improves diabetes control further.
Obesity Surgery:
Obesity surgery (bariatric surgery) is increasingly performed. According to the National Institutes of Health standards of 1991, obese patients are eligible if they have a BMI over 40, or have a BMI over 35 plus an IRS related disorder such as diabetes or hypertension. Two kinds of surgery are done. The least invasive is Laproscopic Adjustable Gastric Banding (Lap-Band) approved by the FDA in Feb 2001 which makes a pouch of the stomach such that the patient soon becomes “full” after eating. Weight losses of 55-60% of the excessive weight are common over a period of 2-3 years. Gastric bi-pass which involves reducing the stomach size and rerouting to a new pouch and bypassing some intestine in the process has long been in use, but is more invasive and more prone to complications. Patients often lose 70-80% of their excess weight within 1 year after the procedure, while diabetes may dramatically improve. The Clinic currently refers patients for such surgery if they consider it appropriate to NYH and Lenox Hill.
What research is being done on insulin resistance syndrome?
As you might imagine, this topic is being actively studied because of its’ great importance to the health of our society. Several pharmaceutical companies are producing drugs that suppress appetite, and some will become available in the US soon. Some studies being pursued by BioSeek clinics and colleagues at Weill-Cornell College of Medicine include genetic studies, the development of new diagnostic methods and therapeutic trials. We are able to follow entire families who may have multiple members at different stages of their disease in the BioSeek clinics. It is these families that give the most chance of identification of the responsible genes. If you have such family members, we would welcome your help. We have found that perturbations of certain hormonal binding proteins (Serine Protease Inhibitors or SERPINS) may be important to the development of IRS. One of these (Insulin Like Growth Factor Binding Protein-1 or IGFBP-1) is inversely related to the degree of insulin resistance while another (IGFBP-3) rises in proportion to the degree of insulin elevations. Education of the public is also important, especially as it affects our nation’s children. “Junk foods” still abound in our schools and need to be substituted with more acceptable foods and drinks.
We have developed a Foundation (Freedoms: Foundation for Research and Educationto Eliminate Diabetes, Obesity and the Metabolic Syndrome) to raise funds for this effort. We welcome your participation.
References:
Ten S and Maclaren N: Insulin Resistance Syndrome in Children: June Issue, Clinical Endocrinology and Metabolism, 2004.
Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes. Diabetes Care, 27, #2,596-601, 2004.
Boden et al: “Short term effects of low carbohydrate diet compared with the usual diet in obese patients with type-2 diabetes” March 15 2005 Annals of Internal Medicine