Tuesday, June 20, 2006

Let Them Debate, But You Decide: Low Carb or Low Calorie?

There is a continuous debate over whether people with type 2 diabetes benefit from low carb diets. Naturally, the friends of the drug makers say no, but the low carb diet makers say yes. If you have diabetes or are predisposed to developing this disease then you had better decide now.

But how?

This is easy. There are two things (yeah, and even a third!) you need to bear in mind.

Diabetes is not caused by carbohydrates, so don't blame it on the carbs. Diabetes is the inability to metabolize carbs (glucose) properly.
Fat intake, on the other hand, is a big part of the complex lifestyle conditions that cause type 2 diabetes.
The drug industry does not want to die and the diet designers surely want to live - they strive for economic survival, and our financial patronage is their source of life.
Now, did you hear the ADA saying they don't really disclaim the benefits of low carb diets? Yes, everyone admits that fewer carbs per meal will nean less carbohydrate to spike your blood glucose level after a meal.

Low carb cannot be long-term

Who wants to spend the rest of their lives on a low carb diet? Who can, anyway? No one. It's a temporary solution. A kind of "quick fix."

Even though proponents of the low carb diet say "many people are essentially cured of their type 2 diabetes by low carbohydrate diets," the ADA refuses to endorse the low carb option. They say that they prefer to endorse a diet that people can live with long-term.

The benefits of a high fiber high carbohydrate diet has been shown in research repeatedly. If the type of carbohydrate is right, you can eat a whole lot without suffering the adverse effects. Refined or processed foods tend to elevate blood sugar levels quickly compared to high fiber content carbs.

Problem. Problem. Problem with low carbs

There is usually some problem with low carb diets, especially for diabetics. We know that dietary and body fats are a major culprit in the development of adult onset (type 2) diabetes. This has been shown in experiments by Dr. Anderson at the University of Kentucky. Healthy young men developed diabetic symptoms within two weeks on a high fat diet, whereas a control group on high sugar diet did not show a single symptom after eleven weeks in the experiment.

Given the popularity of the Western diet today the whole world is now more at risk for developing diabetes. You've got to be strong to resist what floats on the air from a fast food kitchen nowadays, especially if you spent most of your life eating that stuff. It's tantalizing.

But diabetics who have this kind of strength have been able to come off their medication and insulin shots. It is nearly impossible to live the rest of your life on low carb food. Many of these diets have been shown to have too much fat and protein content, anyway.

Limiting your carbs means lessening your calorie intake. But your energy has got to come from somewhere. Given what we know about the effects of excess fat and excess protein metabolism, every diabetic (actually, everyone) would do better staying away from these low carb, high fat, high protein options.

It seems clear that the safest option in the long term is the most natural: a complex high carbohydrate, high fiber diet with regular (daily) exercise. It takes a lot of work, but it works.

And it works for a long, healthy, long time. Ask the Okinawans and other groups who don't know what the word "retirement" means. I'll watch the low carb debate, but I want to be around until the truth is clear - I will choose high fiber high carbohydrate foods and build muscle while the argument grows.

Copyright © 2006 by Bentley Thompson

Bentley writes about lifestyle-related conditions such as diabetes, obesity, high cholesterol, and cardiovascular diseases. He advocates the anti-diabetes diet which he describes on his website. You may visit his website and blog using the following URLs: http://www.anti-diabetes-diet-supplements.com/ and http://choosehealthtoday.blogspot.com

The Emotional Impact of Diabetes

Unless someone is diabetic, or very close to someone who is, they do not realize how life changing this disease can be. I believe one of the reasons this is, is because so many people are diagnosed with diabetes; that somewhere down the line, the seriousness of the disease, in people’s minds, have diminished.

Diabetes is a very serious and scary chronic illness. It is totally life changing for those diagnosed. Eating becomes literally a matter of life and death. And the way a person is use to eating is usually changed drastically.

The emotional stress one goes through seems to get ignored and lost in the endless information and directions of how to now live your life. This is not just merely staying alive – it’s trying to stay alive without ending up blind, on kidney dialysis, with severe nerve damage, or amputation, just to name a few.

My life was drastically affected by diabetes twelve years ago when my son, who is now 23, was just eleven years old, and diagnosed with juvenile diabetes.

He has always been hyperactive, so even when he was sick, he was active. I started to notice he was looking a little pale and losing weight, even though he ate constantly. I made him a doctor appointment for the next opening, which wasn’t until a month away. All of a sudden he started wetting the bed. The urine had a very strong odor. He also started complaining of headaches. At first I thought the complaints, was just an excuse for the eleven-year-old to stay out of school. But when they became so severe, I knew they were real. The second day his headaches were so severe, he stayed home from school. He presented no other symptoms, but he slept all day long. This was enough to definitely make me realize something was extremely wrong. I got out my diagnosis health encyclopedia books and after a few hours, I came down to two diagnosis, kidney trouble or diabetes, (this was before I became a nurse, so I was going only by his symptoms and the words on the page). It was about 6:30 at night, when I told my husband something was terribly wrong and I was taking our son to the emergency room.

When we arrived at the emergency room, my son had a hard time keeping his eyes opened. We were finally called to the back, where they started running several tests. Sure enough he was diagnosed with Type 1 Juvenile Diabetes. His blood sugar was well over 600. Normal blood sugar levels range from 90-110. The reason he was sleeping so much was because he was trying to slip into a diabetic coma. The doctor said that if I didn’t bring him in when I did, he would have went into a coma that night. They admitted him to ICU and kept a vigil on him for three days as insulin was delivered through IV. That was the day our lives changed forever; especially my eleven-year-old son’s.

It was over-whelming. Three main meals a day and three snacks a day; mandatory, with a minimum of two shots daily for the rest of his life. To say we were under stress, would be putting it mildly. My son put on a brave face, but about the fourth day after he was diagnosed, I had a heart to heart with him. The poor baby thought he had brought the diabetes on himself and was being punished for something he said. Meanwhile, my nine-year-old at home was going through her own personal hell. After speaking to her, I found out she was scared to death that he was going to die, and that she was next. This came from two children whose parents did talk to them and tried to explain everything to the best of their ability.

Our lives became rigid, at first -- as we tried to cope with the changes. My son, Eddie, could not just run off and play at his friend's house whenever he wanted, or was allowed. He had to make sure he was home to take his shots on time, to eat the regular meals and the snacks in-between. He was a hard player, he had to learn that if he didn't eat like he was supposed to, wheather he was hungry or not, he would end up getting shaky. If he did not get something in him quickly to raise his blood sugar, he may slip so low that an ambulance would have to be called to save his life, if I wasn't there with an emergency glucagon (intra-muscular sugar water) shot -- as he would get extremely lethargic and not be able to communicate, or to understand what was going on around him.

All these changes he was going through, made him feel like he was different than the other children. He was afraid to spend a night for quite some time after being diagnosed; because if his sugar went up too high at night, it could cause him to wet the bed. Something that an eleven-year-old would be horrified to do in front of his friends. We also had to make sure if he did go spend the night with a friend, that they had plenty of food. (Though, his back pack would be packed with extra food for snacks, it couldn't contain the main meals.) We also had to let the parents know he was diabetic, where they could keep an extra eye out. This would sometimes turn into a nightmare, as Eddie did not want to go around announcing he was diabetic. He also didn't like being treated differently if a mother was handing out sugared drinks or sugared snacks to the other kids.

As a mother, seeing him go through all of this, tore my heart out. When I did let him leave, I had to worry not only what every mother worries about when her children go off by themselves, but I had to worry if his sugar dropped too low, would he be able to make it home {b}in time{/b} to get something to eat? Even though he carried emergency glucose pills for low sugar, it does not work all the time. (Depending on how low his sugar is and if he is able to chew, and has enough sense to take them.) When your sugar drops extremely low, you are not aware of what you're doing. Many people have been suspected of being high on drugs, when it is their sugar causing the strange behaviour. It's a very scary thing to see, even more so do go through. I also had to worry if he would go off and drink sugar drinks and go to the store and get candy. This was not a simple concern, this could actually kill or disable him. When your sugar gets too high, you are damaging your organs -- and if you start spilling ketones, it becomes a very dangerous situation. It causes ketoacidosis which causes nausea, sometimes severe with projectile vomiting, stomach pains, confusion and drowsiness; because their body is over-worked and worn out. It's literally starving to death. They are also in danger of slipping into a diabetic coma. High sugar often does develop into Diabetic ketoacidosis -- (DKA) which is a life-threatening blood chemical (electrolyte) imbalance that develops in a person with diabetes when the cells do not get the sugar (glucose) they need for energy. As a result, the body breaks down fat instead of glucose and produces and releases substances called ketones into the bloodstream. Severe diabetic ketoacidosis can cause difficulty breathing, brain swelling (cerebral edema), coma, or death. This is also the time when diabetes is doing the most harm to all the organs -- which can lead to heart failure, kidney failure, blindness, neuropathy -- and the list goes on.

Eddie, who is now 23, has kept his sugar under good control, (not tight, sadly -- but good) where he has not had to be hospitalized too often. He mainly has to go into the hospital when he gets a bad illness, such as the flu or stomach virus. When a diabetic's body is stressed with illnesses, it causes the blood sugar to go erratic. High blood sugars read off the chart, even when they have not been able to eat -- then their blood sugar may suddenly drop to a dangerous low. It also makes it more difficult to control because they are not able to eat, or maybe even drink. For diabetics, this is not an option. They are hospitalized where they can receive I.V fluids, and keep a close check on their blood sugar readings. Which sometimes means being pricked in the fingers up to 8 times a day, for several days in a row.

Diabetes causes such a wide array of secondary illnesses. Including stunting growth in a growing child. Eddie lost a whole year of growing. When he was 13, he had the bones of an 11 1/2 yr. old. He was put on intra-muscular testoterone shots at home. Which he took a lot better than most adults would, every night for six months.

It hurts me now, as it has since the day he was diagnosed, to know that he may soon be experiencing some very bad health problems because of the diabetes. Problems start to arise mostly after being diabetic for five years. We are living on borrowed time with decent health -- as he now has had diabetes for twelve years. When he says his chest hurts him, I don't think, "Oh no, he may be getting bronchitis." I think, "Oh Lord, please let it be something as simple as bronchitis." When he tells me his feet hurt and his whole body aches -- I know it may be a sign of neuropathy. At 23 he experiences pains and aches no young adult should have to face. But I praise God for each day that goes by where he is still able to work and live life as close to a young adult as he possibly can. God has spared us from him having any serious conditions. I know that may change any day, but I can relish in each day it does not.

Then there are the emotional changes diabetes puts them through. The anger, restlessness, nervousness, inpatience -- imagine it, and it is effected. It plays roulette with their hormones, causing their emotions and temperment to go into extreme modes. Sadly, this seems to be most of the time. All this happens in all diabetics, but I am concentrating on Type 1, Juvenile Diabetes. Type 1, Juvenile on-set, varies from Type 2, adult on-set, because with type 1, your pancreas does not produce any insulin at all. With Type 2, it produces insulin, but not sufficient enough, or at a normal rate.

These emotional issues are just as important to deal with as the physical disease itself. The emotional needs must be addressed. Not only the needs of the person diagnosed, but the whole family, and if it’s a child, this includes the parents and siblings.

If you are living with diabetes, please make sure you get the emotional help you so need and deserve. It’s absolutely a necessity. You may have to live with diabetes, but make sure you have it under control, and that it does not control you. After all, it’s a matter of life and death – both physical and emotional.

Tracey Wilson is an author on http://www.Writing.Com/ which is a site for Creative Writers. Many of her writings can be found at http://www.writing.com/authors/intuey.

Diabetes and Menopause

You might be thinking what is the connection between diabetes and the menopause? Well, for ladies reaching that certain age, it can be very traumic. Menopause is not necessarily a negative experience. It is sometimes called a "change of life" as there are a lot of changes going on in a woman's body, both as menopause approaches and afterwards.

The menopause marks an important transition into the last third of a woman's life. It gives the woman and her health professionals an opportunity to review health risks, plan preventive activities, and establish monitoring strategies. This is especially important in women with diabetes because of the compounding menopausal cardiovascular risk and those associated with diabetes. The importance of the menopause is often not appreciated by women with diabetes, nor by their health professionals, and opportunities to avoid future problems may be missed.

Menopause is a natural process that women go through as the child-bearing years come to an end and the ovaries cease to release eggs every month. Menopause is usually defined as the point when periods stop. Menopause is not an event, but a slow process, often lasting up to 10 years. It starts during the age of 40s (sometime late 30s) and the average age for most women to have their last period is 51, where the female sex hormones hormones, estrogen and progesterone, begin to decline.

How menopause affects diabetes
As you approach menopause, ovaries gradually stop producing the hormone estrogen and progesterone. Both of these hormones affect insulin which is the hormone produced by the pancreas that deliver glucose which is life sustaing to every cell in the body.

Decrease levels of estrogen and progesterone can:

Increase the blood sugar. This will be mostly during perimenopause where the body may become more resistant to insulin and this causes blood sugar level to rise.

Decrease the blood sugar. This will be during the time when you reach menopause. Where the levels of estrogen and progesterone decline permanently. Where the body may regain its sensitivity to insulin, which causes blood sugar levels to fall.

The hormone fluctuations that characterize menopause may wreak havoc on the hard-earned blood glucose control. With less progesterone, there may be greater insulin sensitivity and with less estrogen insulin resistance increases, and the lack of these hormones can also cause other changes which can worsen diabetes complications. For example, lowered estrogen levels increase the risks of cardiovascular disease, which is already higher for people who have diabetes, and osteoporosis.

Many symptoms are attributed to menopause, and the most common are hot flashes, disturbed sleep, night sweats and the decreased ability to think clearly. Both menopause and diabetes produce similar symptoms. Some mistake menopausal symptoms such as hot flashes, moodiness etc as the symptoms of low blood sugar, so that they incorrectly assume these symptoms are a result of low blood sugar and start consuming unnecessary calories which in turn raises the blood sugar and in advertently cause a surge in blood sugar

Because of diabetes women experience stronger and more frequent episodes of low blood sugar especially at night. This may affect their sleep, already interrupted by menopause – associated with hot flashes and night sweats. Such sleep deprivation causes fluctuations in blood sugar.

In order to combat this women choose to take hormone replacement therapy or HRT.These hormones (estrogen and progesterone) replace the hormones that the body no longer make. But this will not be possible in the case of women if she is a diabetic as these hormones affect the blood sugar. But these doses with HRT are so low and they do not cause much effect. In that case the diabetic medicine needs to be adjusted also .If the woman is exposed to these hormones it has benefits like

Protect the heart


Protect the bones from the loss of calcium which can lead to brittle bones.


Eliminate the symptoms such as hot flashes (which are easy to confuse with hypoglycemia) helps to sleep and think more easily.

Complications of Menopause

Majority of women will experience this complication but the intensity may vary within each women

Irregular bleeding


Hot flushes


Vaginal thinning and dryness


Osteoporosis


Heart diseases

Menopause is complete when you have not menstruated for 12 months. Women with type 1 diabetes experience menopause earlier than average. Women with type 2 diabetes may go through menopause later than average if they are above a healthy weight, as estrogen levels do not decrease as rapidly in women who are overweight.

This is one of the major problems in many women as they gain weight and become less active during this time, which compounds blood glucose control difficulties. So it is vitally important to plan a nutritious, low fat diet with calcium supplements if needed and physical activity. As these measures will lower the risk of cardiovascular disease by keeping the cholesterol level low and protect the bones against the thinning of osteoporosis. Regular exercise benefits the heart and bones, help to regulate weight, contributes to a sense of overall well-being and improvement in mood. Sedentary women are far more prone to coronary heart disease, obesity, high blood pressure, diabetes, and osteoporosis. They also suffer from chronic back pain, stiffness, insomnia, and irregularity. Depression is also a problem. Therefore exercise plays an important and beneficial role as it circumvent these problems and also achieve higher HDL cholesterol levels.

The Benefits of regular exercise

• Increases circulation, and improves the regulation of body temperature.


• Improves weight control by increasing basal metabolic rate and lean body mass.


• Reduces the risk of cardiovascular disease by strengthening the circulatory system, lowering blood pressure and maintaining a healthier blood cholesterol level.


• Increases strength and range of movement.


• Elevates your mood and controls stress.


• Reduces the likelihood of osteoporosis.

Some suggestions that may reduce the discomforts of menopause:

1.Eat well balanced meals that forms the basis for managing the diabetes

2.Cutting out caffeine which may help to reduce hot flashes.

3.Consuming more legumes and soy products which decreases the discomforts associated with menopause as these foods contain phytoestrogen (plant estrogen.

4.Last but not the least being physically active may help to increase energy levels and give you a mental lift.

Therefore menopause is an important phase in women’s life where she undergoes a lot of physical changes. The body goes through changes that can affect her social life, her feelings about herself, and functioning at work. Till recently menopause was often surrounded by misconceptions and myths, but it is a natural; step in the process of aging. So one should accept menopause and age gracefully – for "As a white candle in a holy place so is fine beauty of an aged face."

Benefits of Drinking Alcohol for Diabetes Type II

Diabetes Mellitus comes in two forms, Type I and Type II. Unlike Diabetes Type I, Type II Diabetes Mellitus occurs later in life. The majority of Type II Diabetics are women. Documented in medical journals, drinking alcohol can lower the risks of complications for women who have Type II Diabetes Mellitus. A light to moderate amount of alcohol and life style enhancement has the greatest positive effect and will benefit a woman's future health.

The importance of alcohol and its dangers

The mechanism of alcohol's effects, in moderate amounts of about 2 drinks a day, can decrease the insulin resistance in women with Type II diabetes. In a normal situation, the insulin acts on the peripheral cells where the glucose or sugar is waiting to enter. The insulin binds to the cell and the glucose enters. Unfortunately, in this type of diabetes, the insulin does not bind to the cell where the insulin resistance takes place and the glucose can't go inside. This results in hyperglycemia which is most toxic to the body.

Beer and wine were shown to have greater benefit than hard liquor. On the other hand, too little or too much alcohol has been implicated as risk factors for this type of diabetes. It is dangerous to consume too much alcohol as this can lead to adverse effects such as hypoglycemia, inhibition of insulin secretion, pancreatitis, increased incidence of breast cancer, ketoacidosis, cirrhosis of the liver, and most notably, addiction.

Women who have experienced menopause are at even higher risk for Type II Diabetes. They are also at risk for cardiovascular disease. Alcohol's benefits are that it can increase the level of good cholesterol such as HDL, decrease platelet aggregation, and reduce incidence of myocardial infarction.

The French Paradox

In southwestern France they have high saturated fat diet. The French workers in this study have a 36 percent lower incidence of coronary artery disease when compared to similar U.S. workers. They have a high intake of red wine with antioxidants and they have shown lower platelet aggregation and lower atherosclerosis. As stated previously, this suggests that not only is alcohol good for Diabetes but good for the heart as well.

Lifestyle Changes

Drinking alcohol is not the only way to decrease the chances of acquiring Type II Diabetes. There are many other factors that influence the development of this disease. According to the New England Journal of Medicine researchers led by Dr. Hu, overweight and obesity is the single most important predictor of diabetes. They also say that "lack of exercise, a poor diet, current smoking, and abstinence from alcohol use were all associated with a significantly increased risk of diabetes." Obese women, who choose to exercise regularly and follow a healthy diet while abstaining from smoking, can decrease their chances of acquiring diabetes by 24 percent. It is 50 percent for overweight women.

Symptoms of Diabetes Type II

If you are concerned that you are at risk for Type II Diabetes, the following symptoms are clues that a follow up by your physician is necessary: Frequent urination, increased thirst, increased hunger, slow-healing wounds and sores, prolonged and unexplained fatigue, numbness or tingling of extremities, and gynecological fungal infections in women.

Conclusion

Type II Diabetes Mellitus is a serious illness that necessitates immediate care. There are many behavioral modifications that a woman can take to relieve some of the symptoms and overall illness of diabetes. Alcohol in moderate amounts is a first step and is important to decreasing insulin resistance and even helping the heart and cardiovascular system. Diet, exercise, and cessation of smoking are likewise important. Lifestyle changes are the first step. To begin, see your physician and start a plan of action to help yourself from a potentially debilitating disease and live a healthy and satisfying life.

Copyright 2006 Michael V. Gruber, MPH

Michael V. Gruber, MPH is a contributing author to My Nursing Degree Online, providing articles and resources for nurses looking for continuing education online. Find more information about earning your nursing degree online at: http://nursing.earnmydegree.com

Pre-Diabetes - Are You at Risk?

The latest research reports that more than 40 million Americans have "pre-diabetes". Pre-diabetes (or Impaired Glucose Tolerance) is a combination of factors that you may have right now that puts you at a heightened risk for real, irreversible Type 2 diabetes in ten years. It is usually a combination of inactivity, a fat-laden diet, obesity and genetics that is responsible. When one has pre-diabetes, the level of glucose in the blood is over the normal limit but still has not reached diabetic limits yet.

Pre-diabetes is not diabetes per se and if you are diagnosed with it, it is not a death sentence. With exercise, weight loss and a healthy diet, pre-diabetic people can and have managed to bring down their glucose levels and have escaped the threat of an insulin-dependent life.

You won't necessarily know if you have pre-diabetes because it is asymptomatic. There are no big telltale signs that point toward it but it is of crucial importance to be tested for condition as soon as possible so you can curb it right away. If nothing is done during the pre-diabetic stage, it is very likely that the blood sugar levels will go awry and needlessly boost a person's risk of heart disease and eye damage, as well as a host of other difficult and expensive consequences.

Should you be screened for pre-diabetes? If you answer yes to any of the following questions, you should talk to your doctor about getting screened: Do you have relatives that have heart disease or Type 2 diabetes? Are you overweight? Do you have high blood pressure? Are you part of a "high-risk" group (African American, Latino and Asian)? Do you have more stored fat around your belly than your hips? If you're male, you should be checked if your waistline is more than 40 inches and if you're female, if your waistline is more than 35 inches. If you've had children, did you have diabetes when you were pregnant or deliver a baby that weighed more than nine pounds?

If you think you are pre-diabetic, your doctor will recommend that you go for a fasting plasma glucose test (FPG). To prepare for the FPG, you will be asked to fast for 10 hours before a blood sample is drawn first thing in the morning before breakfast. The normal level is below 100 mg/dl. If your have an FPG level between 100 and 125 mg/dl, you are considered pre-diabetic. But if your blood glucose level is 126 mg/dl or more, you can be considered a diabetic already.

To back up the FPG result, your doctor may ask you to take an oral glucose tolerance test (OGTT) that is similar to the FPG. This time however, you will be asked to drink a glucose-rich beverage and your blood glucose level measured 2 hours after. If normal, your blood glucose would be below 140 mg/dl two hours after the drink. If pre-diabetic, the blood glucose level is between 140 to 199 mg/dl. If your figure is above 200 mg/dl or more, you are considered diabetic. You should also have your cholesterol levels checked. High levels of triglycerides in the blood and low levels of "good" HDL cholesterol do not only put you at risk for diabetes, but also heart disease and certain cancers.

Knowing you are pre-diabetic is a blow for many people, but there is no reason to give up hope yet. More studies show that pre-diabetics who are aware of their condition can do a number of things that can prevent or delay the development of diabetes. The first thing to take care of is really an intense modification in lifestyle. Starting a modest exercise routine like walking for half an hour every day can trigger weight loss. Both exercise and weight loss are proven methods that slow the development of diabetes by returning blood glucose levels to normal in some people. You need not even reach your ideal body weight to reap benefits - a 15% reduction in weight can cut your risk of having full-fledged diabetes by almost 60 percent! This little change is twice as effective as taking medication. Start educating yourself about your condition. See your doctor regularly and meet with a registered dietician and an exercise specialist. Ask your doctor about some supplements like aspirin and niacin that you may benefit from.

Friday, October 14, 2005

Insulin resistance

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Insulin resistance

In medicine, insulin resistance denotes a decompensation of glucose homeostasis where the tissues appear to be less responsive to insulin.

Contents
1 Pathophysiology
2 Investigation
2.1 Glucose tolerance testing (GTT)
2.2 Hyperinsulinemic euglycemic clamp
2.3 Alternatives
3 Causes of insulin resistance
4 Therapy
5 History
6 Sources
7 External links




Pathophysiology
In patients who use insulin, "insulin resistance" is production of antibodies against insulin that lead to lower-than-expected falls of glucose levels (glycemia) after a given dose of insulin.

Insulin resistance denotes decreased sensitivity of target cells (muscle, fat cells) to insulin. It is the metabolic cause of the very common "metabolic syndrome", which is the clustering of diabetes mellitus (type 2), hypertension, combined hyperlipidemia and central obesity in patients. It also underlies most processes behind the metabolic complications of polycystic ovarian syndrome (PCOS).

In a normal person, a small amount of insulin is produced after eating ("postprandial"), and it signals the body to absorb the sugars from the food at a steady rate. In an "insulin resistant" person the message does not get to the cells so the sugar remains in the blood for long periods of time while ever more insulin is released in an attempt to trigger the sugar-uptake. The sugar circulates in the blood for several hours and then is taken into the cells very rapidly, leading to a steep drop in blood sugar and a hypoglycaemic reaction several hours after the meal.

At a later stage, frank hyperglycemia develops as pancreatic β-cells are unable to produce adequate insulin to maintain normal blood sugar levels ("euglycemia").

Various disease states make the body tissues more resistant to the actions of insulin. Example include infection (TNFα) and acidosis. Recent research involves the relative roles of adipokines (the cytokines produced by adipose tissue) in modifying insulin resistance.

Insulin resistance and atherosclerosis often appear together. Insulin resistance in these patients can be detected not only by sophisticated tests but by some simple observations of hypertension, hyperglycaemia and dyslipidemia involving small dense low-density lipoprotein (sdLDL) particles.

These patients also have slightly decreased high-density lipoprotein (HDL) levels, impaired fibrinolysis, a hypercoagulable state and increased inflammatory cytokine levels.


Investigation

Glucose tolerance testing (GTT)
During a glucose tolerance test (GTT), which is generally used to diagnose diabetes mellitus type 2, the patient (who has been fasting) takes a fixed oral dose of glucose, and glucose levels are measured by fingerprick testing every 30 minutes of the following hours.

Interpretation depends on local guidelines, but glycemia exceeding 10 mmol/l is often considered diagnostic for diabetes.

OGTT can be normal or mildly abnormal in simple insulin resistance. Often, there are raised glucose levels in the early measurements, reflecting the loss of a postprandial (after the meal) peak in insulin production. Extension of the testing (for several more hours) will often reveal a hypoglycemic "dip", which is a result of an overshoot in insulin production after the failure of the physiologic postprandial insulin response.


Hyperinsulinemic euglycemic clamp
The gold standard for investigating and quantifying insulin resistance is the "hyperinsulinemic euglycemic clamp", so called because it measures the amount of glucose necessary to compensate for an increased insulin level without causing hypoglycemia. This was first reported by DeFronzo et al in 1979. The test is rarely performed in clinical care, but is sometimes used in medical research - for example, to assess the effects of different medications.

The procedure takes about 2 hours. Through a peripheral vein, insulin is infused at 0.06 units per kg body weight per minute. In order to compensate for the insulin infusion, glucose 20% is infused to maintain blood sugar levels between 5 and 5.5 mmol/l. The rate of glucose infusion is determined by checking the blood sugar levels every 5 minutes.

The rate of glucose infusion during the last 30 minutes of the test determines insulin sensitivity. If high levels (7.5 mg/min or higher) are required, the patient is insulin-sensitive. Very low levels (4.0 mg/min or lower) suggest that the body is resistant to insulin action. Levels between 4.1 and 7.4 mg/min are indetermined and might point at "impaired glucose tolerance", considered an early form of insulin resistance.


Alternatives
Given the complicated nature of the "clamp" technique (and the potential dangers of hypoglycemia in some patients), alternatives have been sought to simplify the measurement of insulin resistance. The first was the Homeostatic Model Agreement (HOMA), and a more recent method is the QUICKI (quantitative insulin check index). Both employ fasting insulin and glucose levels to calculate insulin resistance, and both correllate reasonably with the results of clamping studies.


Causes of insulin resistance
Obesity
Haemochromatosis
Polycystic ovarian syndrome (PCOS)
Hypercortisolism (e.g. steroid use or Cushing's disease)
Drugs (e.g. rifampicin, isoniazid, olanzapine, risperidone, progestogens, possibly alcohol)
Genes

Therapy
Both metformin and the thiazolidinediones improve insulin resistance. Exercise, weight loss, and a low glycemic index diet may help.

The Diabetes Prevention Program showed that exercise and diet were nearly twice as effective as metformin at reducing the risk of progressing to type 2 diabetes (Knowler et al 2002).


History
The concept that insulin resistance may be the underlying cause of diabetes mellitus type 2 was first advanced by Sir Harold Percival Himsworth in 1936.


Sources
DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance.d Am J Physiol; 1979;237:E214-23. PMID 382871.
Himsworth HP. Diabetes mellitus: its differentiation into insulin-sensitive and insulin-insensitive types. Lancet 1936;i:127-130.
Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393-403. PMID 11832527.
Dr. Andrew P. Selwyn. What data is available that shows insulin resistance as a risk factor of CVD? How compelling is it? CME on Diabetes
From Wikipedia, the free encyclopedia.
>>http://en.wikipedia.org/wiki/Insulin_resistance










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Insulin

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Insulin


The structure of insulin
Red: carbon; green: oxygen; blue: nitrogen; pink: sulfur. The blue/purple ribbons denote the skeleton [-N-C-C-]n in the protein's amino acid sequence H-[-NH-CHR-CO-]n-OH where R is the part protruding from the skeleton in each amino acid.Insulin (Latin insula, "island", as it is produced in the Islets of Langerhans in the pancreas) is a polypeptide hormone that regulates carbohydrate metabolism. Apart from being the primary effector in carbohydrate homeostasis, it also has a substantial effect on small vessel muscle tone, controls storage and release of fat (triglycerides) and cellular uptake of both amino acids and some electrolytes. In this last sense, it has anabolic properties. Its concentration (more or less, prsence or absence) has extremely widespread effects throughout the body.

Insulin is used medically in some forms of diabetes mellitus. Patients with Type 1 diabetes mellitus depend on exogenous insulin (injected subcutaneously) for their survival because of an absolute deficiency of the hormone; patients with Type 2 diabetes mellitus have either relatively low insulin production or insulin resistance or both, and a non-trivial fraction of Type 2 diabetics eventually require insulin administration when other medications become inadequate in controlling blood glucose levels.

Insulin has the empirical formula C254H377N65O75S6.

Insulin structure varies slightly between species. Its carbohydrate metabolism regulatory function strength in humans also varies. Pig insulin is particularly close to the human one.

Contents
1 Discovery and characterization
2 Structure and production
3 Actions on cellular and metabolic level
4 Regulatory action on blood glucose
5 Signal transduction
6 The brain and hypoglycemia
7 Diseases and syndromes caused by an insulin disturbance
8 Insulin as a medication
8.1 Principles
8.2 Modes of administration
8.3 Dosage and timing
8.4 Types
8.5 Abuse
9 See also
10 External links




Discovery and characterization
In 1869 Paul Langerhans, a medical student in Berlin, was studying the structure of the pancreas under a new microscope when he noticed some previously unidentified cells scattered in the exocrine tissue. The function of the "little heaps of cells", later known as the Islets of Langerhans, was unknown, but Edouard Laguesse later argued that they may produce a secretion that plays a regulatory role in digestion.


Insulin crystalsIn 1889, the Polish-German physician Oscar Minkowski in collaboration with Joseph von Mehring removed the pancreas from a healthy dog to demonstrate this assumed role in digestion. Several days after the dog's pancreas was removed, Minkowski's animal keeper noticed a swarm of flies feeding on the dog's urine. On testing the urine they found that there was sugar in the dog's urine, demonstrating for the first time the relationship between the pancreas and diabetes. In 1901 another major step was taken by Eugene Opie, when he clearly established the link between the Islets of Langerhans and diabetes: Diabetes mellitus.... is caused by destruction of the islets of Langerhans and occurs only when these bodies are in part or wholly destroyed. Before this demonstration the link between the pancreas and diabetes was clear, but not the specific role of the islets.

Over the next two decades several attempts were made to isolate the secretion of the islets as a potential treatment. In 1906 Georg Ludwig Zuelzer was partially successful treating dogs with pancreatic extract, but unable to continue his work. Between 1911 and 1912 E.L. Scott at the University of Chicago used aqueous pancreatic extracts and noted a slight diminution of glycosuria, but was unable to convince his director and the research was shut down. Israel Kleiner demonstrated similar effects at Rockefeller University in 1919, but his work was interrupted by World War I and he was unable to return to it. Nicolae Paulescu, a professor of physiology at the Romanian School of Medicine published similar work in 1921 that was carried out in France, and it has been argued ever since by Romanians that he is the rightful discoverer.

However the practical extraction of insulin is credited to a team at the University of Toronto. In October 1920 Frederick Banting was reading one of Minkowski's papers and concluded that it was the very digestive secretions that Minkowski had originally studied were breaking down the secretion, thereby making it impossible to extract successfully. He jotted a note to himself Ligate pancreatic ducts of the dog. Keep dogs alive till acini degenerate leaving islets. Try to isolate internal secretion of these and relieve glycosurea.

He travelled to Toronto to meet with J.J.R. Macleod, who was not entirely impressed with his idea. Nevertheless he supplied Banting with a lab at the University, and an assistant, medical student Charles Best, and ten dogs, while he left on vacation during the summer of 1921. Their method was tying a ligature (string) around the pancreatic duct, and when examined several weeks later the pancreatic digestive cells had died and been absorbed by the immune system, leaving thousands of islets. They then isolated the protein from these islets to produce what they called isletin. Banting and Best were then able to keep a pancreatectomized dog alive all summer.

Macleod saw the value of the research on his return from Europe, but demanded a re-run to prove the method actually worked. Several weeks later it was clear the second run was also a success, and he helped publish their results privately in Toronto that November. However they needed six weeks to extract the isletin, dramatically slowing testing. Banting suggested they try to use fetal calf pancreas, which had not yet developed digestive glands, and was relieved to find this method worked well. With the supply problem solved, the next major effort was to purify the protein. In December 1921 Macleod invited the brilliant biochemist, James Collip, to help with this task, and within a month he felt ready to test.

On January 11, 1922, Leonard Thompson, a fourteen year old diabetic, was given the first injection of insulin. Unfortunately the extract was so impure that he suffered a severe allergic reaction and further injections were cancelled. Over the next 12 days Collip worked day and night to improve the extract, and a second dose injected on the 23rd. This was completely successful, not only in not having obvious side-effects, but in completely eliminating the symptoms of diabetes. However, Banting and Best never worked well with Collip, apparently seeing him as something of an interloper, and Collip left soon after.

Over the spring of 1922 Best managed to improve his techniques to the point where large quantities of insulin could be extracted on demand, but the extract remained impure. However they had been approached by Eli Lilly with an offer of help shortly after their first publications in 1921, and they took Lilly up on the offer in April. In November Lilly made a major breakthrough, and were able to produce large quantities of very pure insulin. Insulin was offered for sale shortly thereafter.

For this landmark discovery, Macleod and Banting were awarded the Nobel Prize in Physiology or Medicine in 1923. Banting, apparently insulted that Best was not mentioned, shared his prize with Best, and MacLeod immediately shared his with Collip. The patent for insulin was sold to the University of Toronto for one dollar.

The exact sequence of amino acids comprising the insulin molecule, the so-called primary structure, was determined by British molecular biologist Frederick Sanger. It was the first protein the structure of which was completely determined. For this he was awarded the Nobel Prize in Chemistry in 1958. In 1967, after decades of work, Dorothy Crowfoot Hodgkin determined the spatial conformation of the molecule, by means of X-ray diffraction studies. She also was awarded a Nobel Prize.


1. Preproinsulin (Leader, B chain, C chain, A chain); proinsulin consists of BCA, without L
2. Spontaneous folding
3. A and B chains linked by sulphide bonds
4. Leader and C chain are cut off
5. Insulin molecule remains
Structure and production
Insulin is synthesized in humans and other mammals within the beta cells (B-cells) of the islets of Langerhans in the pancreas. One to three million islets of Langerhans (pancreatic islets) form the endocrine part of the pancreas, which is primarily an exocrine gland. The endocrine part accounts for only 2% of the total mass of the pancreas. Within the islets of Langerhans, beta cells constitute 60–80% of all the cells.

Insulin is synthesized from the proinsulin precursor molecule by the action of proteolytic enzymes known as prohormone convertases (PC1 and PC2). Active insulin has 51 amino acids and is one of the smallest proteins known. Beef insulin differs from human insulin in three amino acid residues, and pork insulin in one residue. Fish insulin is also close enough to human insulin to be effective in humans. In humans, insulin has a molecular weight of 5734. Insulin is structured as 2 polypeptide chains linked by 2 sulfur bridges (see figure shown above). Chain A consists of 21, and chain B of 30 amino acids. Insulin is produced as a prohormone molecule – proinsulin – that is later transformed by proteolytic action into the active hormone.

The remaining part of the proinsulin molecule is called C-peptide. This polypeptide is released into the blood in equal amounts to the insulin protein. Since exogenous insulins contain no C-peptide component, serum levels of C peptide are good indicators of endogenous insulin production. C-peptide has recently been discovered to have itself biological activity; the activity is apparently confined to an effect on the muscular layer of the arteries.


Actions on cellular and metabolic level
The actions of insulin on the global human metabolism level include:

control of cellular intake of certain substances, most prominently glucose in muscle and adipose tissue (about 2/3 of body cells)
increase of DNA replication and protein synthesis via control of amino acid uptake
modification of the activity of numerous enzymes (allosteric effect)
The actions of insulin on cells include:

increased glycogen synthesis – insulin forces storage of glucose in liver (and muscle) cells in the form of glycogen; lowered levels of insulin cause liver cells to convert glycogen to glucose and excrete it into the blood. This is the clinical action of insulin which is useful in reducing high blood glucose levels as in diabetes.
increased fatty acid synthesis – insulin forces fat cells to take in glucose which is converted to triglycerides; lack of insulin causes the reverse
increased esterification of fatty acids – forces adipose tissue to make fats (ie, triglycerides) from fatty acid esters; lack of insulin causes the reverse
decreased proteinolysis – forces reduction of protein degradation; lack of insulin increases protein degradation,
decreased lipolysis – forces reduction in conversion of fat cell lipid stores into blood fatty acids; lack of insulin causes the reverse
decreased gluconeogenesis – decreases production of glucose from various substrates in liver; lack of insulin causes glucose production from assorted substrates in the liver and elsewhere
increased amino acid uptake – forces cells to absorb circulating amino acids; lack of insulin inhibits absorption
increased potassium uptake – forces cells to absorb serum potassium; lack of insulin inhibits absorption
arterial muscle tone – forces arterial wall muscle to relax, increasing blood flow, especially in micro arteries; lack of insulin reduces flow by allowing these muscles to contract

Regulatory action on blood glucose
Despite long intervals between meals or the occasional consumption of meals with a substantial carbohydrate load (e.g., half a birthday cake or a bag of potato chips), human blood glucose levels normally remain within a narrow range. In most humans this varies from about 70 mg/dl to perhaps 110 mg/dl (3.9 to 6.1 mmol/litre) except shortly after eating when the blood glucose level rises temporarily. In a healthy adult male of 75 kg with a blood volume of 5 litre, a blood glucose level of 100 mg/dl or 5.5 mmol/l corresponds to about 5 g (1/5 ounce) of glucose in the blood and approximately 45 g (1 1/2 ounces) in the total body water (which obviously includes more than merely blood and will be usually about 60% of the total body weight in men). This homeostatic effect is the result of many factors, of which hormone regulation is the most important.

There are two groups of mutually antagonistic metabolic hormones affecting blood glucose levels:

catabolic hormones (such as glucagon, growth hormone, and catecholamines), which increase blood glucose
and one anabolic hormone (insulin), which decreases blood glucose
Mechanisms which restore satisfactory blood glucose levels after hypoglycemia must be quick and effective because of the immediate serious consequences of insufficient glucose. This is because, at least in the short term, it is far more dangerous to have too little glucose in the blood than too much. In healthy individuals these mechanisms are indeed generally efficient, and symptomatic hypoglycemia is generally only found in diabetics using insulin or other pharmacologic treatment. Such hypoglycemic episodes vary greatly between persons and from time to time, both in severity and swiftness of onset. In severe cases prompt medical assistance is essential, as damage (to brain and other tissues) and even death will result from sufficiently low blood glucose levels.


Mechanism of glucose dependent insulin releaseBeta cells in the islets of Langerhans are sensitive to variations in blood glucose levels through the following mechanism (see figure to the right):

Glucose enters the beta cells through the glucose transporter GLUT2
Glucose goes into the glycolysis and the respiratory cycle where the high-energy ATP molecule is produced by oxidation
Dependent on blood glucose levels and hence ATP levels, the ATP controlled potassium channels (K+) close and the cell membranes depolarise
On depolarisation, voltage controlled calcium channels (Ca2+) open and calcium flows into the cells
An increased calcium level causes activation of phospholipase C, which cleaves the membrane phospholipid phosphatidyl inositol 4,5-bisphosphate into inositol 1,4,5-triphosphate and diacylglycerol.
Inositol 4,5-biphosphate binds to receptor proteins in the membrane of endoplasmic reticulum. This further raises the cell concentration of calcium.
Significantly increased amount of calcium in the cells causes release of previously synthesised insulin, which has been stored in secretory vesicles
The calcium level also regulates expression of the insulin gene via the calcium responsive element binding protein (CREB).
This is the main mechanism for release of insulin and regulation of insulin synthesis. In addition some insulin synthesis and release takes place generally at food intake, not just glucose or carbohydrate intake, and the beta cells are also somewhat influenced by the autonomic nervous system.

Substances that stimulate insulin release are also acetylholin, released from vagus nerve endings (parasympathetic nervous system), cholecystokinin, released by enteroendocrine cells of intestinal mucosa and gastrointestinal inhibitory peptide (GIP). The first of these act similarly as glucose through phospholipase C, while the last one acts through the mechanism of adenylate cyclase.

Sympathetic nervous system (α2 adrenergic agonists) inhibits the release of insulin.

When the glucose level comes down to the usual physiologic value, insulin release from the beta cells slows or stops. If blood glucose levels drop lower than this, especially to dangerously low levels, release of hyperglycemic hormones (most prominently glucagon from Islet alpha cells) forces release of glucose into the blood from cellular stores. The release of insulin is strongly inhibited by the stress hormone adrenalin (epinephrine).


Signal transduction
There are special transport channels in cell membranes through which glucose from the blood can enter a cell. These channels are, indirectly, under insulin control in certain body cell types. A lack of circulating insulin will prevent glucose from entering those cells (eg, in untreated Type 1 diabetes). However, more commonly there is a decrease in the sensitivity of cells to insulin (eg, the reduced insulin sensitivity characteristic of Type 2 diabetes), resulting in decreased glucose absorption. In either case, there is 'cell starvation', weight loss, sometimes extreme. In a few cases, there is a defect in the release of insulin from the pancreas. Either way, the effect is the same: elevated blood glucose levels.

Activation of insulin receptors leads to internal cellular mechanisms which directly affect glucose uptake by regulating the number and operation of protein molecules in the cell membrane which transport glucose into the cell.

Two types of tissues are most strongly influenced by insulin as far as the stimulation of glucose uptake is concerned: muscle cells (myocytes) and fat cells (adipocytes). The former are important because of their central role in movement, breathing, circulation, etc, and the latter because they accumulate excess food energy against future needs. Together, they account for about 2/3 of all cells in a typical human body.


The brain and hypoglycemia
Though other cells can use other fuels for a while (most prominently fatty acids), neurons are dependent on glucose as a source of energy in the non-starving human. They do not require insulin to absorb glucose, unlike muscle and adipose tissue and they have very small internal stores of glycogen. Thus, a sufficiently low glucose level first and most dramatically manifests itself in impaired functioning of the central nervous system – dizzness, speech problems, even loss of consciousness, are common. This phenomenon is known as hypoglycemia or, in cases producing unconsciousness, hypoglycemic coma (formerly termed insulin shock from the most common causative agent). Because endogenous causes of insulin excess (such as an insulinoma) are extremely rare naturally, the overwhelming majority of hypoglycemia cases are caused by human action (e.g. iatrogenic, caused by medicine), and are usually accidental. There have been a few cases reported of murder, attempted murder or suicide using insulin overdoses, but most insulin shock appears to be due to mismangement of insulin (didn't eat as much as anticipated, or exercised more than expected), or a mistake (e.g. 200 units of insulin instead of 20).

Causes of hypoglycemia are:

oral hypoglycemic agents (eg, any of the sulfonylureas, or similar drugs, which increase insulin release from beta cells in response to a particular blood glucose level)
external insulin (usually injected subcutaneously)

Diseases and syndromes caused by an insulin disturbance
There are several conditions in which insulin disturbance is pathologic:

diabetes mellitus – general term referring to all states characterized by hyperglycemia
type 1 – autoimmune-mediated destruction of insulin producing beta cells in the pancreas resulting in absolute insulin deficiency
type 2 – multifactoral syndrome with combined influence of genetic susceptibility and influence of environmental factors, the best known being obesity, age, and physical inactivity, resulting in insulin resistance in cells requiring insulin for glucose absorption. This form of diabetes is strongly inherited.
other types of impaired glucose tolerance (see the diabetes article)
insulinoma or reactive hypoglycemia

Insulin as a medication

Principles
Insulin is absolutely required for all animal (including human) life. The mechanism is almost identical in nematode worms (ie, C. elegans), fish, and in mammals. In humans, insulin deprivation due to the removal or destruction of the pancreas leads to death in days or at most weeks. Insulin must be administered to patients in whom there is a lack of the hormone for this, or any other, reason. Clinically, this is called diabetes mellitus type 1.

Harvesting pancreases from human corpses is not practical on a large scale, so insulin from cows, pigs or fish pancreases is used instead. All have 'insulin activity' in humans as they are nearly identical to human insulin (2 amino acid difference for bovine insulin, 1 amino acid difference for porcine). Insulin is a protein which has been very strongly conserved across evolutionary time. Differences in suitability of beef, pork, or fish insulin preparations for particular patients have been primarily the result of preparation purity and of allergic reactions to assorted non-insulin substances remaining in those preparations. Purity has improved more or less steadily since the 1920s, but allergic reactions have continued.

Human insulin can now be manufactured, using genetic engineering molecular biology techniques, in sufficient quantity for widespread clinical use, much reducing impurity reaction problems. Eli Lilly marketed the first such synthetic insulin, Humulin, in 1982. Genentech developed the technique Lilly used. NovoNordisk has also developed a genetically engineered insulin independently. Most insulins used clinically is produced this way, for it avoids the allergic reaction problem.


Modes of administration
Unlike many medicines, insulin cannot be taken orally. It is treated in the gastrointestinal tract precisely as any other protein; that is, reduced to its amino acid components, whereupon all 'insulin activity' is lost. There are research efforts underway to develop methods of protecting insulin from the digestive tract so that it can be taken orally, but none has yet reached clinical use. Instead insulin is usually taken as subcutaneous injections by single-use syringes with needles, or by repeated-use insulin pens with needles.

There are several difficulties with the use of insulin as a clinical treatment for diabetes:

mode of administration
selecting the 'right' dose and timing
selecting an appropriate insulin preparation (typically on 'speed of onset and duration of action' grounds)
adjusting dosage and timing to fit food amounts and types
adjusting dosage and timing to fit exercise undertaken
adjusting dosage, type, and timing to fit other conditions as for instance the increased stress of illness
the dosage is non-physiologic in that a subcutaneous bolus dosage of only insulin is given instead of the pancreas releasing insulin and C-peptide gradually and directly into the portal vein
it is simply a nuisance for patients to inject themselves once or several times a day
it may be dangerous in the case of mistake (most especially 'too much' insulin)
There have been several attempts to improve upon this mode of administering insulin as many people find injection awkward and painful. One alternative is jet injection (also sometimes used for some vaccinations) which has different insulin delivery peaks and durations as compared to needle injection of the same amount and type of insulin. Some diabetics find control possible with jet injectors, but not with hypodermic injection. There are also 'insulin pumps' of various types which are 'electrical injectors' attached to a semi-permanently implanted needle (ie, a catheter). Some who cannot achieve adequate glucose control by conventional injection (or sometimes jet injection) are able to with the appropriate pump.

An insulin pump is a reasonable solution for some. However there are several major limitations - cost, the potential for hypoglycemic episodes, catheter problems, and, thus far, no approvable means of controlling insulin delivery in the field based on blood glucose levels. If too much insulin is delivered or the patient eats less than normal, there will be hypoglycemia. On the other hand, if too little insulin is delivered by the pump, there will be hyperglycemia. Both of these can lead to potentially life-threatening conditions. In addition, indwelling catheters pose the risk of infection and ulceration. However, that risk can be minimized by keeping catheter sites clean. Thus far, insulin pumps require considerable care and effort to use correctly. However, some diabetics are able to keep their glucose in reasonable control only on a pump.

Researchers have produced a watch-like device that tests for blood glucose levels through the skin and administers corrective doses of insulin through pores in the skin of the patient. Both electricity and ultrasound have been found to make the skin temporarily porous. The insulin administration aspect remains experimental at this writing. The blood glucose test aspect of such 'wrist appliances' is, at this writing, commercially available essentially as described.

Another 'improvement' would be to avoid periodic insulin administration entirely by installing a self-regulating insulin source. For instance, pancreatic, or beta cell, transplantation. Transplantation of an entire pancreas (as an individual organ) is technically difficult, and is not common. Generally, it is performed in conjunction with liver or kidney transplant surgery. However, transplantation of only pancreatic beta cells is a possibility. It has been highly experimental (for which read 'prone to failure') for many years, but some researchers in Alberta, Canada, have developed techniques which have produced a much higher success rate (about 90% in one group). Beta cell transplant may become practical, and common, in the near future. Several other non-transplant methods of automatic insulin delivery are being developed in the research labs as this is written. None is currently close to clinical approval.

Inhaled insulin is under active investigation as are several other, more exotic, techniques.


Dosage and timing
The central problem for those requiring external insulin is picking the right dose of insulin and the right timing.

Physiological regulation of blood glucose, as in the non-diabetic, would be best. Increased blood glucose levels after a meal is a stimulus for prompt release of insulin from the pancreas. The increased insulin level causes glucose absorption and storage, reducing glycogen to glucose conversion, reducing blood glucose levels, and so reducing insulin release. The result is that the blood glucose level rises somewhat after eating, and within an hour or so returns to the normal 'fasting' level. Even the best diabetic treatment with human insulin, however administered, falls short of normal glucose control in the non-diabetic.

Complicating matters is that the composition of the food eaten (see glycemic index) affects intestinal absorption rates. Glucose from some foods is absorbed more (or less) rapidly than the same amount of glucose in other foods. And, fats and proteins both cause delays in absorption of glucose from carbohydrate eaten at the same time. As well, exercise reduces the need for insulin even when all other factors remain the same.

It is in principle impossible to know for certain how much insulin (and which type) is needed to 'cover' a particular meal in order to achieve a reasonable blood glucose level within an hour or two after eating. Non-diabetics' beta cells routinely and automatically manage this by continual glucose level monitoring and adjustment of insulin release. All such decisions by a diabetic must be based on general experience and training (ie, at the direction of a physician or PA, or in some places a specialist diabetic educator) and, further, specifically based on the individual experience of the patient. It is not straightforward and should never be done by habit or routine, but with care can be done quite successfully in practice.

For example, some diabetics require more insulin after drinking skimmed milk than they do after taking an equivalent amount of fat, protein, carbohydrate, and fluid in some other form. Their particular reaction to skimmed milk is different than other diabetics', but the same amount of whole milk is likely to cause a still different reaction even in that same person. Whole milk contains considerable fat while skimmed milk has much less. It is a continual balancing act for all diabetics, especially for those taking insulin.

It is important to notice that diabetics need more insulin than the usual -not less- during physical stress like infections or surgeries.


Types
Medical preparations of insulin (from the major suppliers – Eli Lilly and Novo Nordisk -- or from any other) are never just 'insulin in water'. Clinical insulins are specially prepared mixtures of insulin plus other substances. These delay absorption of the insulin, adjust the pH of the solution to reduce reactions at the injection site, and so on. Some recent insulins are not even precisely insulin, but so called insulin analogs. The insulin molecule in an insulin analog is slightly modified so that they are

absorbed rapidly enough to mimic real beta cell insulin (Lilly's is 'lispro', Novo Nordisk's is 'aspart'), or
steadily absorbed after injection instead of having a 'peak' followed by a more or less rapid decline in insulin action (Novo Nordisk version is 'Insulin detemir' and Aventis' version is 'Insulin glargine')
all while retaining insulin action in the human body.
The management of choosing insulin type and dosage / timing should be done by an experienced medical professional working with the diabetic.

Allowing blood glucose levels to rise, though not to levels which cause acute hyperglycemic symptoms, is not a sensible choice. Several large, well designed, long term studies have conclusively shown that diabetic complications decrease markedly, linearly, and consistently as blood glucose levels approach 'normal' patterns over long periods. In short, if a diabetic closely controls blood glucose levels (ie, on average, both over days and weeks, and avoiding too high peaks after meals) the rate of diabetic complications goes down. If glucose levels are very closely controlled, that rate can even approach 'normal'. The chronic diabetic complications include cerebrovascular accidents (CVA or stroke), heart attack, blindness (from proliferative diabetic retinopathy), toehr vascular damage, nerve damage from diabetic neuropathy, or kidney failure from diabetic nephropathy. These studies have demonstrated beyond doubt that, if it is possible for a patient, so-called intensive insulinotherapy is superior to conventional insulinotherapy. However, close control of blood glucose levels (as in intensive insulinotherapy) does require care and considerable effort, for hypoglycemia is dangerous and can be fatal.

A good measure of long term diabetic control (over approximately 90 days in most people) is the serum level of glycosylated hemoglobin (HbA1c). A shorter term integrated measure (over two weeks or so) is the so-called 'fructosamine' level, which is a measure of similarly glyclosylated proteins (chiefly albumin) with a shorter half life in the blood. There is a commercial meter available which measures this level in the field.


Abuse
There are reports that some patients abuse insulin by injecting larger doses that lead to mild hypoglycemic states. This is extremely dangerous and is essentially equivalent to suffocation experimentation. Severe acute or prolonged hypoglycemia can result in brain damage or death.

On July 23, 2004, news reports claim that a former spouse of a prominent international track athlete said that, among other drugs, the ex-spouse had used insulin as a way of 'energizing' the body. The intended implication would seem to be that insulin has effects similar to those alleged for some steroids. This is not so; eighty years of insulin use has given no reason to believe it to be in any respect a performance enhancer for non diabetics. Improperly treated diabetics are, to be sure, more prone than others to exhaustion and tiredness, and in some of these cases, proper administration of insulin can relieve such symptoms. However, insulin is not, chemically or clinically, a steroid, and its use in non diabetics is dangerous and always an abuse outside of a well-equipped medical facility.

However, when properly administered, insulin can restore body metabolism to something sufficiently close to normal to allow ahtletes to return to their former performance levels. Examples include Bill Talbert, the best male tennis player in the world for an extended time, Gary Hall Jr. the Olympic champion swimmer, at least one young professional Tour golfer, etc. Performace in other fields can also be maintained. Examples include Jerry Garcia of the Grateful Dead, and David Crosby, of Crosby, Stills & Nash.


See also
anatomy and physiolology
glucagon
pancreas
islets of Langerhans
endocrinology
forms of diabetes mellitus
diabetes mellitus
diabetes mellitus type 1
diabetes mellitus type 2
treatment
Diabetic coma
intensive insulinotherapy
insulin pump
conventional insulinotherapy
From Wikipedia, the free encyclopedia.
>>http://en.wikipedia.org/wiki/Insulin








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Anti-diabetic drug

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Anti-diabetic drug

An anti-diabetic drug or oral hypoglycemic agent is used to treat diabetes mellitus. They usually work by lowering the glucose levels in the blood. There are different types of anti-diabetic drugs, and their use depends on the nature of the diabetes, age and situation of the person, as well as other factors.

Insulin is the only non-oral antidiabetic drug. It is the mainstay of treatment in type I diabetes, in which insulin production is impaired. In type II diabetes, it is used when oral medication has become ineffective.

Contents
1 Sulfonylureas
2 Meglitinides
3 Biguanides
4 Thiazolidinediones
5 Alpha glucosidase inhibitors
6 Experimental agents
7 Insulin by mouth
8 Reference




Sulfonylureas
Sulfonylureas were the first widely used oral hypoglycemic medications. They are insulin secretagogues, triggering insulin release by direct action on the KATP channel of the pancreatic beta cells. Seven types of these pills have been marketed in North America. Four, known as "first-generation" drugs, have been in use for some time, but not all remain available. Three "second-generation" drugs, are now more commonly used. They are stronger than first-generation drugs and have fewer side effects.

Sulfonylureas bind strongly to plasma proteins. Sulfonylureas are only useful in type II diabetes, as they work by stimulating endogenous release of insulin. They work best with patients over 40 years old, who have had diabetes mellitus for under ten years. They can not be used with type I diabetes, or diabetes of pregnancy. They can be safely used with biguanides and glitazones. The toxicity of these drugs on the whole is relatively low.

First-generation agents
Tolbutamide (Orinase)
Acetohexamide (Dymelor)
Tolazamide (Tolinase)
Chlorpropamide (Diabinese)
Second-generation agents
Glipizide (Glucotrol)
Glyburide (Diabeta, Micronase, Glynase)
Glimepiride (Amaryl)

Meglitinides
Meglitinides are related to sulfonylureas. The amplification of insulin release is shorter and more intense, and they are take with meals to boost the insulin response to each meal.

Repaglinide (Prandin)
Nateglinide (Starlix)

Biguanides
Biguanides reduce hepatic glucose output. Although it must be used with caution in patients with impaired liver or kidney function, metformin has become the most commonly used agent for type 2 diabetes in children and teenagers.

Metformin (Glucophage)
Phenformin (DBI): used in 1960-1980s, withdrawn due to lactic acidosis risk.

Thiazolidinediones
Thiazolidinediones, also known as "glitazones," bind to PPARγ, a type of nuclear regulatory protein involved in transcription of numerous genes regulating glucose and fat metabolism. They act as "insulin sensitizers" without increasing insulin secretion.

Rosiglitazone (Avandia)
Pioglitazone (Actos)
Troglitazone (Rezulin): used in 1990s, withdrawn due to hepatitis and liver damage risk.

Alpha glucosidase inhibitors
Alpha glucosidase inhibitors are "diabetes pills" but not technically hypoglycemic agents because they do not have a direct effect on insulin secretion or sensitivity. These agents slow the digestion of starch in the small intestine, so that glucose from the starch of a meal enters the bloodstream more slowly, and can be matched more effectively by an impaired insulin response or sensitivity. These agents are effective by themselves only in the earliest stages of impaired glucose tolerance, but can be helpful in combination with other agents in type 2 diabetes.

Miglitol (Glyset)
Acarbose (Precose)

Experimental agents
Many other potential drugs are currently in investigation by pharmaceutical companies. Some of these are simply newer members of one of the above classes, but some work by novel mechanisms. For example, at least one compound that enhances the sensitivity of glucokinase to rising glucose is in the stage of animal research.


Insulin by mouth
The basic appeal of oral hypoglycemic agents is that most people would prefer a pill to an injection. Unlike all the oral drugs described in this article, insulin is a protein. Protein hormones, like meat proteins, are digested in the stomach and gut.

However, the potential market for an oral form of insulin is enormous and many laboratories have attempted to devise ways of moving enough intact insulin from the gut to the portal vein to have a measurable effect on blood sugar. One can find several research reports over the years describing promising approaches or limited success in animals, and limited human testing, but as of 2004, no products appear to be successful enough to bring to market.[1]


Reference
Lebovitz HE. Therapy for Diabetes Mellitus and Related Disorders. 4th edition. Alexandria:American Diabetes Association, 2004.
From Wikipedia, the free encyclopedia.
>>http://en.wikipedia.org/wiki/Anti-diabetic_drug








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