양시영내과의원

### DM and Obesity -- pathogenic mechanism and controllable method
***dec.adiponectin(Fat burning) - inc. by astragalus 500mg Tid : Mg, other supplements, +intermmitent fasting EOD
***dec. leptin(dec. appetite) by Green Coffee Extract and/or Obesity-induced Leptin intolerance by African Mango
***inc.Grehlin(inc. appetite) - dec. by deep sleep at bedtime ave.6-8hrs
***inc.Cortisol(inc. fat production) - dec. by Holy basil 500mg qd : 4sec.nasal insp-2sec breathhold - slow mouth expiration 8sets..
***INS intolerance(inc. fat storage) - inc. sensitivity + normalize pancreas beta cell by cinnamon-Gymnema, : ACV 2 tableSpoon before high CHO food.
***resultant Fat burning by Green Tea Extract + Cayenne Tid

Scientists recently discovered that when you're overweight your body might be storing more fat than it's supposed to. And this fat build-up is not your fault at all!
Researchers reporting in the prestigious New England Journal of Medicine say it's all because of a change in metabolism that can happen to anyone. Scientists as far as Germany and Africa confirm their remarkable findings.

For the first time ever, leading doctors have discovered a safe, natural solution to the metabolic problem that's left millions of people around the world overweight and in poor health.

It's a nutritional discovery that works in a whole new way than ordinary diets, stimulant pills or supplements that you've tried.

Numerous scientific studies confirm it naturally solves the real metabolic reason for "hard to lose" pounds. And the results are remarkable. Studies show people watched fat vanish from their bellies, hips and thighs!1
Plus, they enjoyed amazing improvements in their overall health. Here are just some of the wonderful results from scientific study:
•Weight Loss of 28 pounds: in 10 weeks, confirmed during a double blind clinical study.
•Smaller Waist Size: Waistlines shrunk 6.7 inches as belly fat was burned off.
•Greater Weight Loss: A study group taking this seed extract experienced TWO TIMES MORE weight loss compared to the group taking a placebo.
•Healthy Blood Sugar: Promotes healthier glucose metabolism.
•Healthier Cholesterol: Bad cholesterol plummeted 27% and total cholesterol dropped 26% in 10 weeks.

You don't have to feel embarrassed about your body anymore. Nor struggle through another failed diet attempt or risk angerous stimulant pills. This breakthrough can help you finally get the body you've always wanted. You can grow slimmer, more energetic and more confidant than ever before. And it's just the beginning...

It's Like Nothing Else in the History of Weight-Loss Science
Unlike ordinary diet pills, which often contain dangerous stimulants and caffeine, this breakthrough gives you an additional 8 health improving benefits.
But first, to understand how this breakthrough is helping so many people get thin, you need to know the truth about why fat is so easy to gain and so hard to lose...

Your fat-storing "switch" is in the ON position-and it never turns OFF!
According to a ground-breaking study published in the New England Journal of Medicine, a change in metabolism can trick the body into storing fat.2 It's called "leptin resistance".

Leptin is a fat-balancing hormone that occurs naturally in your body.(adiponectin 과 함께 긴밀하게 협력하면서 이화작용을 수행) It's supposed to keep you fit and trim. It works by signaling when your body needs to burn fat and when you need to store fat for energy. In fact, leptin is the signal that tells you you're full after a meal!
But according to the research, people carrying an extra 20 pounds or more are no longer sensitive to leptin. As a result, their appetites soar and their bodies get stuck in fat storing mode!3 (IBW에서 20파운드 =대략 9kg이 초과되면 렙틴저항증 발현) Indeed, scientists in Germany confirmed that your fat-burning ability declines significantly as your leptin levels rise.4 But weight gain isn't the only danger of leptin resistance...High blood sugar High cholesterol Foggy thinking ---Could be too much leptin...

You might blame foggy thinking on getting older. But if you're overweight it might be leptin resistance. Research in the prestigious Journal of the American Medical Association says leptin resistance can cause foggy thinking, even memory loss.5
In fact, many health problems blamed on aging might actually be caused by leptin resistance!
In the Journal of the American College of Cardiology research confirmed that leptin resistance causes inflammation that can injure your liver, pancreas and blood vessels. Researchers found that leptin significantly increases your danger of highb blood sugar, high blood pressure, and even lifethreatening heart problems.6

Why Diets & Exercise Aren't Enough--4 Warning Signs You're Leptin Resistant
1.You have excess fat around your belly
2.Your lost weight is gained back, and then some
3.You always feel hungry
4.You crave sugary foods and carbohydrates

Leptin resistance and the metabolic changes it creates are the reasons why you can eat low-fat foods, gorge on salads, even skip meals all together and still not see your tummy flatten. And why appetite suppressants and exercise routines are never enough to keep you slim and trim.
Science clearly shows that even if you faithfully embrace a healthy lifestyle from this day forward, leptin resistance will make it harder for you to lose weight and keep it off.7

Clinical Studies confirm that the heavier you are, the more leptin you have!
Clinical studies show that if you're overweight, you have far more leptin in your bloodstream than people with normal weight.
A study at Howard Hughes Medical Institute at Rockefeller University in New York revealed that your total amount of body fat-plus the size of individual fat cells-correlates directly to the amount of leptin produced in your body.
Meanwhile, in Germany, scientists found that over time, your tissues become "immune" to leptin and your fat-burning ability declines significantly. As a result, fat builds up around your belly, hips, thighs or arms and your clothes get tighter.

Research shows Irvingia gabonensis seed increases adiponectin, the hormone that's involved in processing fat and sugar. Scientists concluded that Irvingia seed "significantly blocks" your fat cells from storing fat.11
What this means is that your body more effectively burns fat and sugar for energy instead of storing it in fat cells all over your middle or your behind.
In fact, results show Irvingia seed changes your metabolic hormones to levels that a healthy, normal weight person would have.

****Leptin Drops 48% in Clinical Study!12
The results of a clinical study show that significantly overweight people taking Irvingia seed extract watched their leptin levels fall 48% in just 10 weeks. As a result...
They lost 28 pounds, 6.7 inches vanished from their bellies, they even improved their overall health! What's more, no one suffered any dangerous side effects.

"The drop in leptin really helps get weight down in my patients."-Dr. Alwyn Wong,

Scientific Advisor and Lead Researcher behind Real African Mango Weight Loss
That's because Irvingia seed couldn't be safer. Unlike most diet pills and supplements which contain dangerous chemical stimulants like ephedra, Irvingia seed is 100% stimulant free-there's not even natural caffeine! Actually, Irvingia is a food that people in West Africa have eaten for more than a century.

@@@ An Historic Discovery in a Tropical African Jungle
This amazing seed grows inside a tropical fruit called Irvingia gabonensis or bush mango, as it's known locally. For more than a hundred years West Africans have enjoyed the sweet fruit of the bush mango tree and they've dried its seed for flavoring traditional Nigerian and Cameroonian dishes. In fact, for many tribal people living near the jungle, bush mango seeds are an important part of their daily meals.
Recently, medical researchers examined members of two of these tribes and discovered something amazing: they were uncommonly lean, with controlled blood sugar and healthy cholesterol!
"There was an unexplained resistance to weight gain and high blood sugar," says one of the researchers, Dr. Julius Oben. "And we discovered members of both tribes used Irvingia seeds as soup thickeners. They ate it 10 times a week and have been doing that their whole lives."
Impressed, Dr. Oben developed an extract of Irvingia seed for laboratory research and a clinical study in overweight people.
His results are astonishing: No other nutrient or herb has ever shown this seed's clinically documented results for reducing leptin resistance and helping people quickly lose weight.

@@Confirmed in Human Clinical Study in a Leading Medical Journal
In 2009, Dr. Oben tested Irvingia in a study of 102 people weighing an average of 212 pounds. He divided them into two groups and gave one group 300mg of Irvingia seed extract every day for 10 weeks. The other group received an identical looking placebo.
After only four weeks, the people taking Irvingia were shocked by the amazing changes they saw in the mirror. And by the end of the study the Irvingia group...
•LOST TWICE AS MUCH FAT!
In just 10 weeks, overweight people enjoyed an average fat loss of 18% compared to only 5% for the control group.
•LOST 18 TIMES MORE POUNDS!
They lost a remarkable 28 pounds on average compared to only 1.5 pounds for the control group over the 10-week test period.
•WATCHED THEIR WAISTLINES SHRINK!
In the same 10 week period they lost 6.7 inches in waist size compared with only 2 inches for the control group. That's FOUR MORE inches!
And it's only the beginning. Some of my patients have already tried Irvingia seed extract. Like the people in the study they watched their weight loss frustration turn into joy! They easily lost pounds and inches without extreme dieting or extreme exercise.

Plus, they're rejoicing in other marvelous health benefits of weight loss such as higher energy, improved mood,- even sharper thinking.

@@Clinical Dosage Now Available in North America!
There's only one brand of Irvingia seed I recommend to my patients, Real African Mango Weight Loss. I've found it works best because it's the same 300mg of Certified IrvingiaTM patented by Dr. Oben and used with overweight people in his clinical studies. Not only that, but Real African Mango Weight Loss was developed by nutrition and fitness expert, Dr. Alwyn Wong.
Dr. Wong is a sought-after lecturer throughout North America and the author of The 4 Week Fat Loss Challenge. He counts dozens of professional and Olympic athletes as patients.
"In 15 years of helping people lose weight and build muscle, I've never seen a more effective way to achieve long term weight loss than Irvingia seed extract," says Dr Wong.
"Leptin resistance is very real," explains Dr. Wong. "Research clearly indicates that it will be more difficult for you to lose weight if you're leptin-resistant. And if you're overweight, you're almost certainly suffering from some degree of leptin resistance. Real African Mango Weight Loss solves the leptin problem so losing weight happens naturally."
Besides Certified IrvingiaTM seed extract, Dr. Wong added 8 supportive antioxidants and vitamins to help people who've battled weight problems achieve vibrant good health.
In fact, many of Dr. Wong's patients tried numerous diets and exercise programs but were still frustrated by hard-to-lose pounds. That is the main driving force behind his reasearch and development of Real African Mango Weight Loss.

Now YOU Can Look Better Than Ever!
Just imagine finally watching unsightly weight disappear from your belly, hips and thighs for the first time in years...
Imagine stepping on the scale week after week and instead of disappointment feeling joy as you watch the number drop...
Imagine how wonderful it'll feel shopping for brand-new clothes to fit your shrinking waistline...
You'll love your slim new body-and all the health benefits that go with it- and so will your family and friends.
Besides providing the clinical dosage of Certified IrvingiaTM seed extract, Dr. Wong's revolutionary formula gives you extra help to digest fat, carbohydrates, protein and sugar.
Why is this important Because if you want to ensure you're burning the maximum number of calories to support healthy weight loss, then you need effective digestion.

Real African Mango Weight Loss gives you aproprietary extract of capscicum, better known as red pepper.

"Red pepper has been traditionally used for more than 100 years to improve 'feeble digestion' and support a healthy weight," says Dr. Wong. "The secret is capsaicinoids which naturally stimulate your stomach and can help suppress your appetite."

Research in Japan reveals capsaicinoids can support the secretion of digestive juices and wake up sluggish digestive tracts.18 And that's why Dr Wong formulated Real African Mango Weight Loss using a patent-pending extract that's highly concentrated in capsaicinoids, called CapsimaxTM. But that's not all...

Numerous studies confirm remarkable Irvingia seed helps your digestion, too! It contains a special fiber that delays the emptying of your stomach for more healthful digestion of nutrients. That means you won't experience a "spike" in blood sugar after you eat, or the energy "crash" that follows. And speaking of energy...

You know all too well how diets can leave you dragging and pills can make you anxious. But you never have to go through those discomforts again.

Real African Mango Weight Loss energizes your body-and without taking a single stimulant or one drop of caffeine like ordinary weight loss formulas. Instead, it helps your body make energy naturally.

A report by the National Institutes of Health confirms that being overweight puts you in great danger of suffering chronically high blood sugar. Research shows that an excess of fatty acids floating in your bloodstream makes it hard for sugar to enter your cells, so your blood sugar rises.23

High blood sugar can damage your vision, heart and kidneys. It can cause pain in your arms and legs, and even cause trouble for your teeth and gums! Experts at the Mayo Clinic warn that blood sugar actually coats your red blood cells, causing them to become "stiff." Stiff cells interfere with healthy circulation and choke off vital blood flow to your organs and limbs.24

But you no longer have to worry. Real African Mango Weight Loss gives you 300mg of Certified IrvingiaTM seed extract to help maintain healthy blood sugar-even after a sugary meal. Indeed, the research shows Irvingia seed extract gets to the root of high blood sugar and...

•Slows the rate at which sugar enters your bloodstream.
It does this by naturally blocking the digestive enzyme amylase which breaks down carbohydrates into sugars.
•Stimulates the production of more insulin sensitive cells.
Research shows these new insulin sensitive cells improve your body's response to sugar when it does enter your bloodstream.
Significantly overweight people who took 300mg of irvingia seed extract watched their blood sugar drop 22.5% during a 10-week clinical study. (The group taking a placebo only experienced a 5% improvement.)26 Even more incredible, these people made no major dietary changes. They maintained their regular habits throughout the study!

Your billions of cells contain tiny mitochondria -tiny powerplants that make energy from calories derived from nutrients in fat, carbohydrates, protein and sugar. This miraculous energy is called ATP, and it's what your body uses to function.

In fact, you could eat constantly, but if your cells can't turn calories into ATP, your body will break down and waste away. You'll literally starve to death!

Dr. Wong formulated Real African Mango Weight Loss to contain a precise combination of mitochondrial nutrients to help support each part of this important calorie burning process. For example...

It takes two steps to turn a calorie into life-sustaining ATP energy. First, your mitochondria turn calories into sugar. Then, they use enzymes to turn the sugar into ATP energy. But to do this successfully, your body needs B vitamins, thiamine and riboflavin.

These B vitamins make the enzymes that transform sugar into energy. According to research by Dr. Elizabeth Parks, associate professor of clinical nutrition at UT Southwestern Medical Center and lead author of a recent study on sugar metabolism, having enough enzymes is crucial to remaining slim and trim. Without them, sugar gets into your liver where it can be turned into fat! But there's good news...

Real African Mango Weight Loss provides you with the additional thiamine and riboflavin your cells need when you're overweight.

Real African Mango Weight Loss gives you Certified IrivingiaTM seed extract that's shown in clinical study to help people burn more fat. Plus you will get essential vitamin B-12 and niacin. Niacin is vital for the proper function of more than 50 enzymes, including many necessary to turn fats, carbohydrates and proteins into ATP energy.

Vitamin B-12 has an even more important job-it helps creates new red blood cells. Red blood cells carry energizing nutrients and oxygen to your cells. Unfortunately, they only live for four months! But your body will use the vitamin B-12 in Real African Mango Weight Loss to make new ones. Plus, this formula gives you a boost of another essential B vitamin...

Vitamin B5 or pantothenic acid is often overlooked, and that's too bad. Pantothenic comes from the Greek word meaning "everywhere," and vitamin B5 is indeed everywhere in your body.

Among its most important jobs is making the proteins and chemicals necessary for healthy processing of fats and cholesterol. You also need it to make acetylcholine, an important neurotransmitter linked to sharp, clear thinking.

If you're overweight and don't have problems with your cholesterol yet, you will eventually. The legendary Framingham Heart Study found that "carrying a spare tire" around your middle puts you in grave danger of developing high cholesterol and heart problems. Researchers confirmed that men with a waist size larger than 40 inches and women with a waist size larger than 35 inches almost always have high cholesterol.

One reason is that weight gain raises the level of fats circulating in your blood stream, so your "bad" LDL cholesterol rises and your "good" HDL cholesterol falls. Research by the National Institutes of Health on overweight people confirms this.

The research shows that a healthy diet and exercise program can bring your cholesterol back into a healthy balance. So can taking Real African Mango Weight Loss.

In 2009, researchers discovered that people with an average weight of 212 pounds improved their cholesterol profile by taking the active ingredient in Real African Mango Weight Loss. After 10-weeks of taking 300mg of Certified IrvingiaTM seed extract daily, their "bad" LDL cholesterol dropped an average of 27%.

They experienced a similar drop in total cholesterol: Total cholesterol plummeted 26% over the same time period.

Even more remarkable, these people made no changes in their regular diet or exercise program.
Real African Mango Weight Loss gives you the same 300mg dosage of Certified IrivingiaTM seed extract used in clinical research, plus 8 supportive nutrients and antioxidants. Just by taking two tablets daily, you'll not only look and feel better than you have in years, you can rest assured you're protecting your heart.

I don't have to tell you that being overweight puts a strain on your body. You can feel it in your stiff, aching joints, in your sluggish digestion and in your labored breathing. It's due not only to the extra fat you're carrying, but also to the changes the fat is causing in your body. For instance...

When you're heavy, molecules called "free radicals" are attacking every cell and organ in your body, round the clock. The damage they cause wears out your organs and results in premature aging.

But that's not all. Inflammation, too, is running rampant. It's weakening biological processes that are critical to a strong heart, clear lungs, vibrant energy and comfortable joints, to name just a few.

Numerous medical studies from around the world confirm that overweight people suffer from more free-radical damage and inflammation than people with normal weight. But now you can get the best first line of defense...

Dr. Wong formulated Real African Mango Weight Loss to give you the most powerful free-radical destroying, inflammation soothing antioxidant in nutritional science today.

•It has 55 times more antioxidant potency than red grapes...
•It has 5 times more free-radical fighting power than any fruit or vegetable tested-and researchers tested more than 5031...
•It has the highest antioxidant activity of any food reported to date32...
It's Açaí (pronounced ah-sigh-ee).

Açaí is a deep purple berry from the rain forest of South America. For centuries it was a health secret known only to the indigenous people of the rain forest. They've prized it as a main dietary staple since before 1492, when Christopher Columbus set sail for the New World! And for good reason...

Açaí is packed full of antioxidants...amino acids...essential fatty acids...fiber...minerals...even protein-all necessary for good health.

Most important, research shows that all of this nature-made goodness goes directly into cells that hunger for it...

Research published in 2006 shows açaí can enter human cells in "fully functional" form. In fact, açaí has so much antioxidant power that even at very low doses it can knock out free radicals.33 And that can make a huge difference in the way you look, feel and age, from the inside out.

Choosing the highest-quality açaí extract is critical. That's because açaí loses its nutritional power within 24 hours of extraction. But Dr. Wong formulated Real African Mango Weight Loss to contain 150mg of açaí extracted while it's still at its peak and standardized for potency.

What's more, you'll also get 150mg of an even rarer antioxidant fruit extract...

In 2006, New York Times writer David Karp wrote-"I've waited so long for this moment" as he savored the juicy, sweet flavor of what many call one of the world's most delicious fruits... the mangosteen. Not related to the more common mango, the mangosteen grows in Southeast Asia.

The delicate flesh of this rare fruit is rich in antioxidants, vitamins and minerals that help you fight free radicals that cause early signs of aging.

This superfruit also contains xanthones that natural healers across Asia have prized for centuries for maintaining people's good health and well-being

One of the biggest threats to the health of your heart is a nasty compound called "C-reactive protein," or CRP for short. CRP is linked to high levels of inflammation that can cause poor circulation. In 2008, a study published in the American Journal of Cardiology confirmed that having high levels of CRP can actually DOUBLE your chances of dying of a heart problem.34 But there's more you should know...

CRP is produced by fat cells. Research shows that when you're overweight, you're more likely to have higher CRP levels than people with normal weight.

It's another reason why you shouldn't wait another minute to try Real African Mango Weight Loss. This revolutionary formula can help protect your overall heart health. Clinical research on its active ingredient confirms...

A randomized, double-blind placebo controlled trial shows Irvingia seed extract can dramatically reduce levels of CRP in the blood of significantly overweight people.

You can keep trying the same old fad diets, supplements and exercise programs and keep getting the same old, frustrating results. Or you can join thousands of people just like you who are discovering Dr. Wong's Real African Mango Weight Loss - and the thrill of losing weight in just weeks and keeping it off for the first time!

Remember, if you're 20 pounds or more overweight, the latest studies confirm it's not your fault! When you lower your leptin levels you can finally enjoy a flatter stomach... leaner legs... a smaller behind... thinner arms... and slimmer hips in just weeks!

The results are astonishing: No other nutrient or herb has ever shown Irvingia seed extract's clinically documented results for eliminating leptin resistance.

Can't Get Thin Now You Can Finally Lose Weight and Grow Healthier at the Same Time...

"To date, there is not another compound in existence-neither pharmaceutical nor nutraceutical-that can approach the magnitude and range of the broad spectrum results observed during the 10-week clinical trial of Irvingia"
Dr. Chris Lydon, Author Understanding the Risks of Leptin Resistance, Life Extension Magazine

Real African Mango Weight Loss is radically different from ordinary weight loss supplements or diet pills. Some contain fiber that increases peristalsis, the muscular action of moving food through your digestive tract. Some contain herbs that boost thermogenesis, the process your body uses to create energy from calories.

But those products have a dark side. Many are high in stimulants such as ephedra that are dangerous for your heart. "Natural" weight loss formulas are loaded with caffeine that burn out your adrenal glands and leave you feeling exhausted. Even some kinds of fiber can cause problems for your digestion and elimination.

Real African Mango Weight Loss works differently. It contains the revolutionary discovery, Irvingia seed, in a patented certified extract which promotes weight loss and good health. It's shown in clinical study to succeed where other weight loss pills fail by beneficially effecting the way your body processes nutrients and stores fat. It does this in three critical ways:

Lowers blood leptin levels
Studies confirm leptin is the hidden cause of weight gain, lower levels result in weight loss and better overall health.
Increases blood "adiponectin"(지방세포에서 분비, 혈장농도는 체지방율과 역관계임, 당뇨병 및 대사증후군 때 감소, 대사증후군의 독립인자로 작용.--증가시 인슐린감도 증강 효과 발현 -->체중 감소 유발)
This is your fat burning hormone, which also blocks the formation of fat.
Delays stomach emptying
for more gradual absorption of dietary sugar resulting in balanced blood sugar. Studies show spikes in blood sugar cause your body to store more fat.
Plus, Real African Mango Weight Loss contains 8 more antioxidants and nutrients shown in studies to help overweight people enjoy optimum health and energy. Like so many of my patients, you may find that Real African Mango Weight Loss gives you the weight loss results you've been waiting years to experience.

Also, you may discover some wonderful added health benefits. For instance, you might take Real African Mango Weight Loss to shrink your waistline, then be amazed to learn that your blood sugar, cholesterol and energy level improve, too!

In clinical study they lost an average of 28 pounds of fat and 6.7 inches from their waistlines in 10 weeks! It's that good.

What's more, as they slimmed down they enjoyed dramatic improvements in their health, too. They enjoyed healthier blood sugar and lower cholesterol.

Now it's your turn to watch fat vanish from your belly, hips and thighs and grow healthier than you've been in years...

Recent work from Harvard researchers has tied leptin to a crucial pathway in fat metabolism in muscle. This pathway suggests a role for leptin in clearing fat out of cells.

While it is clearly established that leptin directs signaling to the brain to control eating and induce satiety, leptin also disposes of cellular fat by up-regulating thermogenesis and metabolic rate. Clinical findings show that the vast majority of overweight people have elevated levels of leptin due to "leptin resistance."

"Leptin resistance" in the overweight, or obese, is similar in nature to "insulin resistance" in diabetics, and it's extremely common. "Leptin resistance" occurs when the body fails to transport leptin past the blood-brain barrier to the hypothalamus.

In order for leptin to control body weight and metabolism, it must do so from the hypothalamic centers in the brain, through the central nervous system-mediated signaling mechanisms. When brain levels of leptin are low(as a result, provokes relatively high grehlin effect !!!) due to "leptin resistance" - even if there are high circulating blood levels of leptin - food cravings and weight gain occur because the body believes that it is hungry and goes into a state of continued fat storage.

Research shows that "leptin resistance" happens when there is an over-expression of Protein Tyrosine Phosphates 1B (PTP1 B), which down-regulates or degrades leptin signaling. Inhibiting, or blocking, PTP1 B is shown in studies to be effective for restoring normal leptin signaling from the hypothalamic centers in the brain. By reversing "leptin resistance," through the blocking of PTP1 B, the function of the protein hormone leptin is restored so that the hypothalamic center can normally and effectively modulate body weight and metabolism.

Published studies demonstrate that the botanically derived phytochemical, isolated and purified single-peak Isoquinoline Alkaloid Berberine Hel, specifically and potently inhibits human Protein Tyrosine Phosphates 1B (PTP1 B).

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Nature's most powerful and studied weight loss agent
that works directly in the brain. ...
In addition to its specific and potent inhibiting of human Protein Tyrosine Phosphates 1B (PTP1 B) - The botanically-derived phytochemical, isolated and purified single-peak Isoquinoline Alkaloid Berberine HCI, is shown to help regulate weight by a number of distinct and important mechanisms:

--Increases cyclic AMP (cAMP) levels, and ratios of cAMP to cATP, which is critical in the regulation of glycogen, sugar, and ~ lipid metabolism.
--Enhances glucose metabolism, improves glucose tolerance, and up regulates carbohydrate metabolism via multiple pathways. Displays anti-adipogenic (anti-fat) and anti-inflammatory properties via down-regulation of adipogenic (fat) enzymes and transcription factors.
--Down-regulates lipogenesis and up-regulates energy expenditure (thermogenesis) in adipose (fat) tissue.

The protein hormone leptin has been identified in published research as a principal modulator of body weight and metabolism.

Leptin acts centrally in the brain's hypothalamus to inhibit food intake and increase energy expenditure.

다이어트를 시작해 어렵게 어렵게 살을 빼도 1년도 채 안돼 체중이 고무줄처럼 다시 원래대로 돌아가는 것은 ‘배고픔 호르몬’ 때문이라는 연구결과가 나왔다.

호주 연구팀이 과체중이거나 비만인 사람 34명을 대상으로 10주 동안 저칼로리 다이어트를 하게 한 뒤 식욕과 배고픔 호르몬을 측정해 보았다. 그 결과, 다이어트 후 일부 호르몬 수치가 높아진 반면, 그 밖의 다른 호르몬들은 다이어트를 하기 전보다 낮게 측정됐다. 이와 같은 변화는 ‘잃어버린 체중을 다시 되찾으려고 하는 우리 몸의 노력’ 때문인 것으로 조사됐다.

연구팀은 실험 초기와, 10주간의 저칼로리 다이어트가 끝난 무렵, 마지막으로 다이어트가 끝나고 1년 뒤 3번에 걸쳐 혈액 검사를 실시해 실험 참가자들의 체내에 있는 9가지 호르몬의 수치를 비교했다.

그 결과, 식욕을 촉진하는 호르몬 그렐린(ghrelin)은 살을 뺀 뒤부터 계속 증가한 것으로 나타났다. 이는 연구 기간 동안에도 마찬가지 경향을 보였다. 반면, 식욕을 억제하는 호르몬인 렙틴(leptin)은감소했다.

연구를 주도한 호주 멜버른 대학의 죠세프 프로이에토(Joseph Proietto)박사는 “이와 같은 결과는 살을 뺀 뒤에도 (살이 다시 찌지 않기 위해) 경계를 소홀히 해선 안된다는 사실을 의미한다”며 “살을 뺐다고 해서 살과의 싸움은 결코 끝난 것이 아니며, 뺀 살을 유지하기 위해서는 무기한 노력해야 할 수도 있다”고 말했다.

다른 비만 전문가들은 요요현상과 호르몬에 관한 많은 연구가 있어 왔지만 그간의 연구는 단기간의 호르몬 관찰만 조사한 반면, 이번 연구는 식욕 호르몬의 변화가 1년 동안이나 계속된다는 사실을 밝혔다는 점에서 의미있는 성과라고 평가했다.

이 연구결과는 저명 학술지 ‘뉴 잉글랜드 저널 오브 메디신(New England Journal of Medicine)’ 10월 27일 온라인판에 게재됐으며, 미국 의학뉴스 사이트 헬스데이가 26일(현지시간) 보도했다.

출처: 건강을 위한 첫걸음 하이닥 (www.hidoc.co.kr)

###Berberine is Superior to Metformin

Metformin is a widely used first-line antidiabetic drug prescribed by doctors for the treatment of type 2 diabetes, particularly in the overweight and obese.---By Will Block

A new review focuses on several studies showing that the plant alkaloid berberine can lower blood glucose as effectively as the drug metformin at similar doses (500 mg, taken 3 times/day), and perhaps even better in some ways.1

Berberine is found in Coptis chinensis (goldenthread), Berberis aquifolium (Oregon grape), Berberis vulgaris (barberry), Hydrastis canadensis (goldenseal), and Berberis aristata (tree turmeric). Traditionally, it has been used for more than 2500 years in both Ayurvedic and Chinese medicine, with growing interest in its effects in metabolic and cardiovascular disease in the Western world in the last decade. Berberine has a wide range of healthful uses that include cardiovascular, anti-inflammatory, and antimicrobial (it acts against bacterial diarrhea, intestinal parasites, fungal infections, Candida albicans, yeast, and possibly methicillin-resistant Staphylococcus aureus).

@@Berberine for Diabetes Mellitus Type 2

As we have already reported (see “Take This Dye for Diabetes” in the November 2010 issue), two recent studies (also covered in the recent review) show the effectiveness of berberine compared to metformin for type 2 diabetes.2 In the first study, 36 adults with newly diagnosed type 2 diabetes were randomly assigned to treatment with berberine or metformin (500 mg 3 times/day) in a 3-month trial. The hypoglycemic effect of berberine was similar to that of metformin. Metformin is a widely used first-line antidiabetic drug prescribed by doctors for the treatment of type 2 diabetes, particularly in the overweight and obese, and those with normal kidney function. Significant changes were observed in the berberine group:

Hemoglobin A1c (glycosylated hemogblobin, an AGE*) decreased from 9.5% to 7.5% (about a 21% reduction)
Fasting blood glucose (FBG) decreased from 190.8 to 124.2 mg/dl
Postprandial blood glucose (PBG) decreased from 356.4 to 199.8 mg/dl
Plasma triglycerides from 100.5 to 79.2 mg/dl

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* Advanced glycation end-products (AGEs) result from a chain of chemical reactions after an initial glycation reaction. The intermediate products are known, variously, as Amadori, Schiff base, and Maillard products (named after the researchers who first described them). Side products generated in intermediate steps may be oxidizing agents (such as hydrogen peroxide), or not (such as beta amyloid proteins). “Glycosylation” is sometimes used for “glycation” in the literature, usually as “non-enzymatic glycosylation.”

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The researchers were surprised that the glucose-lowering effects of berberine were found to be very similar to that of metformin. In fact, it was superior in several ways.

In the second study, 48 adults with poorly controlled type 2 diabetes were supplemented with berberine in a 3-month trial:

Hemoglobin A1c decreased from 8.1% to 7.3% (about a 10% reduction)

In the first 7 days of treatment, berberine led to a reduction in FBG from 172.8 to 140.4 mg/dl and PBG from 266.4 to 210.6 mg/dl

During the second week, FBG and PBG declined further, reaching a low point that was 38 mg/dl below the baseline of 135 mg/dl for FBG and 60 mg/dl below the baseline of 189 mg/dl for PBG, and remained at these levels thereafter

Fasting plasma insulin was reduced by 28.1%

The homeostasis model assessment of insulin resistance index was reduced by 44.7%

Total cholesterol and low-density lipoprotein cholesterol were decreased significantly

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The researchers were surprised that the glucose-lowering effects of berberine were found to be very similar to that of metformin. It was superior in several ways.

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Of further interest, both fasting and postprandial proinsulin C-peptides increased significantly in patients when berberine was used together with insulin. These peptides facilitate the efficient assembly, folding, and processing of insulin in the endoplasmic reticulum, and their increase suggests that long-term berberine treatment may improve insulin secretion of the patients. During the trial, 20 patients experienced transient gastrointestinal adverse effects. Functional liver or kidney damages were not observed in any patients.

@@Berberine Decreases Cholesterol and Triglyceride

Another recent study, covered in the review, showed that berberine benefits type 2 diabetes.3 In this study, 116 patients with type 2 diabetes and dyslipidemia were randomly allocated to receive berberine (1 g daily) or placebo for 3 months. In the berberine group,

Hemoglobin A1c decreased from 7.5% to 6.6% (about a 12% reduction)
FBG decreased from 7.0 to 5.6 mm/L (126 to 100.8 mg/dl)
PBG decreased from 12.0 to 8.9 mm/L (216 to 160.2 mg/dl)
Triglycerides decreased from 2.51 to 1.61 mm/L (220 to 141 mg/dl)
Total cholesterol decreased from 5.31 to 4.35 mm/L (205 to 168 mg/dl)
LDL cholesterol decreased from 3.23 to 2.55 mm/L (124.9 to 98.6 mg/dl)

The glucose disposal rate was increased after berberine treatment, although no significant change was found between berberine and placebo groups. Mild to moderate constipation was observed in 5 participants in the berberine group. Transient gastrointestinal adverse effects with berberine were fairly common and may be related to its antimicrobial action. Berberine may be particularly useful in cases involving both type 2 diabetes, dyslipidemia, and possibly infection.

@@Berberine Offers Antiobesity Effects

Obesity is a major cause of metabolic syndrome and is due to an increase in the number and hypertrophy (volume increase) of adipocytes. But if the differentiation and proliferation of adipocytes is inhibited, then metabolic syndrome may be treated and prevented. A new study investigated the effects of 50 commonly used Kampo (the Japanese study and adaptation of Traditional Chinese medicine) preparations on the differentiation of 3T3-L1 preadipocytes to search for a drug with an antiobesity effect.4

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Long-term berberine treatment may improve insulin secretion.

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Kampo medicines were screened, and the strongest differentiation-inhibitory effect was noted with Orengedokuto (OGT). To explore the active ingredients in OGT, the effects of four crude components of OGT were investigated, and it was found that the differentiation-inhibitory effects of OGT was accounted for by Coptidis rhizome and Phellodendri cortex, both of which contain berberine, which upon examination also showed a differentiation inhibitory effect.

In fact, berberine was found to inhibit the mRNA and protein expression of PPARγ (see “Cinnamon Swoops Down to Retard Diabetes” in the May 2010 issue) as well as the CCAAT/enhancer binding protein α (C/EBPα).* Moreover, berberine inhibited lipid accumulation in adipocytes. These findings suggest that an antiobesity effect could be a new indication for OGT and that its active ingredient is berberine, with a mechanism involving the inhibition of PPARγ and C/EBPα expression. This means that berberine could reduce the size of your fat cells and cut down on their number as well.

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* C/EBPα is a member of a family of transcription factors, composed of six members. They promote the expression of certain genes through interaction with their promoter. C/EBPα is required for both adipogenesis (fat cell creation) and normal adipocyte (fat cell) function.

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@@Berberine for Memory Too

We should not forget that berberine has also recently been found to enhance memory function in rats. In research done in India, berberine is reported to inhibit cholinesterase (ChE) activity and increase glucagon-like peptide (GLP-1) release.5 ChE is the enzyme that breaks down the memory molecule acetylcholine, a neurotransmitter that is crucial for the important memory activities of focus and concentration. GLP-1, as recent evidence suggests, plays an imperative role in diabetes, along with cognitive dysfunction, learning, and neuroprotection.

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Berberine could reduce the size of your fat cells and cut down on their number as well.

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Based on the unavailability of prior research for the influence of berberine on streptozotocin (STZ)-induced memory impairment, the researchers designed their study to investigate if there could be any benefits. The researchers used the Morris water maze model as a measure of memory. In the Morris test, rats are trained to find a submerged platform in a tank of water. Around the sides of the tank are symbols, and the goal entails (pun intended) that the rats remember the location of the platform, to save themselves from exerting energy to stay afloat by refinding the platform and emerging from the water.

Also, lipid peroxidation and glutathione levels (as parameters of oxidative stress) and ChE activity (as a marker of cholinergic function) were assessed in the cerebral cortex and hippocampus. The greater the activity of ChE, the less effective is the cholinergic system, as ChE breaks down acetylcholine. Thirty days after diabetes induction with STZ, rats showed a severe deficit in learning and memory associated with increased lipid peroxidation, decreased reduced glutathione, and elevated ChE activity.

In contrast, diabetic rats treated chronically with orally administered berberine at doses of 25, 50, or 100 mg/kg, but especially the 50 and 100 mg dose, twice daily for 30 days, and then subjected to the Morris water maze test, were all found to have improved cognitive performance, along with lowered hyperglycemia, oxidative stress, and ChE activity. Also administered was vitamin C (100 mg/kg) or metformin (500 mg/kg) or vehicle (1 ml/kg) as placebo, twice daily. Both vitamin C and metformin were comparable in effects to berberine.

@@Diabetes Implicated in Cognitive Dysfunction

Prior studies have identified that when memory impairment is induced in rats, changes consequently occur in the central nervous system that are secondary to hyperglycemia, including impaired oxidative stress, cholinergic dysfunction, and changes in GLP-1. Indeed, in a model of treatment that uses antihyperglycemics, antioxidants, and cholinergic agonists, beneficial effects have been produced.

In the second leg of the Indian study, 30 days after confirmation of diabetes, berberine was given at the same dose range given during training trials in the Morris water maze that lasted 5 days (days 31–35). Alternatively, vitamin C at 100 mg/kg or metformin at 500 mg/kg, or donepezil (an AChEI that is similar to the plant nutrient galantamine) at 3 mg/kg or placebo at 1 ml/kg were also used. The result for berberine ingestion was improved learning and memory, with lowered hyperglycemia, oxidative stress, and ChE activity. Chronic treatment (30 days) with vitamin C, or metformin, or donepezil during training trials also improved diabetes-induced memory impairment and reduced oxidative stress and/or cholinesterase activity. In a prior study with berberine, its effects were found to be very similar to metformin, and this was upheld in the current study.

@@Significant Beneficial Effect on Diabetes

Berberine has been shown to have a significant beneficial effect on type 2 diabetes, and may be as effective, or more so, than metformin. Berberine acts through several mechanisms, including mimicking insulin; improving insulin action by activating AMPK; reducing insulin resistance through protein kinase C-dependent up-regulation of insulin receptor expression; inducing glycolysis; and on incretins by promoting GLP-1 secretion and modulating its release, and by inhibiting DPP-4 (see sidebar).

@@Berberine’s Probable and Possible Mechanisms of Action

The studies encompassed by the review that is the central topic of the article “Berberine is Superior to Metformin” (of which this sidebar is a part) have found that berberine is beneficial for glucose metabolism and insulin activity through a number of distinct mechanisms:

@Mimicking insulin action1

Berberine mimics insulin action by increasing glucose uptake ability by 3T3-L1 adipocytes (fat cells) and L6 myocytes (muscle cells) in an insulin-independent manner. Furthering this mimicking process, berberine inhibits activity of protein tyrosine phosphatase 1B (an important negative regulator of insulin and leptin signaling in vivo). It also increases phosphorylation in 3T3-L1 adipocytes. In diabetic mice, berberine lowers hyperglycemia and improves impaired glucose tolerance, but does not increase insulin release and synthesis.

The results suggest that berberine represents a different class of anti-hyperglycemic agents.

AMPK (AMP-activated protein kinase) is an enzyme that plays a role in cellular energy homeostasis. Principally, the effect of AMPK activation is stimulation of hepatic fatty acid oxidation and ketogenesis,* inhibition of cholesterol synthesis, lipogenesis (the formation of fat), and triglyceride synthesis, inhibition of adipocyte lipolysis and lipogenesis, stimulation of skeletal muscle fatty acid oxidation and muscle glucose uptake, and modulation of insulin secretion by pancreatic beta-cells.6

AMPK is expressed in a number of tissues, including the liver, brain, and skeletal muscle, where it acts as a “metabolic master switch” that regulates several intracellular systems, including the cellular uptake of glucose, the beta-oxidation of fatty acids, and the biogenesis of glucose transporter 4 (GLUT4).7

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* Ketogenesis is the process by which ketone bodies are produced as a result of fatty acid breakdown. Glucose is usually used by cells for energy. But, when there’s no insulin to help it transport out of the blood and into the cells, the body has an “energy crisis” and starts to break down body fat into ketones as an alternative fuel source. This is called ketosis.

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@Reducing insulin resistance through protein kinase C (PKC)-dependent up-regulation of insulin receptor (InsR) expression8,9

Berberine induced InsR gene expression through a PKC-dependent activation of its promoter. Inhibition of PKC abolished berberine-caused InsR promoter activation and InsR mRNA transcription. In animal models, treatment of type 2 diabetes mellitus rats with berberine lowered fasting blood glucose and fasting serum insulin, increased insulin sensitivity, and elevated InsR mRNA as well as PKC activity in the liver.

Berberine has recently been reported to activate AMPK and increase its phosphorylation, which was associated with persistent elevation in AMP/ATP ratio and reduction in oxygen consumption. An increase in glycolysis was observed with a rise in lactic acid production.

The results of this suggest that berberine enhances glucose metabolism by stimulation of glycolysis, which is related to inhibition of glucose oxidation in mitochondria. Berberine-induced AMPK activation is likely a consequence of mitochondria inhibition that increases the AMP/ATP ratio.

Glucagon-like peptide (GLP)-1 is a potent glucose-dependent insulinotropic gut hormone released from intestinal L cells. GLP-1 is one of the incretins, a group of gastrointestinal hormones that cause a short-term increase in the amount of insulin released from the beta cells of the Islets of Langerhans (which also produce insulin in the pancreas) after eating (see above image). Several approved drugs act on incretins, but there are many side effects, a significant number of which are gastrointestinal. This is ironic because berberine has been used to treat gastrointestinal problems.

Berberine increased GLP-1 secretion in streptozotocin-induced diabetic rats. In vivo, 5-week treatment of berberine enhanced GLP-1 secretion induced by glucose load and promoted proglucagon mRNA expression as well as L cell proliferation in intestine. In vitro, berberine concentration-dependently stimulated GLP-1 release in NCI-H716 cells. Berberine also promoted both prohormone convertase 3 and proglucagon mRNA expression. This demonstrates that berberine showed its modulation on GLP-1 via promoting GLP-1 secretion and GLP-1 biosynthesis.

Berberine was investigated as an inhibitor of human dipeptidyl peptidase IV (DPP IV) in an attempt to explain its anti-hyperglycemic activities. The investigation included simulated docking experiments to fit berberine within the binding pocket of DPP IV. Berberine was found to readily fit within the binding pocket of DPP IV in a low energy orientation characterized with optimal electrostatic attractive interactions bridging the isoquinolinium positively charged nitrogen atom (berberine) and the negatively charged acidic residue of glutamic acid-205 (GLU205) of DPP IV.

Experimentally, berberine was found to inhibit human recombinant DPP IV in vitro with IC(50) = 13.3 microM. These findings suggest that DPP IV inhibition is, at least, one of the mechanisms that explain the anti-hyperglycemic activity of berberine. The fact that berberine was recently reported to potently inhibit the pro-diabetic target human protein tyrosine phosphatase 1B (h-PTP 1B) discloses a novel dual natural h-PTP 1B/DPP IV inhibitor.
Inhibition of hepatic gluconeogenesis14

Berberine is a compound originally identified in a Chinese herbal medicine Huanglian (Coptis chinensis French). It improves glucose metabolism in type 2 diabetic patients. The mechanisms involve in activation of adenosine monophosphate activated protein kinase (AMPK) and improvement of insulin sensitivity. However, it is not clear if berberine reduces blood glucose through other mechanism. In this study, we addressed this issue by examining liver response to berberine in diabetic rats, in which hyperglycemia was induced in Sprague-Dawley rats by high fat diet. We observed that berberine decreased fasting glucose significantly. Gluconeogenic genes, Phosphoenolpyruvate carboxykinase (PEPCK) and Glucose-6-phosphatase (G6Pase), were decreased in liver by berberine. Hepatic steatosis was also reduced by berberine and expression of fatty acid synthase (FAS) was inhibited in liver.

Activities of transcription factors including Forkhead transcription factor O1 (FoxO1), sterol regulatory element-binding protein 1c (SREBP1) and carbohydrate responsive element-binding protein (ChREBP) were decreased. Insulin signaling pathway was not altered in the liver. In cultured hepatocytes, berberine inhibited oxygen consumption and reduced intracellular adenosine triphosphate (ATP) level.

The data suggest that berberine improves fasting blood glucose by direct inhibition of gluconeogenesis in liver. This activity is not dependent on insulin action. The gluconeogenic inhibition is likely a result of mitochondria inhibition by BBR. The observation supports that berberine improves glucose metabolism through an insulin-independent pathway.

Chen C, Zhang Y, Huang C. Berberine inhibits PTP1B activity and mimics insulin action. Biochem Biophys Res Commun Jul 2 2010;397(3):543-7.
Turner N, Li JY, Gosby A, et al. Berberine and its more biologically available derivative, dihydroberberine, inhibit mitochondrial respiratory complex I: a mechanism for the action of berberine to activate AMP-activated protein kinase and improve insulin action. Diabetes May 2008;57(5):1414-8.
Lee YS, Kim WS, Kim KH, et al. Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states. Diabetes Aug 2006;55(8):2256-64.
Ma X, Egawa T, Kimura H, et al. Berberine-induced activation of 5’-adenosine monophosphate-activated protein kinase and glucose transport in rat skeletal muscles. Metabolism 2010 Nov;59(11):1619-27.
Hwang JT, Kwon DY, Yoon SH. AMP-activated protein kinase: a potential target for the diseases prevention by natural occurring polyphenols. N Biotechnol Oct 1 2009;26(1-2):17-22.
Winder WW, Hardie DG. AMP-activated protein kinase, a metabolic master switch: possible roles in type 2 diabetes. Am J Physiol Jul 1999;277(1 Pt 1):E1-10.
Viollet B, Mounier R, Leclerc J, Yazigi A, Foretz M, Andreelli F. Targeting AMP-activated protein kinase as a novel therapeutic approach for the treatment of metabolic disorders. Diabetes Metab Dec 2007;33(6):395-402.
Zhang H, Wei J, Xue R, et al. Berberine lowers blood glucose in type 2 diabetes mellitus patients through increasing insulin receptor expression. Metabolism Feb 2009;59(2):285-92.
Kong WJ, Zhang H, Song DQ, et al. Berberine reduces insulin resistance through protein kinase C-dependent up-regulation of insulin receptor expression. Metabolism Jan 2009;58(1):109-19.
Yin J, Gao Z, Liu D, Liu Z, Ye J. Berberine improves glucose metabolism through induction of glycolysis. Am J Physiol Endocrinol Metab Jan 2008;294(1):E148-56.
Lu SS, Yu YL, Zhu HJ, et al. Berberine promotes glucagon-like peptide-1(7-36) amide secretion in streptozotocin-induced diabetic rats. J Endocrinol Feb 2009;200(2):159-65.
Yu Y, Liu L, Wang X, Liu X, Xie L, Wang G. Modulation of glucagon-like peptide-1 release by berberine: in vivo and in vitro studies. Biochem Pharmacol Apr 1 2009;79(7):1000-6.
Al-masri IM, Mohammad MK, Tahaa MO. Inhibition of dipeptidyl peptidase IV (DPP IV) is one of the mechanisms explaining the hypoglycemic effect of berberine. J Enzyme Inhib Med Chem Oct 2009;24(5):1061-6
Xia X, Yan J, Shen Y, Tang K, Yin J, Zhang Y, Yang D, Liang H, Ye J, Weng J. Berberine improves glucose metabolism in diabetic rats by inhibition of hepatic gluconeogenesis. PLoS One 2011 Feb 3;6(2):e16556.

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The result for berberine was improved learning and memory, with lowered hyperglycemia, oxidative stress, and ChE activity.

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@Plus, berberine is likely to have an antiobesity effect, and to operate as a memory enhancer.

Thus, you are less likely to forget the connection that can help cut down on your weight, reduce the likelihood of metabolic syndrome, and possibly help prevent type 2 diabetes, or allow you to live more easily with it, with fewer consequences and better health. Not bad!

Steriti R. Berberine for diabetes mellitus type 2. Natural Medicine Journal 2010 October;2(10):5-6.
Yin J, Xing H, Ye J. Efficacy of berberine in patients with type 2 diabetes mellitus. Metabolism May 2008;57(5):712-7.
Zhang Y, Li X, Zou D, et al. Treatment of type 2 diabetes and dyslipidemia with the natural plant alkaloid berberine. J Clin Endocrinol Metab Jul 2008;93(7):2559-65.
Ikarashi N, Tajima M, Suzuki K, Toda T, Ito K, Ochiai W, Sugiyama K. Inhibition of Preadipocyte Differentiation and Lipid Accumulation by Orengedokuto Treatment of 3T3-L1 Cultures. Phytother Res 2011 May 9. doi: 10.1002/ptr.3493. [Epub ahead of print]
Bhutada P, Mundhada Y, Bansod K, Tawari S, Patil S, Dixit P, Umathe S, Mundhada D. Protection of cholinergic and antioxidant system contributes to the effect of berberine ameliorating memory dysfunction in rat model of streptozotocin-induced diabetes. Behav Brain Res 2011 Jun 20;220(1):30-41.