How to revert diabetes

ScienceDaily (Nov. 7, 2007) — Researchers at the University of California, San Diego (UCSD) School of Medicine have discovered that inflammation provoked by immune cells called macrophages leads to insulin resistance and Type 2 diabetes. Their discovery may pave the way to novel drug development to fight the epidemic of Type 2 diabetes associated with obesity, the most prevalent metabolic disease worldwide.

In recent years, it has been theorized that chronic, low-grade tissue inflammation related to obesity contributes to insulin resistance, the major cause of Type 2 diabetes. In research done in mouse models, the UCSD scientists proved that, by disabling the macrophage inflammatory pathway, insulin resistance and the resultant Type 2 diabetes can be prevented.

The findings of the research team, led by principle investigators Michael Karin, Ph.D., Professor of Pharmacology in UCSD's Laboratory of Gene Regulation and Signal Transduction, and Jerrold Olefsky, Distinguished Professor of Medicine and Associate Dean for Scientific Affairs, will be published as the feature article of the November 7 issue of Cell Metabolism.

"Our research shows that insulin resistance can be disassociated from the increase in body fat associated with obesity," said Olefsky.

Macrophages, found in white blood cells in the bone marrow, are key players in the immune response. When these immune cells get into tissues, such as adipose (fat) or liver tissue, they release cytokines, which are chemical messenger molecules used by immune and nerve cells to communicate. These cytokines cause the neighboring liver, muscle or fat cells to become insulin resistant, which in turn can lead to Type 2 diabetes.

The UCSD research team showed that the macrophage is the cause of this cascade of events by knocking out a key component of the inflammatory pathway in the macrophage, JNK1, in a mouse model. This was done through a procedure called adoptive bone marrow transfer, which resulted in the knockout of JNK1 in cells derived from the bone marrow, including macrophages.

With this procedure, bone marrow was transplanted from a global JNK1 knockout mouse (lacking JNK1 in all cell types) into a normal mouse that had been irradiated to kill off its endogenous bone marrow. This resulted in a chimeric mouse in which all tissues were normal except the bone marrow, which is where macrophages originate. As a control, the scientists used normal, wild-type mice as well as mice lacking JNK1 in all cell types. These control mice were also subjected to irradiation and bone marrow transfer.

The mice were all fed a high-fat diet. In regular, wild-type mice, this diet would normally result in obesity, leading to inflammation, insulin resistance and mild Type 2 diabetes. The chimeric mice, lacking JNK1 in bone marrow-derived cells, did become obese; however, they showed a striking absence of insulin resistance -- a pre-condition that can lead to development of Type 2 diabetes.

"If we can block or disarm this macrophage inflammatory pathway in humans, we could interrupt the cascade that leads to insulin resistance and diabetes," said Olefsky. "A small molecule compound to block JNK1 could prove a potent insulin-sensitizing, anti-diabetic agent."

The research also proved that obesity without inflammation does not result in insulin resistance. Olefsky explained that when an animal or a human being becomes obese, they develop steatosis, or increased fat in the liver. The steatosis leads to liver inflammation and hepatic insulin resistance.

The chimeric mice did develop fatty livers, but not inflammation. "Their livers remained normal in terms of insulin sensitivity," said Olefsky, adding that this shows that insulin resistance can also be disassociated from fatty liver.

"We aren't suggesting that obesity is healthy, but indications are promising that, by blocking the macrophage pathway, scientists may find a way to prevent the Type 2 diabetes now linked to obesity and fatty livers," Olefsky said.

                                                    Causes of inflammation

The immune system and the inflammatory response

Many experts now see inflammation as arising from an immune system response that’s out of control. When you catch a cold or sprain your ankle, your immune system switches into gear. Infection or injury trigger a chain of events called the inflammatory cascade. The familiar signs of normal inflammation — heat, pain, redness, and swelling — are the first signals that your immune system is being called into action.

In a delicate balance of give-and-take, inflammation begins when pro-inflammatory hormones in your body call out for your white blood cells to come and clear out infection and damaged tissue. These agents are matched by equally powerful, closely related anti-inflammatory compounds, which move in once the threat is neutralized to begin the healing process.

Acute inflammation that ebbs and flows as needed signifies a well-balanced immune system. But symptoms of inflammation that don’t recede are telling you that the “on” switch to your immune system is stuck. It’s poised on high alert — even when you aren’t in imminent danger. In some cases, what started as a healthy mechanism, like building scar tissue or swelling, just won’t shut off.

Chronic inflammation and its roots in the digestive system

At our medical practice we are convinced that the seeds of chronic inflammation (and a lot of other health issues) start with the gut. Two-thirds of the body’s defenses reside in the gastrointestinal (GI) tract — yet it is often the last place traditional practitioners look.

Intestinal bloating, frequent bouts of diarrhea or constipation, gas and pain, heartburn and acid reflux are early signs of an inflamed digestive tract. It’s not surprising that your immune system first clicks into hyperdrive in your digestive tract — it was designed to eliminate viruses and bacteria in your food before they infect your body. It has to glean the wheat from the chaff: taking sustenance from the food you eat and ridding your body of the rest.

And we give our digestive systems plenty of work to do. Our evolution from the hunter-gatherer diet to convenience and fast food is overwhelming our metabolism and GI tract. The deck is now stacked in inflammation’s favor. The modern diet offers us an upside-down ratio of fatty acids (omega-3, -6, and -9), too much sugar and carbs, and high levels of wheat, dairy, and other common allergens.

Foods that cause inflammation

Most polyunsaturated vegetable oils like safflower, sunflower, corn, peanut and soy, are high in linoleic acid, an omega-6 essential fatty acid that the body converts into arachidonic acid, another omega-6 fatty acid that has a predominantly pro-inflammatory influence. These same oils contain almost no omega-3’s (found in rich supply in coldwater fish, phytoplankton, and flaxseed), which soothe inflammation. Our prehistoric ancestors ate a diet with an omega-6 to omega-3 ratio of 1:1. Our current ratio is anywhere between 10:1 and 25:1!

For most people, high-carb, low-protein diets are inflammatory. We’ve seen repeatedly that low-carb diets reduce inflammation for most women. But you will need to listen to your own body and carefully observe which foods fuel inflammation for you. (You may also want to consider our tips for following an anti-inflammatory diet.)

Refined sugar and other foods with high glycemic values jack up insulin levels and put the immune system on high alert. (The glycemic index measures the immediate impact of a food on blood sugar levels; surges of blood sugar trigger the release of insulin.) Short-lived hormones inside our cells calledeicosanoids act as pro- or anti-inflammatory compounds depending on their type. Eicosanoids become imbalanced — that is, skewed toward pro-inflammatory — when insulin levels are high. As if this weren’t enough, high insulin levels activate enzymes that raise levels of arachidonic acid in our blood.

There’s also a complicated interaction between the inflammatory messengers, cytokines and prostaglandins, and insulin and glucose levels. In some cases, depending on what other stressors come into play, insulin inhibits the inflammatory agents and in other cases it fuels them. Studies are currently underway to unravel the links between obesity and type 2 diabetes and this mechanism. (To learn more, see my overview of the links between inflammatory imbalance and your weight, or read about these pathways in more depth in my book, The Core Balance Diet.)

Common allergens like casein and gluten (proteins found in dairy and wheat) are quick to spark the inflammatory cascade. Anyone suffering from celiac disease knows how inflammatory wheat can be. Foods high in trans fats create LDL’s, or “bad cholesterol,” which feeds inflammation in the arteries. Trans fats also create renegade cells called free radicals that damage healthy cells and trigger inflammation. (For more on trans fats, see our article on cholesterol and fat.)

So the first step in cooling inflammation on a cellular level is to pay attention to your diet, in particular your glycemic load (a measure of the glycemic index and portion of a food), essential fatty acid intake, and food sensitivities. As we get older, foods that never bothered us before, like dairy and wheat, may trigger chronic low-grade indigestion or other seemingly minor symptoms that put our immune system on guard — with additional inflammatory concerns to follow. Probiotics (supplements containing the “good” bacteria that support healthy digestion) have been proven to be as effective in treating symptoms of irritable bowel as
medications like Zelnorm and Lotronex.

If you think you might have a food sensitivity, we recommend going on an elimination diet for two weeks to see how you feel. You may find that avoiding certain foods restores more than just your digestive health.

But your digestive tract is only the beginning of the story. Let’s take a look at some other causes of chronic inflammation.

Inflammation and menopause

Changing levels of estrogen, progesterone, and testosterone have a role to play in age-related inflammation. We still don’t understand all the connections, but it appears that a decrease in estrogen corresponds with a rise in the cytokines interleukin-1 and interleukin-6. This changes the rate at which new bone is formed, a leading indicator of osteoporosis.

We suspect that before menopause the balance of hormones has a calming effect on inflammation, but hormones work on so many levels that it is difficult to identify the exact process. What we do know is that symptoms of chronic inflammation often become more apparent during and after menopause.

The hormonal changes leading up to menopause also contribute to weight gain. And there is clear evidence that extra fat cells, especially around the middle of the body, add to systemic inflammation by creating extra cytokines and C-reactive protein. Just one more reason to lose those extra pounds! Much of this research has helped form the basis of our Personal Program for Core Balance: Hormones.

Environmental causes of inflammation

I once walked into a giant office supply store, and within two minutes I had a numbing headache, my eyes were swimming, and my throat felt dry and tight — typical signs of an allergic response. I noticed an odor and asked the checkout clerk what it was. He didn’t know, but when I told him how I felt, he said he went home with a headache everyday — and often a bloody nose!

Synthetic fibers, latex, glues, adhesives, plastics, air fresheners, cleaning products — these are just some of the vast array of chemicals we are exposed to every day. Many of us work in hermetically sealed office buildings with re-circulated air that only increases our exposure.

Sick buildings make sick people. As do pesticides, pollution, and heavy metals. Lead and mercury are just two of the 30 heavy metals in our environment that our bodies must detoxify. And these toxins are in everything: our drinking water, our food, even our breast milk. Many of these chemicals are fat-soluble, meaning they are stored in fat and accumulate in our bodies until they reach toxic levels.

Chemical sensitivity is just the most visible end of the spectrum.

Constant exposure to noxious chemicals and airborne irritants — even if it’s a low dose — makes your immune system crazy. Some people are naturally better detoxifiers and can withstand more exposure before they have symptoms. Others need more support. Learning as much as you can about the products you use, the buildings you live in and the water you drink is crucial to preventing or fighting inflammation.
Psychological stress — cortisol and inflammation

Have you ever had a panic attack? Woken from a scary dream in a cold sweat with your heart pounding? These are vasoreactions initiated by a perceived threat that dilates your blood vessels — just like inflammation. Wider capillaries mean more blood and nutrients to your organs to better ward off an attack or deal with a situation. This “fight or flight” response is orchestrated by your HPA axis and triggers the release of the stress hormone cortisol from your adrenal glands.

Cortisol directly influences your insulin levels and metabolism. It also plays a role in chronic inflammation and your immune system. I’m sure you’ve seen this relationship in your own life: how many times have you worked endless hours only to go on vacation and get sick? Your body is good at keeping a lid on things, but it can’t do it forever. Coping with persistent stress takes a steady toll on your immune system, your adrenals, and your central nervous system.

Your body reacts to stressors universally, whether they are biological or psychological. The more acute the threat feels, the more dramatic the response will be. With inflammation, painful emotional baggage is as incendiary as physical stress. Think about asthma. An emotional shock will trigger an attack in some people as often as physical exertion or an allergen. Thoughts and internalized feelings are very powerful — and they manifest themselves physically all the time with symptoms of inflammation. Stress makes your skin break out. Your intestines go into revolt during a painful break-up. But the good news is your feelings can — and should — be enlisted as allies in the healing process.

With all the other factors contributing to inflammation, coping with stress and emotional pain is often overlooked — but it’s really important. And it can play a big part in restoring your immune system’s balance before it gets overloaded.

Why chronic inflammation is on the rise

Our bodies weren’t designed for a daily barrage of toxins, infectious agents and stress, seen and unseen. This kind of demand requires a lot of support to maintain your immune’s system resilience. Our go-go lifestyle just doesn’t make room unless we pay attention — to everything: what we breathe, eat, drink and absorb and feel. It all has a pro- or anti-inflammatory effect, and for most of us, the factors are skewed toward inflammation.

Well-documented research links depression and stress to a rise in the inflammatory markers, such as CRP, signaling an increased risk for atherosclerosis and coronary heart disease (CHD). One study showed that a depressive state increases the odds of developing CHD by 50%. (For more on CHD, please see our articles on heart disease.) And one thing is certain about society today: we appear to be more stressed and depressed than ever.

While the incidence of inflammation and inflammatory disease is rising in all developed countries, it’s important to remember that each of us has an individual response to the stressors in our life. Some of that unique response is determined by genetics. But much of it is within our control — if we understand how our choices affect our health.

You can see that countering chronic inflammation takes a combination approach because it arises from a combination of causes. The good news is that so much of it is in your control. For more information on what you can do, see our article on reducing inflammation — a natural anti-inflammatory approach.

Our Personal Program is a great place to start

The Personal Program promotes natural hormonal balance with nutritional supplements, our exclusive endocrine support formula, dietary and lifestyle guidance, and optional phone consultations with our Nurse–Educators. It is a convenient, at-home version of what we recommend to all our patients at the clinic.

1. · To learn more about the Program, go to How the Personal Program works.
2. To select the Program that's right for your symptoms, go to Choose the plan that works for you.
3. To assess your symptoms, take our on-line Hormonal Health Profile.
4. If you're ready to get started, learn about our risk-free trial.