Edward (Lev) Linkner, MD.

Type 2 diabetes and its precursors like impaired glucose tolerance and insulin resistance represent “a complex set of interrelated problems requiring a comprehensive treatment approach,” said Lev Linkner, MD, at a course on holistic medicine sponsored by the American Board of Holistic Medicine (ABHM).

While insulin therapy and insulin-sensitizing drugs have clearly improved the long-term prospects for individuals who already have Type 2 diabetes (T2D), they do little to prevent the disease, which endocrinologists agree begins years if not decades before “classic” symptoms emerge. Further, the cost of a lifetime of insulin and other drugs, multiplied by the millions of people now on the fast track toward T2D, carries enormous fiscal ramifications.

Dr. Linkner, a founder of the ABHM, and a member of the family medicine clinical faculty, University of Michigan, Ann Arbor, stressed these disorders beg for a broad-based holistic view including individualized nutritional, botanical, pharmacologic and psychosocial interventions. This needs to begin early—as soon as the first sign of insulin resistance (IR) appears.

Scary Numbers

According to Stephen Davis, MD, Chief of Diabetes & Endocrine Metabolism, Vanderbilt School of Medicine, Nashville, an estimated 17 million Americans have diabetes, and 90%–95% of them have T2D. Eighty percent are obese or overweight. Another 20 million have impaired glucose tolerance (fasting glucose of between 110 and 126), the first signal of insulin resistance or pre-diabetes. “People with IGT have a 10% risk of progressing to T2D every year,” said Dr. Davis, at a press conference on the diabetes epidemic sponsored by the New York Academy of Sciences.

Diabetes may not be a modern disease—history credits an Egyptian physician, Hesy-Ra, with recognizing frequent urination as a symptom of a serious problem. But there is no doubt that modern, industrialized life has stoked the incidence to near epidemic levels. There’s been a 5-fold increase in T2D in the latter half of the 20th century, and it shows no sign of relenting. “It is increasingly prevalent in children. There’s been a 10-fold increase among children and adolescents in the last decade. We saw it in a 4-year-old at our clinic last year,” said Dr. Davis.

The costs are simply staggering. Richard Beaser, MD, director of continuing medical education at the Joslin Diabetes Center, Boston, noted that 1 in every 5 health care dollars is spent on diabetes. On an annual per-capita basis, people with T2D spend an average of $13,243 as compared to only $2,560 for people without the disease. Direct health care costs reached $92 billion in 2002, with an additional $40 billion in indirect costs (lost work productivity, permanent disability, mortality costs), putting the total bill at $132 billion. The number is expected to hit $192 billion by the end of this decade.

And these numbers were computed before the recent UK Heart Protection Study, which some diabetes experts now cite as rationale to put all diabetics on cholesterol-lowering statins even if their cholesterol levels are normal.

Clearly something needs to be done—and soon.

The good news, said Dr. Linkner, is that progression of IR to T2D can be prevented if IR is detected early and physicians work together with patients to make every possible effort. Bear in mind that beta cell loss starts at least 10 years prior to emergence of symptoms. The cardiovascular, renal and ocular complications that disable and claim the lives of so many diabetics reflect processes that have been going on for many years. Data from the Bogalusa Heart Study suggest the process begins in childhood and young adulthood. Dr. Linkner noted that the first CV risk factor to emerge in young people is often IR.

Testing Insulin Sensitivity

Prevention begins with proper diagnosis, and the key features to detect are IR and IGT. Dr. Linkner strongly recommended periodic insulin sensitivity testing for patients at risk. The process is simple: after 2 days of carbohydrate loading, measure the fasting glucose and insulin levels. Then have the patient take a 75 g glucose drink, and measure the glucose and insulin levels once again after 2 hours. A fasting glucose level greater than 115 mg/dl and a fasting insulin over 15 microunits/ml are suggestive of IR. If the 2-hour post-glucose load readings are over 200 for glucose and 30 for insulin, the patient is insulin resistant.

Another simple way of identifying IR is to take the ratio of fasting glucose over fasting insulin. A ratio of 6 or below is highly suggestive of IR, said Jeffrey Bland, PhD, director of the Institute for Functional Medicine. Speaking at a course on Food as Medicine, sponsored by the Center for Mind Body Medicine, Dr. Bland said that the glucose/insulin ratio can identify nearly all IR patients. “It is a clue—not something to hang a definitive diagnosis on, but definitely part of the whole picture.”

Waist-to-hip ratio is another quickie indicator, especially in women. A waist to hip ratio of 0.8 in women is strongly suggestive of IR. For men the number is 1.0.

If a patient has IR and beginning to show symptoms suggestive of T2D, begin monitoring glycohemoglobin (HbA1c). The American Diabetes Association’s current consensus consider anything above 7% to be a significant risk factor for future complications, and all therapeutic efforts should be directed to getting the number down to 7. The American College of Endocrinology has proposed an even tighter target of 6.5%. Because the numbers are simple, HbA1c is easy for patients to understand, which helps in engaging them in their own care. Be aware, however, that a patient can have a normal HbA1c and still be insulin-resistant, reminded Dr. Linkner.

The Ravages of Insulin Resistance

Inefficient use of insulin, the hallmark of IR, puts increasing metabolic pressure on the pancreas to generate ever more of this hormone, ultimately resulting in burnout of the beta cells. But it has other, wide-ranging effects in nearly all organ systems. IR stimulates HMG-Co A reductase, resulting in increased cholesterol synthesis. It also increases triglycerides and platelet adhesiveness. IR patients tend to have decreased levels of Apolipoprotein A1 and HDL, but increased levels of Von Willebrand Factor and Platelet Activating Factor, setting them up for CV complications.

IR is also associated with elevated levels of proinflammatory cytokines, as well as increased generation of free radicals. IR patients are at increased risk for both inflammatory bowel disease and colorectal cancer. They also have increased circulating uric acid, predisposing them to gout, as well as increased incidence of calcium oxalate kidney stones.

To design an appropriate therapeutic program, it is important to understand the mechanisms of glucose metabolism and how the process is altered in IR.

Mechanisms of Insulin Resistance

GLUT-4 is the main transport molecule that brings glucose into cells, Dr. Linkner explained. “But 90% of GLUT-4 is stored in the cytoplasm. Stimuli like insulin cause it to move toward and embed in the cell membrane. Impairment of insulin-stimulated movement of GLUT-4 is the most obvious manifestations of IR.” He added that tyrosine phosphatase, an intracellular enzyme, and TNF-α, a pro-inflammatory cytokine, interfere with the insulin signal that stimulates the movement of GLUT-4 to the cell surface (see diagram).

Insulin Signaling Pathways. This diagram depicts the steps in target cell insulin signaling and glucose transport. Interventions like exercise, vanadate and PPAR-agonists affect specific aspects of the process. Courtesy of Dr. Lev Linkner.

Translation of the TNF-α gene is controlled by peroxisome proliferator-activator receptors (PPARs), which are key players in control of lipid homeostasis and insulin action. Thiazolidinedione (TZD) drugs actually work by binding to PPAR-γ, thus reducing TNF-α inhibition of the insulin signal and increasing the flow of GLUT-4 to the cell surface where it increases glucose transport. PPAR-γ agonists reduce serum glucose, insulin and triglycerides. They also reduce pro-inflammatory cytokines.

But before you reach for the prescription pad, bear in mind that a number of natural substances including conjugated linoleic acid (CLA) have measurable PPAR agonist activity. For patients with early stage IR, CLA at a dose of 1,000–3,000 mg per day, may be a better, lower-cost way to go.

Exercise, Weight Loss and Diet

Exercise and weight loss should be at the core of a holistic approach, and their power should not be underestimated. Exercise reduces IR by increasing GLUT-4 mediated transport of glucose into target tissues. According to Dr. Davis, 150 minutes of exercise per week (less than 3 hours) and small increments of weight loss could cut the progression rate of IGT to T2D by 50%–60%. A 7%–10% weight loss can dramatically improve IR, and has many additional benefits, not the least of which is improved sense of well-being.

Dr. Linkner stressed that as health interventions go, exercise is extremely inexpensive, and can be fun. It need not be strenuous or overly time-consuming. Any increase in physical activity will benefit IR patients.

There are countless dietary plans advocated for improving insulin sensitivity and reducing risk of diabetes. But Dr. Linkner said they all come down to one thing: reducing highly glycemic foods and increasing low-glycemic ones. The glycemic index refers to the refined carbohydrate content of a food. A convenient way to think about it is to take a patient’s glucose response to a 50 g serving of white bread as a reference point of “1.” Other foods can be compared with this standard. High-fiber, low-glycemic index foods like lentils, soy, and whole grains are in the range of 0.4–0.6 compared with white bread. Something like white potato starch gives a number around 1.3.

Dr. Linkner has had success in getting many of his patients to accept a Mediterranean style diet, high in fruits and vegetables, legumes, whole grains, olive oil and omega-3 fatty acids. It is particularly effective if augmented with soy foods rich in isoflavones that positively influence beta-signalling pathways and improve glucose transport. If a patient has normal kidney function, there’s nothing wrong with increasing the protein content of the diet, while lowering carbohydrates. Proteins are more slowly absorbed, and they stimulate the production of glucagon, which opposes insulin and promotes burning of stored fats and glycogen.

Low-glycemic index foods release their sugars slowly, in a timed-release manner. According to Alan Gaby, MD, who specializes in nutritional medicine and was formerly professor of nutrition, Bastyr University, beans are a diabetic or IR patient’s best friend. They are very low-glycemic, high protein foods, which diabetics and pre-diabetics should eat as frequently as they can. “It is perfectly okay for diabetics to eat beans twice a day, even at breakfast.”

But it is essential that patients understand this means unprocessed beans as close as possible to their natural state—the ones that are purchased dry and must be soaked for hours before cooking. Canned baked beans, barbecued beans or other sugar-laden quick-fix versions will probably do more harm than good. “You need to teach patients about healthy cooking and healthy eating,” said Dr. Gaby.

Dietary Supplements

A number of nutritional supplements are extremely helpful in managing IR, and possibly, in preventing progression to T2D. Chromium picolinate is the best studied, and it can significantly improve insulin sensitivity (see page 1). According to Dr. Linkner, the following are also effective:

• Omega-3 fatty acids: Increased intake of omega-3 polyunsaturates improves insulin sensitivity in skeletal muscle, reduces fasting glucose, and markedly improves lipid profiles, an important consideration for preventing diabetes-associated CVD. Omega-3’s are obtainable from cold water ocean fish, flax seed, walnuts and soy, but most patients will need supplements to obtain optimal levels. Dr. Linkner recommended 1,500–4,000 mg per day of eicosapentaenoic acid (EPA) and 1,000–2,000 mg per day of docosahexaenoic acid (DHA).
• Magnesium: This important mineral improves the function of peripheral insulin receptors, increasing glucose transport and insulin-mediated glucose uptake. The daily intake should be in the range of 200–400 mg.
• Vanadium: This element is an insulin signal enhancer, which increases movement of GLUT-4 to cell surfaces. In its vanadyl sulfate form, it demonstrates insulin-like effects on glucose metabolism. IR patients should take 15–50 mg vanadyl sulfate daily.
• L-Arginine: This amino acid improves insulin sensitivity in patients with T2D, and stimulates production of nitric oxide (NO), which is important because IR is directly correlated with reduced NO production in skeletal muscle. L-arginine also reduces oxidative stress in T2D. The optimal dose is 2 g per day.
• Alpha Lipoic Acid: ALA can improve insulin sensitivity and reduce circulating insulin and glucose levels. It appears to promote cellular uptake of glucose, and also has antioxidant effects. ALA is particularly useful in reducing diabetic neuropathy. Dr. Linkner recommend doses in the range of 50–200 mg per day.
• Vitamin C: Increased vitamin C intake is associated with a decrease in both plasma glucose and HbA1c. It is also a good antioxidant, and appears to decrease LDL while increasing HDL. IR patients should take between 2–6 g daily.
• Vitamin E: A potent antioxidant, anticoagulant, and anti-inflammatory, vitamin E also appears to reduce circulating glucose and decreases glycosylation of proteins. The daily dose should be in the range of 400–800 IU.

Dr. Linkner has had excellent results with a medical food called UltraGlycemX, made by Metagenics (www.metagenics.com or 800-692-9400). The soy-based formula contains vanadium, chromium, ALA, biotin, magnesium, calcium, β-carotene, vitamins A, C, and E, zinc, manganese and copper, and is specially formulated for management of IR, T2D and “Syndrome X.” The powder mixes easily with water to create a low-glycemic shake that also provides 9 g of dietary fiber and only 150 total calories per serving.

In practice, he has found most of his patients do well with UltraGlycemX. “It has practically everything you would want to give to an IR patient, with the exception of conjugated linoleic acid and omega-3s, which you can add as supplements.” He has patients take the shake twice daily. In some with frank T2D, he has been able to use it in conjunction with insulin therapy, gradually weaning patients off of insulin over the course of 6 months.

Botanical Medicine for IR and Diabetes

While herbal medicines probably won’t replace pharmaceuticals for the management of T2D, they can be useful in early stages. Metformin (Glucophage), the widely used diabetes medication, was originally derived from a plant called Galega officinalis (Goat’s Rue), so even conventional drug therapy still has its roots in the ground of plant medicine. Dr. Linkner has found the following herbs helpful for managing IR:

• Panax Ginseng: 1–3 grams of Panax ginseng taken 40 minutes before a meal can slow digestion and absorption of carbohydrates, as well as increase NO-mediated insulin secretion. The anti-glycemic effect is attributed to ginsenoside Rb-2. Ginseng also has additional benefits of improving mood and energy level. However, it can inhibit the effect of warfarin, and probably should not be taken by patients on warfarin.
• Bitter Melon (Momordica charantia): A popular medicinal plant in Asia, Africa and South America, bitter melon contains polypeptide P, which has insulin-like activity. Though it won’t alter insulin sensitivity, it can help reduce blood glucose levels. Dr. Linkner recommended daily doses in the range of 5–15 ml of a standardized tincture. This herb is extremely bitter, so many patients will prefer it in 100 mg capsules. One or two capsules, thrice daily, are a good therapeutic dose.
• Gumar (Gymnema sylvestre): Native to India, Gumar (Gymnema) stimulates endogenous production of insulin, though it does not alter insulin sensitivity. It may also reduce glucose absorption in the gut. He recommended a dose of 400–600 mg per day.
• Fenugreek (Trigonella foenum graecum): Taken as a powder via capsules, the seeds of the Fenugreek plant contain trigonelline, nicotinic acid and coumarin. and can lower blood glucose, total cholesterol and triglycerides, while increasing HDL. Roughly 50% of the seed content is fiber, which slows glucose absorption in the gut. Dr. Linkner advised 10–100 g Fenugreek seed powder per day, in divided doses. It should not, however, be taken with oral medications.
• Garlic (Allium sativum): Patients who like garlic should be encouraged to incorporate as much as they want into their diets. Allicin contained in garlic appears to compete with insulin receptor sites in the liver, thus increasing free insulin, which lowers blood glucose levels. To obtain this therapeutic effect, one needs at least 4 g fresh garlic, or 200–400 mg of encapsulated garlic. Dr. Linkner added that onion (Allium cepa) also works, at a dose of 400 mg/day.

Stress Management and Patient Empowerment

Beyond the specific treatment modalities used—and this includes pharmaceuticals, which are sometimes necessary—it is also important to consider the psychosocial factors that contribute to diabetes and IR. The disorder occurs in a complex psychosocial context called the patient’s life. In many cases, that context is highly stressful.

Dr. Bland explained that there is a strong and consistent relationship between chronic stress and IR. “Stress is related to weight gain, and it is not due just to eating more (for stress relief). Constant stress predisposes to an adipose accumulating state, particularly manifested as accumulation of visceral adipose tissue. And visceral adipose tissue increase tracks very directly with IR, hyperinsulinemia and T2D,” he said at the recent annual meeting of the American Holistic Medical Association. This process is mediated by the hypothalamic-pituitary-adrenal axis.

“You lose cortisol receptiveness under chronic stress or PTSD. The system cannot shut itself off.”

Try to help your IR and diabetic patients identify the major stressors in their lives and the factors that contribute to behavior like over-eating and tobacco smoking, which induces insulin resistance.

It can be very difficult for many patients to make the life changes they need in order to remain healthy. Patient education and empowerment programs can make a big difference. “We do a free seminar on insulin resistance once every month at our clinic,” said Dr. Linkner. When counseling his patients he emphasizes that lifestyle changes now will have big rewards later on. “I tell my patient that we’d really like it if he or she not die 10 or 20 years too soon.”