Nutritional Approaches to Optimal Blood Glucose and Insulin Levels Key Factors in Longevity and Resistance to Diabetes and other Degenerative Diseases
by Kimberly Pryor and Ward Dean, MD
Although hyperinsulinemia (abnormally elevated blood insulin) is often mentioned in connection with diabetes, in reality it is associated with a far broader array of chronic degenerative diseases. Hyperinsulinemia is now recognized not only as a major risk factor for coronary heart disease in healthy middle- aged men,1 but has also been linked to the rise in plasma free radicals associated with oxidative stress, a contributor to heart disease.2 In addition, cell damage resulting from elevated insulin and blood sugar levels can lead to degenerative diseases such as hypertension and cancer. Concern over hyperinsulinemia has increased recently with the discovery of an emerging epidemic of non-insulindependent diabetes mellitus (NIDDM— or Type II diabetes) among children. Previously, this disease—strongly related to obesity—was most commonly diagnosed in individuals over the age of 40. Children rarely contracted Type II diabetes. But with the increasing prevalence of childhood obesity, it is now becoming all too common in the youth of America. Today, approximately 20% of new cases of childhood diabetes are Type II, and as many as 300,000 children in the United States are afflicted with the disease.3 The effects of insulin resistance and hyperinsulinemia in diabetes are well-documented. Among Europeans, atherosclerosis is the most common complication of Type II diabetes. In addition, coronary artery, cerebrovascular and peripheral vascular diseases occur two to five times more often in diabetics than in non-diabetics.4 Children who contract Type II diabetes risk an encounter with these hyperinsulinemiarelated consequences —heart attacks, strokes, hypertension, and cancer—at farearlier ages than in the past.
A common occurrence of aging is the progressive dysfunction of the glucoseinsulin portion of the energy homeostat (See “The Neuroendocrine Theory of Aging—The Energy Homeostat,” Vitamin Research News, May/June, 1999), with a resultant loss of glucose tolerance. This is manifested by hyperinsulinemia, insulin resistance, and a progressively decreased ability to efficiently metabolize carbohydrates (i.e., glucose). Examples of carbohydrates include sugars, glycogen, starches, dextrins, and celluloses (and even alcohol and GHB)— all substances that contain only carbon, oxygen and hydrogen. Glucose and its polymers (including starch and cellulose) are thought to be the most abundant organic chemical compounds on earth, with quantities exceeding even the massive reserves of fuel hydrocarbons beneath the earth’s crust.5Although carbohydrates are essential for survival, the way the body metabolizes carbohydrates can adversely affect health and longevity by altering the fine balance that exists between insulin and glucose. Clearly, the development of hyperinsulinemia should be a concern to everyone over 30. Hyperinsulinemia’s ability to wreak havoc on the cellular system and escalate the risk of degenerative diseases suggests that carbohydrate management is potentially one of the most beneficial life extension factors there is.
Hyperinsulinemia and Cancer
In addition to diabetes, a strong link exists between high insulin levels and some cancers. In one study, ten postmenopausal women with endometrial cancer had significantly higher fasting serum insulin levels than 10 healthy controls. The women with cancer also experienced significantly higher insulin responses after glucose administration. Furthermore, the researchers found insulin receptors in the postmenopausal ovaries.6 A larger study of 752 women with endometrial cancer and 2,606 controls confirmed an association between NIDDM and an increased risk of endometrial cancer.7 Insulin is thought to affect the development of endometrial cancer through its hormone-stimulating properties. In 22 endometrial cancer patients, those with high hyperinsulinemia had significantly more steroid hormone receptors in the tumor compared to patients with low insulinemia.8-9 Researchers also have discovered a connection between colon cancer and insulin levels, a connection that may involve insulin’s role as a growth factor in the colon. In studying 102 cases of colorectal cancer, scientists found that patients with the highest levels of fasting glucose had almost twice the increased risk of colon cancer. The highest fasting insulin levels also were associated with an increased risk of colon cancer.10
Nutritional Approaches to Optimize Carbohydrate Metabolism: N-Acetyl Cysteine (NAC)
Elevated free radical production activates nuclear factor-kB (NFkB), a genetic regulator that acts within the cell nucleus. NFkB activation intensifies inflammatory responses, resulting in an even greater production of free radicals and eventually to beta cell death. N-acetyl cysteine is a precursor to glutathione (GSH), a cysteine- containing tripeptide and antioxidant that modulates cellular metabolism and gene expression. GSH is thought to prevent oxidation-induced beta-cell damage by inhibiting NFkB activation. In mice with chemically-induced diabetes, N-acetyl cysteine supplementation prevented NFkB activation in the pancreas in vivo, whereas controls experienced heightened NFkB activity. The supplemented mice also experienced lower blood glucose levels and a lower degree of weight loss, a symptom of diabetes. The researchers concluded, “If NFkB activation is the critical step in the development of diabetes, then N-acetyl cysteine, which is able to inhibit NFkB activation, should also prevent the onset of the disease.”17 In the presence of oxidants, NFkB can activate the vascular cell adhesion molecule (VCAM)-1. This molecule helps circulating cells attach to the endothelium, promoting the development of clogged arteries. VCAM-1 upregulation has been shown to be one of the most important events initiating atherosclerosis. Type II diabetics and glucose intolerant hypertensive patients often have elevated levels of plasma VCAM-1.16 In humans, N-acetyl cysteine has been shown to reduce plasma VCAM-1 activity. In one double-blind trial, 15 Type II diabetics received either oral N-acetyl cysteine (1,200 mg per day) or placebo. After one month, N-acetyl cysteine reduced plasma VCAM-1 concentrations and increased GSH levels compared to the placebo group.18 In diabetics, N-acetyl cysteine may synergize with the antioxidant vitamins C and E. Together, these three nutrients have been shown to reduce blood glucose levels in diabetic mice. In addition, they increased beta-cell mass and preserved insulin content, the decline of which is associated with the development of Type II diabetes.19
In diabetic rats, this herb of Southeast Asian origin significantly reduces serum glucose concentrations, raises serum insulin levels closer to normal fasting levels, and doubles the number of islets and beta cells in the pancreas. One in vivo study indicated that gymnema sylvestre may be superior to insulin in reducing the glycogen content in diabetic livers. In glucose-fed hyperglycemic rats, insulin maintained a normal level of glycogen in the liver, whereas gymnema sylvestre leaf extract substantially lowered the content. The two substances combined produced an even greater reduction. 20-22 In humans with Type I diabetes (insulin dependent, or IDDM) gymnema sylvestre enhances endogenous insulin, possibly through beta cell regeneration. Twenty seven IDDM patients on insulin therapy were given 400 mg per day gymnema sylvestre extract, which lowered the insulin requirements and fasting blood glucose and returned serum lipid levels to near normal.23 This potent herb may have significant anti-aging properties, as well. In one study, gymnema sylvestre significantly prolonged the lives of diabetic rats.24
Vanadyl sulfate, a trace element that mimics insulin, has been found to restore elevated blood glucose to normal in diabetic animals. In chemically induced Type II diabetes in rats, vanadyl sulfate lowered the insulin requirement by up to 75%.25 Vanadyl sulfate can reverse diabetes in rats for up to 20 weeks after supplementation ceases. Short-term treatment with vanadium, prior to and for a twoweek period following the induction of diabetes, eliminated hyperglycemia in rats, even after withdrawal from treatment. The researchers stated, “This property of vanadium would appear to be useful in the treatment of prediabetic and newly diagnosed patients with insulindependent diabetes mellitus.”26 In humans with Type II diabetes, low doses of vanadyl sulfate increased insulinmediated glucose uptake and glycogen synthesis, and suppressed endogenous glucose production. This resulted in decreased lipid oxidation rates and reduced plasma free fatty acid concentrations. 27 Vanadyl sulfate is considered to be safe and relatively nontoxic to both animals and humans. Although vanadyl sulfate can be nephrotoxic (damaging to the kidneys) at very high dosages, one group of researchers stated that vanadyl sulfate “may be an alternative to insulin in the near future, due to its low cost, low toxicity and ready availability.”28
Vitamin E, as tocopherol (alpha, beta and gamma), along with its “cousin,” the increasingly recognized tocotrienols, is a free radical scavenger that has been demonstrated to improve insulin sensitivity in both diabetics and the elderly. The majority of studies in both humans and animals support the role for vitamin E in improving glycemic balance. In one study, obese, insulin-resistant rats supplemented with vitamin E experienced a reversal of glucose-stimulated hyperinsulinemia without worsened glucose tolerance. 29 In a human double-blind study, 24 hypertensive patients were given 600 mg of vitamin E per day. Those given vitamin E showed increased insulin sensitivity and improved concentrations of cellular magnesium. Magnesium is believed to protect against oxidative damage and normalize circulating glucose levels. 30
Vitamin B6 is an essential component in carbohydrate metabolism. A deficiency of B6 is associated with impaired glucose tolerance. B6 works together with its activated coenzyme form, pyridoxal-5-phosphate (P5P), which is produced in the liver from pyridoxine. When glucose is ingested, circulating plasma P5P and total vitamin B6 levels decline. Studies suggest that the more simple carbohydrates an individual consumes, the lower the plasma levels of P5P and vitamin B6.31 Vitamin B6 is thought to inhibit the amino acid glutamate dehydrogenase (GDH), a substance that accumulates in the brain and causes neuronal degeneration in diabetics. Insulin does not completely reverse this enhanced GDH activity, nor the resulting toxicity. 32 Vitamin B6, however, is a promising GDH-lowering agent. In one study of diabetic rats, P5P brought GDH levels back to the state of the healthy control animals. In addition, the combined administration of insulin and pyridoxine was found to be better at controlling hyperglycemia than insulin alone, returning blood glucose levels nearer to normal. “From our results,” the researchers wrote, “we suggest that administration of pyridoxine along with insulin serves as a good control measure for diabetes.”33
Insulin assists with the cellular uptake of vitamin C (ascorbic acid), whereas hyperglycemia interferes with the nutrient’s ability to nourish cells. For this reason, individuals with Type I diabetes can experience “tissue scurvy.” It has been proposed that reduced levels of ascorbic acid can lead to a number of harmful effects, including leaving the body susceptible to the damaging effects of aldose reductase, an enzyme responsible for many diabetic complications, including the formation of cataracts and impaired motor nerve function.34 The benefits of vitamin C supplementation have been demonstrated in a number of studies. For example, when researchers gave 20 diabetic men 1000 mg of vitamin C along with 24 mg of beta-carotene and 800 IU of alpha-tocopherol a day, diabetic patients were less susceptible to LDL oxidation.35 In another study, 30 males with recurrent calcium urolithiasis (kidney stones) and eight healthy controls were given a carbohydrate- and calcium-rich meal. Sixteen of the thirty males dined on meals also supplemented with a supraphysiological dose of ascorbic acid. The non-supplemented group developed hyperinsulinemia and insulin resistance, whereas the ascorbicacid- enhanced meal abolished the hyperinsulinemia. 36
This bioflavonoid is another powerful aldose reductase inhibitor — especially effective in the eye lens. Aldose reductase has been blamed for the genesis of human cataracts and diabetic neuropathy. Quercetin has inhibited lens aldose reductase by up to 50%, a level nearly equivalent to sorbinil, an aldose-reductaseinhibiting drug. Furthermore, quercetin helps escort glucose out of the body. It has been found to be safe and non-toxic. 37-38
Bitter Melon (Momardica charantia)
In India, diabetics regularly consume dietary bitter melon because of its reported anti-diabetic effects. Unlike many glucose- lowering agents, bitter melon is thought to work outside the pancreas by suppressing glucose transport from the small intestine. Numerous studies support bitter melon’s glucose-lowering abilities. In one study, bitter melon extract reduced the fasting glucose levels of hyperglycemic and normal mice.39 In normally fed rats, bitter melon (500 mg/kg) lowered plasma glucose levels by 10-15% at one hour without increasing insulin secretion. In diabetic rats, bitter melon has improved glucose tolerance by 26% at 3.5 hours. Bitter melon extract also caused a 4-5 fold increase in glycogen synthesis in the liver compared to normally fed rats. 40
Goats Rue (Galega officinalis)
In medieval Europe, goats rue was traditionally used as a treatment for diabetes. Goats rue contains guanidine, the herbal prototype of the pharmaceutical drug Metformin, which improves insulin sensitivity and is used to treat both Type I and II diabetes. Metformin has been claimed to be one of the most effective anti-aging drugs currently available (Dean, 1999). Goats rue causes a longlasting reduction of blood sugar content in rats and an increase in carbohydrate tolerance. In one study, goats rue extract lowered the blood sugar of diabetic rats by 32%.41 Goats rue extracts have increased glycogen levels in the liver and myocardium of both healthy and diabetic rabbits. In addition, this potent herb lowers blood sugar in both normal and diabetic humans.42
Recently a group of researchers investigated biotin’s effects on the islets of Langerhans, pancreatic cells that regulate blood glucose levels by controlling insulin secretion in both humans and rats. Beta cell glucokinase is responsible for controlling insulin secretion in response to changes in blood glucose levels in the beta cells. In cultured rat islet cells, biotin increased glucokinase activity by as much as 143%, whereas in biotin-deficient rats, glucokinase activity in the islets was reduced by 50%. Treatment with biotin for 24 hours increased insulin secretion in both normal and hyperglycemic animals. Human trials generated equally promising results. One group of Type I patients who received 16 mg/day (!) of biotin for one week experienced reduced levels of blood sugar. In Type II subjects, elevated fasting blood glucose levels plummeted by approximately 45% after one month treatment with oral doses of 9 mg/day (!) of biotin.43
Chromium is an essential nutrient for sugar and fat metabolism. The adequate daily dietary intake for chromium is 50 to 200 micrograms, but most diets contain less than 60% of this intake. Insufficient chromium causes complications similar to those seen in diabetes and cardiovascular diseases.44 Chromium picolinate supplementation, on the other hand, improves insulin sensitivity in those with hypoglycemia, hyperglycemia, diabetes and hyperlipidemia. In one controlled study, subjects were administered a placebo or 100 or 500 micrograms of chromium picolinate two times per day for four months. Those subjects receiving 100 micrograms twice per day demonstrated no significant improvements, while the group receiving 500 micrograms twice per day saw highly significant improvements in the glucose/insulin system.45 Chromium picolinate and biotin work synergistically to support glucose metabolism. Chromium picolinate appears to improve insulin sensitivity in Type II diabetics, whereas biotin exerts its main effects on glucose levels and insulin secretion without affecting insulin sensitivity directly. Researchers believe these two nutrients work together to combat insulin resistance, improve beta-cell function, enhance glucose uptake by both liver and skeletal muscle cells, and inhibit excessive glucose production in the liver. The authors of a recent study on biotin and chromium picolinate wrote, “Conceivably, this safe, convenient, nutritional regimen will constitute a definitive therapy for many type II diabetics, and may likewise be useful in the prevention and management of gestational diabetes.” 46
Alpha-lipoic acid has recently been demonstrated to have potent antioxidant activity. Lipoic acid protects against the oxidative stress associated with insulin resistance. In vitro research has demonstrated that cells pretreated with lipoic acid prior to exposure to an oxidative stress had 85% greater insulin-stimulated glucose transport than untreated cells. Lipoic acid also protects cells against the reduction in GSH content following oxidative stress. In Type II diabetes patients, lipoic acid has acted as an insulin mimetic and improved glucose utilization. 47
In animals, selenium improves glucose tolerance and has demonstrated other insulin-like effects. In diabetic mice with hyperglycemia and decreased GSH levels, selenium reversed these conditions to near normal in almost all cases.48 Diabetic rats treated with sodium selenate have exhibited improved blood glucose levels and normal heart function at eight weeks, compared to non-treated diabetics.49
Rats pre-treated with the amino acid taurine prior to the induction of diabetes experienced a reduction of the primary diabetic symptoms of polydipsia (excessive thirst) and polyuria (excessive urination). In addition, plasma triglyceride levels in these animals fell after taurine administration. Those animals treated with taurine after the induction of diabetes and normal control animals both experienced a decline in LDL cholesterol, the “bad” cholesterol.50 Taurine’s additional benefits may be of interest to hypertensive patients. In normal rats, fructose feeding causes moderate increases in blood pressure, a condition linked to hyperinsulinemia, insulin resistance and impaired glucose tolerance. These same fructose-fed animals have elevated plasma levels of insulin and glucose, much higher than controls. Rats that consumed a 2% taurine-drinking water cocktail did not experience the expected increased blood pressure nor the hyperinsulinemia usually seen in fructose-fed rats.51
Calcium AEP is a cell membrane integrity factor required for cellular membrane functions. Treatment with Ca-AEP has benefited individuals with Types I and II diabetes. Ca-AEP treatment has resulted in lowered insulin requirements and inhibition of pancreatic autoimmune disorders. In clinical studies of patients with Type II diabetes, the administration of Ca- AEP improved blood glucose regulation and eliminated unbalanced blood sugar levels. Ca-AEP acts as a “cellular gatekeeper,” restoring glucose transport into cells while at the same time “sealing” the cell membrane to prevent the entrance of damaging toxic glucose metabolites. Research also has demonstrated Ca- AEP’s ability to prevent and reverse diabetic retinopathy.52
The hormone dehydroepiandrosterone (DHEA) undergoes an age-related decline that many researchers have linked to impaired glucose metabolism. Male rats administered a diet supplemented with 0.3% DHEA experienced 30% higher glucose disposal than sedentary controls due to greater insulin sensitivity. Body fat in the DHEA-supplemented animals was reduced by 25%. DHEA was as effective as exercise in reducing body fat content and maintaining insulin responsiveness. 53 Diabetic patients with hyperinsulinemia have lower levels of serum DHEA than controls. Evidence connects elevated glucose levels with declining DHEA. High levels of glucose were administered to 12 Type II subjects with hyperinsulinemia and 12 Type II subjects without hyperinsulinemia. DHEA concentrations in the hyperinsulinemic diabetics started off and remained low. Interestingly, DHEA levels in both control subjects and non-hyperinsulinemic diabetics showed a more significant decline of serum DHEA than in the hyperinsulinemic diabetics.54 The connection between elevated glucose and declining DHEA may extend to ischemic heart disease. Researchers studied 32 male patients with newly-diagnosed ischemic heart disease and without metabolic disorders, along with 11 healthy matched controls. Seventy-eight percent of the heart disease patients had insulin resistance and DHEA levels below controls. Induced hyperinsulinemia further decreased DHEA levels in both controls and heart disease patients.55
Maintenance of optimum glucose metabolism is a major factor in the maintenance of health and for protection against chronic degenerative diseases like cancer, diabetes, atherosclerosis, and immune-related diseases. In addition, there is increasing awareness of the important roll of this key homeostatic system in anti-aging medicine. Optimum glucose metabolism can be maintained by regular exercise, consumption of a reduced-carbohydrate diet, and utilization of a broad spectrum of nutrients that have known effects to restore hypothalamic and peripheral sensitivity to glucose and insulin, and to maintain blood concentrations of these substances at their optimum levels.
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