Diabetes And Minerals Vitamins And Dietary Supplements

It is important for patients with diabetes to be counseled about the importance of consuming adequate amounts of minerals and vitamins from natural food sources and to be aware of the potential toxic effects of megadoses of vitamin and mineral supplements. Interest in antioxidant vitamins in people with diabetes has increased with the knowledge that diabetes may be a state of increased oxidative stress.

At present, megadoses of dietary antioxidants, such as selenium, P-carotene, vitamin E, and vitamin C, have not demonstrated cardioprotection in diabetic patients; in some clinical trials, such as the Heart Outcomes Prevention Evaluation (HOPE) trial, they have actually been shown to be inferior to certain medications, particularly angiotensin-converting enzyme (ACE) inhibitors (16).

Oxidation is the removal of electrons from a molecule. This process can cause tissue damage by modifying lipids, proteins, and nucleic acids, thus, leading to various diseases, such as arteriosclerosis and cancers.

Antioxidants significantly retard or inhibit this destructive oxidative process. Certain antioxidants are endogenous, such as ferritin, transferrin, and urate, whereas other antioxidants are acquired.

Exogenous oxidants, such as vitamins E, A, and C, by counteracting oxidative damage, have stimulated research into their effects. There have been various observation studies that report benefits from these vitamins. The problems with observational studies are as follows:

1. The people usually enrolled in these studies are nonsmokers, health conscious, exercise regularly, and limit fat intake.

2. These trials rely heavily on subjective data that is self-reported and depends on 24-hour recall.

3. Various diets and supplements contain a variety of substances, making it irksome at times to sort out which specific nutrient is beneficial.

4. More often than not, when a double-blind, randomized, placebo-controlled trial is designed to prove the efficacy of these supplements, the beneficial effects are not demonstrated.

Some studies of merit include the following (17):

1. The Iowa Women's Health Study (19). This study evaluated the intake of various antioxidant vitamins found in foods and supplements to their relationship to coronary artery disease and overall mortality. This study evaluated close to 35,000 postmenopausal women (aged 55-69 years) with no history of cardiovascular disease for 7 years. Intake of vitamins A, E, and C were estimated by questionnaires and then correlated with

Table 2 Basic Nutrition Principles

• Medical nutrition therapy should be individualized according to the metabolic profile, desired goals, and clinical outcomes, in accordance with the usual dietary habits of the patient.

• Regular monitoring of glucose, A1-C, lipids, blood pressure, renal function, body weight, and quality of life are crucial to assess the ongoing needs of the patient and ensure successful outcomes.

• Family members of individuals with type 2 diabetes should be encouraged to engage in regular physical activity and dietary management to decrease their risk of developing the disease.

plasma levels of P-carotene and vitamin E (a-tocopherol). A high intake of vitamin E and not vitamin A or vitamin C protected against death from coronary artery disease.

2. The Rotterdam Study (20). This study evaluated the relationship between dietary intake of P-carotene, vitamin C, and vitamin E in 4800 people aged 55-95 years with no history of myocardial infarction. This study demonstrated that P-carotene and not vitamins E or C was protective against myocardial infarction.

3. The Established Populations for Epidemiologic Studies of the Elderly (21). This study followed more than 11,000 people aged 67-105 years for 8-9 years to evaluate the effects of vitamins E and C on overall mortality and risk of death from coronary artery disease. In this study, vitamin E was associated with a reduced mortality from coronary artery disease.

4. The Nurses' Health Study (9). This study evaluated more than 87,000 female nurses aged 34-59 years with no cardiovascular disease or cancer, demonstrating that vitamin E supplementation for more than 2 years decreased the risk of coronary heart disease.

5. The Scottish Heart Health Study (22). This trial involved more than 4000 men and 3800 women aged 40-59 years with no history of heart disease and investigated the effects of dietary and supplemental intake of vitamin C, P-carotene, and vitamin E on coronary artery disease. Vitamin E conferred no benefit in this study, although vitamin C and P-carotene reduced coronary artery disease events in men only.

6. The Finnish Study (23). This study evaluated more than 5100 Finnish men and women aged 30-69 years who were free of coronary disease and followed for 14 years to evaluated the effects of dietary P-carotene, vitamin C, and vitamin E on coronary mortality. Here, vitamin E conferred protection to both men and women, with P-carotene and vitamin C conferring benefit in women only.

7. The National Health and Nutrition Examination Survey I (24). This study evaluated more than 11,300 US adults aged 25-74 years for all-cause mortality and cardiovascular disease, with regard to intake of vitamin C. This study showed a benefit from vitamin C intake in men but not in women.

Although we can see that these studies showed some benefit from antioxidant use, especially vitamin E, the results were inconsistent. This data is to be contrasted with studies, such as the Heart Protection Study (25), the Primary Prevention Project (26), and the Gruppo Italiano por lo Studio della Streptochinasi nell'Infarto Miocardico study (11), that demonstrated no benefit from vitamin E. Data from the HDL Atherosclerosis Treatment Study, which evaluated 160 men under age 63 years and women under age 70

years with established coronary artery disease, showed that vitamin E diminished the beneficial effect of simvastatin and niacin by blunting the HDL-2 elevations seen with niacin.

Both the a-Tocopherol P-Carotene Cancer Prevention Study (27) and the P-Carotene and Retinal Efficacy Trial (28) showed that patients taking supplemental P-carotene had a statistically higher incidence of lung cancers and increased mortality compared with placebo.

The Cambridge Heart Antioxidant Study (CHAOS) (29) evaluated more then 2000 patients with angiographically proven coronary artery disease. Patients received either 400 IU or 800 IU of vitamin E, and although the number of cardiovascular deaths was not reduced, there were fewer nonfatal myocardial infarctions in those taking vitamin E.

The role of folate supplementation to lower homocysteine levels and subsequently reduce cardiovascular events is still not clear. However, the role of folate in preventing birth defects is widely accepted. Serum homocysteine levels are elevated in folate deficiency, as well as B12, B6 deficiencies, renal insufficiency, hypovolemia, hypothy-roidism, psoriasis, and inherited metabolic defects.

In obtaining homocysteine levels, it is prudent to obtain methylmalonic acid levels, because 96% of B12 deficiency is associated with hyperhomocysteinemia and 98% of B12 deficiencies are associated with elevated methylmalonic acid levels.

Hyperhomocysteinemia is considered by many to be an independent risk factor for cardiovascular disease and mortality, especially in women and diabetic patients. This topic will be discussed in detail in Chapter 13 of this book.

The intake of vitamins B1, B6, and B12 has not been established to be of benefit in the treatment of diabetic neuropathy and cannot be recommended based on clinical evidence.

The prevention of osteoporosis is important in older patients, particularly in female diabetic patients, with a recommendation of 1500 mg/day of elemental calcium. This amount can be reduced to 1000 mg/day with concurrent bisphosphonate therapy.

Currently, a beneficial effect of nicotinamide to preserve p-cell mass in newly diagnosed type 1 diabetic patients is under investigation. Deficiencies of zinc and chromium may aggravate carbohydrate intolerance, and benefits have recently been reported on glycemic control with chromium supplementation. There are, however, other studies questioning the benefits, if any, from chromium intake. Thus, the benefit of chromium ingestion in the patient with diabetes remains to be determined (30).

The trace element chromium, particularly chromium picolinate, has been shown to be of benefit in some limited trials for glycemic control. Interest in chromium was reported in the 1950s when Walter Mertz (31) at the US Department of Agriculture published data indicating a benefit of chromium picolinate in lowering blood glucose.

Low chromium levels have been associated with impaired glucose tolerance, and the beneficial effects have been thought by many to apply only to deficiency states. Chromium levels tend to decline with aging, despite playing a role in regulating insulin-dependent reactions, including glucose uptake, glucose storage, and glucose oxidation.

As reported by Cefalu (32), the US Department of Agriculture sponsored a study of 180 patients in China in 1997 showing that 200 Mg/day of chromium picolinate lowered A1-C from 8.5 to 7.5% and to 6.5% in those taking 1000 Mg/day. Cefalu found that 100 Mg of chromium picolinate vs placebo resulted in significant improvements in insulin sensitivity in both 4-month and 8-month studies in obese, nondiabetic, insulin-resistant individuals and not the placebo group.

Cefalu and others contend that chromium exerts stronger effects in obese vs lean individuals based on rat models. Lydic and others also report benefit of chromium supplementation in polycystic ovary syndrome using the 100-^.g dose.

Chromium appears to be well-tolerated with no associated adverse effects reported in the Council for the Advancement of Diabetes Research and Education (32) summit reports at the 100-^.g doses, and showed no significant drug interactions.

The human body cannot synthesize chromium, thus it must be supplied through foods or supplements. Foods that contain chromium include apples, coffee, mushrooms, green beans, broccoli, bananas, wine, tea, cheese, brewer's yeast, and whole-grain wheat bread.

Chromium picolinate has the highest bioavailability of the supplements available.

Chromium appears to exert its effects at the cellular level by influencing phosphory-lation of tyrosine kinase. It may do so by both inhibiting protein tyrosine phosphatase and by directly enhancing tyrosine phosphorylation, along with glucose transporter-4 activity (GLUT-4), enhancing glucose uptake and metabolism in skeletal muscle (31).

A number of nutritional supplements have been touted as beneficial in managing insulin resistance. These include the following:

1. ffl-3 fatty acids. Daily intake of 1500-4000 mg of EPA and 1000-2000 mg of DHA have been shown to improve insulin sensitivity in skeletal muscle, reducing fasting glucose and improving lipids.

2. Magnesium. Daily intake of 200-400 mg of magnesium has been reported by some to improve insulin receptor function and glucose transport.

3. Vanadium has been reported to be an insulin signal enhancer, increasing movement of glucose transporter-4 to the surface of the cell when given in doses of 15-50 mg.

4. L-Arginine has been reported to improve insulin sensitivity and stimulate nitric oxide production at 200 mg/day, which can enhance endothelial functioning.

5. a-Lipoic acid has been shown to be of some benefit in managing diabetic peripheral neuropathy and enhancing insulin sensitivity.

Further clinical investigation and trials need to be done to determine any official recommendations or endorsements by the ADA for any of these supplements.

Although herbal medicines have been touted, they cannot compete with standard pharmaceuticals for type 2 diabetes. Interestingly, metformin was originally derived from Galega officinalis (Goat's Rue) (33). Some notable herbals include the following:

1. Panax ginseng. When taken 30-40 min before a meal, 1-3 g of Panax ginseng can slow absorption and digestion of carbohydrates. Panax ginseng can also inhibit warfarin and should not be taken by patients taking warfarin.

2. Gumar (Gymnema sylvestre). This stimulates insulin secretion from the pancreas without affecting insulin sensitivity. It may also decrease glucose absorption in the intestine. The recommended dose is 400-600 mg/day.

3. Bitter melon (Momordica charantia). This medicinal plant contains a substance called polypeptide P, which reportedly has an insulin-like activity. This is available as a liquid and given in capsule form, with one to two capsules (5-15 cc of liquid) three times daily being the suggested dose.

4. Fenugreek (Trigonella foenum graecum). The seeds of this medicinal plant contain trigonelline, nicotinic acid, and coumarin, which reportedly can lower glucose, cholesterol, and triglycerides, and raise HDL. The recommended dose is 10-100 g/day.

5. Garlic (Allium sativum). This contains allicin, which is reported to enhance insulin activity through its effects on receptor sites. One needs to ingest 4 g of fresh garlic daily, or 200-400 mg in the encapsulated form.

6. Onion (Allium cepa). Allegedly works in the same manner as garlic at a dose of 400 mg/ day.

7. Cactus (Opuntia streptacantha). Used in Mexico as a food additive in diabetics. Effects on glucose likely due to soluble fiber and pectin content.

Currently, none of these herbs has the endorsement of the ADA and each would need more clinical-based evidence before achieving that plateau. The list is supplied here as a guideline and source of information for the physician when asked about these substances.

The same precautions regarding the use of alcohol that apply to the general population are applicable in the diabetic patient. Women during pregnancy and patients with advanced neuropathy, severe hypertriglyceridemia, history of alcohol abuse, or pancreatitis should abstain from alcohol ingestion. Alcohol has been shown to have both hyperglycemic and hypoglycemic effects in people with diabetes. This depends largely on the amount of alcohol acutely ingested, whether the use is chronic, or excessive and binged, and whether food is concomitantly consumed. Some clinical trials have suggested that light to moderate alcohol ingestion may be associated with increased insulin sensitivity and decreased risk for coronary disease.

Although a strong association exists between chronic excessive intake of alcohol and blood pressure in men and women when the intake is greater than 30-60 g/day, light to moderate amounts of alcohol (2-4 oz of100% alcohol or its equivalent daily) do not raise blood pressure. If individuals choose to drink alcohol, daily intake should be limited to one drink for adult women and two drinks for adult men, with portions limited to 1.5 oz of distilled spirits, 5 oz of wine, or 12 oz of beer. Ideally, the alcohol should be ingested with food to avoid the risk of hypoglycemia.

Of interest is the presence of catechins or flavonoids in red table wines, black and green teas, dark chocolates, and black grapes. The possibility of cardiovascular benefits in consuming these substances has received considerable attention recently.

Many studies have attributed the beneficial effects of decreased coronary heart disease in red wine drinkers to the polyphenols. Increased tea consumption (especially green and black) has been reported to reduce the risk of myocardial infarction. This is believed to be related to the flavonoids, specifically catechins, in the tea.

However, which flavonoid is being reviewed seems to be problematic. Not all fla-vonoids have been shown to be beneficial. Flavonoids are very potent compounds and intake should be restricted only to foods and not to supplements. Two reports have linked a high intake of flavonoids to increased risk of fetal gene damage and risks for leukemia in infants.

Flavonoids in cocoa powder and dark chocolate reduced LDL, oxidative susceptibility, and prostaglandin levels in some studies, but the clinical importance or relevance of this effect is not known. Flavonoid-rich cocoa, along with green and black tea and black grapes seem to have antiplatelet effects and delay clotting time. Purple grape juice and tea have been shown to significantly increase brachial artery dilatation in patients with cardiovascular disease (17).

Most recently, the antioxidant effect of the flavonoids and other polyphenols have been of interest, particularly their role in cancer prevention and inhibition of oxidation of LDL. Moderate ingestion of tea has been shown in some studies to protect against cancer, cardiovascular disease, and kidney stones. The flavonoid content of herbal teas is much lower than the green teas. The consumption of one to two cups of tea daily has been associated with a decreased mortality from stroke in men by 50%, and from cancers of the mouth, pancreas, colon, esophagus, skin, lung prostate, and bladder by 20-40%. These data, however, reflect association rather than direct causation. Thus, it is not prudent at present to officially recommend the consumption of large amounts of pheno-lics in foods or supplements without further convincing data.

Clinical trials currently in progress may help to clarify some of these intriguing therapeutic possibilities.

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