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Discussion |
Department of Nutrition, University of Massachusetts, Amherst, Massachusetts
Dr. John J. Cunningham.
The presentations in this initial session provide ample documentation of the potential for nutrient-based interventions to ameliorate the pathologies associated with several chronic diseases. The important and recurring theme is that evidence is not the plural of anecdote. Intervention trials based on mechanistic hypotheses and published in peer reviewed journals set the standard by which efficacy is clearly established. Additionally, nutrient interventions are acknowledged to be complementary to medical treatments rather than competitive with effective medicines or pharmaceuticals. The image has been one of George and Rodney as noted in the opening remarks for this conference. Our adherence to scientific rigor and standards together with providing clear advice to our constituents will bring us to a future identity as "the twins". Considerations such as availability, patient acceptance, and cost could favor a single supplement or functional food approach over a prescribed medicine, even when both approaches are equally safe.
The spectrum for medical interventions begins with over-the-counter preparations offering analgesia, generalized symptomatic relief or palliative effects. Similarly, nutritionists have long focused on food-based programs to increase the consumption of dietary substances conferring benefit for disease prevention. The presentations in this session suggest that foods rich in phytoestrogens may protect against CVD and cancer and that the consumption of diets rich in glucomannans and oligosaccharides will benefit diabetics. Such regimens could be incorporated into a plan providing high dietary fiber, moderate saturated fat and cholesterol and "five a day" fruits and vegetables, that integrates program recommendations for CVD, cancer, and diabetes. Farther along on the spectrum are the so-called nutraceutic supplement (single bioactive compound) and functional food (enriched matrix component) nutrition approaches. As a generalization, these deliver two to three times the Recommended Dietary Allowance (RDA) for a nutrient or a similarly increased consumption above average for a non-nutrient compound. This session points to soy isoflavones (possibly delivered within their native protein matrix), while recent meta-analyses suggest psyllium or B-glucans for those at risk for CVD. Professor Vuksan makes a compelling case for American Ginseng as a "functional food" or a ginsengoside supplement for diabetics. Finally, both medical and nutritional practitioners consider pharmaceutic therapies at the high end of this spectrum. Antioxidants such as vitamins C and E find applications at 10 to 100 times the RDA. There is no similar benchmark for the blend of herbs collectively termed PC SPES (PC for prostate cancer, "spes" from the Latin "hope"); however, the regimen as prescribed is undoubtedly in this range. For diabetes, the fast insulin analog lispro and the "modified release" sulfonylurea gliclazide target euglycemia through insulin action.
The chronic degenerative complications of non-insulin dependent diabetes mellitus (NIDDM) can be prevented by a combination of medical and nutritional interventions employed synergistically. Interventions are founded either on primary treatment—enhancing insulin release; secondary interventions—promoting "tight" (euglycemic) glycemic control; or on ameliorating the consequences of chronic hyperglycemia—as tertiary interventions. The Diabetes Control and Complications Trial (DCCT) revealed an estimated 45%–65% risk reduction for retinopathy, nephropathy and neuropathy from tight control, that is, control approximating 7% glycosylated hemoglobin. Beyond those complications, the majority of patients with NIDDM, perhaps as many as 75%, encounter CVD as a sequela. In that regard, soy phytoestrogens offer great promise.
The record thus far for interventions in NIDDM leaves much to be desired. Efforts at primary or secondary treatment demonstrate low long-term success rates (glycolsyaled Hb maintained at < 7%) ranging from 10% success with diet to 15% success with metformin and 20% with sulfonureas to a high of 25% with insulin therapy. To be fair, the latest generation of pharmaceutical interventions has well focused effects with minimal untoward consequences and should improve on this picture. Diet strategies, such as the provision of prepared meals or a combination of a customized NIDDM diet with nutraceutic vitamin E (400 mg daily) show positive short-term outcomes that may help to break through this barrier of dismality.
The fast-acting insulin analog lispro elicits an earlier insulin response peak, diminishes the total insulin required for glucose clearance (C-peptide measurement) and suppresses endogenous glucose production. The modified release sulfonylurea gliclazide restores the "first phase insulin response," minimizes rebound hypoglycemia, and is itself an antioxidant. These represent primary medical therapies with good promise.
Nutritional strategies target secondary intervention. The multi-center meal study demonstrates that weaknesses in education/intervention can be overridden. A recent study showed an improvement in glycosylated hemoglobin approximating a reduction by two percentage points by diet alone. An additive effect from "nutraceutic" vitamin E was coupled with improvement in reactive oxygen species as well.
Combinations of diet plans, insulin therapies, nutrient supplements (vitamins C and E), and adjunct "nutri-medicines" (acarbose, Konjac-mannan, ginsengosides) may portend a better outlook for the prevention of diabetic complications. Figure 2 identifies the locus of action for interventions with respect to the pathways of pathology for the disease. Medical interventions are underlined while nutritional interventions are italicized. Synergies among strategies are apparent from this illustration. The potential for efficacy from isoflavones against the corollary risk for CVD, while not shown, should be reinforced in a synergistic approach.
Dr. Michael B. Zemel.
It is problematic to look at intermediate end points, in this case, glycemic control. Glycemic control can be improved by enhancing insulin sensitivity (e.g., by guanides) or by increasing insulin secretion (e.g., by providing exogenous insulin). In all cases, at some point glycemic control will be improved. The question is at what cost.
I prefer to focus on enhancing insulin sensitivity because raising insulin levels can increase risk factors associated with diabetes, such as hypertension and sympathetic neuropathy. We need to find dietary approaches that focus on enhancing insulin action, rather than increasing insulin secretion.
Dr. Vladimir Vuksan.
Dietary therapies address more than just glycemia. They can also improve blood pressure, diabetes, and blood lipid profiles. I agree with Dr. Zemel that glycemia is not the only consideration. Without treating risk factors for diabetes, prevention or treatment will not be realized.
Dr. Kedar N. Prasad.
Dr. McDonald, since oxidative stress is associated with diabetes complications, would you recommend a multiple antioxidant approach rather than a single nutrient approach?
Dr. Cunningham.
A couple of years ago I recommended a combination of vitamins E and C because of their safety and efficacy. Although this combination may be beneficial in diabetes treatment, it should not be used at the expense of conventional treatments, and it should be taken only under medical supervision.
Dr. Roger McDonald.
I am not convinced that dietary practices at any level will significantly reduce oxidation to control the complications of diabetes. Animal data demonstrate that long-term supplementation with antioxidant nutrients has little effect on extending the animal’s life span. However, because animals do not develop diabetes, findings from these studies are difficult to interpret. Most studies that have examined antioxidants are extremely short term, and the few studies that are longer in duration show that antioxidants have no, or a potentially negative, effect on oxidative stress.
Dr. Prasad.
I question the long-term effects of individual vitamins, which can become oxidized and lead to contrary effects. Based on available data, one cannot generalize about the effects of individual antioxidant vitamins. However, multiple vitamins or multiple antioxidant approaches, rather than single nutrient approaches, may have a longer beneficial effect, and studies are needed to investigate their benefits.
Dr. Cunningham.
My focus is more toward the person with insulin-dependent diabetes who has dealt with hyperglycemia for a long time and who may be at increased risk from diabetes-related complications rather than heart disease.
We need to identify mechanisms by which antioxidants potentially protect against disease. For example, we need to be able to show that nutraceuticals such as vitamin C are aldose reductase inhibitors, which prevent build up of sorbitol.
Dr. Carl L. Keen.
The experimental animal and clinical data regarding antioxidants are overwhelming at this point. Evidence from Martland’s transgenic studies indicates that increasing manganese superoxide dismutase changes endogenous oxidant defense systems and effectively eliminates diabetic embryopathies. Neither vitamin E nor vitamin C exerts this effect. We need to be more imaginative about the antioxidants used in studies.
Dr. Kevin L. Fritsche.
Is there concern about early exposure to, and long-term effects of, phytoestrogens? What is their impact on the onset of subsequent estrogen-related disease?
Dr. Kenneth D. R. Setchell.
The concern about phytoestrogens is based on a study published in Lancet, which showed excessively high blood levels of isoflavones in 4-month-old infants who had been exclusively fed soy formula from the first few weeks of life. Unfortunately, the misconception that isoflavones are estrogens created considerable alarm, particularly in the media.
We did animal model studies to learn more about the effects of early exposure to phytoestrogens and susceptibility to breast and prostate cancer later in life. The earlier the animals were exposed to phytoestrogens, the greater the protective effect later in life when the animals were subjected to carcinogens that specifically induce either breast or prostate cancer. This inhibition of tumor development and tumor incidence is dramatic, even more so when the animals receive phytoestrogens repeatedly. Further, exposure to phytoestrogens during the neonatal period reduces cancer in animals.
Breast cancer occurs predominantly in breast structures called terminal end buds. Estrogens can cause marked differentiation of terminal end buds into nonsusceptible structures called lobules. When animals are fed phytoestrogens early in life, the breast develops with more lobules relative to terminal end buds. This may explain why phytoestrogen-fed animals, when exposed to a carcinogen, develop far fewer tumors.
If animals are fed isoflavones early in life, prostate size is smaller and testosterone levels are significantly lower later in life. Both these effects would be consistent with a markedly reduced risk for developing prostate cancer. Although phytoestrogens are more likely to be beneficial than negative in the long term, concern about their risk for disease persists. When the Food and Drug Administration was reviewing evidence for a health claim for soy proteins and heart disease, some researchers raised concern that soy intake could reduce T3T4 production as a result of its inhibitory effect on thyroid peroxidase, thus leading to thyroid disease. However, this same effect can result from daily intake of flavonoids found in fruits and vegetables, so a link between soy and thyroid disease seems unlikely based on this evidence.
In terms of early exposure, we know that thyroid hormones are crucial to growth and development. The studies that have compared the impact of soy formulas and breastfeeding with regard to their effect on growth and development have found no differences. Thus, the effects of soy on thyroid hormone must be insignificant.
Dr. David J. Strobl.
I predict that we are going to have an epidemic of diabetes in this country because of the overload of simple sugars in our diets. Many people are following diets very low in fat and high in simple carbohydrates. These diets have been shown to increase blood triglyceride and blood sugar levels, which in the long term could increase insulin resistance.
Dr. McDonald.
The long-term effect of dietary sucrose or any other sugar, including high fructose corn syrup, on insulin resistance is really quite minimal. This issue points out the importance of consuming a nutritionally balanced diet containing a variety of foods in moderation.
Dr. Vuksan.
The basic problem with our diets today is too much energy, whether from sugar or any other energy-yielding nutrient. Although sucrose in itself is not harmful, from a public health perspective, we have a major problem because we consume too much energy, as evidenced by the dramatic rise in obesity among adults and children.
Dr. Strobl.
You can see the problem in the supermarket aisles. All the low-fat foods are loaded with sugar. Americans are suddenly shifting away from the recommended 40/30/30 dietary balance (i.e., 40% carbohydrate, 30% fat, 30% protein).
This article has been cited by other articles:
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  T. Kuroki, K. Isshiki, and G. L. King Oxidative Stress: The Lead or Supporting Actor in the Pathogenesis of Diabetic Complications J. Am. Soc. Nephrol., August 1, 2003; 14(90003): S216 - 220. [Full Text] [PDF]
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