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Biomedical subjects

M F McCarty

Publications and source records attributed to M F McCarty.

At least 55 records · Page 3Linked to original sources
PubMed2001

Does regular ethanol consumption promote insulin sensitivity and leanness by stimulating AMP-activated protein kinase?

There is good reason to believe that regular moderate alcohol consumption promotes insulin sensitivity of skeletal muscle; conceivably, this benefits the protective effects of moderate drinking on vascular health and risk for obesity and diabetes. The mechanism responsible for alcohol's insulin-sensitizing activity remains obscure. As a working hypothesis, it is proposed that metabolism of acetate in peripheral tissues generates sufficient levels of AMP to temporarily stimulate the AMP-activated protein kinase, which in turn induces the synthesis of certain long-lived proteins that act to boost insulin sensitivity and possibly aid the efficiency of fat oxidation as well.

Alcohol Drinking↗
PubMed2000

Parathyroid hormone may be a cancer promoter - an explanation for the decrease in cancer risk associated with ultraviolet light, calcium, and vitamin D.

Epidemiological studies reporting an inverse association between sunlight exposure and risk for cancers of the breast, colon, and prostate, have not yet been explained. Since ultraviolet (UV) light promotes dermal vitamin D generation, studies suggesting that dietary calcium and vitamin D may likewise have cancer-preventive activity are potentially of relevance. UV light, calcium, and vitamin D have the common property of suppressing parathyroid hormone (PTH) production; these considerations raise the possibility that PTH may have promotional activity for certain cancers. PTH might function indirectly in this regard, by increasing hepatic production of the progression growth factor IGF-I, a likely cancer promoter. A more direct role is suggested by recent evidence that many cancers express receptors for PTH/PTH-related protein; these receptors mediate co-mitogenic and/or pro-invasive signals in some cancers. High risk for previous or concurrent neoplasms has been reported in patients with parathyroid adenomas. In light of the increase in cancer risk associated with hypertension, it is notable that PTH levels are typically increased in salt-sensitive hypertensives. Prospective case-control studies examining serum PTH in relation to subsequent cancer risk appear warranted.

Calcium↗
PubMed2000

Toward a wholly nutritional therapy for type 2 diabetes.

It may now be feasible to target specific supplemental nutrients to each of the key dysfunctions which conspire to maintain hyperglycemia in type 2 diabetes: bioactive chromium for skeletal muscle insulin resistance, conjugated linoleic acid for adipocyte insulin resistance, high-dose biotin for excessive hepatic glucose output, and coenzyme Q(10) for beta cell failure. Nutritional strategies which disinhibit hepatic fatty acid oxidation (involving hydroxycitrate, carnitine, pyruvate, and other adjuvants) may likewise prove beneficial - in the short term, by decreasing serum free fatty acids and, in the longer term, by promoting regression of visceral obesity. The nutrients and food factors recommended here appear to be safe and well tolerated, and thus may have particular utility for diabetes prevention.

Biotin↗
PubMed2000

The origins of western obesity: a role for animal protein?

A reduced propensity to oxidize fat, as indicated by a relatively high fasting respiratory quotient, is a major risk factor for weight gain. Increased insulin secretion works in various ways to impede fat oxidation and promote fat storage. The substantial 'spontaneous' weight loss often seen with very-low-fat dietary regimens may reflect not only a reduced rate of fat ingestion, but also an improved insulin sensitivity of skeletal muscle that down-regulates insulin secretion. Reduction of diurnal insulin secretion may also play a role in the fat loss often achieved with exercise training, low-glycemic-index diets, supplementation with soluble fiber or chromium, low-carbohydrate regimens, and biguanide therapy. The exceptional leanness of vegan cultures may reflect an additional factor - the absence of animal protein. Although dietary protein by itself provokes relatively little insulin release, it can markedly potentiate the insulin response to co-ingested carbohydrate; Western meals typically unite starchy foods with an animal protein-based main course. Thus, postprandial insulin secretion may be reduced by either avoiding animal protein, or segregating it in low-carbohydrate meals; the latter practice is a feature of fad diets stressing 'food combining'. Vegan diets tend to be relatively low in protein, legume protein may be slowly absorbed, and, as compared to animal protein, isolated soy protein provokes a greater release of glucagon, an enhancer of fat oxidation. The low insulin response to rice may mirror its low protein content. Minimizing diurnal insulin secretion in the context of a low fat intake may represent an effective strategy for achieving and maintaining leanness.

Animals↗
PubMed2000

Toward practical prevention of type 2 diabetes.

Even in individuals who are unwilling to make prudent changes in their diets and sedentary habits, the administration of certain nutrients and/or drugs may help to prevent or postpone the onset of type 2 diabetes. The evident ability of fiber-rich cereal products to decrease diabetes risk, as documented in prospective epidemiological studies, may be mediated primarily by the superior magnesium content of such foods. High-magnesium diets have preventive (though not curative) activity in certain rodent models of diabetes; conversely, magnesium depletion provokes insulin resistance. Epidemiology also strongly suggests that regular moderate alcohol consumption has a major favorable impact on diabetes risk, particularly in women; this may reflect a direct insulin-sensitizing effect on muscle and, in women, a reduced risk for obesity. Chromium picolinate can also aid muscle insulin sensitivity, and initial reports suggest that it is an effective therapy for type 2 diabetes. High-dose biotin has shown therapeutic activity in diabetic rats and in limited clinical experience; increased expression of glucokinase in hepatocytes may mediate this benefit. Other nutrients that might prove to aid diabetic glycemic control, and thus have potential for prevention, include coenzyme Q and conjugated linoleic acids (CLA). Since the nutrients cited here - including ethanol in moderation - appear to be quite safe and (with the exception of CLA) quite affordable, supplementation with these nutrients may prove to be a practical strategy for diabetes prevention. Drugs such as metformin and troglitazone, which are expensive and require regular physician monitoring to avoid potentially dangerous side-effects, would appear to be less practical options from cost-effectiveness, convenience and safety standpoints, given the fact that the population at-risk for diabetes is huge.

Animals↗
PubMed2000

The insulin-sensitizing activity of moderate alcohol consumption may promote leanness in women.

Cross-sectional epidemiology reveals that women who drink alcohol regularly and moderately, on average, tend to have a decidedly lower body-mass index (BMI) than non-drinking women, despite slightly higher caloric intakes. In men, moderate drinkers are no heavier than non-drinkers, yet they consume considerably more calories. The thermogenic effect which this implies is not explained by the modest acute thermic effect of ethanol ingestion. However, there is indirect evidence that regular alcohol consumption has an insulin-sensitizing effect on skeletal muscle that down-regulates insulin secretion. Decreased insulin activity on adipocytes and the liver may discourage fat storage and promote hepatic mechanisms of ketogenesis, gluconeogenesis, and associated thermogenesis, thus possibly accounting for the relative leanness of female drinkers. The possibility that prescribing moderate alcohol intake could aid weight control in non-drinking overweight females should receive clinical evaluation. The impact of moderate drinking on risk for diabetes in women appears to be quite dramatic.

Body Composition↗
PubMed2000

Sulfated glycosaminoglycans and glucosamine may synergize in promoting synovial hyaluronic acid synthesis.

High-molecular-weight hyaluronic acid (HA) produced by the synovium may function physiologically to aid preservation of cartilage structure and prevent arthritic pain; both the size and concentration of HA in synovial fluid are diminished in osteoarthritis (OA). Glucosamine therapy for OA can be expected to increase synovial HA production by providing rate-limiting substrate. In addition, certain sulfated glycosaminoglycans and polysaccharides - including chondroitin sulfate (CS), dermatan sulfate, and pentosan polysulfate - stimulate synovial HA production, apparently owing to a hormone-like effect triggered by the binding of these polymers to membrane proteins of synovial cells. Surprisingly, a significant proportion of orally administered CS is absorbed as intact polymers - apparently by pinocytosis. These considerations may rationalize clinical studies concluding that oral CS provides slow-onset but durable pain relief and functional improvement in OA. The possibility that oral glucosamine and CS may interact in a complementary or synergistic fashion to improve synovial fluid HA content in OA should be assessed in clinical studies, and the potential of adjunctive CS administration to improve the clinical response achievable with optimal intakes of glucosamine should likewise be evaluated. In light of the fact that the synovium virtually functions as a 'placenta' for cartilage, focusing on synovium as the target for therapeutic intervention in OA may be a rational strategy.

Administration, Oral↗
PubMed2000

High-dose pyridoxine as an 'anti-stress' strategy.

Pyridoxine nutritional status has a significant and selective modulatory impact on central production of both serotonin and GABA - neurotransmitters which control depression, pain perception, and anxiety - owing to the fact that the decarboxylases which produce these neurotransmitters have a relatively low affinity for pyridoxal phosphate (PLP). Pyridoxine deficiency leads to increased sympathetic outflow and hypertension in rodents, possibly reflecting decreased central production of these neurotransmitters; conversely, supplemental pyridoxine lowers blood pressure in many animal models of hypertension, and there is preliminary evidence for antihypertensive activity in humans as well. Additionally, physiological levels of PLP interact with glucocorticoid receptors to down-regulate their activity. Thus, high-dose pyridoxine, by amplifying tissue levels of PLP, may be expected to have a favorable impact on certain dysphoric mental states, while diminishing sympathetic output and acting peripherally to blunt the physiological impact of corticosteroids. In light of growing evidence that chronic dysphoria, particularly when accompanied by hopelessness or cynicism, has a major negative impact on morbidity and mortality from a wide range of disorders, high intakes of pyridoxine may have the potential to improve prognosis in many individuals. With respect to cardiovascular health, reduction of homocysteine levels should contribute to this benefit. These predictions are consistent with recent epidemiology correlating plasma PLP levels with risk for vascular events and overall survival.

Animals↗
PubMed2000

Prenatal high-dose pyridoxine may prevent hypertension and syndrome X in-utero by protecting the fetus from excess glucocorticoid activity.

The increased risk for hypertension, insulin resistance syndrome, and coronary events associated with small-for-gestational-age birth, has plausibly been attributed to excessive prenatal exposure to glucocorticoids; this may up-regulate glucocorticoid activity throughout life by permanently decreasing expression of hippocampal glucocorticoid receptors crucial for feedback control of cortisol secretion. Since pyridoxal phosphate is a safe physiological antagonist of glucocorticoid activity, it is proposed that prenatal supplementation with high-dose pyridoxine may counteract the adverse impact of glucocorticoids on fetal growth, as well as on subsequent cardiovascular risk.

Dose-Response Relationship, Drug↗
PubMed2000

Insulin secretion as a potential determinant of homocysteine levels.

The recently reported association between insulin resistance and elevated plasma homocyst(e)ine may reflect the fact that hyperinsulinemia suppresses hepatocyte expression of cystathionine beta-synthase, as demonstrated in rats. Thus, other measures which enhance diurnal insulin secretion - such as a high-glycemic-index diet - can be expected to increase homocysteine levels.

Animals↗
PubMed2000

Monoselenolipoic acid may be an outstanding pharmaceutical antioxidant with direct thioredoxin-like activity.

Owing to the low pKa of its selenohydryl group, reduced monoselenolipoic acid (MSL) can be expected to be a very versatile antioxidant with direct thioredoxin-like activity. Since MSL supports the growth of lipoate-dependent bacteria, it can be anticipated that MSL will be susceptible to reversible reduction by one or more of the enzymes that reduces lipoic acid - thus greatly potentiating MSL's utility as an antioxidant. If it is not metabolized to release toxic free selenide, MSL may have interesting pharmaceutical potential.

Antioxidants↗
PubMed2000

Activation of PPARgamma may mediate a portion of the anticancer activity of conjugated linoleic acid.

A number of human cancer cell lines express the PPARgamma transcription factor, and agonists for PPARgamma are reported to promote apoptosis in these cell lines and impede their clonal expansion both in vitro and in vivo. Conjugated linoleic acid (CLA) can activate PPARgamma in rat adipocytes, possibly explaining CLA's antidiabetic effects in Zucker fatty rats. It is thus reasonable to suspect that a portion of CLA's broad spectrum anticarcinogenic activity is mediated by PPARgamma activation in susceptible tumors.

Adipocytes↗
PubMed2000

Co-administration of equimolar doses of betaine may alleviate the hepatotoxic risk associated with niacin therapy.

High-dose niacin has versatile and substantial efficacy for the treatment of hyperlipidemias, but its utility is compromised by various side effects, the most serious of which is liver damage. It is proposed that this hepatotoxicity reflects the high demand for methyl groups imposed by niacin catabolism, leading to a reduction in hepatic levels of S-adenosylmethionine (SAM). Depletion of the hepatic SAM pool has likewise been shown to mediate, at least in part, the hepatotoxic effects of ethanol, methotrexate, and niacinamide. If niacin does indeed decrease SAM, a likely consequence would be a counterproductive elevation of plasma homocysteine. Conceivably, methyl group deficiency, by altering membrane properties of skeletal muscle, also contributes to niacin-induced insulin resistance. Concurrent betaine supplementation - preferably administered as a complex with equimolar amounts of niacin - may represent the most cost-effective way to prevent niacin-mediated depletion of SAM and thus avoid hepatotoxicity (and possibly other adverse effects) while controlling homocysteine. Betaine also merits evaluation as an adjuvant to methotrexate and niacinamide therapies.

Animals↗
PubMed2000

Glucosamine for migraine prophylaxis?

Following a fortuitous observation that migraine headaches ceased in a patient receiving glucosamine therapy for osteoarthritis, a further ten patients with migraine or migraine-like vascular headaches, refractory to established preventive or abortive therapies, have been treated with daily oral glucosamine. After a lag of 4-6 weeks, a substantial reduction in headache frequency and/or intensity has been noted; in some cases, the benefit appears to be dose-dependent. Since glucosamine can be a rate-limiting precursor for mucopolysaccharide synthesis, it is germane to note previous reports that heparin and pentosan polysulfate may have migraine-preventive activity. There is reason to suspect that mast cells are central mediators of the neurogenic inflammation associated with migraine and cluster headaches. The heparin produced by mast cells may function to provide feedback down-regulation of mast cell activation, and exerts a range of other anti-inflammatory effects. We postulate that supplemental glucosamine can boost mast cell heparin synthesis - perhaps correcting a functional heparin deficiency - thereby preventing or ameliorating the neurogenic inflammation that mediates pain in vascular headache. Whether or not this idea has validity, a controlled study of glucosamine for migraine prophylaxis appears to be warranted.

Glucosamine↗
PubMed2000

DL-phenylalanine markedly potentiates opiate analgesia - an example of nutrient/pharmaceutical up-regulation of the endogenous analgesia system.

In the author's clinical experience, concurrent treatment with DL-phenylalanine (DLPA) often appears to potentiate pain relief and also ease depression in patients receiving opiates for chronic non-malignant pain. An analysis of this phenomenon suggests that it may be mediated, at least in part, by up-regulation of the 'endogenous analgesia system' (EAS), a neural pathway that projects caudally from medullary nuclei to the dorsal horn of the spinal column; when stimulated by chronic pain or therapeutic measures such as opiates or acupuncture, the EAS suppresses activation of second-order pain-receptive neurons in the dorsal horn, and thereby alleviates pain. Since serotonin and enkephalins are key neurotransmitters in the EAS, it is reasonable to predict that measures which promote serotonin activity (such as 5-hydroxytryptophan and serotonin-reuptake inhibitors) as well as enkephalin activity (such as D-phenylalanine, an enkephalinase inhibitor) should potentiate EAS-mediated analgesia - a view consistent with much previous medical research. Comprehensive support of the EAS with well-tolerated nutrients and pharmaceuticals may amplify the analgesic efficacy of chronic opiate therapy, while enabling dosage reductions that minimize opiate side-effects. Analogously, this approach may complement the efficacy of acupuncture and other analgesic measures that activate the EAS.

Analgesia↗
PubMed2000

Increased homocyst(e)ine associated with smoking, chronic inflammation, and aging may reflect acute-phase induction of pyridoxal phosphatase activity.

Smokers, patients with chronic inflammatory disorders, and the elderly, are characterized by increased production of IL-6 as well as increased plasma levels of homocyst(e)ine. Analysis of cirrhotic livers suggests that IL-6 may stimulate the activity of pyridoxal phosphatase in hepatocytes, thereby diminishing pyridoxal phosphate levels, compromising cystathionine beta-synthase activity, and raising plasma homocyst(e)ine. Adequate supplemental intakes of pyridoxine may be corrective in this regard.

Acute-Phase Reaction↗
PubMed2000

Up-regulation of endothelial nitric oxide activity as a central strategy for prevention of ischemic stroke - just say NO to stroke!

Nitric oxide (NO) produced by the endothelium of cerebral arterioles is an important mediator of endothelium-dependent vasodilation (EDV), and also helps to prevent thrombosis and vascular remodeling. A number of risk factors for ischemic stroke are associated with impaired EDV, and this defect is usually at least partially attributable to a decrease in the production and/or stability of NO. These risk factors include hypertension, high-sodium diets, homocysteine, diabetes, visceral obesity, and aging. Conversely, many measures which may provide protection from ischemic stroke - such as ample dietary intakes of potassium, arginine, fish oil, and selenium - can have a favorable impact on EDV. Protection afforded by exercise training, estrogen replacement, statin drugs, green tea polyphenols, and cruciferous vegetables may reflect increased expression of the endothelial NO synthase. IGF-I activity stimulates endothelial NO production, and conceivably is a mediator of the protection associated with higher-protein diets in Japanese epidemiology and in hypertensive rats. These considerations prompt the conclusion that modulation of NO availability is a crucial determinant of risk for ischemic stroke. Multifactorial strategies for promoting effective cerebrovascular NO activity, complemented by measures that stabilize platelets and moderate blood viscosity, should minimize risk for ischemic stroke and help maintain vigorous cerebral perfusion into ripe old age. The possibility that such measures will also diminish risk for Alzheimer's disease, and slow the normal age-related decline in mental acuity, merits consideration. A limited amount of ecologic epidemiology suggests that both stroke and senile dementia may be extremely rare in cultures still consuming traditional unsalted whole-food diets. Other lines of evidence suggest that promotion of endothelial NO activity may decrease risk for age-related macular degeneration.

Animals↗