The healing relationship is best conceived of as a form of “dialogue”—
not only between patient and practitioner but also between nutrient triggers and self-regulating systems.
Health is the result of balanced interchange between mutually interacting physiologic processes: a change in one system affects the function of the entire organism.1Imbalance in one system may modify the function of other organ systems; similarly, imbalance in one system may be minimized by changes in interacting systems.
Homeostatic mechanisms interact to maintain bodily functions within viable limits. Negative feedback systems tend to minimize fluctuations and restore the status quo. Positive feedback systems prime the organism to cope with untoward events.
Homeostasis depends on successful communication. Messages are trans- mitted by means of one of two distinct systems. The nervous system trans- mits messages as electrical impulses along neural pathways, and the endocrine system conveys chemical information in the blood and interstitial fluid. Three prerequisites to a homeostatic system are a receptor, a control center, and an effector. The receptor receives information from the environ- ment in the form of stimuli. Stimuli may be physical, chemical, microbial, or psychosocial in nature. The control center determines the set point at which a process is to be maintained. The effector provides an afferent pathway that feeds information back to influence the stimulus. Consistent with the infomedical model, the flow of information in a homeostatic feedback sys- tem is circular, rather than linear. Multiple triggers, interacting at the level of diverse organ systems, converge and diverge at various interfaces to deter- mine health or disease, wellness or dysfunction. Nutrition is one factor that contributes to the cybernetic circularity of mutual causality.
This chapter explores how diet, herbs, and supplements can modify phys- iologic and pathologic mechanisms. It demonstrates how biologic plausibil- ity provides a sound basis for guiding investigation into nutritional
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management and shows how the complex interactions involved in home- ostasis make it difficult to accurately predict clinical outcome despite sound pathophysiologic principles.
NEGATIVE FEEDBACK SYSTEM OF GLUCOSE HOMEOSTASIS Negative feedback systems prevent extreme change. They continually adjust the system to maintain function within an acceptable range. A negative feed- back system is one in which the afferent pathway depresses the control mechanism and seeks to neutralize the input. It keeps a balance between input and output. Most homeostatic systems depend on negative feedback.
Examples include control of blood glucose levels, blood pressure, heart rate, and respiratory rate.
Adenosine Triphosphate: The Currency of Cellular Energy Complete catabolism of glucose produces energy (adenosine triphosphate [ATP]), water, carbon dioxide, and heat. Glucose is the major source of fuel for all cells; it is immediately available from the blood, and the levels are replenished as required. The gastrointestinal tract extracts simple sugars from foods and absorbs monosaccharides into the bloodstream, elevating the blood sugar level. As organs extract glucose from the bloodstream to meet their particular metabolic requirements, blood glucose levels start to fall. Glycogen, the storage form of carbohydrate in animals, is then con- verted to glucose. Glycogen, the human equivalent of starch in plants, is pro- duced and stored in the liver and skeletal muscle. The liver stores about 100 g of glycogen and provides an immediately available reserve of glucose (see Figure 3-1). When energy is required, glycogen is broken down to glucose, which is further catabolized to pyruvate with the generation of two mole- cules of ATP. Under aerobic conditions, pyruvate enters the tricarboxylic acid cycle and generates reduced nicotinamide adenine dinucleotide and the reduced form of flavin adenine dinucleotide, which produce cellular energy via the electron transport chain. Hepatic glycogen can maintain blood glu- cose levels for about 4 hours after absorption. Glucose released from muscle glycogen is used to fuel skeletal muscle.
Glycogen from skeletal muscles may indirectly contribute to restoration of blood glucose levels by release of metabolic intermediates such as pyru- vic acid or lactic acid. Only glucose derived from liver glycogen directly restores blood glucose levels. As glycogen is depleted, new sources of glu- cose are sought. Gluconeogenesis is the process whereby noncarbohydrate sources of energy are recruited. Glucogenic amino acids and glycerol can be
A negative feedback system dampens biologic responses, keeping them within an acceptable physiologic range.
used to restore blood glucose levels and, in conjunction with fatty acids, boost energy reserves. With prolonged fasting, the body adapts by relying more on fat and protein as its energy sources. All tissues, except the brain, increasingly use fatty acids as their dominant energy source. If fasting con- tinues for longer than 5 days, the brain starts to supplement its use of glu- cose with ketone bodies as its fuel source (see Figure 3-2). When glucose is plentiful and intracellular ATP levels are high, further glucose breakdown is inhibited. Glucose is then converted to the energy storage forms of glycogen or fat. Fat is the major form of stored energy.
GLYCOLYSIS
GALACTOSE
FRUCTOSE
Pyruvate Anaerobic conditionsLactate Aerobic conditions
Glyceraldehyde−3-phosphate GLYCEROL
TCA cycle Acetyl Co A
Dihydroxyacetone phosphate
GLUCOSE GLYCOGEN
Glucose−1-Phosphate
Glucose-6-Phosphate Fructose-1,6-diphosphate
TRIGLYCERIDES
LACTIC ACID GLYCEROL
GLUCOSE
Glycogen depleted
TCA cycle - Tricarboxylic acid cycle (Krebs) PYRUVATE
GLUCOGENIC AMINO ACIDS KETOGENIC AMINO ACIDS
ACETYL Co A TCA CYCLE
Ketone bodies FATTY ACIDS
FIG. 3-1 Carbohydrates as a source of energy. *Liver glycogen serves as a store to regulate blood glucose levels between meals; muscle glycogen cannot release glucose into the blood.
FIG. 3-2 Energy sources.
A Finely Poised Negative Feedback System
Voluntary triggers, such as exercise intensity and dietary selection, affect blood glucose levels, which can be maintained between 4.5 and 7.5 mmol/L.
The blood glucose level is the result of the interaction of multiple systems that combine to stabilize blood glucose levels within a defined range (see Figure 3-3). After ingestion of a high-carbohydrate meal, glucose is absorbed directly into the bloodstream, and blood glucose levels peak. When blood glucose levels are high, the liver converts glucose to glycogen for short-term storage and to fat for long-term storage, reducing blood glucose levels.
Hormones secreted in response to rising blood glucose levels assist the liver in reducing blood glucose levels. Thyroxin increases cellular uptake and uti-
HIGH BLOOD SUGAR
Hormonal changes increase blood sugar
increase cellular uptake of glucose stimulate glycogen formation GLUCAGON stimulates glycogenolysis
gluconeogenesis
hepatocyte release of glucose CORTISOL
provokes gluconeogenesis mobilises fat from adipose tissue GROWTH HORMONE
decreases glucose uptake & metabolism mobilises fatty acids
enhances glycogenolysis EPINEPHRINE
increases glyconeogenesis
Stimulates hyperglycemic hormone release
LOW BLOOD SUGAR
INSULIN
Lowers blood glucose Stimulates insulin release
FIG. 3-3 Blood glucose—a negative feedback system. Gluconeogenesis is the formation of glu- cose from noncarbohydrate sources (i.e., fat and protein). Glycogenolysis is the breakdown of glyco- gen to glucose.
Liver glycogen is depleted after 12 to 15 hours of fasting; muscle glycogen is depleted by prolonged strenuous exercise.
lization of glucose for energy, while insulin binds to membrane receptors of target cells and facilitates the entry of glucose. Within minutes of its release, insulin increases the cellular uptake of glucose some 20-fold. Only brain cells can actively take up glucose in the absence of insulin.
Insulin reduces blood glucose levels by stimulating utilization of glucose for energy, stimulating glucose uptake by cells, and enhancing synthesis of glycogen (glycogenesis) and by inhibiting production of glucose (gluconeo- genesis). This endocrine-mediated, homeostatic, negative feedback system seeks to restore blood glucose levels to within a physiologically acceptable range.
Hours after the last meal, blood glucose levels are maintained above 4 or 5 mmol/L by the liver, which makes glucose available through glycolysis.
When hepatic glycogen stores are depleted and blood glucose requires replenishing, the liver converts amino acids and glycerol to glucose. The increase in blood glucose levels is achieved by increased gluconeogenesis with the help of glucagon, epinephrine, cortisol, and growth hormones and by glycogenolysis with the aid of glucagon and epinephrine.
The liver, along with various hormones, plays a particularly important role in blood glucose homeostasis (see Figure 3-3). The endocrine system secretes hormones that elevate or depress blood glucose levels as required.
Disorders of Blood Glucose
Given all the variables that converge to influence blood glucose levels, it is scarcely surprising that blood glucose levels may deviate outside a physio- logic range. When the blood glucose level rises, the condition is called hyper- glycemia; when it falls, it is called hypoglycemia.
Hypoglycemia. Hypoglycemia may be triggered by extraneous adminis- tration of insulin, by fasting, or by alcohol abuse. Hypoglycemia occurs within 24 hours of a drinking binge unaccompanied by food. Symptomatic hypoglycemia appears to be related to the rate of decline in the blood glu- cose level, the actual blood glucose level, and the intensity of the homeosta- tic response attempting to normalize blood glucose levels.
When the blood glucose level drops to around 4 to 5 mmol/L, epineph- rine and glucagon are secreted to increase blood glucose levels. Increased levels of catecholamine have a physical impact, and persons with hypo- glycemia may experience headache, palpitations, sweating, tremors, and restlessness. At a level of 4 mmol/L, sophisticated tests can detect early cog- nitive changes. As the blood glucose level falls below 4 mmol/L, cognitive changes become more marked; at this level, neurogenic evidence of hypo- glycemia appears. Neuroglycopenic symptoms range from confusion and
Blood glucose levels trigger release of hormones that increase or decrease utilization or production of glucose as needed.
impaired performance to behavioral changes, such as irrational anger and aggression. Visual disturbances such as diplopia may be experienced. When the blood glucose level falls below 3 mmol/L, neuroglycopenic symptoms predominate and drowsiness is noted; there is also a substantial risk for coma and seizures when the blood glucose level drops below 2.5 mmol/L.
Fasting hypoglycemia is gradual in onset, and symptoms persist until fasting ceases. In contrast, functional or reactive hypoglycemia occurs sud- denly, 2 to 5 hours after a meal, and symptoms are transient. Catecholamine- mediated symptoms include transient episodes of dizziness, weakness, poor concentration, anxiety, and depression. Characteristic neuroglycopenic symptoms are chronic or intermittent fatigue, episodic tiredness within 1 hour of eating, and sleep disturbance. Although the underlying mechanism remains disputed, fasting hypoglycemia has been hypothesized to be trig- gered by enhanced insulin sensitivity, impaired glucose homeostatic mecha- nisms, and food or chemical sensitivity. The condition is more often encountered in persons who consume large quantities of coffee, tea, alcohol, and tobacco and in those who have a sweet tooth.
Hyperglycemia. Hyperglycemia may result from increased levels of corti- sol, epinephrine, or glucagon; defective insulin release; or increased insulin resistance. It is estimated that around one in three persons in countries with a Western lifestyle have a degree of insulin resistance and the health conse- quences associated with this metabolic derangement.2
Blood glucose levels tend to rise because tissues are less responsive to the insulin-driven clearance of glucose from the bloodstream. A self-perpetuating, disturbed, positive-feedback, metabolic cycle may be established as persist- ent hyperglycemia further enhances insulin resistance.
Insulin resistance, also characterized by higher fasting and postglucose- loading insulin levels, seems to be a common feature and a possible con- tributing factor to various health problems including polycystic ovary disease, dyslipidemia, hypertension, cardiovascular disease, sleep apnea, certain hormone-sensitive cancers, obesity, and type 2 diabetes mellitus.3
Diabetes mellitus is a prevalent condition of aberrant carbohydrate and lipid metabolism characterized by increased blood glucose levels. Two vari- ants of diabetes mellitus have been described. Lean patients with diabetes are usually insulin-deficient, whereas obese patients with diabetes are character- istically insulin-resistant and have a relative insulin deficiency. Insulin-
No single threshold at which the blood glucose level triggers symptoms of hypoglycemia has been established.
The ability of insulin to dispose of glucose in the liver, skeletal muscle, and other peripheral tissues is compromised in insulin resistance
dependent diabetes usually presents in young people who complain of weight loss, thirst, and frequent urination. Without insulin replacement, ketosis may develop and these patients may lose consciousness. In contrast, patients with noninsulin-dependent, or type 2, diabetes are usually older and obese, often have a family history of diabetes, and experience excessive fatigue. Insulin resistance or decreased tissue sensitivity to insulin is associated with an increased prevalence of abnormal blood lipids, hypertension, and a tendency for blood to clot.4In patients with type 2 diabetes, lifestyle and dietary man- agement may be sufficient to control blood glucose levels. Lifestyle and nutri- tional management of diabetes mellitus are discussed in detail in Part II.
Natural Intervention Measures
An intact negative feedback system usually compensates for dietary and energy utilization fluctuations. In persons in whom this system is defective, lifestyle choices may exacerbate or minimize clinical repercussions.
Glycemic Index: A Useful Guide to Food Selection. The glycemic index is the degree to which a food raises blood glucose levels relative to the same amount of oral glucose. Sugar, fruit juice, white bread, and pasta have a high glycemic index. A meal rich in simple sugars taxes the system by suddenly delivering a large bolus of glucose to the pancreas. The blood glucose level determines the amount of insulin secreted by the pancreas. A large bolus of absorbed glucose stimulates release of a large amount of insulin. Because a diet of simple sugars is rapidly absorbed, the glucose substrate for insulin is rapidly exhausted, and the blood glucose level drops rapidly. On the other hand, a diet rich in complex carbohydrates results in slower absorption of glucose because digestive juices take longer to reach and break down the polysaccharides in whole foods. Prolonged slower absorption of glucose results in both a smaller amount of insulin being released and a more pro- longed delivery of substrate. Foods with a low glycemic index (i.e., foods that cause a more controlled and moderate rise in the blood glucose level) include legumes, barley, oats, and rice. A high-fiber diet is reputed to reduce postprandial blood glucose levels, maintain a lower basal blood glucose con- centration, and enhance sensitivity to insulin.5
The glycemic index of food is influenced by its texture and content (e.g., the physical state of fiber, the type of carbohydrate present, and the presence of fat).6Rice, for example, has a lower glycemic index than potatoes because rice has a branched chemical structure and potatoes have a linear chain
Pathophysiologic stress can be modulated by dietary choices.
Control of the blood glucose level is enhanced by selecting foods with a low glycemic index.
chemical structure. White rice is preferred, because brown rice contains lectins to which the patient may be sensitive. Although the precise mecha- nisms that determine a food’s glycemic index remain obscure, it has been noted that the quality of fiber is itself an important glycemic determinant.
Like fat, viscous fiber may induce a smaller glycemic response because of its slower gastric emptying time. In addition to delaying gastric emptying, water-soluble fiber delays glucose absorption from the small intestine by cre- ating an unstirred water barrier and reducing intestinal motility. In contrast, insoluble fiber retards glucose absorption by insulating starch from intes- tinal hydrolytic enzymes and accelerating intestinal transit. In any event, persons with reactive hypoglycemia benefit from dietary choices that result in a low-sugar, high–complex-carbohydrate diet. Frequent small meals may also be helpful.
Carbohydrates and Athletic Performance. Knowledge of glucose home- ostasis is useful to endurance athletes. High-carbohydrate diets can increase an athlete’s endurance by increasing glycogen stores. Exercise depletes mus- cle glycogen. When muscle glycogen is depleted, muscles become fatigued.
The complete breakdown of glycogen to glucose and energy can only occur in the presence of sufficient oxygen. During intense exercise, an oxygen debt can develop, and muscle glycogen is converted by means of pyruvic acid into lactic acid. Pain results when lactic acid accumulates in muscle faster than the circulation removes it. Lactic acid is converted to glucose in the liver.
The first 20 minutes of moderate exercise is fuelled mainly by glycogen.
As muscle glycogen stores decrease, the blood glucose level rises as liver glycogen is broken down. With time, glycogen utilization and stores decrease, and fat becomes an important source of energy. Training increases the quantity of glycogen stored in muscle; it increases the muscle mitochon- dria, and therefore, the aerobic metabolism of muscle; and it increases lean body mass. An adequate protein intake is also necessary.
Athletes can use a diet high in carbohydrates to trigger increased glycogen storage. Athletes require a daily intake of 9 to 10 g of carbohydrates per kilo- gram body of weight, or 60% to 70% of their energy intake from carbohy- drates, to maximize their potential. Glycogen repletion should be started as soon as possible after exercise. Consumption of about 0.7 g of carbohydrate per kilogram of body weight is recommended every 2 hours for the first 4 to 6 hours after exercise. Simple sugars are more effectively absorbed than starches, and liquid supplements are often the preferred option after exercise.
Carbohydrate loading may be undertaken by either of the following:
● Reducing training efforts and increasing carbohydrate intake 48 to 72 hours before competition. Body weight should be increased by 1 to 2 kg.
Associated with each gram of glycogen stored are 3 g of water.
Glycogen stores can be increased by eating a diet rich in carbohydrates.
● Reducing carbohydrate intake to 50% of total calories for the first half week before competition while gradually decreasing training intensity.
During the second half of the week, training is further reduced, but car- bohydrates are boosted to 70% of calories or 10 g/kg body weight.
Meals should be eaten 3 to 6 hours before the event and should contain at least 100 g of carbohydrates or approximately 4.5 g/kg body weight.
Carbohydrates should be avoided 30 to 45 minutes before competition.
Recent research suggests that a high-carbohydrate maintenance diet coupled with cutting down on training for one or more days before a major sporting event can result in equally high levels of muscle glycogen. This strategy pre- vents the side effects of extreme fatigue during the depletion phase and muscle soreness caused by water retention in muscle fibers during the glyco- gen repletion/high-carbohydrate intake stage.
During exercise, carbohydrates will improve performance if the exercise lasts for more than 1 hour. The optimal range of intake is 20 to 30 g of car- bohydrate for each 30 minutes. After exhaustive exercise, it can take 24 hours to replenish glycogen muscle stores. Because the rate of glycogen synthesis is potentially 50% greater during the first 2 hours after exercise, optimal recovery after exercise can be achieved by the following:
● Consuming carbohydrate-rich foods and drinks as soon as possible after finishing exercise. High levels of glycogen synthetase are present, and muscle cell walls are highly permeable and sensitive to insulin immedi- ately after exercise. Carbohydrates are most rapidly absorbed if no fat or protein is present. Fruit and fruit juices are ideal choices.
● Continuing to drink over the next few hours, even if not thirsty.
● Keeping alcohol, and to a lesser extent caffeine, consumption to a mini- mum.
Recent studies suggest that the glycemic index of foods is an important con- sideration in exercise. It appears that consumption of foods with a low glycemic index before prolonged exercise may provide a more slowly released source of glucose for exercising muscles and result in greater endurance. It has therefore been suggested that generous amounts of foods with a low glycemic index (apples, peaches, baked beans, lentils, bran cere- als, milk, and yogurt) should be eaten before prolonged exercise. In contrast, during exercise, high–glycemic-index drinks are beneficial to prevent hypo- glycemia and dehydration. After intense exercise, optimal recovery of mus- cle glycogen stores is achieved by consuming high–glycemic-index foods such as bread, pasta, corn flakes, potatoes, bananas, honey, fruit juice, and sports drinks.7
The dominant effect of a negative feedback system is prevention of unacceptable fluctuations; it maintains biologic functions within a
physiologically acceptable range.