Bea Selmass’s studies confirmed that her fasting serum glucose levels were These events contribute to the long-term below normal generic 17.5 mg lisinopril fast delivery. She continued to experience the fatigue purchase lisinopril 17.5 mg fast delivery, confusion cheap lisinopril 17.5 mg mastercard, and blurred microvascular and macrovascular complica- vision she had described on her first office visit generic lisinopril 17.5mg line. These symptoms are called tions of diabetes mellitus, which include dia- neuroglycopenic (neurologic symptoms resulting from an inadequate supply of glucose betic retinopathy, nephropathy, and neu- to the brain for the generation of ATP). Stimulation of the sympathetic nervous system (because of the low lev- eral artery insufficiency (macrovascular). Elevated epinephrine levels cause tachycardia, palpitations, anxiety, tremulousness, pallor, and sweating. In addition to the symptoms described by Bea Selmass, individuals may experience confusion, lightheadedness, headache, aberrant behavior, blurred vision, loss of con- sciousness, or seizures. Selmass’s doctor explained that the general diagnosis of “fasting” hypoglycemia was now established and that a specific cause for this disorder must be found. CHAPTER 26 / BASIC CONCEPTS IN THE REGULATION OF FUEL METABOLISM BY INSULIN, GLUCAGON, AND OTHER HORMONES 481 Glycogen Liver + – Protein – + Glucose + Fatty acids Amino + acids Protein VLDL + Glucose CO2 Glycogen + Fatty acids Skeletal muscle – + Triacylglycerols Adipocyte Fig 26. Insulin and glucagon are not the only regulators of fuel metabolism. The inter- tissue balance between the utilization and storage of glucose, fat, and protein is also accomplished by the circulating levels of metabolites in the blood, by neuronal sig- The message carried by glucagon nals, and by the other hormones of metabolic homeostasis (epinephrine, norepi- is that “glucose is gone”; i. These hormones oppose the actions of current supply of glucose is inade- insulin by mobilizing fuels. Like glucagon, they are called insulin counterregulatory quate to meet the immediate fuel require- hormones (Fig. Of all these hormones, only insulin and glucagon are synthe- ments of the body. Glycogen Liver – + Glucose – + Fatty acids Amino acids Glucose Fatty acids Fatty acids No efffect + Skeletal Triacylglycerols muscle Adipocyte Fig 26. Physiologic Actions of Insulin and Insulin Counterregulatory carbohydrate Hormones meal Hormone Function Major Metabolic Pathways Affected Insulin • Promotes fuel storage after • Stimulates glucose storage as glyco- 120 a meal gen (muscle and liver) • Promotes growth • Stimulates fatty acid synthesis and 100 storage after a high-carbohydrate meal Glucose • Stimulates amino acid uptake and 80 protein synthesis Glucagon • Mobilizes fuels • Activates gluconeogenesis and 120 • Maintains blood glucose glycogenolysis (liver) during fasting levels during fasting • Activates fatty acid release from adipose tissue 80 Insulin Epinephrine • Mobilizes fuels during acute • Stimulates glucose production from stress glycogen (muscle and liver) 40 • Stimulates fatty acid release from adipose issue 0 Cortisol • Provides for changing • Stimulates amino acid mobilization requirements over the from muscle protein long-term • Stimulates gluconeogenesis 120 • Stimulates fatty acid release from Glucagon adipose issue 110 100 90 60 0 60 120 180 240 Minutes Fig 26. Blood glucose, insulin, and glucagon levels after a high-carbohydrate meal. Low Blood Glucose Hypothalamic regulatory center Pituitary ACTH Autonomic nervous system A cells Cortex Medulla Adrenal Pancreas Cortisol Epinephrine Norepinephrine Glucagon Fig 26. The stress of a low blood glucose level mediates the release of the major insulin counterregulatory hormones through neuronal sig- nals. Hypoglycemia is one of the stress signals that stimulates the release of cortisol, epi- nephrine, and norepinephrine. Adrenocorticotropic hormone (ACTH) is released from the pituitary and stimulates the release of cortisol (a glucocorticoid) from the adrenal cortex. Neuronal signals stimulate the release of epinephrine from the adrenal medulla and norepi- nephrine from nerve endings. Neuronal signals also play a minor role in the release of glucagon. Although norepinephrine has counterregulatory actions, it is not a major counter- regulatory hormone. CHAPTER 26 / BASIC CONCEPTS IN THE REGULATION OF FUEL METABOLISM BY INSULIN, GLUCAGON, AND OTHER HORMONES 483 sized and released in direct response to changing levels of fuels in the blood. The The message that insulin carries to release of cortisol, epinephrine, and norepinephrine is mediated by neuronal sig- tissues is that glucose is plentiful nals. Rising levels of the insulin counterregulatory hormones in the blood, reflect, and it can be used as an immediate fuel or can be converted to storage forms for the most part, a current increase in the demand for fuel. SYNTHESIS AND RELEASE OF INSULIN Because insulin stimulates the uptake of AND GLUCAGON glucose into tissues where it may be immedi- ately oxidized or stored for later oxidation, this A. Endocrine Pancreas regulatory hormone lowers blood glucose lev- Insulin and glucagon are synthesized in different cell types of the endocrine pancreas, els.
CHAPTER 9 / REGULATION OF ENZYMES 143 consequence discount lisinopril 17.5mg on-line, an apparent value of Km (Km safe 17.5 mg lisinopril,app) depends on the concentration of cosubstrate or product present 17.5 mg lisinopril fast delivery. RATES OF ENZYME-CATALYZED REACTIONS IN THE CELL Equations for the initial velocity of an enzyme-catalyzed reaction 17.5 mg lisinopril overnight delivery, such as the Michaelis-Menten equation, can provide useful parameters for describing or com- paring enzymes. However, many multisubstrate enzymes, such as glucokinase, have kinetic patterns that do not fit the Michaelis-Menten model (or do so under non- physiologic conditions). The Michaelis-Menten model is also inapplicable to enzymes present in a higher concentration than their substrates. Nonetheless, the term “Km” is still used for these enzymes to describe the approximate concentration of substrate at which velocity equals 1⁄2 V. Reversible Inhibition within the Active Site One of the ways of altering enzyme activity is through compounds binding in the active site. If these compounds are not part of the normal reaction, they inhibit the enzyme. An inhibitor of an enzyme is defined as a compound that decreases the velocity of the reaction by binding to the enzyme. It is a reversible inhibitor if it is not covalently bound to the enzyme and can dissociate at a significant rate. Reversible inhibitors are generally classified as competitive, noncompetitive, or uncompetitive with respect to their relationship to a substrate of the enzyme. In most reactions, the products of the reaction are reversible inhibitors of the enzyme producing them. COMPETITIVE INHIBITION A competitive inhibitor “competes” with a substrate for binding at the enzyme’s substrate recognition site and therefore is usually a close structural analog of the substrate (Fig. An increase of substrate concentration can overcome competitive inhibition; when the substrate concentration is increased to a suffi- ciently high level, the substrate binding sites are occupied by substrate, and inhibitor molecules cannot bind. Competitive inhibitors, therefore, increase the apparent Km Reaction A B E E AB B Substrates both bind Enzyme CI is competitive with respect to A Fig. A and B are substrates for the reaction forming the enzyme substrate complex (E-AB). The enzyme has separate binding sites for each substrate, which overlap in the active site. The competitive inhibitor (CI) com- petes for the binding site of A, the substrate it most closely resembles. As ethanol is oxidized in liver cells, NAD is reduced to NADH and the 2. NONCOMPETITIVE AND UNCOMPETITIVE INHIBITION NADH/NAD ratio rises. NADH is an inhibitor If an inhibitor does not compete with a substrate for its binding site, the inhibitor is of alcohol dehydrogenase, competitive with either a noncompetitive or uncompetitive inhibitor with respect to that particular respect to NAD , so the increased substrate (Fig. To illustrate noncompetitive inhibition, consider a multisub- NADH/NAD ratio slows the rate of ethanol oxidation and ethanol clearance from the strate reaction in which substrates A and B react to form a product. An increase of A will not prevent the inhibitor from binding to substrate acids. Consequently, these fatty acids accu- B’s binding site. The inhibitor, in effect, lowers the concentration of the active mulate in the liver, eventually contributing to enzyme and therefore changes the Vmax of the enzyme. Some inhibitors, such as metals, might not bind at either substrate recogni- tion site. In this case, the inhibitor would be noncompetitive with respect to both substrates. An inhibitor that is uncompetitive with respect to a substrate will bind only to enzyme containing that substrate. That inhibitor would be called uncompetitive with respect to A. It would decrease both the Vmax of the enzyme and its apparent Km for A.
Certain inherited diseases that cause the production Antibodies play an important role in the immune system of abnormal hemoglobin may also result in hemolytic (see Chap cheap lisinopril 17.5 mg otc. The hemoglobin in normal adult cells is of the A available for administration to patients in immediate need type and is designated HbA purchase lisinopril 17.5mg. In the inherited disease sickle of antibodies generic lisinopril 17.5mg, such as infants born to mothers with active cell anemia buy discount lisinopril 17.5mg on line, the hemoglobin in many of the red cells is hepatitis. When these cells give up their oxygen to the tissues, they are transformed from the normal disk Checkpoint 13-14 How is blood commonly separated into its shape into a sickle shape (Fig. Because of their odd shape, they also tend to become tangled in masses that can block smaller blood vessels. When obstruction oc- ◗ Blood Disorders curs, there may be severe joint swelling and pain, espe- cially in the fingers and toes, as well as abdominal pain. Abnormalities involving the blood may be divided into This aspect of sickle cell anemia is referred to as sickle cell three groups: crisis. About 8% of African Americans have one of the blood and thus impaired delivery of oxygen to the tis- genes for the abnormal hemoglobin and are said to have sues. These disorders are characterized by an abnormal tendency to bleed due to a breakdown in the body’s clotting mechanism. Anemia Anemia may result from loss of red cells, as through ex- Sickle- cessive bleeding (hemorrhage), or from conditions that shaped cause the cells to hemolyze (rupture). In other cases, cell bone marrow failure or nutritional deficiences impede the production of red cells or hemoglobin. Abnor- mal cells take on a crescent (sickle) shape when they give up Excessive Loss or Destruction of Red Cells He- oxygen. Philadelphia: Lippincott Williams morrhagic loss of red cells may be sudden and acute or & Wilkins, 2003. The average adult has about 5 liters upper left corner of this picture? If a person loses as much as 2 liters suddenly, between the cells? It is only when the involved gene is that may injure the marrow include x-rays, atomic radia- transmitted from both parents that the clinical disease tion, radium, and radioactive phosphorus. About 1% of African Americans have two of The damaged bone marrow fails to produce either red these genes and thus have sickle cell disease. One drug or white cells, so that the anemia is accompanied by has been found to reduce the frequency of painful crisis leukopenia (lu-ko-PE-ne-ah), a drop in the number of in certain adults. Removal of the toxic agent, followed by blood some hemoglobin of an alternate form (fetal hemoglo- transfusions until the marrow is able to resume its activ- bin) so that the red cells are not as susceptible to sick- ity, may result in recovery. People taking hydroxyurea require blood tests every have also been successful. Some Impaired Production of Red Cells or Hemoglo- medications are now available to stimulate bone marrow bin Many factors can interfere with normal red cell pro- production of specific types of blood cells. Anemia that results from a deficiency of some nu- EPO made by recombinant methods (genetic engineer- trient is referred to as nutritional anemia. These conditions ing) can be given in cases of severe anemia to stimulate may arise from a deficiency of the specific nutrient in the red cell production. Deficiency Anemia The most common nutritional ane- Leukemia mia is iron-deficiency anemia. Iron is an essential con- Leukemia is a neoplastic disease of blood-forming tissue. The average diet usually provides It is characterized by an enormous increase in the num- enough iron to meet the needs of the adult male, but this ber of white cells. Although the cells are high in number, diet often is inadequate to meet the needs of growing they are incompetent and cannot perform their normal children and women of childbearing age. A diet deficient in proteins or vitamins can also result As noted earlier, the white cells have two main in anemia.
Similar criticisms can also be levelled at another retrospective study where it was reported that once an initial concussion was sustained buy 17.5mg lisinopril mastercard, the probability of incurring a second concussion greatly increases order lisinopril 17.5mg. Apart from boxing related head injuries purchase lisinopril 17.5mg free shipping, the most widely cited studies of the cumulative effects of concussion have studied patients with injuries sustained in motor vehicle accidents that were severe enough to warrant presentation to hospital generic 17.5 mg lisinopril fast delivery. Generally, concussive injuries suffered in collision sports such as football involve lesser degrees of acceleration-deceleration forces than experienced in motor vehicle accidents. For example, some head injuries in the cited studies were retrospectively assessed up to eight years after their occurrence. Boxing, however, should not be considered as a model for cumulative head injury seen in other sports since it presents unique risks to the athlete in terms of the frequency of repetitive head trauma. These problems include the lack of pre-injury data, selection bias, lack of observer blinding and inadequate control subjects. The authors conclude that the deficits noted in the former soccer players were explained by repetitive trauma such as heading the ball. The pattern of deficits, however, is equally consistent with alcohol related brain impairment, a confounding variable which was not controlled for. To date, there has been no replication of these findings by other independent groups. Other studies have suggested that this may be an effect of environmental factors rather than due to the effect of injury. Concussive injuries in Australian Rules football tend to be mild, with neuropsychological performance returning to pre-injury levels within the first few days following injury. In animal studies of experimental concussion, animals have been repeatedly concussed 20 to 35 times during the same day and within a two-hour period. Despite these unusually high numbers of injuries, no residual or cumulative effect was demonstrated. Recent research in boxers has suggested that chronic traumatic encephalopathy or the so called “punch drunk syndrome” in boxers may be associated with a particular genetic predisposition. Furthermore, ApoE-deficient (knockout) mice have been shown to have memory deficits, neurochemical changes and diminished recovery from closed head injury when compared to controls. Although only in the early stages of our understanding of these issues, the interaction between genetic and environmental factors may be critical in the development of the post-concussive phenomena or concussive sequelae. Return to sport after life threatening head injury Return to sport following a severe or potentially life threatening brain injury is controversial and few guidelines exist for the clinician to follow. There are some situations where the athlete could place himself at an unacceptably high risk of sustaining further injury and hence should be counselled against participation in collision sport. Although sports physicians should keep an open mind when assessing neurological recovery from severe brain injuries nevertheless it is recommended that at least 12 months pass before such a decision is contemplated. Thoughtful deliberation and analysis of all the available medical evidence should occur when making such a decision. It is also recommended that the counsel of a neurologist or neurosurgeon experienced in sporting head injury management be sought. This is an important point because a number of individuals who suffer a moderate to severe TBI may be left with a lack of insight and impaired judgement over and above their other neurological injuries. This in turn may make such an individual unreliable in gauging recovery. The use of neuropsychological assessment as well as information from family and friends may assist the clinician in his deliberation. The assessment of cognitive performance and/or clinical symptoms when fatigued is often useful. Return to collision sport is relatively contraindicated in almost any situation where surgical craniotomy is performed. In such situations, the subarachnoid space is traumatised, thus setting up scarring of the pia-arachnoid of the brain to the dura with both loss of the normal cushioning effect of the CSF and vascular adhesions which may subsequently bleed if torn during head impact. Even if neurologic recovery is complete, a craniotomy for anything other than an extradural haematoma effectively precludes return to collision sport. With an epidural haematoma without brain injury or other condition where surgery is not required, return to sport may be contemplated in selected cases as per the discussion above after a minimum of 12 months assuming neurologic recovery is complete. It seems self evident that athletes with persistent cognitive or neurological symptoms should be withheld from collision sport until such time as their symptoms fully resolve.