كلية الصيدلة والعلوم الطبية

كلية الصيدلة والعلوم الطبية
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Chapter 19 Regulation of Metabolism (Pages 661-699)
Nutritional Requirements Living tissue is maintained by the constant expenditure of energy. Energy is obtained directly from ATP, or indirectly from cellular respiration of glucose, fatty acids, ketone bodies, a.a., and other organic molecules. These molecules are obtained from food, or from glycogen, fat, protein stored in the body. Energy value of food is commonly measured in Kilocalories (1Kcal =1000 calories).

Calorie is the amount of heat required to raise the temperature of 1 cm3 of H2O one degree (1oC).
1 gm of CH2O or protein gives 4 Kcal through the process of cellular respiration. 1 gm of fat gives 9 Kcal through the process of cellular respiration. When energy is released by cell respiration, some of this energy is transferred to ATP and some is lost as heat.

Metabolic Rate and Caloric Requirements
The total rate of body metabolism or the metabolic rate (MR) can be measured by: 1.Amount of heat generated by the body. Or 2.Amount of O2 consumed by the body/minute. MR is influenced by many factors as: 1.Physical activity and eating: both increases the MR. The increased rate of metabolism that accompanies the assimilation of food can last more than 6 hours after a meal. 2.Body temperature is an important factor because: a) It influences the rate of chemical reactions. b) The hypothalamus contains temperature control centers, as well as temperature-sensitive cells that act as sensors for changes in body temperature. In response to deviations from a "set point" for body temperature, the control areas of the hypothalamus can direct physiological responses that influence the total MR.

Basal metabolic rate (BMR) is the metabolic rate (measured by rate of O2 consumption) of an awake, relaxed person 12-14hrs after eating and at a comfortable temperature. BMR is determined primarily by the person's: 1.Age. 2.Sex. 3.Body surface area. 4.Level of thyroid secretion: a person with hyperthyroidism has an abnormally high BMR, and a person with hypothyroidism has a low BMR. 5.Genetic inheritance: it appears that at least some families that are prone to obesity may have a genetically determined low BMR. Individual differences in energy requirements are due to differences in physical activities. Daily energy expenditure may range kilocalories/day. The average values for people not engaged in heavy manual labor but who are active during their leisure time area about 2900 kilocalories/day for men and 2100 kilocalories/day for women.

People engaged in office work, the professions, sales, and comparable occupation consume up to 5 kilocalories/minute during work. More physically demanding occupations may require energy expenditures of kilocalories/minute. When caloric intake is > energy expenditure, excess calories are stored primarily as fat. This is true regardless of the source of the calories (CH2O, protein, or fat) because these molecules can be converted to fat by the metabolic pathways (Figure 5.18 page 125). Weight is lost when caloric value of the food ingested is less than the amount required in cell respiration over a period of time. Weight loss cn be achieved by dieting alone or in combination with an exercise program to raise the metabolic rate. Summary of the caloric expenditure associated with different forms of exercise is provided in table 19.1 page 663.

Figure 5.18 (page 125) The interconversion of glycogen, fat, and protein.
Most reactions are reversible, the reaction from pyruvic acid to acetyl CoA is not. (Only plants can use CO2 to produce glucose.)

Anabolic Requirements
In addition to providing the body with energy, food also supplies the raw materials for synthesis reactions, collectively termed anabolism, that occur constantly within the cells of the body. Anabolism includes those that synthesize DNA, RNA, protein, glycogen, triglycerides, and other polymers. Anabolism occurs constantly to replace those molecules that are hydrolyzed into their component monomers. Catabolism is the hydrolysis reaction of DNA, RNA, protein, glycogen, triglycerides, and other polymers. Cellular respiration that ultimately break the monomers down to CO2 and H2O is a catabolic process. Acting through changes in hormonal secretion, exercise and fasting increase the catabolism of stored glycogen, fat, and body protein.

Turnover rate of a particular molecule is the rate at which it is broken down and resynthesized.
Average daily turnover rate for CH2O is 250g/day. Since some of the glucose in the body is reused to form glycogen, the average daily dietary requirement for CH2O is about 150g/day. Average daily turnover rate for protein is 150g/day. Average daily dietary requirement for protein is 35g/day (since many of the a.a. derived from the catabolism of body proteins can be reused in protein synthesis). Average daily turnover rate for fat is 100g/day. Average daily dietary requirement for fat is very little (other than that which supplies fat-soluble vitamins and essential fatty acids), since fat can be produced from excess CH2O.

Average figures will vary in accordance with individual differences in size, sex, age, genetics, and physical activity. The minimal amounts of dietary protein and fat required to meet the turnover rate are adequate only if they supply sufficient amounts of essential a.a. and f.a. Essential a.a. that cannot be synthesized by the body and must be obtained in the diet are: Lysine, Tryptophan, Phenylalanine, Threonine, Valine, Methionine, Leucine, Isoleucine, and Histidine.

Essential f.a. are: Linoleic and alpha-linolenic acids because mammals lack the enzymes needed to insert the double bond. Linoleic acid is an unsaturated fatty acid, contains 18 carbons and 2 double bonds. The first double bond is on the 6th carbon from the methyl end, and is designated as an n-6 (or omega-6). Alpha-linolenic acid is an unsaturated fatty acid, contains 18 carbons and 3 double bonds. The first double bond is on the 3rd carbon from the methyl end, and is designated as an n-3 (or omega-3). Most people obtain alpha-linolenic acid derivatives primarily from fish. Studies suggest that omega-3 fatty acids may offer some protection against CVDs.

Vitamins and Minerals Vitamins are small organic molecules that serve as coenzymes in metabolic reactions or that have other highly specific functions. Vitamins must be obtained in the diet because the body doesn't produce them, or it produces them in insufficient quantities (Vitamin D is produced in limited amounts by the skin, vitamin K and B are produced by intestinal bacteria). There are 2 classes of vitamins: (Table 19.2 page 664 & 19.3 page 666) 1.Fat-soluble vitamins: A,D,E, and K. 2.Water-soluble vitamins: C (Ascorbic acid), B1 (Thiamine), B2 (Riboflavin) , B3 (Niacin/Nicotinic Acid), B5 (Pantothenic Acid), B6 (Pyridoxine/Pyridoxal/Pyridoxamine), B7 (Biotin), B8 (Inositol), B9 (Folic acid) B10 (PABA: Para-AminoBenzoic Acid), and B12 (Cobalamins/Cyanocobalamin/methylcobalamin)

Minerals (Elements) Are needed as cofactors for specific enzymes and for a wide variety of other critical functions. Some are required daily in relatively large amounts as Na, K, Mg, Ca, P, Cl. Others are essential but called trace elements as Fe, Zn, Mn, Fl, Cu, Mo, Cr, Se. Table 19.2 page 664 shows estimated safe and adequate daily dietary intakes of selected vitamins and minerals.

Neuritis: Inflammation of a nerve or nerves.
Beriberi: Peripheral neurologic, cerebral, and cardiovascular abnormalities. Glossitis: Inflammation of the tongue. Cheilosis: Morbid condition of lips with reddened appearance and fissures at the angles. Scurvy: Hemorrhagic manifestations and abnormal formation of bones and teeth. Sprue: Weekness, loss of weight, steatorrhea (increased secretion of sebaceous glands), and various digestive disorders especially impaired absorption of glucose, fats ,and vitamins. Pellagra: Cutaneous ,gastointestinal ,mucosal ,neurologic ,and mental symptoms

Free Radicals and Antioxidants
Free radical is a molecule that contains unpaired electron in an orbital (electrons in an atom are located in orbitals, with each orbital containing a maximum of 2 electrons). Free radicals are highly reactive in the body. They can oxidize or reduce other atoms. They are produced by many cells in the body and serve some important physiological functions. The major free radicals are: 1.Reactive oxygen species: contain O2 with unpaired electron. 2.Reactive nitrogen species: contain N2 with unpaired electron.

E.g.: Superoxide radical (O˙2), Hydroxyl radical (HO˙),
Nitric oxide radical (NO˙). (The unpaired electron is symbolized with a dot superscript). O˙2 is produced in mitochondria of all cells that undergo aerobic respiration. Some important physiological functions of O˙2 and NO˙, which are produced in phagocytic cells as MΦ and neutrophils to help destroying bacteria, are: 1.O˙2 in phagocytic cells act as nonselective antibiotic killing any infecting bacteria, neutrophils, and also injuring surrounding tissues, as these radicals contribute to the inflammation reaction. 2.O˙2 promote cellular proliferation (mitotic division) of fibroblasts so that scar tissue can form. 3.O˙2 promote proliferation of lymphocytes in the process of clone production. 4.NO˙ promote relaxation of vascular smooth muscle and thus vasodilation so that more blood can flow to the site of the inflammation.

Excessive production of free radicals can damage lipid, proteins, and DNA, i.e. they exert an oxidative stress on the body with the following ill effects: (Fig.19.1 page667) 1.Promotes cell death (apoptosis) 2.Contributes to aging and degenerative diseases associated with aging. 3.Promotes malignant growth of cancer. 4.Contributes to all inflammatory diseases (as glomerulonephritis, rheumatoid arthritis, and lupus erythematosus). 5.Implicated in ischemic heart disease, stroke, hypertension, and a variety of neurological diseases including multiple sclerosis, Alzheimer's disease, Parkinson's disease and other. The wide range of diseases associated with oxidative stress stems from the widespread production of superoxide radicals in the mitochondria of all cells that undergo aerobic respiration.

Fig. 19. 1 Reactive oxygen species (ROS) production and defense
Fig Reactive oxygen species (ROS) production and defense. Normal physiology requires that the reactive oxygen species (those that contain oxygen with an unpaired electron) be kept in balance.

The body protects itself against oxidative stress by:
1.Enzymatic process: enzymes that help to prevent an excessive buildup of oxidants include superoxide dismutase (SOD), catalase, and glutathione peroxidase. O˙2 + HO˙ by the action of SOD→ H2O2 + O2. H2O2 is not a free radical, but it is a potentially toxic oxidant, and it must be eliminated by: a. H2O2 (by the action of catalase) → H2O + O2. b.H2O2 + NADPH + H+ (by the action of glutathione peroxidase) → H2O +NADP+. 2.Nonenzymatic means: using antioxidants as: Glutathione: is a tripeptide which is the major cellular antioxidant. When it is in its reduced state, glytothione can react with certina free radicals and render them harmless. 2. Ascorbic acid (Vitamin C) in the aqueous phase of cells. 3.α-tocopherol (the major form of Vitamin E) in the lipid phase.

Ascorbic acid and α-tocopherol act as antioxidant by picking up unpaired electrons from free radicals. This is said to "quench" the free radicals, although, in the reaction, they gain an unpaired electron and thus become free radicals. Because of their chemical structures, however, they are weaker free radicals than those they quench. Many other molecules present in foods (primarily fruits and vegetables) have been shown to also have antioxidant properties.

All villagers decided to pray for rain,
ONCE All villagers decided to pray for rain, On the day of the prayer all the People gathered but only one boy came with an umbrella. That’s FAITH

Regulation of Energy Metabolism
Molecules oxidized by cellular respiration to get energy may be derived from:(Fig.19.2 page 669) 1.The energy reserves of glycogen and fat (function primarily as energy reserves) 2.The energy reserves of proteins (represents a secondary, emergency function). 3.From the products of food digestion (called circulating energy substrates because they are carried by the blood). Body protein can provide a.a. for energy, it can do so only through the breakdown of proteins needed for muscle contraction, structural strength, enzymatic activity, and other functions. Because of differences in cellular enzyme content, different organs have different preferred energy sources.

Fig. 19. 2 A flow chart of energy pathways in the body
Fig A flow chart of energy pathways in the body. The molecules indicated in the top and bottom are those found within cells, while the molecules in the middle portion of the figure are those that circulate in the blood.

For example: 1. Brain has an almost absolute requirement for blood glucose as
its energy source. 2. Resting skeletal muscles use fatty acids as their preferred energy source. 3. Ketone bodies, lactic acid, and amino acids can be use to different degrees as energy sources by various organs. The plasma contains adequate concentrations of all of these circulating energy substrates to meet the energy needs of the body. Review Table 5.2 page 117.

Regulatory Functions of Adipose Tissue
It is difficult for a person to lose (or gain) weight, many scientists believe, because the body has a negative feedback loops that act to "defend" a particular body weight, or more accurately, the amount of adipose tissue, this regulatory system is called adipostat. When a person eats more than is needed to maintain the set point of adipose tissue, the person's metabolic rate increases and hunger decreases. Homeostasis of body weight implies negative feedback loops. Hunger and metabolism (acting through food and hormones) affect adipose cells, so in terms of negative feedback, it seems logical that adipose cells should influence hunger and metabolism. White adipose tissue (white fat) is the major site of energy storage in the body. In white fat adipocytes (fat cells), triglycerides are stored in a single, large droplet within each cell.

Development of Adipose Tissue
The triglycerides are formed during times of plenty and are hydrolyzed ( in lipolysis) by lipase enzymes to release free fatty acids and glycerol during times of fasting. Because the synthesis and breakdown of fat is controlled by hormones that act on the adipocytes, the adipocytes traditionally have been viewed simply as passive storage depots of fat. However, adipocytes may themselves secrete hormones that play a pivotal role in the regulation of metabolism. Development of Adipose Tissue Some adipocytes appear during embryonic development, but their numbers increase greatly following birth. This increased number is due to both mitotic division of the adipocytes and the conversion of preadipocytes into new adipocytes. This differentiation or specialization is promoted by a high circulating level of fatty acids, particularly of saturated fatty acids.

Endocrine Functions of Adipocytes
Adipocytes secrete regulatory molecules, collectively termed adipokines, which regulate hunger, metabolism and insulin sensitivity. Adipokines are secreted into the blood and act on distant target organs, and so qualify to be categorized as hormones. Adipokines include: 1. Leptin is secreted in proportion to the amount of stored fat. It acts on the hypothalamus to help regulate hunger and food intake. It acts as a signal from the adipose tissue to the brain, helping the body maintain a certain level of fat storage. Known to be increased in obesity. 2.TNFα (tumor necrosis factor-alpha) which is also released as a cytokine by MΦ and other cells of the immune system. When it is secreted by adipocytes, it reduces the ability of skeletal muscles to remove glucose from the blood in response to insulin. The secretion of TNFα is increased in obesity and type 2 diabetes mellitus.

3. Resistin which act as TNFα.
4. Adiponectin: is decreased in obesity and type diabetes mellitus. It stimulates glucose utilization and fatty acid oxidation in muscle cells. Through these actions, adiponectin has an insulin-sensitizing, antidiabetic effect. 5.Retinol-binding protein 4, resistin and leptin also may contribute to the reduced sensitivity of skeletal muscles and other tissues to insulin in obesity and type 2 diabetes mellitus.

Low Adiposity: Starvation
Starvation and malnutrition are the leading causes of diminished immune capacity, which leads to becoming more susceptible to infections. Leptin receptors have been identified on the surface of helper T lymphocytes, which help both humoral and cell-mediated immune responses. Reduced adipose tissue and hence decreased leptin secretion can contribute to a decline in the ability of helper T cells to promote the immune response, and thus can (at least in part) account for the decline in immune competence in people who are starving. The target of leptin action is the hypothalamus that regulates appetite and reproductive system.

Leptin may be involved in regulating onset of puberty and menstrual cycle (menarche).
Very thin adolescent girls enter puberty later than the average age. Very thin women can experience amenorrhea (cessation of menstrual cycle). Adequate amounts of adipose tissue are thus required for proper functioning of the immune and reproductive systems.

Obesity Obesity is a risk factor for cardiovascular diseases, diabetes mellitus, gall bladder disease, and some malignancies (particularly endometrial and breast cancer). Distribution of fat is also important. There is a greater risk of cardiovascular disease when the distribution of fat produces a high waist-to-hip ratio (an "apple shape") as compared to a "pear shape". This is because the amount of intra-abdominal fat in the mesenteries and greater omentum is a better predictor of a health hazard than is the amount of subcutaneous fat. In terms of the risk of diabetes mellitus, the larger adipocytes of the "apple shape" are less sensitive to insulin than the smaller adipocytes of the "pear shape".

Obesity in childhood is due to increase in both size and number of adipocytes.
Weight gain in adulthood is due mainly to increase in adipocyte size. During weight loss, adipocytes get smaller, but their number remains constant. It is important to prevent further increase in the number of adipocytes, particularly in children. Obesity is diagnosed using BMI (body mass index). BMI = w/h2 (weight in kilograms/height in meters) WHO classifies people with a BMI of ≥ 30 as being at high risk for the disease of obesity. NIH set the following standards: BMI = as being a healthy weight. BMI = as being overweight. BMI > as being obese.

According to a recent study, however, the lowest death rates from all causes occurred in men with a BMI in the range of , and in women with a BMI in the range of Obesity is strongly associated with the incidence of type 2 diabetes mellitus. Childhood obesity, and associated childhood incidence of type 2 diabetes mellitus, has increased dramatically in recent years. According to a study done by the Rand Corporation, obesity is a greater risk factor in chronic diseases than either smoking or drinking!

Regulation of Hunger and Metabolic Rate
Humans should eat the kinds and amount of foods that provide adequate vitamins, minerals, essential amino acids, and calories. Proper caloric intake maintains energy reserves (primarily fat and glycogen) and maintains body weight that is optimum for health. Hunger and eating behavior is at least partially controlled by areas of the hypothalamus. Lesions (destruction) in the ventromedial area of the hypothalamus produce hyperphagi, or overeating and obesity in experimental animals. Lesions of the lateral hypothalamus produce hypophagia and weight loss. The NTs in the brain that may be involved in the control of eating are under investigation, and many have been implicated. Among those are the endorphins (naloxone, which blocks morphine receptors, suppresses overeating in rats); norepinephrine (injection into the brains of rats cause overeating); and serotonin (intracranial injections suppress overeating in rats).

Examples of NTs and hormones that regulate hunger:
These results can be applied to humans. For example: the diet pills Redux (D-fenfluramine) and fen-phen (L-fenfluramine) work to reduce hunger by elevating the brain levels of serotonin. However, these drugs have been removed from the market because of their association with heart valve problems. Examples of NTs and hormones that regulate hunger: 1. Leptin: A satiety factor (appetite suppressant) secreted by the adipose tissue It is a 167-amino acid polypeptide is the hormone that is believed to be involved in more long-term hunger regulation than the hormones of the digestive tract. Leptin secretion increases as the amount of the stored fat increases, suppressing appetite and thus reducing further calorie intake. Rather than regulating meal-to-meal food consumption like the hormones of the digestive tract, leptin helps maintain the body's usual level of adiposity (fat storage). Leptin increases the metabolic rate and calorie expenditure of the body.

Its secretion increases in proportion to the amount of stored fat and acts on the hypothalamus to suppress appetite. It does this by inhibiting neurons that release neuropeptide Y and AgRP, while stimulating neurons that release MSH. The gene for human leptin has been cloned, and recombinant leptin is now available for the medical treatment of obesity. A small number of congenitally obese people are deficient in leptin and have been greatly helped by leptin injections. BUT, most obese people do not appear to have a leptin deficiency and are not much benefited by leptin injections. The levels of leptin are instead high in most obese people, suggesting that their obesity is promoted by a resistance of their hypothalamus to the appetite-suppressing effects of leptin. Resistance to leptin action can occur through different mechanisms (including reduced transport into the brain or impaired leptin signaling within neurons) that may be of varying significance in the obesity of different people.

Secreted by the β-cells of the islets of Langerhans of the pancreas.
2. Insulin: Secreted by the β-cells of the islets of Langerhans of the pancreas. Has long been suspected of being a satiety factor. The beta cells secrete more insulin in obese than in lean people, because more insulin is required to maintain homeostasis of blood glucose as the stored fat increases. Insulin like leptin in that: 1. Their secretion increase with increasing adiposity. 2. They both suppress appetite. 3. They can cross the blood-brain barrier. 4. They both suppress the release of neuropeptide Y (Figure 19.3 page 672). However, insulin’s effects on hunger and satiety are complex and its significance in the regulation of eating behavior is not presently well defined.

Leptin and insulin are believed to provide sensory signals for long-term regulation of hunger and indirectly of body weight, whereas several hormones from GI tract provide sensory signals that regulate hunger on a short-term, meal-related basis. 3. Melanocyte-stimulating hormone (MSH): decreases appetite by binding to certain receptors in the hypothalamus. There is evidence that some cases of congenital obesity are caused by defects in some of these receptors. Cigarette smoking may reduce appetite because nicotine binds to these receptors. 4. Neuropeptide Y : A neurotransmitter that promote hunger. 5. Agouti-related protein (AgRP): A neurotransmitter that promote hunger. It antagonizes MSH action.

When eating results in an abundance of circulating energy substrates, the release of MSH produces a suppression of appetite and increased metabolic energy expenditure. At the same time, the neurons that release neuropeptide Y and AgRP are inhibited. Conversely, when there is a reduction in circulating energy substrates, the neurons that release MSH are suppressed, while those that release neuropeptide Y and AgRP are activated to increase appetite. The activation of these hypothalamic neurons and the release of their NTs must be regulated by signals from other brain areas (because psychological factors, and the smell and taste of food, influence hunger) and by signals from the body. In particular, hunger and appetite are responsive to signals from the digestive tract and from adipose tissue. 6. Ghrelin: Is a polypeptide, secreted by the stomach. Rises between meals when the stomach is empty. Stimulates hunger. It secretion rapidly falls as the stomach fills during a meal and hunger is thereby reduced.

The following hormones are polypeptides , regulate appetite by targeting the hypothalamus to stimulate neurons that release MSH and inhibit neurons that release neuropeptide Y. 7. Cholecystokinin (CCK): Intestinal hormone. Its secretion rises during and immediately after a meal and suppresses hunger (promote satiety). CCK acts antagonistically to ghrelin, helping to reduce appetite immediately after a meal. Ghrelin and CCK are involved in the regulation of hunger on a short-term, meal-to-meal basis. 8. Polypeptide YY (PYY): Secreted in greatest amounts by the ileum and colon. May reduce appetite on a more intermediate-time basis. 9. Glucagon-like peptide-I (GLP-I): Secreted by ileum and colon. Suppress hunger.

Figure 19. 3 The action of leptin
Figure 19.3 The action of leptin. Leptin crosses the blood-brain barrier to affect NTs released by neurons in the arcuate nucleus of the hypothalamus. This influences other hypothalamic nucei, which in turn reduce appetite and increase metabolic rate. The figure also shows that insulin stimulates adipose cells to secrete leptin and is able to cross the blood-brain barrier and to act in a manner similar to leptin.

Figure 19.4 Hormonal signals that regulate feeding and energy expenditures.
The inhibitory sensory signals are shown in red, and the stimulatory signal (ghrelin) in green. The CNS integrated this sensory information with other information (smell, taste, and psychological factors) to help regulate hunger and satiety, energy expenditures, as well as growth and reproduction.

ليس عيبا أن نكون فقراء ولكنها جريمة ان نكون متخلفين

Caloric Expenditure Caloric energy expenditure of the body has 3 components: 1.BMR: is the energy expenditure of a relaxed, resting person who is at a neutral ambient temperature (about 28° C) and ho has not eaten in 8-12hrs. This comprises the majority (about 60%) of the total caloric expenditure in an average adult. 2.Adaptive thermogenesis: is the heat energy expended in response to: Changes in ambient temperature. The digestion and absorption of food. Comprises about 10% of the total calorie expenditure, although this contribution can change in response to cold and diet. A cold environment evokes cutaneous vasoconstriction and shivering, which increases the metabolic rate and heat production of skeletal muscles. Since, the skeletal muscles comprise about 40% of the total body weight, their metabolism has a profound effect on body temperature. 3.Physical activity: raises the M.R. and energy expenditure of skeletal muscles. This contribution to the total calorie expenditure is highly variable, depending on type and intensity of physical activity.

Heat production in the absence of shivering is called nonshivering thermogenesis which is the major function of brown adipose tissue, although skeletal muscles and other tissues also play a part. There a 2 types of adipocytes in the body: Brown adipocytes: Have many small fat droplets. Have numerous mitochondria, which impart the brown color. Abundant in infants, who can lose heat rapidly due to their high ratio of surface area to volume and have insufficient skeletal muscle for thermogenesis from shivering. Thought to be absent in adults, but it is found primarily in the supra clavicular region of the neck. Their activity is stimulated by exposure to cold and by the sympathoadrenal system.

Are more in women than in men
Are more in lean people than in those who are overweight or obese. Also lean people who have a lower BMI have more brown fat. People with a higher BMI have less brown fat. This suggests that the calories expended by brown fat in nonshivering thermogenesis could significantly affect body weight. 2. White adipocytes: Have a single large droplet. Have less mitochondria. Abundant in adults.

Hormonal Regulation of Metabolism
Absorption of energy carriers from the intestine is not continuous: 1.It rises to high levels over a 4-hour period following each meal (the absorptive state). 2.Tapers toward zero between meals, after absorptive state has ended (the postabsorptive state or fasting state). The plasma concentration of glucose and other energy substrates doesn't remain high during absorption, nor does it fall below a certain level during fasting. During the absorption of digestion products from the intestine, energy substrates are removed from the blood and deposited as energy reserves from which withdrawals can be made during times of fasting. This ensures as adequate plasma concentration of energy substrates to sustain tissue metabolism at all times.

The rate of deposit and withdrawal of energy substrates into and from energy reserves and the conversion of one type of energy substrate into another are regulated by hormones (Fig page 675). The balance between anabolism and catabolism is determined by the antagonistic effects of the hormons: insulin, glucagon, growth hormone, thyroxine, and others (Table 19.4 & Fig page 676).

Figure 19.6 The regulation of metabolic balance.
The balance of metabolism can be tilted toward anabolism (synthesis of energy reserves) or catabolism (utilization of energy reserves) by the combined actions of various hormones. Growth hormone and thyroxine have both anabolic and catabolic effects.

Figure 19.7 Hormonal interactions in metabolic regulation.
Different hormones may work together synergistically, or they may have antagonistic effect on metabolism

Energy Regulation by the Pancreatic Islets
Scattered within a "sea" of pancreatic exocrine tissue (the acini) are islands of hormone-secreting cells. These pancreatic islets (islets of Langerhans) contain: 1. β cells: most numerous, secrete insulin, about 60% of the islets cells. 2. α cells: secrete glucagon, about 25% of the islets cells. 3. δ cells: the least numerous, secrete somatostatin, which is identical to that secreted by the hypothalamus and the intestine. All the 3 hormones are polypeptides. Insulin is the major hormone that maintains homeostasis of the plasma glucose concentration, with glucagon playing an important supporting role. This homeostasis is required because the brain uses plasma glucose as its primary energy source, and indeed the brain uses about 60% of the blood glucose when the is at rest. The plasma glucose concentration is maintained relatively constant even during exercise, when the skeletal muscle glucose metabolism can increase tenfold. This is possible because the pancreatic islet hormones regulate the ability of the liver to produce glucose and secrete it into the blood.

Regulation of Insulin and Glucagon secretion
Regulated largely by the concentration of glucose in blood, and to a lesser degree, of a.a. Therefore, α and β cells act as both sensors and effectors in this control system. Since the plasma concentration of glucose and a.a. rises during the absorption of a meal and falls during fasting, the secretion of insulin and glucagon likewise fluctuates between the absorptive and postabsorptive states. These changes in insulin and glucagon secretion, in turn, cause changes in plasma glucose and a.a. concentrations and thus help to maintain homeostasis via negative feedback loops (Fig page 347). The targets of insulin action are primarily the cells of skeletal and cardiac muscles, adipose tissue, and the liver. In these cells, intracellular vesicles containing GLUT4 carriers proteins for glucose are stimulated by insulin to fuse with the plasma membrane so that GLUT4 carriers are at the cell surface. This permits the entry of glucose into its target cells by facilitated diffusion (Fig page 347).

Figure 11.31 Glucose homeostasis is maintained by insulin and glucagon.
(a) When the plasma glucose concentration rises after a meal, the beta cells secrete increased amounts of insulin (and alpha cells are inhibited from secreting glucagon). Insulin the promotes the cellular uptake of blood glucose, reducing the plasma glucose concentration so that homeostasis of blood glucose is maintained. (b) When the plasma glucose concentration falls, the secretion of insulin is inhibited and the secretion of glucagon is stimulated. Glucagon promotes glycogenolysis and gluconeogenesis, so that liver can secrete glucose into the blood and maintain homeostasis of blood glucose concentration.

Therefore, insulin promotes the production of the energy-storage molecules of glycogen and fat. Both actions decrease in plasma glucose concentration. Insulin also inhibits breakdown of fat, induces the production of fat-forming enzymes, and inhibits the breakdown of muscle protein. Thus, insulin promotes anabolism as it regulates blood glucose concentration. Mechanisms that regulate insulin and glucagon secretion and actions, prevent plasma glucose concentration from rising above 170 mg/100ml after a meal OR from falling below 50 mg/100ml between meals. This regulation is important because abnormally high blood glucose can damage certain tissues (as may occur in diabetes mellitus), and abnormally low blood glucose can damage the brain. The latter effect results from the fact that glucose enters the brain by facilitated diffusion; when the rate of this diffusion is too low, as a result of low plasma glucose concentrations, the supply of metabolic energy for the brain may become inadequate. This can result in weakness, dizziness, personality changes, and ultimately in coma and death.

I. Effects of Glucose and Amino Acids
Fasting blood glucose is mg/dl. During absorption of a meal, glucose rises in the plasma to mg/dl, this rise: 1.Stimulates the β cells to secrete insulin (Fig.19.8 page 678). 2.Inhibits α cells from secretion glucagon. Insulin then stimulates the cellular uptake of plasma glucose and therefore, decreases glucose concentration in the blood. Because glucagon has antagonistic effect of raising the plasma glucose concentration by stimulating glycogenolysis in the liver, the inhibition of glucagon secretion complements the effect of increased insulin during the absorption of a CH2O meal. A rise in insulin and a fall in glucagon secretion thus help to lower the high plasma glucose concentration that occurs during periods of absorption.

Figure 19. 8 Regulation of insulin secretion
Figure Regulation of insulin secretion. When glucose enters β cells of the pancreatic islets, it stimulates the secretion of insulin .

During fasting, the plasma glucose concentration falls, therefore:
1.Insulin secretion decreases. 2.Glucagon secretion increases. These changes in hormone secretion prevent cellular uptake of blood glucose into organs such as muscles, liver, and adipose tissue, and promote the release of glucose from the liver (through the stimulation of glycogen breakdown by glucagon). A negative feedback loop is therefore completed (Fig page 347), helping to retard the fall in plasma glucose concentration that occurs during fasting. The oral glucose tolerance test is a measure of the ability of β cells to secrete insulin and of the ability of insulin to lower blood glucose (Fig page 683). Insulin secretion is also stimulated by particular a.a. derived from dietary proteins. Meals high in proteins and low in CH2O stimulate: 1.Insulin secretion that promotes entry of a.a. in tissue cells. 2.Glucagon secretion to raise blood glucose.

Figure Oral glucose tolerance in prediabetes and type 2 diabetes. The oral glucose tolerance test showing (a) blood glucose concentrations and (b) insulin values following the ingestion of glucose solution. Values are shown for people who are normal, prediabetic, and type 2 diabeteic. Prediabetics (those who demonstrate “insulin resistance”) often show impaired glucose tolerance without fasting hyperglycemia.

II. Effects of Autonomic Nerves
Islets of Langerhans receive: 1.Sympathetic innervation: its activation stimulates glucagon secretion and inhibits insulin secretion. 2.Parasympathetic innervation: its activation during meals stimulates insulin secretion at the same time that gastrointestinal function is stimulated. Glucagon and epinephrine then work together to produce a stress hyperglycemia (due to hydrolysis of glycogen to glucose and the secretion of glucose from the liver) when the sympathoadrenal system is activated.

III. Effects of intestinal hormones:
Insulin secretion increases more rapidly following glucose ingestion than it does following an intravenous injection of glucose. This is due to the fact that the intestine, in response to glucose ingestion, secretes hormones that stimulate insulin secretion before the glucose has been absorbed. Insulin secretion thus begins to increase "in anticipation" of a rise to blood glucose. This occurs because GIP, and GLP-1 mediate the effect. These and perhaps other intestinal hormones stimulate increased insulin secretion even before there is a rise in blood glucose from the digested food. This helps prevent an excessive rise in the blood glucose concentration following a high-CH2O meal.

Insulin and Glucagon I. Absorptive State:
The lowering of plasma glucose by insulin is, in a sense, a side effect of the primary action of this hormone. Insulin is the major hormone that promotes anabolism in the body. During this state, products of digestion and the subsequent rise in the plasma concentration of circulating energy substrate, insulin promotes: 1.Cellular uptake of plasma glucose and its incorporation into energy-reserve molecules in the liver and muscles, and of triglycerides in adipose tissue (Fig page 334). Quantitatively, skeletal muscles are responsible for most of the insulin-stimulated glucose uptake. 2.Cellular uptake of a.a. and their incorporation into proteins. The stores of large energy-reserve molecules are thus increased while the plasma concentrations of glucose and a.a. are decreased. Glycogen is less efficient as an energy reserve, and less is stored in the body.

There are about 100 g(400 kcal) of glycogen stored in the liver and g (1500 kcal) in skeletal muscles. Once the stores of glycogen have been filled, the continued ingestion of excess calories results in production of fat rather than of glycogen. The high insulin secretion during the absorptive state, when blood glucose levels are rising, also inhibits the liver from secreting more glucose into the blood. Insulin exerts this inhibition directly by acting on liver cells, and indirectly by acting on the hypothalamus, which works though the vagus nerves to inhibit glucose output from the liver. By contrast, during the postabsorptive state, when blood glucose and insulin secretion are falling, the liver is freed from this inhibition and does secrete glucose into the blood.

II. Postabsorptive State:
Plasma glucose concentration is maintained constant during fasting, or postabsorptive, state because of secretion of glucose from the liver, through processed of glycogenolysis, and gluconeogenesis. Glycogenolysis and gluconeogenesis are promoted by a high secretion of glucagon coupled with a low secretion of insulin. Glucagon stimulates and insulin suppresses the hydrolysis of liver glycogen, or glycogenolysis. During times of fasting, when glucagon is high and insulin secretion is low, liver glycogen is used as a source of additional blood glucose. Free glucose is formed from glucose 6-phosphate by the action of an enzyme called glucose 6-phosphatase. Only the liver has the enzyme "glucose 6-phosphatase", and therefore only the liver can use its stored glycogen as a source of additional blood glucose.

Muscle cells lack the enzyme "glucose 6-phosphatase", the glucose 6-phosphate produced from muscle glycogen can be used for glycolysis only by the muscle cells themselves. Adequate blood glucose levels could not be maintained for very long during fasting using stored glycogen in the liver because there are only 100g of stored glycogen in the liver. The low levels of insulin secretion during fasting, together with elevated glucagon secretion, however, promote gluconeogenesis, the formation of glucose from noncarbohydrate molecules. Low insulin allows the release of a.a. from skeletal muscles, while glucagon and cortisol stimulate the production of enzymes in the liver that convert a.a. to pyruvic acid and pyruvic acid into glucose. During prolonged fasting and exercise, gluconeogenesis in the liver using a.a. from muscles may be the only source of blood glucose. The secretion of glucose from the liver during fasting compensates for the low blood glucose concentrations and helps to provide the brain with the glucose that it needs.

Skeletal muscles cannot utilize blood glucose as an energy source, because insulin secretion is very low. Skeletal muscles, the heart, the liver, and kidneys use free fatty acids as their major source of fuel. This helps to spare glucose for the brain. The free fatty acids are made available by the action of glucagon. In the presence of low insulin levels, glucagon activates an enzyme in adipose cells called hormone-sensitive lipase. Lipase catalyzes the hydrolysis of stored triglycerides and the release of free fatty acids and glycerol into the blood. Glucagon activates enzymes in the liver that convert some of these fatty acids into ketone bodies, which are secreted into the blood (Fig.19.9 page 680) Several organs in the body can use ketone bodies, as well as fatty acids, as a source of acetyl CoA in aerobic respiration.

Figure 19. 9 Catabolism during fasting
Figure Catabolism during fasting. Increased glucagon secretion and decreased insulin secretion during fasting favors catabolism. These hormonal changes promote the release of glucose, fatty acids, ketone bodies, and amino acids into the blood. Notice that the liver secretes glucose that is derived both from the breakdown of liver glycogen and from the conversion of amino acids in gluconeogenesis.

Through the stimulation of lipolysis and ketogenesis, the high glucagon and low insulin levels that occur during fasting provide circulating energy substrates for use by the muscles, liver, and other organs. Through liver glycogenolysis and gluconeogenesis, these hormonal changes help to provide adequate levels of blood glucose to sustain the metabolism of the brain by the following: By serving as energy substrates for the muscles and other organs, the free fatty acids and ketone bodies spare blood glucose for use by the brain. Free fatty acids also reduce the activity of hydrolytic enzymes in muscles, hindering the ability of muscles to utilize glucose for energy so that more is available for the brain. These changes, together with the glucose provided by glycogenolysis and gluconeogenesis promoted by high glucagon/low insulin levels, sustain body metabolism during fasting (and exercise) conditions (Fig page 680).

Figure 19.10 The effect of feeding and fasting on metabolism.
Metabolic balance is tilted toward anabolism by feeding (absorption of a meal) and toward catabolism by fasting . This occurs because of an inverse relationship between insulin and glucagon secretion. Insulin secretion rises and glucagon secretion falls during food absorption, whereas the opposite occurs during fasting.

Diabetes Mellitus and Hypoglycemia
Chronic high blood glucose or hyperglycemia is the hallmark of diabetes mellitus. Mellitus means "honeyed" or "sweet". Diabetes means siphon i.e. frequent urination. It results from insufficient secretion of insulin by β cells of the inability of secreted insulin to stimulate cellular uptake of glucose from blood. Diabetes mellitus results from the inadequate secretion or action of insulin. There is also elevated glucagon secretion, because insulin is less able to allow a high plasma glucose concentration to suppress the secretion of glucagon. Evidence suggests that glucagon (through its stimulation of haptic glycogenolysis) contributed significantly to the hyperglycemia of people with type 2 diabetes mellitus.

There are 2 types of diabetes mellitus: (Table 19.5 page 681)
1.Type 1 Diabetes Mellitus: Is an autoimmune disease. Susceptibility for Type 1 diabetes is associated with gene of MHC on chromosome 6. Environmental factors play a triggering role in the genetically susceptible people, such as viruses and bacterial that result in triggering an autoimmune attack of the beta cells in the pancreatic islets. Autoreactive T lymphocytes (helper and killer T cells) are believed to be most important in the progressive destruction the insulin-secreting beta cells, although autoantibodies appear early in the course of the disease and aid diagnosis. Also called Insulin-dependent diabetes mellitus. Was once known as juvenile-onset diabetes because the condition is usually diagnosed in people under the age of 20. Since the incidence of type 2 diabetes in children is rising (due to an increase in the frequency of obesity), however, this term is no longer preferred.

Little or no insulin secretion.
Injections of exogenous insulin are required to sustain the person's life (since insulin is a polypeptide, it would be digested if taken orally; however, the FDA has recently approved the use of an inhaler containing a fine powder of insulin for the control of type 1 diabetes in adults). Amounts to about 5% of diabetic population. Removal of the insulin –secreting beta cells causes hyperglycemia and appearance of glucose in the urine. Without insulin, glucose cannot enter adipose cells, therefore, the rate of fat synthesis is less than the rate of fat break down, and large amounts of free fatty acids are released from the adipose cells. In a person with uncontrolled type 1 diabetes, many of the fatty acids released from adipose cells are converted into ketone bodies in the liver. This may result in an elevated ketone body concentration in the blood (ketosis), and if the buffer reserve of bicarbonate is neutralized, it may also result in ketoacidosis.

During this time, glucose and excess ketone bodies that are excreted in the urine act as osmotic diuretics and cause the excessive excretion of H2O in urine. This can produce severe dehydration, which, together with ketoacidosis and associated disturbances in electrolyte balance, may lead to coma and death (fig page 682). In addition to the lack of insulin, people with type 1 diabetes have an abnormally high secretion of glucagon from α cells of the islets. Glucagon stimulates glycogenolysis in the liver and thus helps to raise the blood glucose concentration. Glucagon also stimulates the production of enzymes in the liver that convert fatty acids into ketone bodies. The full range of symptoms of diabetes may result from high glucagon secretion as well as from the absence of insulin. Lack of insulin may be largely responsible for hyperglycemia and for the release of large amounts of fatty acids into the blood. High glucagon secretion may contribute to the hyperglycemia and in large part causes the development of ketoacidosis.

Figure 19.11. The consequences of an uncorrected insulin deficiency in type 1 diabetes mellitus.
In this sequence of events, an insulin deficiency may lead to coma and death.

2.Type 2 Diabetes Mellitus:
About 95% of the people who have diabetes. Is non-insulin-dependent. Is also called maturity-onset diabetes, since it is usually diagnosed in people over the age of 40. Since the incidence of type 2 diabetes in children is rising (due to an increase in the frequency of obesity), however, this term is no longer preferred. The effects produced by insulin, or any hormone, depend on the concentration of that hormone in the blood and on the sensitivity of the target tissue to given amounts on the hormone. Tissue responsiveness to insulin, for example, varies under normal conditions. Exercise increases insulin sensitivity and obesity decreases insulin sensitivity of the target tissues.

The islets of a nondiabetic obese person must therefore secrets high amounts of insulin to maintain the blood glucose concentration in the normal range. Conversely, nondiabetic people who are thin and who exercise regularly require lower amounts of insulin to maintain the proper blood glucose concentration. Is shown when the initial rise in blood glucose produced by the ingestion of a glucose solution triggers excessive insulin secretion, so that the blood glucose levels fall below normal within 5 hours. Usually slow to develop. Is hereditary (genetic factors are very significant; people at highest risk are those who have both parents with type 2 diabetes and those who are members of certain ethnic groups). Can have normal or even elevated levels of insulin in blood, but is insufficient to control hyperglycemia.

People with type 2 diabetes have abnormally low tissue sensitivity to insulin i.e. insulin resistance. Their Islet beta cells fail to secrete adequate amounts of insulin to compensate for the insulin resistance. This failure seems to result from inflammatory processed in the islets. However, the concordance of identical twins with type 2 diabetes is 70% and the risk of anyone getting diabetes is also almost 70% if both parent s have it. This demonstrates a strong heritable component in type 2 diabetes. The expression of this genetic tendency is increased by obesity. This is particularly true if the obesity involves an "apple shape," with large adipocytes in the greater omentum (visceral fat). Insulin resistance is believed to result from: Increased plasma levels of free fatty acids. Adipokines released by adipocytes.

Insulin resistance : 1. Reduces the ability of insulin to stimulate skeletal muscle, liver, and adipose tissue to take glucose out of the blood. 2. Is less able to inhibit the liver from producing more blood glucose. Also there is an elevated glucagon secretion that contributes significantly to the hyperglycemia of types 2 diabetes by stimulating hepatic glycogenolysis and gluconeogenesis. Thus, insulin resistance of type 2 diabetes raises blood glucose through increased hepatic secretion of glucose and decreased uptake of glucose into skeletal muscles and adipose tissue. People who are prediabetic may have impaired glucose tolerance, which is defined (in an oral glucose tolerance test ;GTT) as plasma glucose level of mg/dl at 2 hours following the glucose ingestion, and is accompanied by higher levels of insulin.

People who are obese appear to have an increased mass of beta cells in their pancreatic islets to compensate for their insulin resistance. Those who are going to become diabetic have a genetic susceptibility to β-cell failure under these conditions, where abnormal function and apoptosis of β-cell eventually leads to an inability of insulin secretion to compensate for the insulin resistance. Thus, type 2 diabetes is usually hereditary and slow to develop, and occurs in people who are overweight. In early, less severe cases, it can be accompanied by elevated and abnormal patterns of insulin secretion. In later, more severe cases, the secretion of insulin is reduced by beta cells apoptosis and other causes of beta cell failure.

People with chronic type 2 diabetes can have both insulin resistance and a deficient secretion of insulin. The incidence of type 2 diabetes has tripled in the past thirty years because of the increase in obesity. People who have a BMI of 30 have a 5-times greater risk of type 2 diabetes than people with a BMI of 25 or less. Since obesity decreases insulin sensitivity, people who are genetically predisposed to insulin resistance may develop type 2 diabetes when they gain weight. Logically, then, weight loss that leads to shrinking of adipocytes should decrease insulin resistance and reduce the symptoms of type 2 diabetes. This is supported by clinical studies which demonstrate that diet and exercise can control the symptoms in most people who have type 2 diabetes.

Exercise is beneficial in 2 ways:
1.By increasing calorie expenditure, it helps a person to lose of weight, and decrease in adipocyte size making them more sensitive. 2.Improves the sensitivity of skeletal muscle fiber to insulin, because it: a. Increases amount of GLUT4 carriers in plasma membrane that are needed for the facilitative diffusion of glucose into the skeletal muscle fibers. b. Enhances the ability of insulin to stimulate skeletal muscle glucose uptake and utilization in other ways, making the skeletal muscles better able to remove glucose from the blood.

If diet and exercise are insufficient, oral drugs to increase insulin secretion from β cells, or to decrease resistance of target tissues are given. Onset of type 2 can be prevented by changes in life style. These changes include exercise and weight reduction, together with an increased intake of fiber, a reduce intake of total fat, and reduced intake of saturated fat. In one recent study, these lifestyle changes decreased the risk of diabetes by 58% after 4 years. In the years preceding the development of hyperglycemia in type 2 diabetes, the insulin resistance associated with obesity can result in a compensatory increase in the number of β cells in the islets. This produces an elevated secretion of insulin, but there may be impaired glucose tolerance despite the increased insulin. Insulin resistance can be associated with hypertension and dyslipidemia ( and thus with increased risk of CVDs).

These conditions associated with the insulin resistance of type 2 diabetes have been called the" metabolic syndrome“. Metabolic syndrome in obesity may be caused by inflammation ; the number of macrophages in adipose tissue increases in proportion to the obesity, as do inflammation markers in the blood such as C-reactive protein. In obesity, adipose tissue (including adipocytes and macrophages) secretes several pro-inflammatory adipokines, including TNFα, interlukin-1, and resistin, that also reduce the insulin sensitivity of target tissues (adipose tissue, liver, and muscles). By contrast, the adipose tissue of lean people releases an anti-inflammatory adipokine-adiponectin-that increases insulin sensitivity and protects against metabolic syndrome. This syndrome is predicted to become even more prevalent as the population becomes more obese and less physically active.

Metabolic syndrome is a term that is used to a constellation of symptoms that surround type 2 diabetes, and also obesity. These symptoms include: 1.obesity, especially involving visceral fat. 2. Insulin resistance and type 2 diabetes. 3. Hypertension. 4. Dyslipidemia (high blood triglyceride levels, and low levels of HDL). 5. Greater risk of atherosclerosis. 6. Greater prevalence of chronic kidney disease. A person has the metabolic syndrome when there is central obesity (defined by waist circumference greater than specific values, which differ by sex and ethnicity) and 2 other conditions in the above list that includes symptoms and hypertension. One study estimated that the metabolic syndrome raises the risk of coronary heart disease and stoke by a factor of three.

People with type 2 diabetes so not usually develop ketoacidosis.
Hyperglycemia can be dangerous on a long-term basis leading to: 1.Blindness. 2.Kidney failure. 3.Amputation of lower extremities. 4.Development of circulatory problems. 5.Increase the tendency to develop gangrene 6.Increase the risk for atherosclerosis The glycated hemoglobin (hemoglobin A1c) test is a measure of the average blood glucose level over a few months and does not require overnight fasting. An A1c measurement of about: 5% is normal, 5.7%-6.4% is prediabetic, Above 6.5% indicates diabetes, 7% or less is considered good diabetic control.

Hypoglycemia A person with type 1 diabetes mellitus depends on insulin injections to prevent hyperglycemia and ketoacidosis. If inadequate insulin is injected, the person may enter a coma as a result of the ketoacidosis, electrolyte imbalance, and dehydration that develop. An overdose of insulin (insulin shock), however, can also produce a coma as a result of hypoglycemia (abnormally low blood glucose levels) produced. The physical signs and symptoms of diabetic and hypoglycemic coma are sufficiently different to allow hospital personnel to distinguish between these 2 types. Less severe symptoms of hypoglycemia are usually produced by an oversecretion of insulin form the islets of Langehans after a CH2O meal. This reactive hypoglycemia, caused by exaggerated response of β cells to a rise in blood glucose, is most commonly seen in adults who are genetically predisposed to type 2 diabetes.

People with reactive hypoglycemia must limit their intake of CH2O and eat small meals at frequent intervals, rather than 2-3 meals/day. Symptoms of reactive hypoglycemia are: 1.Tremor. 2.Hunger. 3.Weakness. 4.Blurred vision. 5.Mental confusion. To confirm a diagnosis of reactive hypoglycemia oral GTT and other tests must be performed (Fig page 659). In the oral GTT, reactive hypoglycemia is shown when the initial rise in blood glucose produced by the ingestion of a glucose solution triggers excessive insulin secretion, so that the blood glucose levels fall below normal within 5 hours.

Figure 19.13 Reactive hypoglycemia.
An idealized oral glucose tolerance test on a person with reactive hypoglycemia. The blood glucose concentration falls below the normal range within 5 hours of glucose ingestion as a result of excessive insulin secretion.

Figure Oral glucose tolerance in prediabetes and type 2 diabetes. The oral glucose tolerance test showing (a) blood glucose concentrations and (b) insulin values following the ingestion of glucose solution. Values are shown for people who are normal, prediabetic, and type 2 diabeteic. Prediabetics (those who demonstrate “insulin resistance”) often show impaired glucose tolerance without fasting hyperglycemia.

Metabolic Regulation by Adrenal Hormones, Thyroxine, and Growth Hormone
The anabolic effects of insulin are antagonized by glucagon and by the actions of a variety of other hormones. The hormones of the adrenals, thyroid, and anterior pituitary (specifically growth hormone) antagonize the action of insulin on CH2O and lipid metabolism. The actions of insulin, thyroxine, and growth hormone can act synergistically in the stimulation of protein synthesis.

regulate Na+ and K+ balance.
Adrenal Hormones The adrenal gland consists of 2 parts that function separate glands. The 2 parts secrete different hormones and are regulated by different control systems. The adrenal medulla secretes catecholamine hormones; epinephrine and lesser amount of norepinephrine, in response to sympathetic nerve stimulation. The adrenal cortex secretes corticosteroid hormones, which are grouped into: 1. Mineralocorticoids, such as aldosterone, which act on the kidneys to regulate Na+ and K+ balance. 2. Glucocorticoids, such as hydrocortisone (cortisol), which participate in metabolic regulation.

Metabolic Effects of Catecholamines (epinephrine & norepinephrine)
The metabolic effects of catecholamines are similar to those of glucagon. They stimulate glycogenolysis and the release of glucose from the liver, as well as lipolysis and the release of fatty acids from adipose tissue. These actions occur in response to glucagon during fasting, when low blood glucose stimulates glucagons secretion, and in response to catecholamines during the fight-or-flight reaction to stress; this will provide circulating energy substrates in anticipation of the need for intense physical activity. The actions of glucagon and epinephrine have similar mechanisms of action; the actions of both are mediated by cyclic AMP (Fig page 686).

Fig. 19. 14 How epinephrine and glucagon affect metabolism
Fig How epinephrine and glucagon affect metabolism. (1) The hormone binds to its receptor, causing G protein to dissociate.(2) The alpha subunit diffuses through the membrane to activate adenylate cyclase, which catalyzes the production of cAMP as a second messenger.(3) The cAMP binds to and removes the regulatory subunit of protein kinase, activating this enzyme.(4) The activation and inactivation of different enzymes by protein kinase promotes glycogenolysis in the liver and lipolysis in adipose tissue.

Metabolic Effects of Glucocorticoids
Hydocortisol (cortisol) and other glucocorticoids are secreted by the adrenal cortex in response to ACTH stimulation. The secretion of ACTH from the anterior pituitary occurs as part of the general adaptation syndrome in response to stress. Prolonged fasting or exercise certainly qualified as stressors, ACTH and glucocorticoids secretion are stimulated under these conditions. The increased secretion of glucocorticoids during fasting or exercise supports the effects of increased glucagon and decreased insulin secretion from the pancreatic islets. Like glucagon, hydrocortisone promotes lipolysis and ketogenesis, it also stimulates the synthesis of hepatic enzymes that promote gluconeogenesis.

Although hydrocortisone stimulates enzyme (protein) synthesis in the liver, it promotes protein breakdown in the muscles, which increases the blood levels of amino acids, and thus provides the substrates needed by the liver of gluconeogenesis. The release of circulating energy substrates (a.a., glucose, fatty acids, and ketone bodies) into the blood in response to hydrocortisone helps to compensate for a state of prolonged fasting or exercise (Fig page 687).

Fig. 19. 15 The metabolic effects of glucocorticoids
Fig The metabolic effects of glucocorticoids. The catabolic actions of glucocorticoids help to raise the blood concentration of glucose and other energy-carrier molecules.

Thyroxine Secreted from the thyroid follicles in response to stimulation by TSH from the anterior pituitary. Also called tetraiodothyronine (T4). Thyroid also secretes smaller amounts of triiodothyronine (T3) in response to stimulation by TSH. Almost all organs in the body are targets of thyroxine action. Thyroxine is not the active form of the hormone within the target cells. Thyroxine is a prehormone that must first be converted to T3 within the target cells to be active (Fig page 326). Acting via its conversion to T3, thyroxine: 1. Regulates the rate of cell respiration. 2. Contributes to proper growth and development, particularly during early childhood.

Fig. 11. 6 The mechanism of action of thyroid hormones
Fig The mechanism of action of thyroid hormones. (1)Thyroxine(T4),carried to the target cell bound to its plasma carrier protein, dissociate from its carrier and passes through the plasma membrane of its target cell. (2) In the cytoplasm, T4 is converted into T3 (triiodothyronine), which (3) uses binding proteins to enter the nucleus. (4) The hormone-receptor complex binds to DNA, (5) stimulating the synthesis of new mRNA. (6) The newly formed mRNA codes fro the synthesis of new proteins, which (7) produce the hormonal effects in the target cell.

Thyroxine (via its conversion to T3 ) stimulates the rate of cell respiration in almost all cells in the body (as effect believed to be due to a lowering of cellular ATP concentrations). This effect is produced by : 1. The production of uncoupling proteins which "uncouples" oxidative phosphorylation in mitochondria by causing the leakage of protons (H+ ) from the intermembrane space This decreases the production of ATP, which inturn stimulate increases cell respiration. 2. Stimulation of active transport Na+/K+ pumps, which serve as an energy sink to further lower ATP concentrations. ATP exerts an end-product inhibition of cell respiration, so that when ATP concentrations decrease, the rate of cell respiration increases. Much of the energy liberated during cell respiration escapes as heat, and uncoupling proteins increase the proportion of food energy that escapes as heat.

Since thyroxine stimulates the production of uncoupling proteins and the rate of cell respiration, the actions of thyroxine increase the production of metabolic heat. The heat-producing, or calorigenic effects of thyroxine are required for cold adaptation. Recent evidence suggests that thyroxine has a permissive effect on the ability of brown adipose tissue to generate heat in response to sympathetic nerve stimulation, thus contributing to adaptive thermogenesis as well as to the basal metabolic rate.

BMR has 2 components: Independent of thyroxine action Regulated by thyroxine. Thyroxine act to "set" the BMR. Thus, BMR can be used as an index of thyroid function. A normal level of thyroxine secretion is required for growth and proper development of the C.N.S. in children. This why hypothyroidism in children can cause cretinism. A normal level of thyroxine secretion is required in order to maintain a balance of anabolism and catabolism. The symptoms of hypothyroidism and hyperthyroidism in adults are compared in table 11.8 page 332. For reasons that are incompletely understood, both hyperthyroidism and hypothyroidism cause protein breakdown and muscle wasting.

Growth Hormone (GH) Secreted by the anterior pituitary in larger amounts than any other of its hormones. Is also called somatotropin. Stimulates growth in children and adolescents. Its continued high secretion in adults, particularly under the conditions of fasting and other forms of stress, implies that this hormone can have important metabolic effects even after the growing years have ended

Regulation of Growth Hormone Secretion
GH secretion is regulated by both a releasing and an inhibiting (somatostatin) hormone from the hypothalamus. GH thus appears to be unique among the anterior pituitary hormones in that its secretion is controlled by both a releasing and an inhibiting hormone from the hypothalamus. Its secretion follows a circadian ("about a day") pattern, increasing during sleep and decreasing during periods of wakefulness. Its secretion is stimulated by an increase in the plasma concentration of a.a. and by a decrease in the plasma glucose concentration. These events occur during absorption of a high-protein meal, when a.a. are absorbed. It is also increased during prolonged fasting, when plasma glucose is low and plasma a.a. concentration is raised by the breakdown of muscle protein.

Insulin-like Growth Factors. (IGFs)
Produced by many tissues. Are polypeptides that are similar in structure to proinsulin. They have insulin-like effects and serve as mediators for some of growth hormone's action. Somatomedins is often used to refer to 2 of these factors; IGF-1 and IGF-2 because they mediate the actions of somatotropin (growth hormone). The liver produces and secretes IGF-1 in response to GH stimulation. IGF-1 then functions as a hormone in its own traveling in the blood to the target tissue. A major target is cartilage, where IGF-1 stimulates cell division and growth. IGF-1 also functions as an autocrine regulator, since the chondrocytes themselves produce IGF-1 in response to GH stimulation.

The growth-promoting actions of IGF-1, acting as both a hormone and an autocrine regulator, thus directly mediate the effects of growth hormone on cartilage. These actions are supported by IGF-2, which has more insulin-like actions. The action of GH in stimulating lipolysis in adipose tissue and in decreasing glucose utilization is apparently not mediated by the somatomedins (Fig page 663).

Fig. 19. 17 The metabolic effects of growth hormone
Fig The metabolic effects of growth hormone. The growth-promoting, or anabolic, effects of growth hormone are mediated indirectly via stimulation of insulin-like growth factor I (also called somatomedin C) production by the liver.

Effects of Growth Hormone on Metabolism (Fig.19.17 page 663)
The fact that GH secretion is increased during fasting and also during absorption of a protein meal reflects the complex nature of this hormone's action. It has both anabolic and catabolic effects: 1. It promotes protein synthesis, and in this respect is similar to insulin. It stimulates the cellular uptake of a.a. and protein synthesis in many organs of the body. These actions are useful when eating a protein-rich meal; a.a. are removed from the blood and used to form proteins, and the plasma concentration of glucose and fatty acids is increased to provide alternate energy sources. This anabolic effect of GH is particularly important during the growing years, when it contributes to increases in bone length and in the mass of many soft tissues.

2.It stimulates the catabolism of fat and the release of fatty acids from adipose
tissue during periods of fasting, as GH secretion is increased at night. A rise in the plasma fatty acids concentration induced by GH results in decreased rates of glycolysis in many organs. This inhibition of glycolysis by fatty acids, perhaps together with a more direct action of GH, results in decreased glucose utilization by the tissues. GH thus acts to raise the blood glucose concentration, and for that reason is said to have "diabetogenic" effect.

Effects of Growth Hormone on Body Growth
GH has stimulatory effects that result from stimulation of mitosis in the epiphyseal growth plates of cartilage in the long bones of children and adolescents. This action is mediated by somatomedins, IGF-1 and IGF-2, which stimulate the chondrocytes to divide and secrete more cartilage matrix. Part of this growing cartilage is converted to bone, enabling the bone to grow in length. This skeletal growth stops when the epiphyseal discs are converted to bone after the growth spurt during puberty, despite the fact that GH secretion continues throughout adulthood. .

An excessive secretion of GH:
1. In children can produce gigantism. 2. In adults can produce acromegaly (an elongation of the jaw and deformities in the bones of the face, hands, and feet. Accompanied by the growth of soft tissues and coarsening of ht skin. (Fig page 663). An inadequate secretion of GH during the growing years results in dwarfism. Laron dwarfism is a condition in which there is a genetic insensitivity to the effects of GH

Fig. 19. 18 The progression of acromegaly in one individual
Fig The progression of acromegaly in one individual . The coarsening of features and disfigurement are evident by age 33 and severe at age 52.

Regulation of Calcium and Phosphate Balance
The calcium and phosphate concentrations of plasma are affected by bone formation and resorption, intestinal absorption of Ca2+ and PO43-, and urinary excretion of these ions. These processes are regulated by parathyroid hormone, 1,25-dihydroxy vitamin D3, and calcitonin (Table 19.7 page 664). Remember that osteoblast is a bone-forming cell, osteoclast is a cell that resorbs bone by promoting the dissolution of calcium phosphate crystals, and osteocyte is a mature bone cell that has become entrapped within a matrix of bone

Bone deposition and Resorption
The skeleton provides support for the body, and serves as a large store of calcium and phosphate in the form of crystals called hydroxyapatite {Ca10(PO4)6(OH)2}. The calcium phosphate in hydroxyapatite crystals is derived from the blood by the action of bone-forming cells, or osteoblasts. The osteoblasts secrete an organic matrix composed largely of collagen protein, which becomes hardened by deposits of hydroxyapatite (bone deposition). The dissolution of hydroxyapatite by the action of osteoclasts, and the return of bone calcium and phosphate to the blood is called bone resorption. The formation of new osteoclasts from their precursor cell is a highly regulated process. The osteoclast precursor cells produce a surface receptor protein known by its acronym, RANK.

Osteolblasts produce the ligand for this receptor, known as RANK ligand or RANKL, which binds to RANK and stimulates osteoclast development. So it seems that osteoblasts can stimulate the production of osteoclasts. However, osteoblasts also produce and secrete a molecule, called osteoprotegerin, which interferes with the ability of RANKL to bind to RANK. Acting through production of osteopretegerin, osteoblasts can thereby also block the formation of new osteoclasts. Bone resorption begins when the osteoclast attaches to the bone matrix and forms a "ruffled membrane" (Fig page 665). Since the bone matrix contains both an inorganic component (the calcium phosphate crystals) and an organic component (collagen and other proteins), the osteoclast must secretes products that both dissolve calcium phosphate and digest the proteins of bone matrix. The dissolution of calcium phosphate is accomplished by transport of H+ by a H+-ATPase pump in the ruffled membrane, thereby acidifying the bone matrix (to a pH of about 4.5) immediately adjacent to the osteoclast.

A channel for Cl- allows Cl- to follow the H+, preserving electrical neutrality.
Finally, despite the extrusion of H+ from the osteoclast, the cytoplasm is prevented from becoming too basic by the action of an active transport Cl-/HCO3-pump on the opposite surface of the osteoclast. The protein component of the bone matrix is digested by enzymes, primarily one called cathepsin K, released by the osteoclasts. The osteoclast can then move to another site and begin the resorption process again, or be eliminated. Estrogen, often given to treat osteoporosis in post-menopausal women, works in part by stimulating the apoptosis of osteoclasts. The formation and resorption of bone occur constantly at rates determined by the relative activity of osteoblasts and osteoclasts. Body growth during the first two decades of life occurs because bone formation proceeds at a faster rate than bone resorption.

Fig. 19. 19 The resorption of bone by osteoclasts
Fig The resorption of bone by osteoclasts. (a) A photomicrograph showing osteoclasts and bone matrix. (b) Figure depicting the mechanism of bone resorption. Notice that the bone is first demineralized by the dissolution of CaPO4 from the matrix due to acid secretion by the osteoclast. After that, the organic component of the matrix (mainly collagen) is digested by the secretion of enzyme molecules (an enzyme called cathepsin K) from the osteoclast.

By age 50 or 60, the rate of bone resorption often exceeds the rate of bone deposition.
The constant activity of osteoblasts and osteoclasts allows bone to be remodeled throughout life. Despite the changing rates of bone formation and resorption, the plasma concentrations of calcium and phosphate are maintained by hormonal control of the intestinal absorption and urinary excretion of these ions. These hormonal control mechanisms are very effective in maintaining the plasma calcium and phosphate concentrations within narrow limits. The maintenance of normal plasma calcium concentrations is important because of the wide variety of effects that calcium has in the body: 1. Calcium is needed for blood clotting.

2. It is needed for a variety of cell signaling functions:
a. As a second messenger of hormone action. b. As a signal for neurotransmitter release from axons in response to action potentials. c. As the stimulus for muscle contraction in response to electrical excitation. 3. Calcium is needed to maintain proper membrane permeability. An abnormally low plasma calcium concentration increases the permeability of the cell membranes to Na+ and other ions. Hypocalcemia enhances the excitability of nerves and muscles and can result in muscle spasm (tetany).

Hormonal Regulation of Bone
I.Parathyroid Hormone and Calcitonin Whenever the plasma concentration of Ca2+ begins to fall, the parathyroid glands are stimulated to secrete increased amounts of parathyroid hormone (PTH). PTH acts to raise the blood Ca2+ back to normal levels. People who have their parathyroid glands removed (as may occur accidentally during surgical removal of the thyroid) will experience hypocalcemia. Hypocalcemia (low plasma calcium concentrations) is a common clinical condition with many potential causes including: 1. Inadequate PTH secretion, or 2. Inadequate activation of PTH receptors, 3. Insufficient vitamin D, 4. Insufficient magnesium.

Hypocalcemia can cause:
1. Muscle twitching, 2. Muscle spasm, 3. Severe tetany, 4. Cardiac abnormalities. PTH helps to raise the blood Ca2+ concentration through: 1. Primarily by stimulating the activity of osteoclasts to resorb bone. 2. Stimulating the kidneys to reabsorb Ca2+ from the glomerular filtrate while inhibiting the reabsorption of PO3-. This raises blood Ca2+ levels without promoting the deposition of calcium phosphate crystals in bone. 3. Stimulating the kidneys to produce the enzyme (1α-hydroxylase) needed to convert 25-hydroxyvitamin D3 into the active hormone 1,25-hydroxyvitamin D3 which promotes the absorption of Ca2+ and PO3+ from food and drink across the intestinal epithelium. The thyroid gland secretes calcitonin from the parafollicular cells or C cell. It inhibits the resorption of bone, so it has an opposite effect of that of PTH and 1,25-hydroxyvitamin D3. People with stress fractures of vertebrae due to osteoporosis may be helped by injections or nasal sprays of calcitonin

II.Estrogen and Testosterone
In both men and women, estrogen is needed for the epiphyseal discs (the cartilage growth plates) to seal (become bone). Estrogen comes from the ovaries via the circulation in women. Estrogen is formed within the epiphyseal discs from circulating testosterone in men. The action of estrogen is also required for proper bone mineralization and the prevention of osteoporosis. Men are less prone to osteoporosis than postmenopausal women because men can form estrogen (derived from circulating androgens) in their bones, whereas, in women, estrogen secretion from the ovaries declines at menopause. Also, testosterone secreted by the testes may have a direct effect on bone to inhibit resorption.

Fig. 19. 20 Scanning electron micrographs of bone
Fig Scanning electron micrographs of bone. These biopsy specimens were taken from the iliac crest. Compare bone thickness in (a) a normal specimen and (b) a specimen from a person with osteoporosis.

Estrogen promotes bone mineralization partly because it stimulates the actions of osteoblasts, which: 1. Produce new bone matrix. 2. Secrete regulatory molecules that influence the action of osteoclasts. Osteoblasts produce RANK ligand (RANKL), which binds to the receptor called RANK on osteoclast progenitor cells and stimulates them to become osteoclasts. Also, ostoeblasts produce osteoprotegerin, a molecule that blocks this effect and thereby inhibits new osteoclast formation. Estrogen acts to suppress the formation of new osteoclast and may even promote the apoptosis (cell suicide) of existing osteoclasts. Thus, estrogen stimulates bone mineralization by both promoting the activity of osteoblasts and by suppressing the formation of osteoclasts.

III.Effects of other Hormones
1. T3 : People who are hyperthyroid are more prone to osteoporosis. Both osteoblasts and osteocytes have receptors for T3. 2. Leptin: Is secreted by adipocytes and: a. Acts on the hypothalamus to reduce hunger and increase metabolic rate. b. Influences the activity of osteoblasts. c. Its net effect appears to be stimulation of osteoblast proliferation. 3. Insulin: Promotes bone growth by suppressing an inhibitor of osteoblast development. It also appears to stimulate osteoblasts to secrete a hormone known as osteocalcin.

IV.1,25-Dihyroxyvitamin D3 (Fig.19.21 page 668)
The production of 1,25-Dihyroxyvitamin D3 begins in the skin, where vitamin D3 is produced from its precursor molecule 7-dehydrocholesterol under the influence of sunlight. When the skin does not make sufficient amounts of vitamin D3, this compound must be ingested in the diet (that is why it is called a vitamin). Vitamin D3 functions as a prehormone; in order to be biologically active, it must be chemically changed. An enzyme in the liver adds (OH) to carbon atom number 25, which converts vitamin D3 into 25-hyroxyvitamin D3. An enzyme in the kidneys adds another (OH) to carbon atom number 1 and produce 1,25-Dihyroxyvitamin D3. The activity of the kidneys enzyme is stimulated by PTH (Fig page 668).

Fig. 19. 21 The production of 1,25-digydroxyvitamin D3
Fig The production of 1,25-digydroxyvitamin D3. This hormone is produced in the kidneys from the inactive precursor 25-hydroxyvitamin D3 (formed in the liver). The latter molecule is produced from vitamin D3 secreted by the skin.

Fig The negative feedback control of parathyroid hormone secretion. A decrease in plasma Ca2+ directly stimulates the secretion of parathyroid hormone (PTH). The production of 1,25-dihydrocyvitamin D3 also rises when Ca2+ is low because PTH stimulates the final hydroxylation step in the formation of this compound in the kidneys.

Increased secretion of PTH, stimulated by low blood Ca2+, is thus accompanied by the increased production of 1,25-Dihyroxyvitamin D3. The hormone 1,25-Dihyroxyvitamin D3 helps to raise the plasma concentrations of calcium and phosphate by stimulating: 1. The intestinal absorption of calcium and phosphate. 2. The resorption of bones. 3. The renal reabsorption of calcium and phosphate so that less is excreted in the urine. Notice that 1,25-Dihyroxyvitamin D3 , but not PTH, directly stimulates intestinal absorption of calcium and phosphate and promotes the reabsorption of phosphate in the kidneys. The effect of simultaneously raising the blood concentrations of Ca2+ and PO3- results in the increased tendency of these two ions to precipitate as hydroxyapatite crystals in bone.

The hormone is needed for proper bone deposition because it directly stimulates bone resorption.
Inadequate amounts of 1,25-Dihyroxyvitamin D3 results in the bone demineralization of osteomalacia and rickets. The primary function of 1,25-Dihyroxyvitamin D3 is stimulation intestinal Ca2+and PO43- absorption. When Ca2+ intake is adequate, the major result of 1,25-Dihyroxyvitamin D3 action is the availability of Ca2+ and PO43- in sufficient amounts to promote bone deposition. Only when Ca2+ intake is inadequate does the direct effect of 1,25-Dihyroxyvitamin D3 on bone resorption become significant and raise blood Ca2+ to maintain homeostasis.

1,25-hydroxyvitamin D3 is also formed as an autocrine/paracrine regulator by the skin, breast, colon, prostate, and some of the cells of the immune system. 25-hydroxyvitamin D3 (from the liver) is converted into the active regulator, which remains within the tissues or organ that produces it. 1,25-hydroxyvitamin D3 promotes: Cell differentiation Inhibits cell proliferation Aids the function of the immune system. One of its clinical applications is that 1,25-hydroxyvitamin D3 is used in treatment for the hyperproliferative skin disease: psoriasis.

Negative feedback control Calcium and Phosphate Balance
The secretion of parathyroid hormone is controlled by the plasma calcium concentrations. Its secretion is stimulated by low calcium concentrations and inhibited by high calcium concentrations. Since parathyroid hormone stimulates the final hydroxylation step in the formation of 1,25-Dihyroxyvitamin D3, a rise in parathyroid hormone results in an increase in production of 1,25-Dihyroxyvitamin D3. Low blood calcium can thus be corrected by the effects of increased parathyroid hormone and 1,25-Dihyroxyvitamin D3 (Fig19.23 page 669). It is possible for plasma calcium levels to fall while phosphate levels remain normal.

Fig. 19. 23 Homeostasis of plasma Ca2+ concentrations
Fig Homeostasis of plasma Ca2+ concentrations. A negative feedback loop returns low blood Ca2+ concentrations to normal without simultaneously raising blood phosphate levels above normal.

The increased secretion of parathyroid hormone an the production of 1,25-Dihyroxyvitamin D3 that result could abnormally raise phosphate levels while acting to restore normal calcium levels. This is prevented by the inhibition of phosphate reabsorption in the kidneys by parathyroid hormone, so that more phosphate is excreted in the urine (Fig page 668). In this way, blood calcium can be raised to normal levels without excessively raising blood phosphate concentrations. Calcitonin, secreted by the parafollicular cells of C cells of the thyroid, is a calcium lowering hormone, i.e. has as effect opposite to that of parathyroid hormone. The secretion of calcitonin is stimulated by high plasma calcium levels and acts to lower calcium levels by: 1. Inhibiting the activity of osteoclasts, thus reducing bone resorption. 2. Stimulating the urinary excretion of calcium and phosphate by inhibiting their reabsorption of the kidneys (Fig page 669).

Fig. 19. 21 The production of 1,25-digydroxyvitamin D3
Fig The production of 1,25-digydroxyvitamin D3. This hormone is produced in the kidneys from the inactive precursor 25-hydroxyvitamin D3 (formed in the liver). The latter molecule is produced from vitamin D3 secreted by the skin.

Fig. 19. 24 The negative feedback control of calcitonin secretion
Fig The negative feedback control of calcitonin secretion. The action of calcitonin is antagonistic to that of parathyroid hormone.

Although it is attractive to think that calcium balance is regulated by the effects of antagonistic hormones, the significance of calcitonin in human physiology remains unclear. The ability of very large pharmacological doses of calcitonin to inhibit osteoclast activity and bone resorption is clinically useful in the treatment of Paget’s disease and sometime, and osteoporosis.

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كلية الصيدلة والعلوم الطبية

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