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The Biology Of The Action Of Leptin 21 The Obese Gene and its Protein Product Leptin

In 1994, the mouse obese (ob) gene and its human homolog were isolated by positional cloning (2). In humans, the gene is positioned at 7q31. The mouse ob gene resides on chromosome 6 and consists of three exons and two introns and encodes a 4.5-kilobase (kb) mRNA. The coding sequence is contained within exons 2 and 3. The wild-type obese gene encodes a 167-amino-acid protein named leptin, expressed almost exclusively in white adipose tissue, although recently its expression has been found at lower levels in the placenta, stomach, and brain (3-5). The homozygous mutant mouse ob ob has a mutation in the obese gene, either as a result of a 5-kb ETn transposon inserted into the first intron of ob (ob2j mice) or of a nonsense mutation causing protein truncation (6). Leptin (leptos Greek thin) is a 16-kDa class I cytokine, with structural similarity to interleukin (IL)-2, the para- digm T-cell growth factor, although there is no sequence similarity (7). It consists of 167 amino acids and is...

The Effects Of Leptin On The Immune System 51 The Innate Immune Reponse

As mentioned earlier, the pattern of leptin release during an acute-phase response mirrors other cytokine gene expression, particularly IL-6 (11-13). It has been shown that LPS, IL-1, TNF-a, and other inflammatory stimuli increase gene expression and serum concentration of leptin as early as 6 h after the initial stimulus. The induction of gene expression makes leptin an ideal candidate to be a key player in an immune inflammatory response. It is of particular interest that LPS binds to a Toll-like receptor (TLR-4) on adipocytes and induces adipocyte expression of TLR-2 and secretion of leptin and other proinflammatory cytokines (102). TLR engagement provides an elegant mechanism whereby the production of leptin is induced at the start of an immune response before cognate recognition of a foreign antigen has occurred, which will, in turn, upregulate Th1 cognate immune responses if appropriate (see Section 5.2). This further illustrates the well-accepted concept of a critical interplay...

Aldosterone and Cortisol Excess

In situations of aldosterone excess causing hypertension, there is usually an adrenal cortical adenoma (Conn's syndrome) or bilateral adrenal hyperplasia. Aldosterone promotes sodium retention and potassium excretion, leading to slight hypernatremia, extracellular volume (ECV) expansion, hypertension, and hypokalemic alkalosis. Unlike secondary causes of hyperaldosteronism, such as renal artery stenosis, in which aldosterone and renin levels are high, in primary hyperaldosteronism, renin is suppressed due to ECV expansion. In states of Cortisol excess, caused by either adrenal overproduction (Cushing's syndrome) or pituitary stimulation from an adrenocorticotrophin (ACTH) secreting adenoma (Cushing's disease), high Cortisol levels produce aldosterone-like mineralocorticoid effects. Two recently recognized causes of hypertension are apparent mineralocorticoid excess and glucocorticoid suppressible hyperaldosteronism. The first is due to failure to metabolize and inactivate Cortisol...

In Vivo Models Of Leptin Deficiency 31 The obob and dbdb Mouse

Mice are phenotypically identical, each weighing three times more than normal mice, with a fivefold increase in body fat content. In his pioneering parabiosis work, Coleman showed that the obesity in the ob ob mouse was the result of the lack of a circulating satiety factor and that the phenotype of the db db mouse was probablycaused by a receptor defect for that factor (73,74). The ob ob phenotype has since been found to result from two different mutations in two different strains of mice. The mutation in ob2j mice prevents synthesis of leptin caused by a mutation that results in the insertion of a retrovirallike transposon in the first intron of the ob gene. This insertion contains several splice acceptor and polyadenylation sites, which leads to the production of chimaeric RNAs in which the first exon is spliced to sequences in the transposon. Thus, mature mRNA is not produced (6). In the C57BL 6 ob ob mutant, a nonsense mutation results in the production of a truncated inactive...

Role of Leptin as a Signal of Starvation

In 1996, Ahima et al. proposed a role for leptin as a signal of energy deficiency (14). Circulating leptin levels fall rapidly in response to starvation when energy intake is limited and energy stores (fat) are declining. It was suggested that leptin may have evolved to signal the shift between sufficient and insufficient energy stores (18). The hypothesis that reduced circulating leptin levels signal nutrient deprivation is supported by the demonstration that prevention of the starvation-induced fall in plasma leptin levels by exogenous replacement is able to prevent the starvation-induced delay in ovulation in female mice. In addition, such a regime of leptin replacement was also shown to partially prevent the fasting-induced rise in plasma corticosterone levels and the fall in plasma thyroid hor mone (total T4) levels (14). It is likely that leptin exerts these effects at the level of the central nervous system (18). 2.4. Peripheral Effects of Leptin In addition to the centrally...

Role of Leptin in the Regulation of Body Weight

Chronic administration of recombinant ob protein has been shown to produce a significant reduction in body weight in ob ob and normal mice because of a reduction in food intake but also an increase in energy expenditure (26-28). Centrally administered leptin (into the lateral or third cerebral ventricles) has been shown to be particularly effective in promoting anorexia and weight loss at doses which when administered peripherally were without effect on feeding behavior (26). This suggests that leptin acts on receptors within the central nervous system, probably at the level of the hypothalamus and clearly implicate leptin as an important factor in the regulation of body weight in rodents (29). Further evidence that implicates leptin as a regulator of body weight is the fact that total deficiency in leptin in mouse and man causes obesity, (29,30) which is reversed by leptin treatment (27.31). However, as mentioned earlier, leptin levels are high in rodent and human models of obesity,...


Leptin was discovered as a first adipocytokine in 1994 (Zhang Y et al., 1994). Team of researchers (Ates et al., 2008) have found relationship between leptin and retinal vein occlusion. The authors suggest that leptin may play a role in pathogenesis of retinal vein occlusion probably by influencing vessel wall homeostasis. In diabetes, leptin may affect angiogenesis process by induction of vascular endothelial growth factor (VEGF) and suppression of pigment epithelium derived factor (PEDF) and also production of intracellular reactive oxygen species (ROS) in retinal vascular endothelial cells. (Gariano et al. 2000, Yamagishi et al., 2003). However, in other studies the authors reported no association between leptin and the development and progression of retinopathy (Sari et al., 2010).

Carbohydratesinsulin resistance

The insulin resistance is presumably largely endocrine-driven, possibly via increased cortisol or hPL. Leptin has been implicated in altered insulin sensitivity outside pregnancy, but appears not to play a role during gestation, while concentrations of glucagons and the catecholamines are unaltered.

Discharge And Home Healthcare Guidelines

Cortisol deficiency causes altered metabolism, decreased stress tolerance, and emotional lability. Aldosterone deficiency causes urinary loss of sodium, chloride, and water, resulting in dehydration and electrolyte imbalances. Androgen deficiency leads to the loss of secondary sex characteristics.

Endocrinology of ageing

The second hormonal system demonstrating age-related changes is the circulating levels of dehydroepiandrosterone (DHEA) and its sulfate (DHEAS), which gradually decline resulting in 'adrenopause' (Ravaglia et al 1996, Herbert 1995). At age 30, DHEAS levels are approximately five times higher than at age 85. The decline in DHEA(S) levels contrasts with the maintenance of plasma cortisol concentrations at the same level, and seems to be caused by a selective decrease in the number of functional zona reticularis cells in the adrenal cortex rather than regulated by a central (hypothalamic) pacemaker of ageing (Herbert 1995).

Depression an allostatic disorder with premature mortality

The neuroendocrinology of human depression closely resembles that of chronic stress models in the laboratory (Checkley 1996, Lopez et al 1998). One sees increased central HPA activity, reduced feedback, and adrenocortical hypertrophy. Mean 24 h plasma cortisol concentrations are normal to slightly elevated, as are urinary free cortisol excretion, plasma and cerebrospinal fluid free cortisol concentrations, and salivary cortisol. Nocturnal plasma cortisol concentrations are significantly raised, whereas daytime plasma cortisol concentrations usually are not. Moreover, body temperatures, both nocturnal and diurnal, are significantly elevated in depression by 0.4-0.6 C (Szuba et al 1997, Rausch et al 2000). These are classical allostatic changes.

Risk Versus Benefit Assessment

A good example of an application of mechanistic modeling in quantitative risk benefit assessments comes from the literature on inhaled corticosteroids (43,44). While inhaled corticosteroids present a viable therapeutic option for asthma, there have been questions on their long-term safety. Specifically, these concerns stem from their potential to suppress development of the adrenal function. Consequently, a clear delineation of the benefit (for asthma) and risk (clinical adrenal suppression) is necessary for development of newer inhaled cor-ticosteroids. Here the benefit is a conglomeration of all favorable attributes of a molecule, including optimal PK properties, drug delivery properties, and increased residence in the lung, which may likely contribute to a more favorable systemic side-effect profile. An assessment of a quantitative risk benefit value would entail the use of cortisol levels in plasma as a biomarker of the suppression in adrenal function. PK PD modeling can then be...

Exogenous Sources of Advanced Glycoxidation End Products

Animal studies have demonstrated the close relationship between increased dietary AGE intake and development and or progression of many diabetes-related complications. Nephropathy, postinjury restenosis, accelerated atherosclerosis, and delayed wound healing were significantly inhibited by lowering dietary AGE intake (27-30). Sebekova and associates demonstrated in the remnant-kidney rat model that feeding an AGE-rich diet for 6 weeks increases kidney weight and causes proteinuria, independent of changes in glomerular filtration rate, pointing to the detrimental effect of such diet on the kidney (31). Of particular interest are studies showing that a low-glycotoxin environment can prevent or delay significantly autoimmune diabetes in successive generations of nonobese diabetic (NOD) mice (32) and to improve the insulin-resistant state in db db (+ +) mice (33). Reduction in exposure to exogenous AGEs of db db (+ +) mice, lacking in leptin receptor and thus prone to insulin resistance...

Exercise and Immune Function

Aging affects the muscle precursor cells (satellite cells or myobloasts) and their regeneration after exercise (Grounds 1998). Aging may also affect proliferation and fusion of myoblasts in response to injury signaling molecules that stimulate satellite cells with aging host environment, inflammatory cells, growth factors and their receptors, and the extracellular matrix. There is a reduction in growth hormone, total and free testosterone, and cortisol, both at baseline and after exercise. The decreased anabolic effects on muscles may explain the loss of muscle mass and strength with aging (Hakkinen et al., 1998). The more primitive components of immune defense, including natural killer cells, phagocytes, acute-phase proteins, and regulatory cytokines, may be altered in elderly. Several investigators have found that the proportion of neutrophils will be increased in the circulation following physical exercise. An increase in neutrophils has been correlated with an increase in plasma...

Management of unexplained recurrent miscarriage

A significant number of couples investigated for recurrent miscarriage will have no cause identified to account for their pregnancy losses. While this is a frustrating situation for both patient and clinician, the prospective live-birth rate of women who are aPL negative is good 32 . The main determinants of future pregnancy outcome are the maternal age and the number of previous miscarriages she has had (Figs 13.4 and 13.5). A woman less than 38 years of age who has had less than five consecutive first trimester miscarriages and who is aPL negative has a 65 chance of her next pregnancy being successful with supportive care alone. While the scientific basis for the benefit of supportive care in early pregnancy remains to be elucidated, it is possible that elevated stress hormones (e.g. cathecholamines and cortisol) may be able to reduce fetal vascularization and oxygen supply and thereby induce miscarriage.

Dynamics and Kinetics of Ligand Receptor Binding

As is the case for the class I cytokine receptors, ObRb probably dimerizes in order to signal optimally (66). Unlike the other receptors of this class that form heterodimers with gp130 (57), ObRb forms homodimers or homo-oligomers (67). This homo-oligomerization is ligand independent and signaling via ObRb is not susceptible to dominant negative repression by the short isoforms, even when they are present in great excess (66). The leptin receptor is able to homo-oligomerize in an isoform-specific manner, such that long isoforms specifically oligomerize even in the presence of an excess of short forms of the receptor. This probably occurs via the JAK-binding motif in the intracytoplasmic domain of ObRb (68). This is an important finding, as it provides a mechanism whereby leptin can exert potent effects even in issues with a relatively low density of ObRb. Following ligand binding, the leptin receptor is internalized via clathrin-mediated endocytosis at different rates ObRb is...

Primary Nursing Diagnosis

The main focus is to find the primary cause of the cortisol excess and remove it if possible. In the case of iatrogenic Cushing's syndrome, care is focused on alleviating as many of the signs and symptoms as possible when the therapy cannot be discontinued. If the patient has primary Cushing's syndrome from an adrenal tumor, the tumor is removed surgically. Even if the tumor is unilateral, the patient is treated for adrenal insufficiency after the surgery because the high levels of cortisol from the tumor may have caused the unaffected adrenal gland to atrophy. Patients with adrenal carcinoma are treated postoperatively with mitotane to treat metastases. Throughout the patient's recovery, fluid, electrolyte, and nutritional assessment and balance are essential. For secondary Cushing's syndrome from a pituitary tumor, the preferred option is a transsphenoidal adenectomy, a procedure that explores the pituitary gland to find microadenomas. It is successful in 20 to 70 of patients. A...

Dysmetabolic Metabolic Syndrome Syndrome X

The obesity in the abdomen tends to be deep or visceral adiposity, which is associated with accelerated atherosclerosis and coronary artery disease (104). The presence of visceral fat in this syndrome is an example of the fact that not all forms of obesity are functionally the same and that different forms can pose different health risks. Patients with fat distributed in subcutaneous regions around the gluteofemoral areas and upper abdomen are at much less risk for complications such as hypertension, lipid abnormalities, and insulin resistance than those with visceral fat (124,125). The idea that adipose tissue releases important metabolites has been fueled by recent findings showing that fat may not be just a storage compartment but rather an active source for production of proteins central to obesity, insulin resistance, and lipid disorders. Adipose tissue has been demonstrated to produce leptin (126), resistin (127,128), and Acrp 30 AdipoQ (129-132), which have been proposed to...

Immunological Abnormalities of the obob and dbdb Mouse

Impaired cellular immune function was noted nearly 20 yr ago in both ob ob and db db mice, long before the discovery of leptin (76-80). Leptin-deficient ob ob mice and receptor-defective db db mice have been found to exhibit defective cell-mediated immunity and lymphoid atrophy analogous to that observed in chronic human undernutrition, in which leptin levels are low. In one study, skin graft rejection from a fully allogeneic mouse strain was delayed when grafted onto db db mice compared with wild-type controls (77). These mutant mouse strains also show increased susceptibility to pathogens, most notably to coxsackie virus. In one study, infection of db db mice with coxsackie virus caused 100 mortality, as opposed to less than 10 mortality in the wild-type control group (80). Of note, there seemed to be a discrepancy between the in vivo and in vitro results in that cellmediated immune responses were significantly impaired in vivo, but in vitro T-cell responses were less affected (77)....

Description Medical Diabetes

The beta cells of the pancreas produce insulin and a protein called C-peptide, which are stored in the secretory granules of the beta cells and are released into the bloodstream as blood glucose levels increase. Insulin transports glucose and amino acids across the membranes of many body cells, particularly muscle and fat cells. It also increases the liver storage of glycogen, the chief carbohydrate storage material, and aids in the metabolism of triglycerides, nucleic acids, and proteins.

Insulin resistance is a state of inflammation

In addition to the fact that components of the metabolic syndrome contribute to cardiovascular disease, increasing data suggests insulin resistance is a proinflammatory state in itself. Adipose tissue secretes substances (adipokines) that decrease insulin-mediated glucose uptake and or promote vascular inflammation (Table 3). Adipocytokines circulate at higher levels in obese animals or in humans with increased viceral adiposity. Tumor necrosis factor-a (TNF-a) directly suppresses activation of tyrosine kinase on the insulin receptor, resulting in insulin resistance (22). TNF-a levels are not only high in atherosclerotic vessels, promoting inflammation, but are elevated in damaged myocardium and have been implicated in heart failure (23). Adiponectin (Acrp 30) also arises from fat but, in contrast to TNF-a, is low in the circulation of obese humans and animals, enhances insulin-mediated glucose uptake, and inhibits inflammatory responses (24). Leptin is another substance from fat...

The role of insulin sensitizers

Activation of peroxisome proliferator-activated receptor-y (PPAR-y), in adipose tissue restores the adipokine balance to increase insulin sensitivity and to decrease vascular inflammation (32). The decrease in FFAs, TNF-a, leptin, and other adipokines and the reciprocal increase in adiponectin that occurs with PPAR-y ligand thiazolidinedione (TZD) administration probably contributes to the action of these ligands to enhance insulin-mediated glucose uptake. Because of these changes and the decrease in PAI-1 and IL-6, PPAR-y ligands also appear to attenuate the proinflammatory state. In addition, the ligands directly

The obob and dbdb Mouse as a Model of Starvation

It has been suggested that the ob ob and the db db mice are models of perceived starvation, despite their obvious obesity. Given that a falling leptin concentration can be considered a signal of starvation, then mice deficient in leptin or its receptor become obese because they perceive that they are starving and thus become hyperphagic (14). Furthermore, these strains of mice share many of the other physiological and behavioral features of chronic starvation such as infertility, reduced thermo-genesis, reduced physical activity, and food-seeking behaviour (18). Indeed, many authors consider these mice to be good animal models of chronic starvation in man (20).

Consequences of fetal growth disorder

Of structurally normal fetuses is also associated with abruption and pre-eclampsia. Both these outcomes are associated with IUGR. Poor growth is also associated with perinatal death due to prematurity. It has been shown that growth restriction in early pregnancy is associated with an increased risk of spontaneous preterm birth. Labour appears to be initiated by the activation of the fetal hypothalamo-pituitary adrenal axis. In sheep, the effector hormone from the adrenal is cortisol, whereas in primates and - it is assumed - in the human, it is likely to be androgenic precursors of oestrogen. The effect in both species is stimulation of labour. Therefore, spontaneous preterm delivery may be a physiologically indicated response to a poor environment. Poor growth is also directly related to prematurity in the context of elective delivery for suspected fetal compromise. Poor fetal growth is also associated with increased morbidity and mortality in infancy. For example, the risk of sudden...

Etiologic Classification

Roidism, hypogonadism, polycystic ovarian syndrome hypothalamic lesions secondary to trauma, surgery, or primary or metastatic tumor genetic syndromes like leptin deficiency, leptin receptor melanocortin receptor defects, Prader-Willi, Bardet-Biedl, and Down's and drugs such as insulin, sulfonylureas, glucocorticoids, antiepileptics, antipsychotics, and depoprovera.

Effects of Estrogen on Hemostatic Factors

On the other hand, reduced fibrinolytic activity is associated with atherosclerosis and has been attributed to increased levels of the antifibrinolytic factor plasminogen activator inhibitor-1 (PAI-1) (53). Increased PAI-1 levels have been found in postmenopausal women, and a close relationship between low fibrinolytic activity, high PAI-1 and hyperinsulinemia has been observed in various populations (54). Even small doses of oral ERT activate the fibrinolytic system via a marked reduction in PAI-1 levels, with the greatest reduction occurring in women with the highest PAI-1 levels. Combination with progestogen does not appear to diminish this beneficial effect. In contrast to oral therapy, transdermal therapy does not seem to change PAI-1 levels (55,56). The activation of the fibrinolytic system by estrogens appears not to be dose-related, unlike the coagulatory activity that appears to be dose-dependent (53). On balance, therefore, HRT at low dosages may affect fibrinolytic activity...

Diabetic Retinopathy DR

A number of proangiogenic, angiogenic and antiangiogenic factors are involved in the pathogenesis and progression of diabetic retinal disease, Vascular Endothelial Growth Factor (VEGF) being one of the most important. Other growth factors, which are known to participate in the pathogenesis of the disease, are Platelet Derived Growth Factor (PDGF), Fibroblast Growth Factor (FGF), Hepatocyte Growth Factor (HGF), Transforming Growth Factor (TGF), Placental Endothelial Cell Growth Factor (PlGF), Connective Tissue Growth Factor (CTGF). Other molecules that are involved in the disease mechanisms are intergrins, angiopoietins, protein kinase C (PKC), ephrins, interleukins, leptin, angiotensin, monocyte chemotactic protein (MCP), vascular cell adhesion molecule (VCAM), tissue plasminogen activator (TPA), and extracellular matrix metalloproteinases (ECM-MMPs).

What are the Effects on Gene Expression by Different Tocopherols

Several events that are associated with inflammation appear to be regulated by toco-pherol. The cytokine interleukin-1P (IL-1P) is decreased by a-tocopherol by a mechanism involving down-regulation of IL-1p mRNA expression 182 . Combined a-tocopherol and selenium deficiency is characterized by alterations in the expression level of genes encoding for proteins involved in inflammation (multispecific organic anion exporter, SPI-3 serine protease inhibitor) and acute phase response (a-1 acid glycoprotein, metallothionein 1). Is-ermann et al. have shown that a-tocopherol induces leptin expression in healthy individuals and also in vitro 183 . Down regulation of matrix metalloproteinase-19 by a-tocopherol has also been described 184 . The adhesion-dependent expression of matrix metalloproteinase

Mct And Smct Transporter Expression

Evidence supporting hormonal regulation of MCT1 transcription has also been reported. In a thyroid cell line (FRTL-5) MCT1 transcription was found to be regulated by thyroid-stimulating hormone (TSH) through cAMP-dependent pathways.36 In a human intestinal cell line (Caco-2), addition of leptin to the apical surface leads to a small but significant increase in MCT1 protein in the apical membrane.37 This increase in MCT1 expression induced by leptin was attributed to increased MCT1 mRNA production and enhanced translocation of the transporter protein to the plasma membrane from intracellular pools.37 Further studies with Caco-2 cells have shown

Harnessing the mutant map to ongoing genomics programmes

A draft human genome sequence is expected by year 2000. Plans to provide a draft sequence of the mouse genome have been initiated. In addition, the provision of finished sequence from several defined regions of the mouse genome is already underway. Comparison of human and mouse sequence in any region is expected to improve the identification and annotation of gene sequences and provide an important adjunct to gene prediction software. Indeed, in at least a few cases to date, the provision of mouse and human comparative sequence has underpinned the identification of novel genes and their mutation scanning. One recent example is the identification of the mouse X-linked Bare patches (Bpa) and Striated (Str) mutations (Liu et al 1999), both dominant male lethals having pleiotropic effects on skin morphology and skeletal development. Comparative sequencing of the region in which the Bpa and Str mutations were known to lie aided the characterization and annotation of a novel 3...

Respiratory disorders

Asthma is the most common respiratory disorder affecting 3 of women of childbearing age. Pregnancy has a variable effect on asthma but for the vast majority of women there is no impact whatsoever. The most common reason that their asthma symptoms deteriorate is patients reducing their treatment because of a belief that the medication may be harmful. All commonly used medications to control asthma aresafein pregnancy. All patients must be reassured that any flairs of their asthma must not be ignored and that treatment with medication such as steroids is safe both for themselves and for their fetus. With regard to the effect of asthma on fetal outcome, there is no evidence that there is any significant impact on fetal growth or outcome. Any patient whose asthma seems to be deteriorating, particularly in the third trimester, should be seen by an obstetric physician for review. It is obviously desirable that control of their asthma should be at its optimum prior to the onset of labour....

Clinical Note continued

Infant Hercules.'' Milder defects may show up simply as growth of excessive facial hair (hirsutism) in women. Overproduction of androgens occurs in the following way. Stimulation of the adrenal cortex by ACTH increases pregnenolone production (see earlier discussion), most of which is normally converted to cortisol, which exerts negative feedback inhibition of ACTH secretion. With a partial block in cortisol production, much of the pregne-nolone is diverted to androgens, which have no inhibitory effect on ACTH secretion. ACTH secretion therefore remains high and stimulates more pregnenolone production and causes adrenal hyperplasia (Fig. 20). Eventually, the hyperactive adrenals produce enough cortisol for negative feedback to be operative, but at the expense of maintaining a high rate of androgen production. The whole system can be brought into proper balance by giving sufficient glucocorticoids to decrease ACTH secretion and therefore remove the stimulus for androgen production.

Clinical Description Dm1

Ninety percent of DM1 patients present at adulthood with delayed muscle maturation, distal muscle weakness, wasting, myotonia, cataracts, cardiac abnormalities, smooth muscle dysfunction, insulin resistance, daytime sleepiness, testicular atrophy (low reproductive fitness), ''difficult'' personality, neuropsychiatric disturbances, and frontal balding. 1 Ten percent of the patients present at infancy with hypotonia (floppy infant), oromotor dysfunction, tent-shaped mouth, feeding and respiratory insufficiency (diaphragmatic hypoplasia), arthrogryposis, and mental retardation in those who survive until adulthood (congenital DM). 1 All manifestations show a progressive course. Usually, creatine kinase is elevated. Muscle biopsy shows type 1 predominance, centrally located nuclei, severe fiber atrophy with nuclear clumps, hypertrophic and angulated fibers, and occasionally, necrotic fibers, fibrosis, or fat deposits. Cardiac involvement comprises conduction defects (mostly HV...

Maurice Goodman

Regulation of Metabolism during Feeding and Fasting 668 Postprandial Period 668 Postabsorptive Period 669 Fasting 669 Hormonal Interactions during Exercise 671 Short-Term Maximal Effort 671 Sustained Aerobic Exercise 671 Long-Term Regulation of Fuel Storage 673 Hypothalamic Control of Appetite and Food Intake 674 Leptin 675 Other Effects of Leptin 678

Glucosefatty Acid Cycle

The self-regulating interplay between glucose and fatty acid metabolism is called the glucose-fatty acid cycle. This cycle constitutes an important biochemical mechanism for limiting glucose utilization when alternative substrate is available, and conversely limiting the consumption of stored fat when glucose is available. Fatty acids that are produced in adipose tissue in an ongoing cycle of lipolysis and reesterification may either escape from fat cells to become the free fatty acids, or they may be retained as triglycerides, depending on the availability of -glycerol phosphate (Fig. 1). The only source of -glycerol phosphate for reesterification of fatty acids is the pool of triose phosphates derived from glucose oxidation, because adipose tissue is deficient in the enzyme required to phosphorylate and hence reuse glycerol released from triglycerides. Consequently, when glucose is abundant, -glycerol phosphate is readily available, the rate of reesterification is high relative to...

Cytokine and metabolicrelated hormone studies

Leptin (an adipocyte-derived hormone) is a crucial mediator of energy homeostasis. Several studies have shown that higher levels of leptin are associated with sleep apnea 109 . Recent studies also suggested the novel function of leptin as a possible explanation of mood disorders. Low levels of leptin have been found to be associated with depressive behaviors in rodents and humans. Pharmacological studies indicate that leptin has antidepressant-like efficacy. Both leptin insufficiency and leptin resistance may contribute to alterations of affective status 110,111 .

Regulation Of Metabolism During Feeding And Fasting

Cortisol (I) secreted by the liver derives from glycogen, and the remainder comes from gluconeogenesis, driven principally by glucagon. Although the rate of glucagon secretion is relatively low at this time, the decline in insulin enables the actions of glucagon to prevail. Growth hormone and cortisol are also secreted at relatively low basal rates in the postabsorptive period. About 75 of the glucose consumed by extrahepatic tissues during this period is taken up by brain, blood cells, and other tissues whose consumption of fuels is independent of insulin. Muscle and adipose tissue, which are highly dependent on insulin account for the remaining 25 . FFA gradually increase as adipose tissue is progressively relieved of the restraint imposed by high levels of insulin during the postprandial period. Blood glucose remains constant during this period, but glucose metabolism in muscle decreases as the restrictive effects of the glucose-fatty acid cycle become operative. Liver gradually...

Regulation Of The Jakstat Pathway Suppressors of Cytokine Signaling

Little is known about specificity within the SOCS family of proteins. To date, most studies of SOCS function have depended on the use of in vitro overexpression systems. These studies have shown that expression of SOCS-1 suppresses signaling in response to a variety of cytokines, including LIF, on-costatin M (OSM), IFNy, TPO, and growth hormone (GH) in addition to IL-6 (46,51,53,61-63). SOCS-3 expression also inhibits signaling in response to IL-6, LIF, GH, and IFN-y (54,61,63,64) in addition to blocking leptin-induced signal transduction (65). CIS expression suppresses cell proliferation in response to IL-3 and EPO cell proliferation (50). However, SOCS-2 has yet to be shown to inhibit cytokine signal transduction pathways.

Suketu Shah md Alina Gavrila md and Christos S Mantzoros md

Our understanding of the function of fat cells has changed dramatically with the realization of the endocrine function of adipose tissue. Initially thought to serve only as a repository for energy via storage of triglycerides, adipocytes are now known to secrete a variety of proteins with diverse metabolic functions. These proteins include leptin, TNF-a, plasminogen activator inhibitor-1, acylation-stimulating protein, resistin, and adiponectin (1,2). Adiponectin has received much attention for its putative role in diabetes and CVD. Besides being associated with the development of diabetes, it may also have a direct role in modulating inflammation and atherosclerosis and thereby be one of the factors that links obesity to CVD. Although its structure and source are known, the regulation of adiponectin remains to be determined. The various factors thought to be involved in controlling adiponectin production and secretion include obesity, nutritional status, hormones such as insulin,...

Obesity and Nutritional Intake

Instead of food intake, the distribution of adipose tissue may be more closely associated with adiponectin. There is a strong inverse correlation between adiponectin levels and visceral or central fat, compared to subcutaneous fat (9,19). In contrast to subcutaneous adipocytes, human omental adipose tissue had a significant negative correlation with BMI, and only it responded to insulin and PPAR-a agonist administration with increased adiponectin production (23). These findings suggest that adipose tissue, particularly in the visceral distribution, may have an inhibitory mechanism for its own production of adiponectin, perhaps mediated by other factors produced by fat cells such as TNF-a (13).

Robert G Spanheimer md

In 1855, Thomas Addison described anemia, general languor, debility, remarkable feebleness of the heart's action, irritability in the stomach, and a peculiar change of color in the skin. These changes were associated with destruction of the adrenal glands as found on autopsy, but no therapy was known and patients inevitably died. In 1949 (2), the synthesis of cortisone and cortisol for treatment of inflammatory diseases led to their availability for adrenal insufficiency and thus changed the course of the disease in patients with Addison's disease.

Diabetes and Insulin Resistance

The majority of data for animal studies thus far suggest that adiponectin acts as an insulin-sensitizing hormone. Adiponectin-knockout mice develop insulin resistance either independently of diet or only after high-fat and high-sucrose diet, and treating these mice with adiponectin ameliorates their insulin resistance (35,42). The insulin resistance in adiponectin-deficient lipoatrophic and obese mice can partially be reversed via adiponectin administration and fully restored with both leptin and adiponectin supplementation (29). Furthermore, in a longitudinal study analyzing the progression of type 2 diabetes in obese monkeys, decrease in adiponectin closely parallels the observed reduction in insulin sensitivity, and the obese monkeys with greater plasma levels of adiponectin had less severe insulin resistance (43).

Chronic Adrenal Insufficiency

The glucocorticoid of choice is cortisol (hydrocortisone) dosed at 20 mg in the am and 10 mg in the pm, usually between 4 and 6 pm to mimic the normal circadian rhythm of glucocorticoids (21). Cortisone acetate is equally acceptable at 25 mg in the am and 12.5 mg in the pm. Adequacy of glucocorticoid replacement is based primarily on clinical judgment. Direct assay of ACTH is only rarely used since serum ACTH measurement is not as sensitive an index of glucocorticoid replacement as thyroid-stimulating hormone (TSH) is for thyroid hormone replacement. Excess replacement of glucocorticoid may lead to weight gain or cushinoid features inadequate doses result in persistent weakness, fatigue, and excess pigmentation.

Glucocorticoid Coverage for Stress

In response to acute illness, trauma, or surgical intervention, there is increased secretion of CRH, ACTH, and finally Cortisol. Patients with primary or secondary adrenal insufficiency will not be able to increase cortisol production and require both physiologic and supplemental stress therapy with glucocorticoid. Because of the large variation in cortisol production in healthy patients under stress, it is difficult to predict cortisol needs of patients exactly during stressful conditions. For minor illness (fever < 100 F, nausea but able to take in fluids and medications) or procedures that take less than 1 h under local anesthesia, only replacement therapy is required and is given prior to the procedure. For moderate illness including bacterial pneumonia, severe gastroenteritis, or prolonged fever as well as cholecystectomy or hemicolectomy, 50-75 mg of hydrocortisone is given on the day of the procedure or acute illness with tapering over 1-2 d to replacement doses. Prior...

Special Treatment Considerations

Although primary adrenal insufficiency is rare, secondary adrenal insufficiency after withdrawal of supraphysiologic corticosteroid therapy is common, and both are potentially fatal conditions if unrecognized and untreated. With the introduction of glucocorticoid replacement in the late 1940s, the survival of patients with adrenal insufficiency now approaches that of the normal population. However, owing to the lack of cortisol production in response to stress, certain everyday life-type experiences must be recognized and treated in patients with adrenal insufficiency to avoid life-threatening conditions. Education of the patient and their family members is crucial to avoid adrenal crisis. Table 5 outlines some special considerations, with recommendations for patients, family members, and caregivers. During pregnancy, replacement of both glucocorticoid and mineralocorticoid usually does not change (23). Occasionally increased sodium intake is required in the second and third trimester...

Early diagnosis and treatment

The period between the onset of the signs and symptoms of Cushing's syndrome and its definitive diagnosis averages 5 yr (1). Thus, the idea of an early diagnosis is somewhat of an oxymoron. The diagnosis requires a convincing combination of clinical findings and biochemical abnormalities (2-8). The obvious combination is an established clinical picture coupled with some reliable measure of an elevated cortisol production rate. The diagnosis can be made in the absence of evidence for an increased cortisol production rate if the clinical picture is unequivocal, and in the absence of a convincing clinical picture if the urine free cortisol excretion is greater than 300 g day (9-11). The various combinations of clinical presentation and cortisol production rate can be lumped into four differential diagnostic categories. These relationships can be seen in Fig. 1. Cortisol Fig. 1. Cortisol production rate and clinical picture in Cushing's syndrome. Fig. 1. Cortisol production rate and...

Gender Ethnicracial And Life Span Considerations

PE is a frequent cause of sudden death for approximately 50,000 people each year in the United States. PE in children is associated with cardiac conditions and coagulopathic diseases such as sickle cell anemia or cancer. Young women are at risk for PE during pregnancy or while they take high-estrogen-content birth control pills. Adults, particularly the elderly, are at risk for PE because of deep vein thrombosis (DVT), cardiac conditions, and increased blood coagulability. Both genders and all races and ethnicities are at risk for PE.

Pathogenesis and Clinical Disease

The mechanism of liver injury associated with persistent HCV infection is believed to be immune-mediated and initiated by virus-specific T-lymphocytes which infiltrate the liver. Such cells are predominantly of a TH-1 phenotype and produce interferon gamma and tumor necrosis factor alpha (TNF-a). Because these cytokines have been implicated in noncytolytic clearance of other viral agents in the liver, other mechanisms of hepatocyte injury and death associated with HCV have been proposed, including Fas-Fas ligand-mediated apoptosis, per-forin-dependent killing by cytolytic T-cells, or TNF-a itself. HCV is not highly cytopathic for hepatocytes however, fat deposits and eosinophilic inclusions are often seen in liver cells. In the absence of virus clearance, repeated episodes of hepatocellular injury and regeneration trigger development of hepatic fibrosis, cirrhosis, and eventual hepatocellular carcinoma. Additional factors that promote this process include coexistent infection with

Pathology and Histopathology

SIN is highly pathogenic to embryonated hens' eggs. Within the host organism, the infected cells include neuron and glial cells, striate and smooth muscle cells, cells of lymphoid origin, synovial cells and brown fat cells. Neonatal rodents develop severe neurocytopathology when virus is given intracere-brally or intraperitoneally. In the CNS, focal cystic degeneration, vascular dilatation and neurolysis occur. Strains of SIN that lead to fatal encephalitis after infection of neonatal mice show lesions associated with a severe stress response including high levels of interferon a fi and toxic cytokines such as tumor necrosis factor a and little evidence of encephalitis. Less virulent strains produce a more classical encephalitis. Adult mice are susceptible to some SIN strains and neuroinvasiveness is attributed to a change in amino acid 55 of the E2 glycoprotein from glutamine to histidine. Other single-site amino acid changes in E2 alter neurovirulence and cyto-pathology of SIN....

High Fat Diets and Obesity Possible Influence of n3 PUFAs

The peptide hormone insulin is produced in the pancreas and secreted in proportion to the degree of adiposity. Similar to leptin, insulin levels are correlated with amount of abdominal fat (Porte et al., 1998 Woods et al., 1996 Woods, Figlewicz Lattemann, Schwartz, & Porte, 1990 Woods et al., 1998). It is transported into the brain where it acts to decrease food intake and body weight (Schwartz, Figlewicz, Baskin, Woods, & Porte, 1992 Woods et al., 1996). High insulin resistance is a characteristic of obesity, hypertension, and non-insulin-dependent diabetes mellitus. There is an inverse relationship between insulin action and triglyceride content. With the ingestion of fat, insulin secretion is increased. Insulin stimulates fatty acid synthase, an enzyme that catalyzes all reactions involved in lipogenesis, and thereby results in the accumulation of triglycerides (Sul, Latasa, Moon, & Kim, 2000). Monounsaturated fatty acids (such as oleate) and saturated fatty acids (such as...

Stress and the Endocrine System

One function of the central nervous system is to evaluate and identify situations that can qualify as stress situations. The major components in the brain that are involved are the cortex, the limbic system, and the hypothalamus. The hypothalamus is the brain structure that bridges the nervous and the endocrine systems. In stress situations (fight or flight), the body mobilizes all of its energy to deal with the stress. The sympathetic nervous system, which is part of the autonomic nervous system, coordinates the effort to cope with the stress. The signal to activate the sympathetic nervous system is provided by the hormone epinephrine that is released from the medulla of the adrenal gland. A simplified description of the chain of events can be represented as follows Beginning with encountering a stress situation, hypothalamic production of a cortico-releasing factor (CRF) signals the pituitary to release the hormone ACTH (adreno-corticotrophic hormone), which, in turn, acts on the...

Antiandrogenic Effects Introduction

Mineralocorticoid antagonists are weak diuretics that act by inhibiting the effect of aldosterone on sodium transport in the cortical collecting duct of the kidney. In the kidney, mineralocorticoid specificity is a result of the action of 11 3-hydroxysteroid dehydrogenase which converts glucocorticoids to meta

Hormone receptors in the retina

Salyer et al. using Long-Evans rats found that prenatally and early postnatally in normal rats males had thicker retinas than females. This increased thickness was reduced using flutamide, an androgen inhibitor, but not significantly so compared to normal males or testosterone-treated males, indicating that the process was not entirely mediated through AR. Females at this life-stage had undetectable testosterone levels, but when these females were treated with testosterone their retinal thickness did not differ significantly from normal or testosterone-treated males. To help rule out the conversion of testosterone to estrogen Salyer et al. using immunocytochemistry found no aromatase present in the neuroretina at this stage of development, but they did find quantities of it in the retinal pigment epithelium (RPE) (Salyer et al. 2001). Interestingly, Kobayashi et al. found evidence of 17 3-hydroxysteroid dehydrogenase type IV in the RPE of chick...

Adipose Tissue Micro Environment

Engine Fan Hub

Within the adipose tissue milieu, there are several ongoing processes (Fig. 1) (i) adipocytes release factors that cause chemotaxis and infiltration of circulating macrophages (ii) macrophages then influence neighbouring adipocyte function (iii) adipocytes, in turn, simultaneously influence macrophage function (iv) both macrophages and adipocytes secrete factors that influence other tissues and systems, which in turn impact on the adipose tissue milieu (i.e. CNS control of satiety via leptin) and finally (v) preadipocytes contribute through cytokine secretion and direct effects on adipocyte function (Bouloumie et al. 2005). With increased size of adipocytes, there is increased local secretion of most adipokines (a decreased secretion of adiponectin is the exception). The mechanism by which adipocytes recruit macrophages and influence their phenotype is currently being studied extensively. Several adipokines have been identified that recruit macrophages (MCP-1, osteopontin, TNFa, IL6,...

Clinical Chronopharmacology

The interpatient variability in 24-h mean level of 5-FU usually required to express each concentration relative to the 24-h mean in the same patient, in order to demonstrate synchronized circadian rhythmicity at a group level (42,44,48). Furthermore, differences in individual circadian time structure, including the prominence of ultradian rhythms, with periods of one to several hours, could not be caught up by sampling times staggered every 4 h for 24 h, as was usually the case. Indeed, approx 30 of the patients with metastatic colorectal or breast cancer displayed a marked damping of their 24-h rhythms in rest-activity or cortisol (53-55). These alterations might influence 5-FU disposition and ablate its rhythmicity especially in patients with extensive tumor burden or poor performance status (49). Interestingly circadian function alteration predicted for poor outcome in advanced cancer patients independently of the known prognostic factors (54-55), and exogenous glucocorticoids...

Prelabour and labour hormonal and immunological mechanisms

Hormones Initiate Labour

Cortisol Everyday clinical experience, not least from the effective use of natural substances or drugs which interfere with their function, suggests that the following may deserve special prominence progesterone, calcium, oxytocin and prostaglandins (especially PGE2 and PGF2 ). Less obviously, to these may be added connexin 43, cortisol, Studies in humans, subhuman primates, domestic species (notably sheep), rodents, and especially guinea pigs have allowed concepts to be elaborated to explain the biological control of human parturition. As emphasized above, the transition from pregnancy maintenance to birth develops gradually during a month or more of 'prelabour'. From early na ve concepts which credited the mother as responsible for initiating labour by producing oxy-tocin from her posterior pituitary, the hypothesis has gradually been developed whereby the control is initiated and largely vested within the fetoplacental unit (Fig. 7.2). The key component appears to be the fetal...

The Role of C5L2 Adipose vs Immune

Interestingly, C3 KO mice, which are deficient in ASP, display delayed triglyceride and fatty acid clearance from the circulation following a fat meal, with a reduced capacity for fat storage in their adipose tissue (review (Cianflone et al. 2003 Xia et al. 2004)). Acute injection of ASP C3adR normalizes the postprandial fat clearance. The alterations in fat clearance are also accompanied by hyperphagia and increased energy expenditure (review (Cianflone et al. 2003 Xia et al. 2004)). Finally, numerous studies have linked alterations in C3 as well as ASP with obesity, diabetes, cardiovascular disease (review (Cianflone et al. 2003 Muscari et al. 2007)). Taken together, this evidence from mice and humans highlights the ASP pathway as an interesting target for obesity research.

Secondary Adrenal Insufficiency

The most common cause of secondary adrenocorticol insufficiency is iatrogenic, caused by withdrawal of therapy from patients who have been treated with pharmocologic doses of glucocorticoids (10). Clinical experience suggests that more than 30 d of supraphysiologic glucocorticoid treatment (e.g., prednisone at doses of > 7.5 mg d) may suppress CRH and ACTH for 3-6 mo an additional 36 mo may then be required for cortisol to respond to ACTH since ACTH is trophic for the adrenal glands. Both topical and inhaled steroids (11) have now been reported to suppress the hypothalamic-pituitary adrenal axis, so withdrawal from prolonged use of these agents must be monitored for adrenal insufficiency.

Somatic theories of sleep function

Studies also shows that simply curtailing sleep in humans increases the risk for diabetes, and negatively impacts blood glucose metabolism 8 . In addition, anatomical and transgenic studies in rodents have revealed interactions between peptides important in feeding and satiety (ghrelin and leptin, respectively), and areas of the brain that control sleep wake expression 58 . For example, studies in mice and rats indicate that leptin and ghrelin interact with hypocretin- and melanin-concentrating hormone (MCH)-containing neurons in the lateral hypothalamus, which in turn regulate arousal and sleep (reviewed in 58 ). Some of the other changes in human metabolism observed after sleep deprivation appear to be strongly influenced by circadian mechanisms or may reflect side-effects of sleep deprivation rather than sleep per se. For example, cortisol release is under circadian control 9 , is known to increase after sleep deprivation 70 , and has been linked to some of the metabolic...

The Acute Phase Response and Alzheimer Disease

For example, administration of Cortisol reduces hippocampal glucose metabolism in the normal elderly but not in AD (75). Peripheral markers of the APR may be induced in AD by excessive cytokine production in the CNS (particularly of IL-1), and possibly also by cytokine production by other tissues such as the thyroid (119) when AD is caused by genetic factors. Elevated plasma levels of cortisol have been found in moderate to severe AD (65,75,132,234,283,313). Orell and O'Dwyer (283) have explained that this may be initiated by excessive cytokine production by injured brain cells which trigger release of corticotropin releasing factor (CRF) from the hypothalamus. CRF stimulates corticotropin release from the pituitary which in turn stimulates glucocorticoid release from the adrenal glands. The activity of this loop is, in part, regulated by the binding of glucocorticosteroid to corti-costeroid receptors in the hippocampus. In animals, aging is...

Women Interested in Fertility

Weight loss counseling is also important. It has been reported that weight loss of 5-7 of body weight will improve menstrual function (64-66). In a randomized trial, weight loss was associated with decrease in total testosterone and insulin levels, and four of six women had documented ovulation (67). In contrast, none of the five women in the control group ovulated. In another study, women with PCOS were placed on a low-calorie diet and randomized to placebo versus metformin (65). After 6 mo, the women in the metformin arm of the study had greater reduction of body weight (mean 9.7 kg) and abdominal fat and a decrease in serum fasting insulin (40 ), testosterone (35 ), and leptin levels. In addition, they had a significant improvement in menstrual irregularity.

Rapid ACTH Stimulation Test

In most patients dynamic testing is recommended, and the rapid ACTH stimulation test is the procedure of choice (14,15). This test should be the initial diagnostic test in either primary or secondary adrenal insufficiency. Corticotropin (250 g) is given intravenously or intramuscularly, and plasma cortisol is measured before and 30 (or preferably) 60 min after the injection. If the patient is hypotensive and possibly not perfusing peripheral tissue, the intravenous route is preferred. Because the test requires minimally only 30 min and bypasses the hypothalamic pituitary axis, in life-threatening situations, dexamethasone can be administered and will not affect results if the ACTH stimulation test is done within 48 h of starting dexamethasone. A cortisol value of 20 g dL or more (either basal or stimulated) excludes primary adrenal insufficiency (15) but may not exclude secondary adrenal insufficiency with decreased (not absent) pituitary ACTH reserve (see discussion just below). An...

The Cognate Immune Response

As mentioned earlier, the innate and cognate immune systems are interlinked, so that many of the effects of leptin discussed in Section 4 will have implications for the behavior of responding lymphocytes. It is also clear that an organism mounts a coordinated immune response to an infectious pathogen that initially comprises innate immunity and then evolves, if appropriate to involve the cognate immune system. An important point of communication between the innate and cognate arms of the immune systems lies with macrophages and dendritic cells. These cells produce cytokines that polarize and activate T-cell responses and act as professional antigen-presenting cells by presenting peptide bound to major histocompatibility complex (MHC) molecules to T-cells along with high levels of costimulation. As leptin can effect the production of proinflammatory cytokines from macrophages (56) and dendritic cells (GM Lord, unpublished data) and also increase expression of MHC molecules and...

C5L2 an Antiinflammatory Molecule or a Receptor for Acylation Stimulating Protein C3adesArg

The adipose tissue plays a crucial role in energy homeostasis and insulin sensitivity. Adipocytes produce a number of hormones which effect energy intake and expenditure. Thereby, ASP, leptin, and adiponectin are considered as such mediators and keyplayers within the carbohydrate and lipid metabolism for a detailed review on lipid metabolism see (Havel 2004) . ASP is regarded as an anabolic determinant of energy homeostasis and insulin action. Moreover, a malfunction of the ASP receptor or ASP-dependent signaling is considered as a potential cause of familial hyperapobetalipoproteinemia (hyperapoB) which leads to arteriosclerosis and coronary artery disease. In hyperapoB patients, an overproduction of hepatic apolipoprotein B-100 (apoB-100) occurs. This is postulated to be responsible for the observed postprandial hyperlipidemia with increased triglyceride-rich remnants from processed chylomicrons, increased plasma fatty acid levels, insulin resistence, as well as elevated levels of...

Dermatologic Physical Exam

When physical findings and history suggest a possible endocrinopathy, the patient should be appropriately tested. The most reliable screen is a dexamethasone suppression test. Alternative tests include 8 am and 4 pm serum cortisol determinations, or a 24-hour urinary free cortisol.

Gender Differences In Pd And Clinical Endpoints

One study cited earlier showed that the oral clearance and the apparent volume of distribution of prednisolone were both higher in men than women, but these PK differences were not accompanied by PD differences (106). Specifically, the 50 inhibitory concentration (IC50) values for effects of prednisolone on cortisol secretion and T-helper lymphocyte or neutrophil trafficking were not statistically different between men and women. However, another group found a significantly smaller IC50 value in women (0.1 vs. 1.7 ng mL) for methylpredni-solone suppression of cortisol secretion, indicating increased sensitivity (131). Gender-based differences in the pharmacodynamics of prednisolone may be mediated by endogenous estrogens for instance, the IC50 values for effects of methylprednisolone on basophil trafficking are related to estradiol concentrations in a log-linear fashion in women, with increased sensitivity found at higher estra-diol concentrations (131). An interesting example of...

Adjusting Your Insulin for Time Changes

The body's sensitivity to insulin varies throughout the day and night. You are most insulin sensitive early in the night and most resistant early in the morning. These changes in insulin sensitivity are due to the daily fluctuations in the levels of hormones, particularly cortisol. The internal body clock that regulates these hormones gets cues from environmental light and temperature. When you go to a different time zone, the body clock and the hormones reset to the new light-dark cycle. This resetting process takes time and explains why you feel jet-lagged. The challenge for people who are on insulin is to figure out how to adjust basal insulin levels while the body is getting used to being in the new time zone. The solution is to make sure that you have a safe basal rate and to use bolus insulin doses to cover any high blood glucose levels

Studies In Man Therapies

In type 2 diabetes some studies suggest that intensified glycemic control may improve cognition (96-99 but see ref. 100). However, the methodological quality of the studies is insufficient to draw firm conclusions (101). Alternative treatment modalities are also being considered. There is some evidence that treatment with the lipid-lowering drug atorvastatin has beneficial effects on learning in type 2 diabetes (102). Moreover, a recent randomized, double-blind, placebo-controlled crossover study showed that administration of the 11P-hydroxysteroid dehydrogenase inhibitor carbenoxolone improved verbal memory after 6 weeks in 12 patients with type 2 diabetes (103). The rationale behind this treatment was that the compound might protect hippocampal cells from glucocorticoid-mediated damage that occurs in association with ageing (103).

DRG Category 296 Mean LOS 54 days Description Medical Nutritional and

Cerebral dysfunction occurs when the central nervous system (CNS) is deprived of glucose for cellular needs. In contrast to muscle and fat cells in the body that can break down amino and fatty acids for energy, the brain cells depend on glucose for energy. When the liver's supply of glycogen is depleted and no replacement is available, brain damage results. Prolonged periods of hypoglycemia can lead to coma, permanent brain damage, and death.

Secondary Adrenocorticol Insufficiency

Early AM serum Cortisol Either test will rule out adrenal insufficiency if normal (serum Cortisol > 20 mg dL), but if low, should be followed with a provocative test to confirm adrenal insufficiency. Provocative testing Primary adrenal insufficiency rapid ACTH stimulation giving 250 g of synthetic ACTH im or iv and measuring cortisol before and 30 min after ACTH. Serum cortisol > 20 mg dL at basal or post ACTH stimulation is normal. Secondary adrenal insufficiency Low-dose (1 g) ACTH stimulation test or insulin-induced hypoglycemia (see text). Serum cortisol > 18 mg dL is normal either basal or post stimulation. An alternative is the overnight metyrapone (dose based on weight see text) test with a plasma 11-deoxycortisol at 8 am > 7 mg dL normal. hyperkalemia and low plasma volume through the renin-angiotensin system. Thus hypotension, salt wasting, and hyperkalemia are uncommon. Symptoms of fatigue, weight loss, weakness, nausea, myalgias, and...

Body Energy Homeostasis

Of the LH and VMN have pronounced disturbances in fat metabolism (Friedman & Stricker, 1976). Animals with a VMN lesion show increased fat storage such that circulating levels of the metabolic products of fat metabolism are decreased. It has been proposed (Friedman & Stricker, 1976) that it is this decreased availability of the metabolic products of fat metabolism that stimulate food intake. Presently, in line with the idea that fat metabolism is crucial to body energy homeo-stasis, evidence suggests that peptides produced in the body and correlated with body fat mass are essential to the long-term control of food intake and body weight. Leptin is one such peptide. Leptin is the protein product of the ob gene. It is primarily produced in white adipose tissue, and the plasma level of leptin accurately reflects total-body adiposity (Friedman, 1997 Porte et al., 1998). It enters the brain from the circulation by a saturable transport mechanism (Friedman, 1997 Seeley & Schwartz,...

Total Lipid Recovery

Most of the organic solvents already mentioned will dissolve the triacylglycerols and free the fatty acids of Figure 3.1. The difficulty in total lipid extraction is twofold (1) Some of the solvents are immiscible with water and (2) some are poor solvents for the polar lipids (mostly phospholipids). The triglycerides may be obvious in fatty streaks or layers, or they may exist in the form of adi-pocytes (fat cells) scattered within muscle tissue. A very small fraction will be found in the cell membrane bilayers, which are mostly phospholipids. It is likely that the latter do not exist in the neat arrangements usually shown but are instead hydrated to some extent because of the affinity for water of both the phosphoric acid and amino acid molecules on the 3-position of the glycerol.

Integrated Actions Of Metabolic Hormones

Metabolic fuels absorbed from the intestine are largely converted to storage forms in liver, adipocytes and muscle. It is fair to state that storage is virtually the exclusive province of insulin, which stimulates biochemical reactions that convert simple compounds to more complex storage forms and inhibits fuel mobilization. Hormones that mobilize fuel and defend the glucose concentration of the blood are called counter-regulatory and include glucagon, epinephrine, norepinephrine, cortisol, and GH. Secretion of most or all of these hormones is increased whenever there is increased demand for energy. These hormones act synergistically and together produce effects that are greater than the sum of their individual actions. In the example shown in Fig. 4, glucagon and epinephrine raised the blood glucose level primarily by increasing hepatic production. When cortisol was given simultaneously, these effects were magnified, even though cortisol had little effect when given alone....

Physiological changes occurring in sleep stages

Several hormones are released during sleep. Growth hormone (GH) secretion occurs early in the night, and peaks during SWS 28 , while prolactin is usually released in the middle of the night 29 . Both of these hormones have feedback effects on sleep GH on SWS 30 , prolactin on REM 31 . Adrenocorticotropic hormone (ACTH) and cortisol, two hormones of the hypothalamic-pituitary-adrenal (HPA) axis, are downregulated at sleep onset but increase and peak toward the end of sleep, when they likely contribute to morning arousal 32 . In contrast, the secretion of thyroid-stimulating hormone (TSH) is maximal in the evening before sleep onset, inhibited by sleep, and enhanced by sleep deprivation 33 . Melatonin, whose secretion by the pineal gland is permitted only at night by the circadian system, is also inhibited by light and promoted by darkness, thus providing information to the brain regarding seasonal day length. Melatonin is often used as a sleep-promoting agent, due to its ability to...

Primary Adrenal Insufficiency Addisons Disease

Suncongentcral Hemorrhage

Primary adrenocorticol insufficiency results from any disease process (Table 1) that damages the entire adrenal cortex, thus resulting in deficiencies of cortisol, aldosterone, and adrenal androgens. Approximately 75-80 of cases are owing to autoimmune adrenalitis (5), a shift from the predominant cause in 1928-1938, which was tuberculous adrenalitis (now only accounting for 10-20 worldwide). Although circulating antibodies to adrenal antigens, predominately 21-hydroxylase (6), are found in 70 of patients, their role in the etiology is not clear, although they may be present years before the clinical diagnosis. It is recommended that adults and children with other organ-specific autoimmune disease (see below) particularly hypoparathyroidism and type 1 diabetes, be screened for the presence of 21-hydroxylase autoantibody if this is positive, such patients should be screened for adrenal function every 6 mo (7). Other causes of primary adrenal insufficiency include adrenal hemorrhage in...

Why Inhibit Il1

Patients given 30-100 ng kg of IL-1P had a sharp increase in cortisol levels 2-3 h after the injection. Similar increases were noted in patients given IL-1 a. In 13 of 17 patients given IL-1P, there was a fall in serum glucose within the first hour of administration, and in 11 patients, glucose fell to 70 mg 100 mL or lower (14). In addition, there were increases in ACTH and thyroid-stimulating hormone but a decrease in testosterone (17). No changes were observed in coagulation parameters such as prothrombin time, partial thromboplastin, or fibrinogen degradation products. This latter finding is to be contrasted to TNF-a infusion into healthy humans which results in a distinct coagulopathy syndrome (19).


Lipids undergo peroxidation in all tissues as part of normal cellular function. Excess production of lipid can result in oxidative stress with damage to the cell membrane. During normal pregnancy, increases in plasma lipid peroxides appear by the second trimester in step with the general rise in lipids and may taper off later in gestation 14 . As the peroxide levels rise so do those of vitamin E and some other antioxidants this rise is proportionately greater than that of peroxides so physiological activities are protected. Lipid peroxidation is also active in the placenta, increasing with gestation. Since the placenta contains high concentrations of unsaturated fats under conditions of low P02, antioxidants such as vitamin A, the carotenoids and provitamin A carotenoids are required to protect both mother and fetus from free radical activity Early in pregnancy fat is deposited but from mid-pregnancy it is used as a source of energy, mainly by the mother so that glucose is available...

Body Weight

Lack of body fat may also result in irregular periods and infertility. A woman who is underweight by 10 to 15 percent has less fat storage and therefore less estrogen. Although it may vary from woman to woman, most medical experts agree that a woman needs a body fat content of approximately 22 percent to allow for the normal hormonal balance and subsequent ovulation process. This topic is covered in more depth in Chapter 5.

Fat as a Nutrient

As a macronutrient, fat is a source of energy (calories). The fat in food supplies about 9 calories per gram, more than twice the number of calories as the same amount of protein or carbohydrate. As a result, high-fat foods are considered calorie-dense energy sources. Any dietary fat that is not used by the body for energy is stored in fat cells (adipocytes), the constituents of fat (adipose) tissue (see


Supportive measures for patients in septic shock and or those with proved adrenocortical insufficiency (serum cortisol level < 15 g 100 ml corticotropin test within 30-60 min after i.m. or i.v. injection of 250 g of adrenocorticotropin hormone, increase of serum cortisol level < 9 g 100 ml), the i.v. i.m. administration of hydrocortisone (4x50 mg day), or equivalent, is indicated (Cooper and Stewart 2003 Hamrahian et al. 2004 Rhen and Cidlowski 2005 Russell 2006)

Animal studies

This is seen after prolonged administration of glucocorticoids at concentrations corresponding to those after stress, resulting in about 50 lower GR density of hippocampal receptors (Sapolsky et al 1985a). Interestingly, the neonatal rat, which has a low number of GRs in critical areas of the brain that develop slowly to adult density, is sensitive to impacts during this developmental period. Interference with this development results in persistent hypersecretion of cortisol (Sapolsky et al 1985b).

Studies in humans

Although the results are not totally consistent, they indicate that the basal, non-stimulated HPA axis and circadian rhythm are not disturbed in old subjects (Seeman & Robbins 1994). Stimulation by adrenocorticotropic hormone (ACTH) is apparently also followed by a normal initial response of cortisol while there might be a delayed return to normal values (Blichert-Toft 1975, West et al 1961). In general, studies with stimulation by corticotrophin-releasing hormone are difficult to evaluate, largely because of small sample sizes. However, one such study also suggests that the return to baseline cortisol values after such stimulations is prolonged in older individuals (Pavlov et al 1986). Tests of the function of the feedback mechanism in humans usually involve the administration of dexamethasone and followed by the inhibition of cortisol secretion. These results are of particular importance in view of the evidence for a deficient feedback regulation in old animals. With the...


Conditions commonly associated with transient low blood glucose are hypothermia, infection, prematurity, intrauterine growth retardation and maternal diabetes. Some infants develop transient hyperinsulinaemia, particularly infants of diabetic mothers with poor antenatal control or those with severe rhesus disease. Rare causes include the Beckwith-Wiedemann syndrome and metabolic defects such as cortisol deficiency, galac-tosaemia and other enzyme defects of glycogenolysis, gluconeogenesis or fatty acid f oxidation. Preterm infants are much less able to mount a ketotic response and hypoglycaemia should be treated promptly.

Exercise Training

A single bout of moderate exercise seems to be well tolerated by the elderly. The NK cell response is found to be equal to that of younger individuals. However, older subjects show less stimulation of lymphocyte proliferation by moderate activity and also show less suppression with exhausting exercise. This depressed response may occur because of the depressed resting immune function or as the elderly have markedly less activity than the young, and thus a moderate training program seems to stimulate immune function to a greater extent in older than in young subjects. During exercise, the release of catecholamines and cortisol may be suppressive to NK activity, whereas the release of IL-1, IFN, and -endorphin may be stimulating. Although NK activity in the healthy elderly may be similar to the young at baseline, they would show a diminution of their response to acute stressors (i.e., exercise or IL-2), as has been commonly observed in other systems with aging. The preserved...

Anatomy Of Emission

An array of lantern types their behavior is little removed from the granules in subdermal fat cells or excretory tubules that glow continuously or in a simple circadian (daily) rhythm (Keroplatus, Orfelia), which is perhaps controlled by changes in hormone level. On the other hand, a flashing lantern is capable of photic finesse that can be appreciated only with electronic detector systems the flashes of male fireflies of some species have very sharp on transients, and field recordings of flying males reveal that a flash can reach its bright peak in 20 ms (Figs. 2A and 2B), the flicker signal of a Florida Photuris species is modulated up to 45 Hz (Fig. 2C), and the four subliminal peaks of what appears to the eye to be a single flash of an Andean Mountain Photinus occur at 25 Hz (Fig. 2D).


Initially, leptin was implicated in the regulation of body weight and reproductive function (29). However, recent reports of its effect on the immune system both in vitro and in vivo indicate that it has a role in modulation of a wide variety of immune responses. The light in which we see the biological role of leptin is changing to reflect its pleiotrophic functions, and the most satisfactory evolutionary explanation is that falling leptin concentrations signal impending energy nutrient deficiency. This is supported by most of the experimental data to date and implies that falling leptin levels reduce the energy utilization of extraneous or nonimmediately vital systems such as the immune system and the reproductive system. This would serve to preserve limited energy for cardiac and cerebral metabolism, but at the expense of an increased risk of infection. Immune responses use up significant amounts of energy, which can be life threatening at times of energy scarcity. We propose that...


Leptin Leptin is a 146-amino acid protein mainly produced by adipocytes its circulating levels reflect, to a great extent, the degree of adiposity or the amount of energy stored in adipose tissue (105). Although leptin has pleiotropic actions including neuroendocrine, metabolic, reproductive, hematopoietic, and metabolic regulation, its role in energy balance has received the most attention. It is the product of the OB gene, which is mutated in the genetically obese (ob ob) mouse its receptor is mutated in the diabetic (db db) mouse and the fatty (fa fa) rat, which are also obese. Mutations in either leptin or its receptor, although quite rare, have been reported in humans these result in hyperphagia and early-onset obesity (106,107). Binding of the peptide to its receptor on hypothalamic neurons leads to increased expression of anorexigenic (appetite-suppressing) pep-tides, such as melanocyte-stimulating hormone (a-MSH), cocaine- and amphetamine-regulated transcript (CART), and...


The interplay between insulin and leptin regulation of glucose and lipid homeostasis is well known and forms the basis for the complexities of the metabolic syndrome-associated phenotypes. As discussed above, recent findings in both diabetic and Zucker rats, may indicate that these hormones may also have a concerted effect on protein peptide homeostasis in part through the modulation of PepT1 expression. In terms of a classical biochemistry view, it would appear obvious and essential that the three major sources of nutrients (lipid, carbohydrates, and protein) would be subject to coordinate regulation. In addition to insulin, other hormonal PepT1 regulators have been identified and studied, such as epidermal growth factor (EGF) and leptin. In contrast to insulin, EGF was found to inhibit PepT1 by decreasing the number of transporter molecules on the apical membrane.147 Kinetic studies demonstrated a significant decrease in Vmax on the apical uptake of Gly-Sar, whereas Km remained...


3 3-hydroxysteroid dehydrogenase activity. Resolution may be accompanied by erythema, initially at the base of the lesion, and a predominantly mononuclear infiltrate has been taken to imply a cell-mediated immune response. In one study, two-thirds of patients had an antibody response, predominantly of the IgG class. The lack of response in the remainder may be due to the superficial site of infection and the outward migration of infected cells within the epidermis. Most patients retain virus-specific antibody after resolution. The involvement of immune responses in the resolution of molluscum contagiosum lesions is implicated by the observation that lesions may be numerous, widespread and long-lasting in the iatro-genically immunosuppressed, those with atopic dermatitis and those with acquired immunodeficiency syndrome (AIDS).

Sex Hormones

In addition, there is evidence that hormones such as androgens and estrogens might influence cognition, even postnatally. For example, Maki, Rich, and Rosenbaum (2002) studied 16 young women during two different stages of their menstrual cycle. During the follicular stage of the menstrual cycle, both estrogen and progesterone are low, and during the midluteal phase, both are high. These investigators found that whereas explicit memory was unchanged during the high estrogen phase, visuospatial functions were not as well-performed as during the low estrogen phase. Choi and Silverman (2002) studied the relationships between route-learning strategies and circulating testosterone and estrogen in a large population of students by obtaining salivary assays from the students. They found that testosterone levels were positively correlated with the use of route-learning strategies in men, but not in women. In addition, Wisniewski (1998) compared the spatial ability of hypogonadal men to normal...

Barbara Orlans

Behaviors, the singly caged individual often developed symptoms of behavioral and mental disease, such as self-aggression, withdrawal, and passivity. Handling procedures traditionally implied that individuals were forcefully subdued, thereby experiencing extreme anxiety, fear, and discomfort. Typical reactions to the immobilization distress are struggling, fear-induced diarrhea, screaming, alarm vocalization, and increased stress-hormone (cortisol) secretion.

Adrenal Cortex

Adrenal cortical hormones have been divided into two categories based on their ability to protect against these two causes of death. The so-called mineralocorti-coids are necessary for maintenance of sodium and potassium balance. Aldosterone is the physiologically important mineralocorticoid, although some deoxycor-ticosterone, another potent mineralocorticoid, is also produced by the normal adrenal gland (Fig. 2). Cortisol


These effects are mediated by the glucocorticoid receptor. The negative feedback effects on secretion depend on transcription of genes that code for proteins that either activate potassium channels or block the effects of PKA-catalyzed phosphorylation on these channels and may also act at the level of secretory vesicle trafficking. Initial actions of glucocorticoids suppress secretion of CRH and ACTH from storage granules. Subsequent actions of glucocorticoids result from inhibition of transcription of the genes for CRH and POMC in hypothalamic neurons and corticotropes perhaps by direct interaction of the glucocorticoid receptor with transcription factors that regulate synthesis of CRH and POMC. The inhibitory effect of cortisol on the cortico-trope are shown in Fig. 16. This feedback system closely resembles the one described earlier for regulation of thyroid hormone secretion even though the adrenal-ACTH system is much more dynamic and subject to episodic...

Hormone Regulation

Leptin and glucocorticoids have also been thought to be involved in adiponectin regulation, because leptin is also secreted by adipose tissue and both hormones affect insulin sensitivity (28,29). Although a cross-sectional study reported a strong inverse relationship between serum adiponectin and leptin levels (30), leptin given exogenously to rodents or humans had no significant effect on the plasma concentration of adiponectin (18,19). In vitro studies show that dexamethasone suppresses adiponectin gene expression (24,25), but in human studies, cortisol was found to have no correlation with circulating levels of adiponectin (19). Further studies are necessary to evaluate if glucocorticoids have a local effect on adiponectin production not reflected by their serum concentrations. Catecholamines may also suppress expression of adiponectin, because -adrenergic agonists reduced adiponectin gene expression in cultured mouse fat cells and human adipose tissue and decreased plasma levels...

Growth hormone axis

To reflect GH receptor expression in peripheral tissues, in PCI patients are in line with recovery of GH-responsiveness with time during severe illness. The low levels of IGF1, IGFBP3, ALS and IGFBP5 are tightly related to biochemical markers of impaired anabolism such as low serum osteocalcin and leptin (Van den Berghe et al 1999). These findings suggest that relative GH deficiency, epitomised by reduced pulsatile GH secretion participates in the pathogenesis of the 'wasting syndrome' especially in the chronic phase of critical illness. Furthermore there is a gender dissociation in that men show a greater loss of pulsatility and regularity within the GH secretory pattern than women (despite indistinguishable total GH output) and concomitantly lower IGF1 and ALS levels (Van den Berghe et al 2000). It remains unknown whether the sexual dimorphism within the GH IGF1 axis and the fact that males seem to be at higher risk for an adverse outcome from PCI than females is a casual or causal...

Acute Adrenal Crisis

Therapy should not be delayed in the acute setting for laboratory confirmation. Since death results from shock and vascular collapse, intravenous rehydration with saline 0.9 and 5 glucose should be vigorous. Blood should be drawn for electrolytes, cortisol, and ACTH. A rapid ACTH stimulation test will provide additional information, and dexamethasone 4-8 mg may be given as initial glucocorticoid replacement since it will not interfere with the ACTH stimulation test or cortisol assay. If time permits, an ACTH level should be drawn before dexamethasone since ACTH will be suppressed after the dexam-ethasone is given.


Prenatal growth and development of the mammary glands are independent of sex hormones and genetic sex. Until the onset of puberty, there are no differences in the male and female breast. With the onset of puberty, the duct system grows and branches under the influence of estrogen. Surrounding stromal and fat tissue also proliferate in response to estrogens. Progesterone, in combination with estrogen, promotes growth and branching of the lobuloalveolar tissue, but for these steroids to be effective prolactin, growth hormone, IGF-1, and cortisol must also be present. Lobuloalveolar growth and regression occur to some degree during each ovarian cycle. Growth, differentiation, and proliferation of mammary alveoli are pronounced during pregnancy, when estrogens, progesterone, prolactin, and hCS circulate in high concentrations.

Cushings Syndrome

Ectopic production of adrenocorticotrophic hormone (ACTH) by renal cell carcinoma has been reported. However, of the 232 patients with Cushing's syndrome reported, three of them were found to have hyperneph-roma one patient had an adrenal adenoma as well as a renal tumor, another had an incidental renal tumor found during adrenalectomy, and the other had a lapse of 21 years between the finding of increased ACTH production and renal cell carcinoma (Riggs and Sprague 1961). The mechanism of Cushing's syndrome is the enzymatic conversion of inactive proopiomelanocortin (POMC) to ACTH by the tumor. This leads to symptoms of cortisol excess, including weakness, muscle atrophy, fatigue, hypertension, and glucose intolerance. These symptoms resolved following nephrectomy (Wa-tanobe et al. 1988).

Intersex disorders

True Hermaphrodite Genitalia

CAH is the most common cause of female intersex and is an autosomal recessive disorder resulting in enzyme deficiency related to the biosynthesis of cortisol and aldos-terone. The commonest enzyme defect is 21-hydroxylase deficiency which results in a failure of conversion of 17a-hydroxyprogesterone to desoxycortisol and also failure of conversion of progesterone to desoxycorticos-terone (Fig. 34.18). Two other enzyme deficiencies are recognized, although less common -hydroxysteroid hydrogenase deficiency and 11 -hydroxylase deficiency. In 21-hydroxylase deficiency, which accounts for 90 of cases of CAH, the deficiency results in an increase in progesterone and 17a-hydroxyprogesterone, which is therefore converted to androstenedione and subsequently to testosterone. -CORTISOL Fig. 34.18 Diagram of the enzyme steps necessary to convert cholesterol through its various intermediate stages to aldosterone, cortisol and testosterone. Note that 3 -dehydrogenase (labelled 2) is active at two...


Menarche in girls in the UK is around 12.6 years, but the onset of menstruation is influenced by a number of factors. There is no doubt that this is genetically controlled, and the release of gonadotrophin-releasing hormone (GnRH) by the neurones in the arcuate nucleus of the hypothalamus is controlled by central factors influencing DNA within the cells. It is hypothesized that neurotransmitters, endorphins, interleukins, leptin and other paracrine and autocrine factors modulate the onset of puberty and new data suggest that growth factors including transforming growth factor alpha and epidermal growth factor appear to play key roles in this regulatory process. The process is linked to an increase in percentage body fat and this percentage body fat is influenced by a number of external factors, for example, socio-economic status, allowing good nutrition or psychological problems to influence body weight, for example, anorexia nervosa 1 . However, there is little doubt that body fat is...

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