Catherine Mae G. Basa SGD 36: Endocrine Generalities 1.

A 48 y/o female, known type 2 Diabetic is wondering why her Fasting Blood Sugar is 300 mg/dl despite the reduced intake of meals, regular exercise and good compliance with the doctors order regarding her medication. Her FBS used to be controlled with the same regimen. She has been having sleepless nights lately because of unpaid credit card bills. She is experiencing loss of appetite and occasional palpitations. What is the probable cause of her hyperglycemia? Signs - 300 mg/dl Symptoms - sleepless nights - loss of appetite - palpitations Cause of Hyperglycemia Stress hyperglycemia (also called stress diabetes or diabetes of injury) is a medical term referring to transient elevation of the bloodglucose due to the stress of illness. It usually resolves spontaneously, but must be distinguished from various forms of diabetes mellitus. Stress hyperglycemia is especially common in patients with hypertonic dehydration and those with elevated catecholamine levels (e.g., after emergency department treatment of acute asthma with epinephrine). Steroid diabetes is a specific and prolonged form of stress hyperglycemia. In some people, stress hyperglycemia may indicate a reduced insulin secretory capacity or a reduced sensitivity, and is sometimes the first clue to incipient diabetes. Because of this, it is occasionally appropriate to perform diabetes screening tests after recovery from an illness in which significant stress hyperglycemia occurred. Mayo Clinic: Stress-induced hyperglycemia is a common problem in patients admitted to the ICU, even when glucose homeostasis has previously been normal. Hyperglycemia is a near-universal finding in diabetic persons suffering catabolic illnesses and may worsen prognosis, although this possibility is controversial. The presence of hyperglycemia is associated with an increased risk of infectious complications in surgical patients, and indirect evidence indicates that maintenance of euglycemia can reduce the risk of infection. The causes of stress hyperglycemia include the presence of excessive counterregulatory hormones (glucagon, growth hormone, catecholamine, and glucocorticoid, either endogenous or exogenous), high circulating or tissue levels of cytokine (in particular tumor necrosis factor [TN] and interleukin-1). This metabolic milieu results in failure of insulin to suppress hepatic gluconeogenesis despite hyperglycemia; in addition, insulin-mediated glucose uptake into skeletal muscle is impaired. Patients given excessive nutritional support, especially by the intravenous route, are particularly likely to encounter hyperglycemia. Insulin remains the obvious treatment for hyperglycemia, although evidence documenting the clinical benefit of aggressive insulin therapy in the ICU is sparse. 2. Discuss the role of leptin in the body. Leptin (Greek leptos meaning thin) is a 16 kDa protein hormone that plays a key role in regulating energy intake and energy expenditure, including appetite and metabolism. It is one of the most important adipose derived hormones.[2] TheOb(Lep) gene (Ob for obese, Lep for leptin) is located on chromosome 7 in humans.[3] Biosynthesis Human leptin is a protein of 167 amino acids. It is manufactured primarily in the adipocytes of white adipose tissue, and the level of circulating leptin is directly proportional to the total amount of fat in the body.

In addition to white adipose tissuethe major source of leptinit can also be produced bybrown adipose tissue, placenta (syncytiotrophoblasts), ovaries, skeletal muscle, stomach(lower part of fundic glands), mammary epithelial cells, bone marrow, pituitary and liver.[6] Leptin has also been discovered to be synthesised from gastric chief cells and P/D1 cells in the stomach.[7] Function Leptin acts on receptors in the hypothalamus of the brain where it inhibits appetite by (1) counteracting the effects of neuropeptide Y (a potent feeding stimulant secreted by cells in the gut and in the hypothalamus); (2) counteracting the effects of anandamide (another potent feeding stimulant that binds to the same receptors as THC), and (3) promoting the synthesis of -MSH, an appetite suppressant. This inhibition is long-term, in contrast to the rapid inhibition of eating by cholecystokinin (CCK) and the slower suppression of hunger between meals mediated by PYY3-36. The absence of leptin (or its receptor) leads to uncontrolled food intake and resulting obesity. Several studies have shown that fasting or following a verylow-calorie diet (VLCD) lowers leptin levels.[8] It might be that, in the short-term, leptin is an indicator of energy balance. This system is more sensitive to starvation than to overfeeding; leptin levels change more when food intake decreases than when it increases.[9] It might be that the dynamics of leptin due to an acute change in energy balance are related to appetite and eventually to food intake. Although this is a new hypothesis, there are already some data that support it.[10][11] There is some controversy regarding the regulation of leptin by melatonin during the night. One research group suggested that increased levels of melatonin caused a downregulation of leptin.[12] However, in 2004, Brazilian researchers found that melatonin increases leptin levels in the presence of insulin, therefore causing a decrease in appetite during sleeping.[13] Mice with type 1 diabetes treated with leptin alone or in conjunction with insulin did better (blood sugar did not fluctuate as much; cholesterol levels decreased; mice formed less body fat) than mice with type 1 diabetes treated with insulin alone, raising the prospect of a new treatment for diabetes.[14] [edit]Adiposity signal To date, only leptin and insulin are known to act as an adiposity signal. In general, Leptin circulates at levels proportional to body fat. It enters the central nervous system (CNS) in proportion to its plasma concentration. Its receptors are found in brain neurons involved in regulating energy intake and expenditure. It controls food intake and energy expenditure by acting on receptors in the mediobasal hypothalamus[15] What are the modulators of feeding behavior? Satiety Leptin binds to neuropeptide Y (NPY) neurons in the arcuate nucleus, in such a way that decreases the activity of these neurons. Leptin signals to the brain that the body has had enough to eat, producing a feeling of satiety. A very small group of humans possesshomozygous mutations for the leptin gene that leads to a constant desire for food, resulting in severe obesity. This condition can be treated somewhat successfully by the administration of recombinant human leptin.[17] However, extensive clinical trials using recombinant human leptin as a therapeutic agent for treating obesity in humans have been inconclusive because only the most obese subjects who were given the highest doses of exogenous leptin produced statistically significant weight loss. It was concluded that large and frequent doses are needed to provide only modest benefit because of leptins low circulating half-life, low potency, and poor solubility. Furthermore, these injections caused some participants to drop out of the study due to inflammatory responses of the skin at the injection site. Some of these problems can be alleviated by a form of leptin called Fc-leptin, which takes the Fc fragment from the immunoglobulin gamma chain as the N-terminal fusion partner and follows it with leptin. This Fc-leptin fusion has been experimentally proven to be highly soluble, more biologically potent, and contain a much longer serum half-life. As a result, this Fc-leptin was successfully shown to treat obesity in both leptin-deficient and normal mice, although studies have not been undertaken on human subjects. This makes Fc-leptin a potential treatment for obesity in humans after more extensive testing.[18][19][20] Circulating leptin levels give the brain input regarding energy storage so it can regulate appetite and metabolism. Leptin works by inhibiting the activity ofneurons that contain neuropeptide Y (NPY) and agouti-related peptide (AgRP), and by increasing the activity of neurons

expressing -melanocyte-stimulating hormone (-MSH). The NPY neurons are a key element in the regulation of appetite; small doses of NPY injected into the brains of experimental animals stimulates feeding, while selective destruction of the NPY neurons in mice causes them to become anorexic. On the converse, -MSH is an important mediator of satiety, and differences in the gene for the receptor at which -MSH acts in the brain are linked to obesity in humans. Mechanism of action Leptin interacts with six types of receptors (Ob-RaOb-Rf, or LepRa-LepRf) that in turn are encoded by a single gene, LEPR.[68] Ob-Rb is the only receptor isoform that can signal intracellularly via the Jak-Stat and MAPK signal transduction pathways,[69] and is present inhypothalamic nuclei.[70] It is unknown as to whether leptin can cross the blood-brain barrier to access receptor neurons, because the blood-brain barrier is attenuated in the area of the median eminence, close to where the NPY neurons of the arcuate nucleus are. It is generally thought that leptin might enter the brain at the choroid plexus, where there is intense expression of a form of leptin receptor molecule that could act as a transport mechanism. Once leptin has bound to the Ob-Rb receptor, it activates the stat3, which is phosphorylated and travels to the nucleus to, it is presumed, effect changes in gene expression. One of the main effects on gene expression is the down-regulation of the expression ofendocannabinoids, responsible for increasing appetite[citation needed]. There are other intracellular pathways activated by leptin, but less is known about how they function in this system. In response to leptin, receptor neurons have been shown to remodel themselves, changing the number and types of synapses that fire onto them. There is some recognition that leptin action is more decentralized than previously assumed. In addition to its endocrine action at a distance (from adipose tissue to brain), leptin also acts as a paracrine mediator.[6] 3. Describe the physiological response-driven feedback loop and an endocrine axis driven feedback loop? CONFIGURATION OF FEEDBACK LOOPS WITHIN THE ENDOCRINE SYSTEM The predominant mode of a closed feedback loop among endocrine glands is negative feedback. In a negative-feedback loop, "hormone A" acts on one or more target organs to induce a change (either a decrease or increase) in circulating levels of "component B," and the change in component B then inhibits secretion of hormone A. Negative-feedback loops confer stability by keeping a physiological parameter (e.g., blood glucose) within a normal range. There are also a few examples of positive feedback in endocrine regulation. A positive closed feedback loop, in which hormone X increases levels of component Y and component Y stimulates secretion of hormone X, confers instability. Under the control of positive-feedback loops, something has "got to give." For example, positive-feedback loops control processes that lead to rupture of a follicle through the ovarian wall or expulsion of a fetus from the uterus. page 653 page 654 Figure 37-1 Glands of the endocrine system.

Figure 37-2 Physiological response-driven and endocrine axis-driven negative-feedback loops. There are two basic configurations of negative-feedback loops within the endocrine system: a physiological response-driven feedback loop (referred to simply as "response-driven feedback") and an endocrine axisdriven feedback loop (Fig. 37-2). The response-driven feedback loop is observed in endocrine glands that control blood glucose levels (pancreatic islets), blood Ca++ and Pi levels (parathyroid glands, kidney), blood osmolarity and volume (hypothalamus/posterior pituitary), and blood Na+, K+, and H+ (zona glomerulosa of the adrenal cortex and atrial cells). In the response-driven configuration, secretion of a hormone is stimulated or inhibited by a change in the level of a specific extracellular parameter (e.g., an increase in blood glucose stimulates insulin secretion). Altered hormone levels lead to changes in the physiology of target organs (e.g., decreased hepatic gluconeogenesis, increased uptake of glucose by muscle) that directly regulate the parameter (i.e., blood glucose) in question. The change in the parameter (i.e., decreased blood glucose) then inhibits further secretion of the hormone (i.e., insulin secretion drops as blood glucose falls). Much of the endocrine system is organized into endocrine axes, with each axis consisting of the hypothalamus and the pituitary and peripheral endocrine glands (Fig. 37-2). Thus, the endocrine axis-driven feedback loop involves a three-tiered configuration. The first tier is represented byhypothalamic neuroendocrine neurons that secrete releasing hormones. Releasing hormones stimulate (or, in a few cases, inhibit) the production and secretion of tropic hormones from the pituitary gland (second tier). Tropic hormones stimulate the production and secretion of hormones from peripheral endocrine glands (third tier). The peripherally produced hormones, namely, thyroid hormone, cortisol, sex steroids, and IGF-I, typically have pleiotropic actions (e.g., multiple phenotypic effects) on numerous cell types. However, in endocrine axis-driven feedback, the primary feedback loop involves feedback inhibition of pituitary tropic hormones and hypothalamic releasing hormones by the peripherally produced hormone. In contrast to response-driven feedback, the physiological responses to the peripherally produced hormone play only a minor role in regulation of feedback within endocrine axis-driven feedback loops. An important aspect of the endocrine axes is the ability of descending and ascending neuronal signals to modulate release of the hypothalamic releasing hormones and thereby control the activity of the axis. A major neuronal input to releasing hormone-secreting neurons comes from another region of the hypothalamus called the suprachiasmatic nucleus (SCN). SCN neurons impose a daily rhythm, called a circadian rhythm,on the secretion of hypothalamic releasing hormones and the endocrine axes that they control (Fig. 37-3). SCN

neurons represent an intrinsic circadian clock, as evidenced by the fact that they demonstrate a spontaneous peak of electrical activity at the same time every 24 to 25 hours. The 24- to 25-hour cycle can be "entrained" by the normal environmental light-dark cycle created by the earth's rotation such that the periodicity of the clock appears to be environmentally controlled (Fig. 37-4). Neural input is generated from specialized light-sensitive retinal cells that are distinct from rods and cones and from signals to the SCN via the retinohypothalamic tract. Under constant conditions of light or dark, however, the SCN clock becomes "free running" and slightly drifts away from a 24-hour cycle each day.