Pathophysiology of diabetes mellitus | Endocrine physiology

 Diabetes mellitus occurs due to deficiency of insulin function which may occur due to 

1. decreased insulin release or 

 2.  insulin resistance. 

 In diabetes, storage and utilisation of glucose decreases in fed state leading to increase in blood glucose concentration after food i.epost-prandial hyperglycemia. Due to continuing glycogenolysis and gluconeogenesis, glucose concentration in  blood rises in between meals too i. e fasting hyperglycemia 

Due to excess blood glucose concentration, the glucose filtered through nephron is also high. This exceeds the capacity of nephrons of absorbing glucose i.e transport maximum is reached, above which the nephrons are not able to reabsorb further glucose and hence glucose starts appearing in urine i.e glucosuria occurs. The presence of glucose in nephron acts as anosmotic pull for water preventing the reabsorption of water also from the nephron. So water loss also increases causing increase in the volume of urine i.e polyuria. Due to increase in water loss from the body, and hyperosmolarity of blood due to increased blood glucose concentration, water moves out of cells. This when happens in osmoreceptors…thirst centres are activated causing increase in the intake of water i.e polydipsia.

 Hyperphagia:  When insulin is deficient, the satiety centre neurons are not able to utilise glucose and become inactive. Thus they do not inhibit feeding centre.   Since feeding centre is not inhibited, the person feels hungry and eats often i.e polyphagia occurs. 

In insulin deficiency  lipolysis starts in adipose tissue causingrelease of  free fatty acids in circulation, proteolysis also starts. So with  increased lipolysis and proteolysis , there is weight loss.  The free fatty acids enter liver and undergo beta oxidation leading ultimately to formation of acetyl COA. In diabetes, most of the acetyl coA is channeled away from Krebs cycle and is utilised for production of ketone bodies (ketosis). When rate of productions of ketone bodies is too high which occurs when insulin levels are very low or virtually absent as seen in type 1 diabetes mellitus,  ketone bodies decrease blood pH (ketocacidosis) . 

Since blood pH decreases, body starts compensatory mechanisms for excretion of excess acids by increasing respiratory rate and depth. This is known as Kussmaul’s breathing or air hunger, Some ketone bodies i.e acetone is also excreted by breath causing fruity smell of breath. Ketoacidosis is always accompanied by dehydration. This leads to activation of renin-angiotension-aldosterone system. Thus causing hyperaldsteronism causing potassium loss from the body. 

 In type 2 DM, ketocacidosis is not that common, since insulin receptor defect starts slowly, i.e some actions of insulin are preserved so lipolysis and proteolysis are not that severe. Since lipolysis is not severe, formation of ketone bodies is also not excessive.  In contrast, another problem may occur in type 2 diabetes i.e hyperglycemia hyperosmolar state. In this also, there is hyperglycemia, causing high serum osmolarity ,  also causing glucosuria and poyluria and hence depletion of watre. However, ketoacidosis is not present. 

Functionsof insulin: https://youtu.be/JjUaj6v2vqI 

Insulin signal transduction pathways | Endocrine physiology

Insulin signal transduction pathways | Endocrine physiology 

There are 2 fundamental signal transducing pathways by which insulin acts: 

1. Phosphotidylinositol-3 kinase or PI3-Kinase pathway 

2. Ras-MAP kinase pathway. 

Insulin acts by binding to its receptors which are present on the cell membrane of its target cell. Insulin receptors are enzyme linked receptors which have inherent tyrosine kinase enzyme activity. 

The insulin receptors are present as tetramers i.e they have 4 polypeptides or subunits which assemble to form the receptor. Two of these subunits are alpha subunits while the other two are beta subunits. Alpha subunits project outside the membrane i.e form the extracellular part of the receptor which has the binding site for insulin. The beta subunits traverse through the membrane  and protrude into the cytoplasm and has  intrinsic tyrosine kinase activity i  When insulin is not bound to the receptors, the tyrosine kinase is inactive. 

When the insulin binds to its receptors, the tyrosine kinase activity of beta subunits activates which then cross-phosphorylate tyrosine residues of each other. This receptor then binds to insulin receptor substrates.  Once that happens this insulin receptor substrate becomes a docking site for other kinases and adaptor proteins. 

 1. PI3-Kinase pathway: 

 Phosphotidylinositol-3 kinase  phosphorylates  phosphatidylinositol 4-5 biphosphate. For this, initially it binds to IRS. This brings it close to its substrate which is present on the membrane and also activates it by phosphorylation. Then, it phosphorylates, PIP2 forming phosphotidyinositol 3,4,5 triphosphate.  Now this triphosphate also acts as a docking site for 2 other kinases i.e  phosphoinositide dependent kinase 1 and Protein kinase B. Now  PDK-1 phosphorylates  protein kinase B or AKT thus activating it. 

It is this protein kinase B which now dissociates and moves into the cytoplasm which then causes insertion of GLUT 4 receptors on the membrane, activates glycogen synthase for conversion of glucose to glycogen, inactivates glycogen phosphorylase for preventing glycogenolysis and hence causes varied effects on metabolism. 

 2. RAS-MAPK pathway 

 Monomeric G-proteins (Ras) have the ability to bind GDP and GTP. In inactive state , they are bound to GDP while when active they bind to GTP just like our trimeric G proteins. For activating it,  insulin receptor substrate binds with another adaptor protein GRB2 which in turn binds and activates a Guanine exchange factor protein SOS  which replaces Ras GDP with GTP causing its activation. The activation of Ras inturn leads to activation of kinase cascade including Raf, MEK and then ultimately leading to the activation of MAPKinase.  After activation, MAP kinase translocates into the nucleus and phosphorylates many transcription factors that regulate expression of important cell-cycle and differentiation-specific proteins. So that’s how insulin has effects on cell proliferation, growth and differentiation. 

 In summary, insulin acts by 2 signal transduction pathways: PI3-Kinase pathway responsible for its metabolic actions and some survival actions also and Ras MAP kinase pathway responsible for its effects on cell proliferation, growth and differentiation.

Biosynthesis of thyroid hormones

Thyroid hormones are iodinated tyrosine which is an amino acid.   Synthesis of thyroid hormones occurs in multiple steps 

 1. Synthesis of thyroglobulin: Thyroglobulin is synthesised by follicular epithelial cells just like any other protein synthesis by cells and is secreted into the colloid by exocytosis. So this protein is stored in the colloid. 

 2. Trapping and transport of iodide: Iodine is present in circulation as iodide ion. This iodide is taken up into the cytoplasm by NaI- symporter which is a secondary active transporter present on the basolateral membrane of thyrocytes. This Iodide then enters into the colloid via the apical membrane through the Cl-/I- exchanger which is also known as ‘pendrin’ 

 3. Organification: So now we got both iodide and thyroglobulin in the colloid. However, the iodide cannot react with tyrosine residues. For that it should be oxidised to iodine. So this process of oxidation of iodide to iodine and iodination of the tyrosine residues of the thyroglobulin is known as organification.  This occurs in presence of the enzyme thyroid peroxidase present on the apical membrane of thyrocytes.  Many tyrosine residues of thyroglobulin are iodinate either at single site forming monoiodotyrosines i.e MIT or two sites forming diiodotyrosines i.e DIT. 

 4. Coupling reaction: MIT and DIT are not thyroid hormones. It is the coupling or combination of these iodinated tyrosines which produces thyroid hormones. One MIT and one DIT couple to form triiodothyronine i.e. T3 and 2 DITS couple to form Tetraiodothyronine i.e T4 or thyroxine in presence of enzyme thyroid peroxidase. This is known as coupling reaction. 

So basically, thyroid hormones form within the thyroglobulin molecule.

When the gland is stimulated by Thyroid stimulating hormone, all these steps of synthesis of thyroid hormones i.e  synthesis of thyroglobulin, uptake of iodide, organification and coupling reaction are stimulated. 

Also, the follicular cells start taking up the stored iodinated thyroglobulin from the colloid by endocytosis. Intracellularly lysosomes fuse with the phagocytosed thyroglobulin and cleave T3 and T4 from thyroglobulin by proteases which are then released from the basolateral side and enter into the circulation. The separated amino acids are reused to produce thyroglobulin. The MIT and DIT which are not coupled are acted upon by the enzyme ‘deiodinase’ which as its name suggests detaches the iodine from the tyrosine both of which are recycled. 

 

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G-protein coupled receptors

G protein coupled receptors have an extracellular binding site to which the hormone binds and an intracellular cytoplasmic tail region to which G-proteins may bind.  

G proteins act as a switch and functionally couple the receptor to their target enzymes or ion channels. Switch means there is an inactive state when the hormone is not bound to the receptor and when the hormone binds, there is activation. G-proteins or heterotrimeric GTP binding proteins is a set of 3 proteins, G alpha, G beta and G- gamma which are present as an inactive complex bound to membrane just near the hormone receptor.   

The alpha subunit of G proteins is bound to GDP in inactive state.When the hormone binds to its receptor, receptor interacts with the G proteins and GDP bound to alpha subunit is replaced by GTP, which is now said to be in active state. This replacement of GDP with GTP causes alpha subunit to dissociate from beta and gamma subunits and move and associate with some other proteins causing  either opening/closing of ion channels or they affect the activity of enzymes like adenyl cyclase and phospholipase C. 

G proteins which stimulate adenyl cyclase activity are known as G stimulatory proteins i.e Galpha s. while that which inhibits their activity ate known as inhibitory G proteins i.e Galphai. The G proteins which affect the activity of phospholipase C are known as G q proteins. The effect of the hormone on the cell depends on the type of the receptor it binds for e.g. same hormone in one cell may have a receptor which is linked to stimulatory G proteins while in other cells it may have a receptor which is linked to inhibitory G proteins. By the change in the activity of these enzymes, second messenger systems or we can say signalling pathways are activated. 

 Adenylcyclase-cAMP pathway 

When adenyl cyclase enzyme is activated, it causes the conversion of ATP to cAMP. cAMP in turn cause the activation of cAMP dependent protein kinase A which causes phosphorylation of some proteins/enzymes in the cell. Now these proteins may be involved in biological reactions or these phosphorylated protein inturn activate or inhibit other proteins which are involved in cellular reactions. So ultimately this process affects the function of the cells. In addition,PKA can also increase/decrease the transcription of some genes.Close to these genes, is present a region known as cAMP-responsive element (CRE) region of DNA.  A subunit of PKA moves to the nucleus and phosphorylates another protein, the cAMP-responsive element binding protein (i,e CREB protein) which then binds to CRE and alters transcription of the genes where CRE is present. The set of proteins activated by cAMP varies in different cells. So adenyl cyclase activation  in different cells leads to different actions. However if same adenyl cyclase is activated by different ligands in the same cell, it leads to same actions. So in this pathway, cAMP acts as a second messenger.

Phospholipase C-IP3-DAG-Calmodulin pathway 

 When phospholipase C is activated by Gq proteins, it causes breakdown of the membrane phospholipid phosphatidylinositol 4,5 bi or di phosphate (PIP2) into IP3, i.e inositol triphosphate and Diacyl glycerol (DAG). Ip3 acts on IP3 receptor (IP3R) present on endoplasmic reticulum. This IP3R is itself a ligand gated calcium channel. When IP3 binds, it opens up causing release of calcium ions from ER into the cytososl. The calcium ions in turn bind with calmodulin causing activation/inhibition of calmodulin dependent protein kinases.  

DAG activates protein kinase C which then phosphorylates other proteins just as we saw for adenyl cyclase dependent kinases. So in this case IP3, DAG and calcium are second messengers.

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adrenal physiology powerpoint

Hi guys,
Get going with adrenal physiology

Integrated endocrinology :Concepts

Integrated endocrinology

We can regard the endocrine system as having the following physiological missions

Regulation of sodium and water balance: preservation of the volume/pressure reservoir required for tissue perfusion

Regulation of calcium balance: preservation of extracellular fluid concentrations required for membrane integrity, intracellular signaling, hemostasis,etc., and preservation of skeletal integrity

Regulation of energy balance: preserving, accessing, and interconverting metabolic fuels to meet

cellular energy demands

Coordination of processes for coping with a hostile environment

Coordination of growth and development

Coordination of processes associated with reproduction and lactation

It is clear that at least some aspect of virtually every physiological system lies within the realm of endocrine control

No single hormone or endocrine gland can accomplish any of these missions alone, and virtually every hormone participates in fulfilling multiple missions

Consequently, it is to understand not only how hormones act but also how they interact.

                Control of hormone action

Negative feedback

The essence of negative feedback control of hormone secretion is that some consequence of secretion blocks or dampens further secretion

 Hypothalamic input to the negative feedback system allows for episodic override and adjustment of the set point in response to environmental inputs

Positive feedback

 In positive feedback systems, the consequences of hormone secretion feed back is to reinforce the drive for secretion rather than dampen it.

Rather than maintaining matters stable and unchanging, positive feedback creates instability and leads to explosive changes . Consequently, positive feedback is rare in biology

Eg: During parturition

      Coagulation

      Generation of action potential

Concepts of  Specificity

Because of “internal secretion” of hormones into the blood, hormones are widely disseminated throughout the body and have access to virtually all cells. However, only certain cells respond to any particular hormone. These “target” cells differ from all other cells in the respect that they express receptors for that hormone.

The information delivered to the target cell is present in the structure and three-dimensional conformation of the hormone and is sufficient only to activate the receptor.

 It appears that activation of one particular receptor is an all-or-none phenomenon, with gradations in response resulting from gradations in the numbers of receptors that are activated in each cell.

 The receptor, by virtue of the biochemical changes it triggers in transducing the signal, initiates a particular biochemical change or group of changes. The signals generated in the target cell are determined by the signal-transducing component of the receptor.

In many cases, there is more than a single class of receptors for a particular hormone, and each class usually activates a different biochemical pathway.

The nature of the final response elicited in a target cell is not determined by the intracellular signal generated by the receptor but, rather, by the effective machinery expressed in the cell as a consequence of its  differentiated state

For example,

Receptors for the parathyroid hormone are present in the basal membranes of cells of both the proximal and distal portions of the nephron . Binding of the hormone initiates the same signaling cascade in both cell types,but the proximal tubules respond by decreasing phosphate reabsorption from the glomerular filtrate and increasing hydroxylation of vitamin D, while the distal cells respond by increasing reabsorption of calcium

CONCEPTS RELATED TO TARGET CELL RESPONSIVENESS

Responsiveness of target cells to stimulation by their hormones is not constant but may vary widely in different physiological states and is often adjusted by the actions of other hormones or local paracrine or autocrine agents as well as the primary hormone

Factors that govern the magnitude of the response to a hormone.

1)  Concentration of the hormone

        which in turn is determined by

a)      The rate of hormone secretion

b)      The rate of delivery by the circulation to the target cell surface, which is slower if the hormone circulates bound to plasma proteins than if it is unbound

c)       The rate at which the hormone is degraded or excreted

2) Number of competent target cells that express functional receptors

3) The sensitivity of each target cell to hormonal stimulation is not constant and depends on

a)      The number of functional receptors that are expressed

b)      The affinity of the receptor for the hormone

c)       The status of postreceptor amplification mechanisms

d)      The status and abundance of effector molecules

The sensitivity to a hormone of target organ is often defined as the concentration needed to produce a half-maximal response

Target organ sensitivity is not constant and is often adjusted in accordance with physiological circumstances.

Can be done by:

a)      Changing the number of receptors expressed.

b)      On the cellular level, upregulation or downregulation of effector molecules such as enzymes, ion channels

c)       On the tissue/organ level aggregate of the contributions of all of the respond-ing cells, so that the magnitude of the response to a particular concentration of hormone is a function of the number of available cells as well as the competence of each cell.

Factors that govern the duration of the response to a hormone.

1)  The duration of hormone availability, which is determined by

a)      The duration of secretion

b)      The rate of hormone clearance from the blood, usually described as its half-life

2)  Whether the response results from

a)      A rapidly reversible covalent change, i.e., phosphorylation or dephosphorylation of key enzyme

b)      Or genomic events involving synthesis of proteins and the half-lives of the proteins

Fun and interesting facts about thyroid

In Switzerland in the 1880's Theodor Kocher demonstrated that total thyroidectomy caused hypothyroidism but thought initially that the symptoms were due to chronic air way obstruction. Kocher performed over 2000 thyroidectomies. 

He reported his early experience of thyroidectomy for Grave's disease which had at that time a mortality of 13%. Later in in 1883 his mortality for total thyroidectomy for Grave's fell to a remarkable 1%. It was not until 1888 that he realised that the symptoms of total thyroidectomy were due to lack of thyroid.

He then recommended as a treatment for total thyroidectomy "half a sheep's thyroid lightly fried and taken with current jelly once a week". The modern treatment of hypothyroidism was born. Kocher was awarded the Nobel Prize for Medicine in 1909.

The American surgeon William Halsted could trace accounts of only eight operations in which the scalpel was used between 1596 and 1800. During one of these procedures, described by Fabricius in 1646, the patient, a 10‐yr‐old girl, died on the table and the surgeon was gaoled!

Thyroid hormones affect function of virtually every organ system & every tissue in the body

When overactive, everything is turned up – feel hot (increase in metabolism), restless/anxious, hyperactive heart , respiratory rate increase & GI motility, secretion (causing diarrhoea) etc.

When underactive, everything is dialed down –

slow, cool, fatigue, constipation etc

Thyroid enlargement (goitre) can be present in hypothyroid, hyperthyroid or euthyroid state

Though T3 is the active form, T4 is the preferred hormone for treatment of hypothyroidism.

Long circulatory half life of T4 provides remarakable stability ensuring a steady supply of t3 once a therapeutic dose is established.

Shorter half life of T3 makes it less appropriate for long term use.

Also there is an additional disadvantage of bypassing regulatory mechanisms controlling T4 to T3

Parathyroid

Hi everyone,

Here goes my another powerpoint in endocrinology series

Parathyroid and calcium homeostasis

Keep reading and remain updated




Soon I will be posting interesting facts about the the topics

Feedback and suggestions invited

thyroid powerpoint

hey,

This is my first power point help for students both undergraduate and postgraduates.

All feedback suggestions are invited.

Also if explanation is desired on any subtopics, you can always post a comment, and i would try to elaborate  on that topic to my best possible capacity.

Also u can let me know of any topic, you need the power point of.

so here goes the first power point on Thyroid physiology with some pathological aspects