Endocrine 2 Flashcards
what is the main fuel source for the brain and what is the issue when this is at low levels
- Predominant fuel source for brain is glucose (but ketones can also be used).
○ CNS can’t synthesize, store or concentrate glucose and hypoglycaemia can cause profound dysfunction of the CNS eventually leading to coma and death.
What results from the fed state and what are the 3 things fasting results in
- The fed state (anabolic) after a meal results in fuel substrates such as sugars, glucose, fats and amino acids being added to the body.
○ Fed state liver stores carbohydrates as glycogen, amino acids are stored in muscle and fats are stored in adipose tissue. - Fasting results in
○ breakdown of fats to form fatty acids and glycerol which go to liver to form glucose and ketones
○ muscle is degraded to release amino acids which are converted to glucose in liver by gluconeogenesis
○ liver breaks down glycogen to glucose
What are the main hormones involved with minute to minute regulation of fuel balance and how act and what range is plasma glucose maintained at
insulin and glucagon
As well as
○ Stress metabolic hormones cortisol and adrenalin (flight and fright) and growth hormone increase glucose
○ Thyroid hormones during starvation states reduce metabolic rate conserve glucose.
- relatively narrow range 4.4-6.6 mmol/L
What are the 3 main hormones involved in regulating feeding, where produced and their role
Insulin (pancreas) & leptin (produced by stomach and pancreas) supresses hunger, ghrehlin (produced by adipose tissue) increases hunger by acting on hypothalamus
Pancreas what is it, where located and function/structure
- soft lobulated gland located in the dorsal part of the abdominal cavity in close proximity to the duodenum
- dual function gland with an exocrine and endocrine component.
1) The exocrine component consists of acinar cells that secrete digestive enzymes (such as trypsin and chymotrypsin to digest proteins, amylase for the digestion of carbohydrates and lipases to break down fats).
2) The endocrine component consists of islets of langerhans (tiny clusters of endocrine cells)
What are the 5 cell types present within the islets of langerhans (in the pancreas), how much of the cells they make up and what hormone produce
Major cell types
1. Alpha cells that produce glucagon
○ make up 20-25%
○ Glucagon raises blood glucose levels by stimulating the liver to release glucose.
2. Beta cells produce insulin (and amylin).
○ make up 60-80%
○ Insulin lowers blood lowers blood glucose levels whereas amylin slows gastric emptying and prevents spikes in blood glucose levels
3. Delta cells produce somatostatin.
○ Suppresses the release of other hormones made in the pancreas.
○ make up 5-10%
Minor cell types
4. Gamma cells secrete pancreatic polypeptide 3-5% of total islet cells.
○ Regulates both endocrine and exocrine pancreatic secretions
5. Epsilon cells secrete ghrelin which stimulates hunger.
○ Less than 1% of islets cells.
What is the structure of insulin, is it similar between species and what shapes can insulin take and therefore biological characteristics
composed of two chains termed A (21 aa) and B (30 aa) linked by disulphide bonds.
Have regions that are highly conserved between species
- can form dimers by hydrogen bonding between B chains or form hexamers in the presence of zinc ions.
○ Clinically in insulin formulations these properties are relevant as monomers diffuse faster and hexamers are absorbed more slowly.
how is measuring C-protein useful in determining insulin levels
C-protein can be used as an indicator of endogenous and exogenous sources of insulin as it is released together with insulin from beta cells but is cleared more slowly from the circulation than insulin.
What are the 4 steps in the biosynthesis of insulin
- It is first synthesized as pre-proinsulin (a single chain 86 aa polypeptide)
- Proteolytic cleavage of the amino terminal signal peptide in endoplasmic reticulum results in proinsulin (A & B chain plus a connecting “C” peptide).
- Within the endoplasmic reticulum endopeptidases cleave the C-peptide and both insulin and the C-peptide are packaged within the Golgi apparatus to form secretory granules which are stored in the cytoplasm.
- Exocytosis occurs following fusion of secretory granules with cell membrane.
What are the positive and negative stimuli for the secretion of insulin
POSITIVE
main -> increased plasma glucose concentration >5.5-6 mmol/L
Other
- Amino acids (arginine and lysine)
- Fructose and fatty acids
- GI tract hormone Glucagon like peptide-1(GLP-1).
- Primes beta cell to produce more insulin.
- Parasympathetic stimulation
○ Smell and taste of food.
NEGATIVE
- Sympathetic stimulation -> Stress response. Insulin secretion reduced as want to increase blood glucose not decrease
What are the 4 steps in the release of insulin from the pancreas
- Glut 2 transports glucose into beta cells within the pancreas and makes ATP via glycolysis
- K+ channel gated by ATP and increased intracellular ATP causes channel to close causing depolarization
- Voltage gated Ca2+ channel opens and Ca2+ enters cells
- Increased calcium leads to exocytosis of insulin secretory granules.
what is the stimulus for the release of glucagon
- glucagon secreted by alpha cells if plasma glucose falls < 4.4mmol/L
- Insulin major inhibitor of glucagon release. Reduction in insulin leads to glucagon secretion.
Insulin, where secreted to, what are the target cells and the 2 steps in the pathway once bound to the target cells
- secreted into portal vein for delivery to the liver
- target cells: liver, muscle and adipose
Pathway of insulin on target cells
1. Activates intrinsic tyrosine kinase activity leading to receptor autophosphorylation and activation of insulin receptor substrate.
2. Complicated second messenger pathways activated including PIP2 pathways and MAP kinase pathways
Insulin what is its activity in the muscle and liver
Muscles
- Stimulates glucose transport from blood into muscle and adipose tissue by Glut4 transporters
- Glut4 also inserted into the membrane via oxygen levels
- stimulates protein metabolism by increasing the transport of amino acid to muscle and stimulates their synthesis into proteins
Liver
- Increases glycolysis by driving two rate limiting glycolytic enzymes, phosphofructokinase (PFK) and pyruvate kinase by increasing the level of Fructose 2,6 biphosphate (F-2,6-BP).
- Activates glycogen synthetase to store glucose as glycogen
- Promotes the synthesis of fatty acids
Insulin what is its activity in adipose tissue and in what state
- In a fed state , insulin promotes the synthesis of fatty acids by the liver and they are transported via blood lipoproteins to the adipose tissue.
○ Promotes fatty acid storage as triglycerides in adipose tissues by increasing lipoprotein lipase which hydrolyses VLDL so that FFA (fatty acids) can enter cells and be stored as triglycerides
○ Inhibits hormone sensitive lipase that breaks down triglycerides into fatty acids (increase the amount stored by inhibiting) - Activates acetyl CoA carboxylase that promotes triglyceride formation within adipose cells
Glucagon what is the main function, how binds to cells and 2 main functions within
- Glucagon major effect is to increase blood glucose levels
- Binds to a G protein coupled receptor and via cAMP second messenger stimulates depolymerisation of glycogen stored in liver to glucose.
- Activates hepatic gluconeogenesis (eg fructose 1,6, biphosphatase(FDPase)) so that non hexose substrates such as amino acids are converted to glucose to.
- Activates a lipoprotein lipase in adipose tissue that causes lipolysis of triglycerides into glycerol and free fatty acids.
○ Provides alternative energy source conserving glucose.
What is diabetes mellitus, some general causes and how best described functionally
- Diabetes mellitus is a group of metabolic disorders characterized by hyperglycaemia as a consequence of a defect in insulin secretion and /or insulin sensitivity in target tissues.
○ Several pathogenic abnormalities such as autoimmune mediated destruction or of the beta cells, pancreatitis or endocrinopathies can lead to insulin deficiency and/or insulin resistance and result in diabetes mellitus - functionally with persistent increased fasting blood glucose > 8 mmol/L
List and describe the 4 types of diabetes mellitus
1) Type 1 DM - destruction of Beta-cells and insulin dependency
2) Type 2 DM - combination of impaired insulin secretion and insulin resistance
3) Gestational diabetes - increased insulin resistance in animals that already have some beta cells dysfunction or loss
4) Hypercortisolism and hypersomatotropism (common) can cause DM in animals with pre-existing defects in insulin secretion or receptor capacity.
Type 1 DM what are the 3 main different types of causes
1) caused by immune mediated destruction of beta cells in pancreas
- Autoantibodies detected to insulin, and other intracellular components of β-cells. (humans 95%, dogs 50% )
2) Other diseases as well include pancreatitis, trauma, infection, and pancreatic neoplasia
- Inflammatory conditions of the pancreas often caused by viral infections
3) impairment of the beta cells of the pancreas due to chemical poisoning or to drug treatment (e.g. certain corticosteroids) of an unrelated disease
- Chronic hyperglycaemia causes glucose toxicity
Type 1 DM which species most common in, what is it most commonly characterised by and treatment
- Main form DM in dogs rare in cats
- In dogs Type 1 diabetes is the most common characterised by
○ Permenant hypoinsulimaemia
○ No increase in c peptide with insulin secretagogues - Need insulin administration to avoid ketoacidosis
Type 2 DM what occurs, what may progress to and which species most common in
- Combination of impaired insulin secretion and insulin resistance - 2 parts of disease
○ In established cases DM there is reduced beta cell secretion of insulin.
○ However, disease probably starts with reduced function of insulin receptors or numbers (insulin resistance) - May progress to become insulin dependent ie Type 1 DM
- No evidence in dogs (despite obesity) but main type DM in cats and humans
What are the 2 main aspects of Type 2 DM and caused by
- Insulin resistance
○ Target cell less sensitive to insulin
○ Down regulated of receptors
○ Reduced response (at target cell) reduced signal transduction) - Abnormal secretion by beta cells
○ Caused by amylin deposition, decreased beta cell mass, β-cells dysfunction decreased target cell sensitivity or alpha cell dysfunction.
Amyloidosis in cats what caused by and what lead to
□ Increased amyloid deposition may be caused by increase glucose toxicity or underlying infectious/inflammatory process
□ IAPP - Islet amyloid polypeptide (IAPP, or amylin) is one of the major secretory products of β-cells which is secreted together with insulin and is unable to be processed properly by cats -> accumulation -> conversion to amyloid
□ The amyloid or IAPP (or both) lead to physical disruption of the β cell and insulin resistance, resulting in diabetes
Gestational diabetes how occurs in dogs
○ In dogs no evidence of placental effects rather progesterone stimulates mammary gland to produce increased growth hormone which can lead to insulin resistance
○ Glucocorticoids cause insulin resistance but also affect β cell function by direct cytotoxicity and reduce β cell secretion by interfering with incretin affect of GLP-1
Diabetes Mellitus in general what are the clinical signs and what do they include
Insidious and chronic
- Clinical signs include polyuria, polydipsia, bilateral cataracts, polypagia with loss of weightand weakness
- In severe cases vomiting and diabetic coma may occur and the untreated disease can be lethal.
○ Severe diabetes results in high levels of glucose in the urine and the excretion of ketone bodies, namely the salts of acetoacetic acid and beta hydroxybutyric acid.
What occurs in terms of glucose in the blood and tissues with diabetes mellitus and their levels and what occurs as a result
- Glucose deprivation of cells and tissues results in its accumulation in the blood -> decrease insulin or resistance to insulin so decreased transporters
○ In dogs and cats the normal fasting glucose concentration in blood is about 4mM.
○ In diabetic animals the blood glucose level can exceed 8mM; this is well over the renal threshold (about mM). - Its concentration exceeds the renal threshold (about 7mM) and it is excreted in high amounts leading to dehydration
□ Osmotic diuresis due to increase glucose in the blood resulting in increased water and volume of urine - Glucose absence from cells profoundly affects energy metabolism.
What are the 3 main things that occur in terms of metabolic failure in diabetes mellitus
1) Glycolysis cannot occur in muscle and other tissues due to absence of intracellular glucose
○ The level of all glycolytic intermediates including pyruvate and phosphoenolpyruvate fall below “safe” thresholds.
○ Glucagon, without antagonism or control stimulates both glycogenolysis and gluconeogenesis in liver and glycogen stocks are seriously depleted.
2) Fatty acid oxidation is increased.
3) Hormone sensitive lipase releases free fatty acids and glycerol from triglycerides.
○ Insulin inhibits this enzyme glucagon promotes.
§ The absence of insulin in the diabetic patient thus causes an increased exit to the blood of fats and they accumulate.
What are the 7 general acute effects of diabetes mellitus
- Hyperglycemia (elevated blood glucose levels) due to reduced uptake of glucose by cells and increased output of glucose from the liver.
- Glucosuria (glucose in urine) due to exceeding reabsorption capacity of kidneys.
- Osmotic diuresis. Glucose in urine associated with H2O and polyuria. —> dehydration
- —> peripheral circulatory failure due to reduced blood volume. - Circulatory failure can lead to low cerebral blood flow or secondary renal failure due to inadequate filtration pressure.
- Cell shrinking as extracellular fluid becomes hypertonic––>nervous system damage
- Lipolysis increases ––> Increased mobilization of fatty acids (as alternative energy source) & increased ketogenesis—->ketosis (excessive ketone bodies in blood).
- Ketone bodies include several different acids eg acetoacetic acid –––> metabolic acidosis–––> diabetic coma and death - Protein degradation –––> muscle wasting
Parathyroid hormone what is the stimulus for release and 4 functions
- Parathyroid hormone -> secreted when there is a decrease Ca2+ in the blood
- Function
1) Increase release of Ca from bone
2) Increase absorption from the GI tract
3) Increase reabsorption of Ca from the kidney
4) Decrease reabsorption of phosphorus from the kidney
What are the 4 main things calcium concentration is needed for and what is the normal limit calcium is maintained within
- Muscle contraction
- Nerve cell activity - nervous action potentials
- Intracellular signalling
- Enzyme activity
Serum total calcium concentration normally maintained within very narrow limits (~ 2.12 – 2.62 mM); of the total blood calcium concentration
What are the 3 types of calcium within the extracellular fluid with percentage and where is calcium found in the body (percentage)
3 types of calcium within extracellular fluid
1. ionised calcium (45%) is the biologically active portion
2. bound to albumin (45%)
3. complex with citrate or phosphate ions (10%)
• 99% calcium is in bones and teeth, and of remaining 1%, 0.9% is intracellular and 0.1% in extracellular fluid (ECF)
Calcium were absorbed, stores and excreted and what hormones are involved in that absorption and excretion
Calcium is absorbed from the digestive tract, stored in bone and excreted in urine.
○ Gastrointestinal absorption, release from bones and renal excretion are collectively controlled by three hormones:
1) Parathyroid hormone (parathyroid gland)
2) Calcitonin (thyroid gland)
3) Vitamin D (skin)
Parathyroid hormone what is the main function, type of hormone, where secreted and metabolised
Main hormone responsible for maintaining plasma Ca2+ concentration
• Peptide hormone (84 amino acids)
• Secreted by parathyroid gland and metabolised by liver and kidney (half-life about 5- 10 minutes in blood)
Parathyroid gland how many glands made of and where located in dog,cat, horse, cattle, pig and ruminants
Normally four glands (bilateral ‘internal’ and ‘external’ parathyroid glands).
○ Location is variable within species, but in general:
§ Internal glands:
□ Dog, cat and small ruminants - embedded within thyroid glands
□ Horse and cattle – close to thyroid gland
□ Pig – not present in adult
§ External glands (carried down neck by developing thymus):
□ Dog, cat – at cranial end of thyroid gland
□ Horse - close to thoracic inlet
□ Ruminants – between carotid bifurcations and thyroid glands
□ Pig – on surface of thymus at cranial end
What cells secrete parathyroid hormone and when occur
Secretory cells called chief (or principal) cells -> close contact of capillaries
○ Secretion of PTH under conditions of low Ca2+ concentration in ECF
○ ECF Ca2+ concentration sensed by calcium-sensing receptor (see below)
What are the 3 organs parathryoid hormone acts on, what type of effect and what occurs
1) Bone: DIRECT EFFECT
§ PTH causes release of calcium and phosphate (present in bone extracellular matrix in the form of hydroxyapatite) from bone through stimulation of osteoblast-mediated osteoclast differentiation and activity, i.e. bone resorption (induction of RANKL expression by osteoblasts)
2) Kidney: DIRECT EFFECT
§ PTH acts on distal convoluted tubules to increase calcium reabsorption and on proximal tubules to decrease phosphate reabsorption
§ PTH stimulates activation of vitamin D in kidney
3) Gastrointestinal tract: INDIRECT EFFECT
§ Through promotion of renal activation of vitamin D, stimulates absorption of calcium from gut
Calcitonin what is its function, what cells secreted by and how achieve function
• Opposes effect of PTH on calcium metabolism, but less important than PTH in overall regulation of calcium levels
• Peptide hormone
• Secreted by parafollicular (C cells) of thyroid gland - in between follicles of the thyroid gland
○ Secretion continuous but increased in response to high Ca2+ concentration in ECF, mediated by the calcium-sensing receptor
• Decreases blood Ca2+ (and phosphate) concentrations through inhibition of osteoclastic bone resorption (direct effect on calcitonin receptor on osteoclasts)
• Increases renal excretion of calcium and phosphate
Extracellular calcium-sensing receptor structure, what are the 2 activation pathways and what cells expressed in
7-transmembrane domain G-protein-coupled receptor family
Activates intracellular signalling through multiple pathways including:
1. Activation of phospholipase C, leading to generation of diacylglycerol and inositol triphosphate
2. Inhibition of adenylate cyclase, thus reducing intracellular concentrations of cyclic AMP
• Expressed by parathyroid gland chief cells, thyroid gland C cells and several cell types in kidney (among others)
○ In kidney contributes to regulation of calcium re-absorption
Vitamin D what does it do, where produced and how activated
- Activated vitamin D stimulates calcium absorption in the intestine
- produced in the skin from a cholesterol-related precursor in response to sunlight
- PTH is needed to activate Vit D
What are the 4 main functions of activated vitamin D
1) stimulates both forms of calcium absorption in the intestine:
1. Active transcellular, mainly in the duodenum
2. Diffusional or paracellular (across tight junctions and intercellular spaces between neighbouring intestinal epithelial cells), throughout intestine
2) enhances intestinal phosphorus absorption
3) enhances calcium reabsorption in distal renal tubules, partly through increasing expression of the PTH receptor
4) enhances osteoclast differentiation and activity
