1
Q
what is the main fuel source for the brain and what is the issue when this is at low levels
A
- 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.
2
Q
What results from the fed state and what are the 3 things fasting results in
A
- 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
3
Q
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
A
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
4
Q
What are the 3 main hormones involved in regulating feeding, where produced and their role
A
Insulin (pancreas) & leptin (produced by stomach and pancreas) supresses hunger, ghrehlin (produced by adipose tissue) increases hunger by acting on hypothalamus
5
Q
Pancreas what is it, where located and function/structure
A
- 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)
6
Q
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
A
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.
7
Q
What is the structure of insulin, is it similar between species and what shapes can insulin take and therefore biological characteristics
A
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.
8
Q
how is measuring C-protein useful in determining insulin levels
A
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.
9
Q
What are the 4 steps in the biosynthesis of insulin
A
- 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.
10
Q
What are the positive and negative stimuli for the secretion of insulin
A
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
11
Q
What are the 4 steps in the release of insulin from the pancreas
A
- 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.
12
Q
what is the stimulus for the release of glucagon
A
- 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.
13
Q
Insulin, where secreted to, what are the target cells and the 2 steps in the pathway once bound to the target cells
A
- 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
14
Q
Insulin what is its activity in the muscle and liver
A
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
15
Q
Insulin what is its activity in adipose tissue and in what state
A
- 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
16
Q
Glucagon what is the main function, how binds to cells and 2 main functions within
A
- 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.
17
Q
What is diabetes mellitus, some general causes and how best described functionally
A
- 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
18
Q
List and describe the 4 types of diabetes mellitus
A
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.
19
Q
Type 1 DM what are the 3 main different types of causes
A
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
20
Q
Type 1 DM which species most common in, what is it most commonly characterised by and treatment
A
- 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
21
Q
Type 2 DM what occurs, what may progress to and which species most common in
A
- 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
22
Q
What are the 2 main aspects of Type 2 DM and caused by
A
- 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.
23
Q
Amyloidosis in cats what caused by and what lead to
A
□ 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
24
Q
Gestational diabetes how occurs in dogs
A
○ 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
25
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.
26
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.
27
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.
28
What are the 7 general acute effects of diabetes mellitus
1. Hyperglycemia (elevated blood glucose levels) due to reduced uptake of glucose by cells and increased output of glucose from the liver.
2. Glucosuria (glucose in urine) due to exceeding reabsorption capacity of kidneys.
3. Osmotic diuresis. Glucose in urine associated with H2O and polyuria. ---> dehydration
- ---> peripheral circulatory failure due to reduced blood volume.
4. Circulatory failure can lead to low cerebral blood flow or secondary renal failure due to inadequate filtration pressure.
5. Cell shrinking as extracellular fluid becomes hypertonic––>nervous system damage
6. 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
7. Protein degradation –––> muscle wasting
29
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
30
What are the 4 main things calcium concentration is needed for and what is the normal limit calcium is maintained within
1. Muscle contraction
2. Nerve cell activity - nervous action potentials
3. Intracellular signalling
4. Enzyme activity
Serum total calcium concentration normally maintained within very narrow limits (~ 2.12 – 2.62 mM); of the total blood calcium concentration
31
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)
32
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)
33
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)
34
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
35
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)
36
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
37
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
38
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
39
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
40
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
41
How is the increase in demand for calcium in egg-laying birds fulfilled
Medullary bone:
○ bone tissue formed on endosteal surface of medullary cavity of bones of female birds prior to and during egg-laying in response to sex steroid hormones
○ provides calcium reservoir to be mobilised for shell formation
○ mostly trabecular woven bone with large surface area and higher abundance of osteoclasts than present in cortical bone
42
How is the increased demand for calcium during lactation in a cow fulfilled
* High concentration of calcium in milk causes lowered Ca2+ concentration in plasma, which is detected by calcium-sensing receptor in parathyroid glands, leading to secretion of PTH
* PTH causes normalisation of plasma Ca2+ concentration through its actions on bone (increased resorption) and kidney (increased calcium reabsorption and increased activation of vitamin D, leading to increased calcium absorption from gut)
* There is still net loss of calcium from the bone
43
Secondary hyperparathyroidism (PTH hypersecretion) what caused by, what are the 2 situations it occurs and what are the 4 things it leads to
• Excess secretion of PTH due to low ECF calcium concentrations
• Occurs in domestic animals with:
1. calcium-poor diet (e.g. an all meat diet in carnivores)
2. chronic kidney disease (increased calcium diuresis and retention of phosphates)
• Leads to:
○ Reduced excitability of muscle and nervous tissue, leading to muscle weakness and neurological disorders
○ Excessive mobilisation of calcium and phosphate from the skeleton leads to osteopenia and increased fracture risk
○ Soft tissue mineralisation
○ Kidney stones due to precipitation of excess quantities of calcium being filtered through the kidney
44
Parturient paresis (milk fever, parturient hypocalcaemia) when and how occurs, what can lead to in cattle and dogs
Occurs in high-producing dairy cows a few days after parturition
○ Following parturition, calcium demand increases markedly due to lactation, while calcium intake is decreased due to inappetence and post-partum gastrointestinal stasis -> PTH unable to respond rapidly to changes in calcium supply and demand -> Hypocalcaemia develops
○ If untreated leads to recumbency "downer cow", coma and death
• Hypocalcaemia in dogs occurs 1-2 weeks after parturition when heavily lactating
○ Manifest as involuntary muscle spasms and contractions of groups of muscles (tetany or eclampsia)
45
What are the 8 steps in the metabolism of fat
1) Digested from GI tract (small intestine)
2) Epithelial cells converted to triglyceride
3) Form chylomicrons (triglycerides carried in the blood)
4) Most Is taken up in the liver
5) LPL (lipoprotein lipase) break downs
6) Liver use for energy or repackaged for redistribution
7) VLDL (very low density lipoprotein) what triglycerides placed within
8) LPL breaks down triglycerides to fatty acid at cells or skeletal muscle as triglycerides cannot cross the membrane
46
What occurs when you need to use stored fat
1) Lipolysis (hormone sensitive lipase) drives the break down triglycerides into fatty acids
2) Fatty acids bound as NEFA (non-esterified fatty acids) in the blood
3) Back to the liver
a. Ketone bodies
b. Beta oxidation
c. Redistribution to other areas of the body again
47
What are the 4 adipose-derived hormones and action
1. Leptin
- Informs the brain of levels of stored fat
○ Animal aware of the metabolic state
- Higher amount of fat more release of leptin
- Decreases appetite
2. Adiponectin
- enhances insulin sensitivity
3. Apelin
- inhibits glucose-induced insulin secretion
4. Visfatin
- expressed in visceral fat, levels correlate with obesity
48
Leptin what is the main function, where play important role, what occurs with low levels or resistance
control of appetite and feed intake
eptin plays an important role in satiety:
○ Lack of appetite when in high levels
○ If high amount of fat stores then activates reproduction and cycling, also growth
- Leptin deficient animals show ravenous feeding behaviour and develop extreme obesity.
- Obesity may be associated with leptin resistance (high level of leptin but still have large appetite)
49
Obesity define, how common in dogs, cats and horses and what can it be characterised as
considered to be present when bodyweight exceeds optimum weight for body size by at least 15%, or the animal reaches a body condition score of 4 or 5 out of 5.
Dog - 50%
Cat - 40%
Horse - 45%
OBESITY CAN BE PRO-INFLAMMATION
- Chronic low-grade inflammatory conditions
50
What are the 4 main causes of obesity and how occur
1. Dietary carbohydrate intake:
- When blood glucose is high, the metabolism shifts towards storing energy
- Important roles of insulin and glucagon
2. Leptin resistance:
- Leptin deficient animals have ravenous appetites and become rapidly obese;
- however, most obese animals have high plasma leptin concentrations.
- In this situation, hypothalamus may be less responsive
3. Neutering:
- loss of circulating sex hormones following spaying of female dogs
- slows the metabolism,
- Energy requirements ~ 20% lower after ovariectomy
4. Many other factors:
- high fat diets,
- environment,
- Breed disposition and genetic polymorphisms
51
List 9 general consequences of obesity and the 3 diseases it can be associated with
1. Reduced lifespan
2. Osteoarthritis –increased weight bearing on joints; wear and tear.
3. Exercise intolerance
4. Tracheal collapse
5. Urethral sphincter mechanism incompetence
6. Hyperlipidaemia
7. Mammary neoplasia
8. Heat intolerance
9. Increased anaesthetic risk
Diseases
- Diabetes mellitus
-Hyperadrenocorticism (increases severity)
- Hypothyroidism (affects thyroid homeostasis)
52
How is obesity related to insulin resistance
- Decreased number of insulin receptors and post-receptor failure to activate tyrosine kinase.
- Other factors: inflammatory cytokines (TNF, resistin); fatty acids.
- Insulin resistance also in fat cells
○ Excess insulin production
○ Eventually the pancreas may become exhausted and type II diabetes mellitus may result.
§ Insulin resistance in this case can be reversed
53
Equine metabolic syndrome (EMS) what are the 2 things involved, what lead to, what are some risk factors
- Insulin resistance + obesity = predisposition to laminitis
- Esp ponies and some breeds of horses
○ Different have different metabolism in terms of insulin levels
- Grazing on lush grass (high sugar content) can result in very high plasma insulin levels.
○ All of these factors may contribute a risk for acute laminitis.
54
What are 3 ways to prevent obesity
1. Caloric restriction and especially diets with a low glycaemic index - most important
2. Low blood sugar levels encourage metabolic pathways that burn fat because low blood sugar decreases insulin levels and increases levels of glucagon
3. Exercise –promotes ‘burning’ of fat, also increases the number and efficiency of mitochondria
55
Hyperlipidaemia in dogs what is the clinical significance, what clinical signs, what caused by and the 2 mecahnisms
- Linked with causing pancreatitis and diabetes mellitus
- (If severe) hypertriglyceridaemia may cause abdominal pain, vomiting and diarrhoea, hepatomegaly and siezures
- Increased plasma triglycerides (>150 mg/dl) and/or cholesterol (>300 mg/dl)
1. Primary (min schnauzers)
2. Or secondary to various conditions, including endocrine diseases:
○ diabetes mellitus;
○ hyperadrenocorticism;
○ hypothyroidism
56
What are the 3 mechanisms involved with secondary hyperlipidaemia in dogs and how cause that
• Diabetes mellitus:
- lack of insulin stimulation of lipoprotein lipase
• Hyperadrenocorticism:
- Cortical inhibiting insulin actions -> insulin resistance, also downregulation of LDL receptors and decreased liver uptake of LDL
• Hypothyroidism:
- thyroxine may enhance lipoprotein lipase and increase fatty acid consumption by the liver
57
Hyperlipaemia in ponies and donkeys, what can lead to, what caused by
- May even be fatal
- Initiated by negative energy balance in obese individuals, sometimes in pregnant or nursing mares.
○ Could be from starving the animal of proper feed
- Insulin resistance is the other key factor:
○ ponies / donkeys are insulin resistant vs large breeds obesity and increased cortisol levels exacerbate
58
How can physiological stress (illness or surgery) lead to hyperlipaemia
causes cortisol and catecholamine levels to rise, upregulating HSL activity and lipolysis.
-> Excessive NEFA levels overwhelm the liver’s capacity to process
○ (limited ability to convert fatty acids into ketone bodies in the horse therefore pack up into triglycerides into the blood to the vital organs -> liver or kidney -> liver or kidney failure
-> Triglyceride levels build in the liver and blood -> HYPERLIPAEMIA
59
What are the 5 main consequences of negative energy balance in obese individuals
1. Metabolic rate slows to decrease the consumption of glucose.
2. Glucagon secretion increases and insulin secretion decreases.
3. Gluconeogenesis, glycogenolysis and peripheral lipolysis
4. Shift towards using fatty acids as a primary energy source - overwhelming release of fatty acids
5. Release of leptin is also increased.
60
How to treat hyperlipaemia
- Correction of negative energy balance
○ high carbohydrate feeds
- Parenteral nutrition may be required.
- Insulin therapy
○ insulin will both suppress HSL activity and activate LPL.
- Heparin
○ stimulates LPL activity and promote peripheral triglyceride use.
61
What are the 3 types of hyperparathyroidiism
1) primary -> uncommon to rare
2) renal secondary
3) nutritional secondary
62
Primary Hyperparathyroidism what caused by, clinical signs, 3 main electrolyte findings and how to diagnose
○ typically a parathyroid gland adenoma
§ autonomous secretion of PTH results in marked hypercalcaemia
- Dogs may be well or present with PU/PD, anorexia, urinary tract signs
- Lab findings: ↑Ca, ↑ i(ionised)Ca, ↓Phos
○ PTH should drop with high iCa - Diagnosis:
○ rule out other causes of hypercalcaemia
○ PTH assay with concurrent iCa - is PTH appropriate with levels of iCa
§ If high iCa then should be decreased PTH so even if normal levels this is "inappropriately" high
□ PTH is increased (25%)
□ or PTH normal but inappropriate for Ca level (75%)
63
Renal Secondary Hyperparathyroidism what is the main cause, what electrolyte imbalances seen and clinical signs
```
Chronic kidney disease
↑Phos ↓iCa and ↓vitD activation
↑ PTH
↑ bone Ca resorption
→Fibrous osteodystrophy - rubbery jaws
↑renal Ca reabsorption
Dx: clinical signs, azotaemia, ↑Phos and ↑ PTH (not currently available in Australia)
```
64
Nutritional Secondary Hyperparathyroidism what caused by, clinical signs and calcium levels
- Diets with low Ca:Phos ratio or high in oxalates (bind calcium so not available for absorption)
- Shifting lameness (osteopenia and pathologic fractures)
- thickened facial bones (“big head”)
- Dx: diet, clinical signs, ↑ PTH
- Calcium levels usually normal
65
what are the 4 differentials for Hypercalcaemia and the mnemonic used to remember
- Hyperparathyroidism
- Addisons(dogs)
- Renal failure (esphorses)
- D vitamin D toxicosis
- Idiopathic (cats)
- Osteolysis - tumours, infection in the bone
- Neoplasia - MOST COMMON IN CATS AND DOGS
- Spurious - second most common
HARD IONS
66
Hypercalcaemia of malignancy what also called, what usually caused by, 3 main electrolyte imbalances and diagnoses
- Also called pseudohyperparathyroidism paraneoplastic hypercalcaemia - secondary from tumour
- Usually caused by tumour secretion of PTH-related Protein (PTHrP)
- Common tumours: lymphoma, adenocarcinoma of anal sac, multiple myeloma, squamous cell carcinoma, mammary carcinomas
- Lab findings: ↑Ca, ↑ iCa, ↓Phos
- Diagnosis: ↑PTHrP (labile) - require special collection and storage
○ PTH very low - negative feedback from high calcium
67
Hypercalcaemia what is the most common clinical sign and 3 reasons why this occurs
PU/PD
1) Impaired renal tubular response to ADH - most potent effect
○ results in a lack of Aquaporin2 water channel expression in renal collecting ducts
2) Reduced renal tubular Na reabsorption
○ resulting in osmotic diuresis & lack of medullary concentration gradient
3) Renal damage
○ metastatic mineralisation
68
Hypoparathyroidism how common, what are the 2 types and what caused by, clinical signs and calcium and phosphate levels
- Rare
1) Absolute deficiency of PTH
- iatrogenic (thyroidectomy), lymphocytic-plasmacytic parathyroiditis (presumed autoimmune parathyroid destruction)
2) Functional deficiency of PTH
○ secondary to severe hypomagnesaemia
- Clinical signs reflect marked hypocalcaemia:
○ seizures, muscle tremors, rear leg cramping, restless, aggressive, hypersensitive, weight loss, inactivity
- Lab findings: ↓Ca, ↓iCa, ↑Phos
69
What are the 7 most common causes of hypocalcemia and 2 less common causes
1. Hypoalbuminaemia (all species) - MOST COMMON
2. Spurious (EDTA contamination - EDTA binds calcium (clotting))
3. Renal disease (dogs and cats)
4. Pancreatitis - more common in dogs
5. Milk fever or eclampsia
6. Ethylene glycol toxicity
7. Enteritis (esp horses)
Less common
1) hypoparathyroidism
2) sepsis (foal)
70
Pancreatitis cause hypocalacemia pathogenesis, and what level is the hypocalcaemia
- Multifactorial pathogenesis
○ Binding of calcium to fatty acids in mesentery “saponification”
○ Hormone dysregulation (amylin, glucagon, calcitonin, PTH (via hypoMg) - Magnesium is important in making PTH
○ Hypoproteinaemia
- Hypocalcaemia often mild and subclinical
○ concurrent metabolic acidosis increases ionised fraction of Ca (active form)
71
Hypocalcaemia with ethylene glycol toxicity how common in australia and how occurs
not common in Australia
- Metabolism by kidneys generates toxic metabolites
○ glycolic acid and oxalate
- Acute tubular necrosis
○ azotaemia, isosthenuria, ↑Phos
- Metabolic acidosis
- Calcium is chelated by oxalate metabolites:
72
What are the 2 main endocrine diseases of beta cells, and 1 of alpha, G and beta cells
```
β-cells
- Diabetes mellitus
- Insulinoma
α-cells –Glucagonoma(rare)
G cells –Gastrinoma(rare)
δ cells –Somatostatinoma(very rare)
```
73
What are the 3 main diagnostic tests for diabetes mellitus and what do they measure
1. Routine biochemistry tests
- Glucose
- Betahydroxybutyrate (BOHB) - ketone within the blood
2. Urinalysis
- Glucosuria
- Ketonuria
3. Evaluation of longer term glucose control
- Fructosamine - common for animals
- Glycosylated haemoglobin
- Glycated albumin
74
What are 8 differentials for hyperglycaemia
1. Diabetes mellitus
2. Stress hyperglycaemia(cortisol) - especially in cats
3. Sepsis (can also cause hypoglycaemia) - any change in glucose
4. Hyperadrenocorticism
5. Hyperthyroidism
6. Drug Rx
7. BVD in cattle
8. Glucagonoma(rare)
75
Betahydroxybutyrate (BOHB) when get elevation
- Elevation of serum BOHB with ketoacidoticdiabetes mellitus, acute pancreatitis
76
Urine glucose what filtered by, reabsorbed by how get increased levels and the normal renal thresholds for dog, cat, horse and cow
- Filtered by glomerulus then resorbed by tubule
- Hyperglycaemia exceeding renal threshold causes glucosuria
- Renal glucosuriacan also occur with tubular disease (normo glycaemic)
- Normal renal thresholds for Glucose:
~ 10 mmol/L in dogs,
~ 15 mmol/L in cats
~ 9 mmol/L in horses,
~ 5 mmol/L in cows
77
Urine ketones where filtered, what is detected on dipstick and what is important about this detection
- Freely filtered by glomerulus
- Detects: acetone, acetoaceticacid NOT BOHB
- Dipstick does not measure β-hydroxybutyrate (major intermediate in ketosis)
- Ketonuria often precedes ketonaemia - may not see rise in BOHB at this point but see increase acetone in urine
78
Fructosamine what is it, what is it used for, when increased and give 6 examples of when levels are lower and therefore can mask an increase
- Glycosylated protein - accumulates when glucose levels are high over time
- Distinguishes transient hyperglycaemia (stress) from diabetes mellitus
- Useful to monitor control of diabetes mellitus
○ Has glucose been maintained at high level for an extended period of time
- Increased with persistence of hyperglycaemia for 1-4 weeks - IMPORTANT
- Mild increase in fructosamineis seen with hypothyroidism
- Levels are lower with: - mask hyperglycaemia
1) Hyperthyroidism in cats (increased protein catabolism)
2) Insulinoma(persistent hypoglycaemia)
3) Hypoproteinaemia
4) Lean cats vs normal or obese cats
5) Female cats than male cats
6) Dogs with hyperlipidaemia or azotaemia
79
Glycosylated haemoglobin and glycosylated albumin what used for, what does elevated levels indicate, how common
Diagnostic tests for Diabetes mellitus
Haemoglobin
- Elevated levels indicate persistence of hyperglycaemia for 4-6 weeks
- Uncommon veterinary use, common use in people
Albumin
- Elevated levels indicate persistence of hyperglycaemia for 1-3 weeks
- Not in common veterinary use
80
What is a common cause of insulin resistance in dogs and treatment
Hyperadrenocorticism
- Common concurrent disease with diabetes mellitus (10-22% of hyperA cases)
Glucocorticoid or progestogen therapy
81
what are 2 common causes of insulin resistance in cats with clinical signs and treatment
1) Hypersomatotropism
- Clinical signs: pu/pd, polyphagia, weight gain, enlarged kidneys and liver, broad facial features and prognathiainferior, clubbed paws
- insulin resistant diabetes mellitus
- Common in diabetic cats (prevalence 25% in UK)
2) Hyperadrenocorticism (Rare)
- Clinical signs: pu/pd, weight loss with muscle wasting, thin fragile skin, hepatomegaly, coat colour change
- Insulin resistant diabetes mellitus in 80-90% of cases
Glucorticoid or progesterone therapy
82
What are the 2 causes of insulin resistance in horses and what caused by, leads to
1) equine metablic syndrome
- Regional or generalised obesity
- Hyperinsulinaemiaand insulin resistance (hypertriglyceridaemia)
- Laminitis
2) Pituitary pars intermedia dysfunction (PPID)
- Laminitis
- Muscle wastage
- Regional hypertrichosis
- Polyuria and polydipsia
- Abnormal sweating
83
List 7 differentials for hypoglycaemia
1. Insulinoma
2. Other Neoplasia
3. Liver disease
4. Sepsis
5. Hypoadrenocorticism
6. Sample storage artefact
7. Neonatal or juvenile hypoglycaemia
84
Insulinoma what is it, how common, are they functional, metastasis
- Neoplasm of islet βcells
- Uncommon in dogs, usually medium to large breeds
- Rare in cats
- 60-70% are functional
- Weakness, ataxia, tremors, seizures
- High rate of metastasis to liver and lymph nodes (30-50%)
85
Gastrinoma what is it, what result in and metastasis rates
- Non-βcell islet cell tumour
- Results in gastric acid hypersecretionand ulceration (Zollinger-Ellison syndrome)
- High rate of metastasis (>75%)
86
Thyroid gland where situated in the body, what is the functional unit, what composed of and another cell type what secrete
- The thyroid is usually bilobed and is situated in the neck, caudal to the larynx and adjacent to trachea. In all domestic mammals other than the pig it consists of left and right lobes that are connected caudally by connective tissue strand-isthmus extending on the ventral side of the trachea
- The functional unit of the thyroid gland is the follicle, which is composed of epithelial cells.
○ The follicle is filled with a glycoprotein colloid called thyroglobulin where thyroid hormones are stored.
- Parafollicular C-cells are also present in the thyroid and they secrete calcitonin.
87
What are the 3 different thyroid hormones and their structure and general function
○ Thyroxine (T4), contains four atoms of iodine two atoms on each of its phenolic rings.
○ Triiodothyronine (T3) has three atoms two on the A ring but only one on the outer, or B, ring
§ 10 times more potent than thyroxine -> higher biological functions
○ Reverse T3 (rT3) has two iodine's on the B ring and one on the A ring and although devoid of biological activity, it is nevertheless important as a major metabolite of T4 -> if converted to in the tissues -> switches off thyroid hormone
88
What are the 10 steps in the biosynthesis of thyroid hormones
1. Iodide from the diet is transported and concentrated in the follicular cells of the thyroid by a Na/I cotransporter
2. Iodine is transported to the - follicular lumen from the cytoplasm by the transporter pendrin
3. Thyroid peroxidase converts Iodide (I-)--> Iodine (Io) and facilitates conjugation. .
4. Thyroid hormones are partially synthesised and stored extracellularly in the follicular lumen.
5. Organification: Addition of iodine molecules to tyrosine within thyroglobulin , occurs at the luminal surface of follicular cells.
○ The initial products formed are monoidotyrosine (MIT) and diiodotyrosine (DIT).
6. Conjugation occurs through a folding process, involving an oxidative step, whereby MIT and DIT are coupled to form T3 and T4
7. Thyroid hormones are stored extracellularly in the follicular lumen as part of the thyroglobulin molecule.
8. Following TSH (thyroid stimulating hormone) stimulation large thyrogobulin molecule is taken into the follicular cells by endocytosis.
9. Endocytic vesicle fuses with a lysosome to from a phagolysosome.
○ Proteolysis digests thyroglobulin releasing free MIT, DIT, T3 and T4.
10. Free T4 and T3 are transported out of the follicular cell into the bloodstream via MCT monocarboxylate transporters
89
How does TSH lead to the release of TSH
Thyrotrophin releasing hormone (TRH) which is synthesized and released by the hypothalamus.
○ TRH blinds to specific receptors on the surface of thyrotropes (cell within the anterior pituitary) and activates phospholipase C, which cleaves phosphatidylinositol 3,4-bisphosphate into IP3 and diacylglycerol (DAG) and induces secretion of TSH
90
TSH how does it promote the production of thyroxine
○ Increases activity Na/I transporter -> increases thyroxine production
○ Stimulates activity of thyroid peroxidase -> allow more T3 and T4 to be placed on thyroglobulin molecule
○ Stimulates iodination and conjugation of thyroid hormones
○ Stimulates endocytosis of iodinates thyroglobulin
○ Stimulates proteolysis of iodinated thyroglobulin
○ Induces follicular cell hyperplasia -> increase in size and the number of follicular cells
91
What regulates the levels of thyroid hormone secretion
1) T4 and T3 has negative feedback
1. act to inhibit secretion of TSH
2. thyrotropes (in anterior pituiatry) to decrease receptor sensitivity to TRH
3. decrease the secretion of TRH
Additional factors
1) Iodide at low levels stimulates growth of the thyroid gland whereas at high levels, inhibits thyroid hormone production
2) eating (excess calories) ---> increased (T3) -> more substrates for fuel present so want to use it
3) exposure to cold stimulates thryoid hormone secretion -> increase basal metabolic rate
4) stress such as starvation or prolonged fasting can result in decreased secretion -> don't have enough substrates to run metabolism
92
how is thyroid hormone present in the plasma, which thyroid hormone is more biologically active and how is T4 converted to T3
- more than 99% of thyroid hormone circulating in blood is bound mainly to a plasma protein thyroid binding globulin (TBG)
- T3 is the more
T4 - T3
- biologically active
activation/production of 5’ deiodinase (enzymes) to form T3 (Active form) and a 5 deiodinase to form inactive rT3 (inactive form) -> depends on the stimulus to whether active or inactive
93
What does active T3 do and the 4 types of receptors and why expressed
Binding of T3 to thyroid hormone receptor (TRH) induces conformational change & removes a co-repressor complex (replaced by a coactivator) on the DNA which activates transcription
○ Receptors are present in two places in the mitochondria and nucleus
Four different THR exist a1 a2 b1 b2 - differentially expressed
○ alpha-1 is the first isoform expressed in the foetus, and there is a profound increase in expression of beta receptors in brain, liver , kidney and heart shortly after birth.
Beta-1 gets switched on after birth
94
What is the main action of thyroid hormones and the 5 actions
increase the basal metabolic rate
1) calorigenic effect - increase ATP production
2) stimulating synthesis of new proteins in the cell
3) increase the responsiveness of target cells to adrenaline and noradrenaline,
4) increased secretion of other hormones due to increased metabolic requirements (eg - growth hormone)
5) Increases cardiac output by increasing heart rate and force of contractions
95
Hypothyroidism what are the 3 different causes
1) Primary hypothyroidism.
○ Primary failure of the thyroid gland (95% of cases ) Majority due to immune mediated destruction of the thyroid. Autoantibodies against thyroglobulin (occassionally against thyroid hormones) and lymphocytic thyroiditis as well as thyroid atrophy
2) Secondary hypothyroidism
○ Deficiency of TRH &/or TSH due to trauma, neoplasia, cyst formation and congenital disease
3) Inadequate dietary supply of iodine
○ Natural atropy of thyroid (idiopathic)
○ Iatrogenic eg surgery, antithyroid medications, radioactive thyroid treatment
96
What are 6 main clinical signs of hypothyroidism
1) hair loss (alopecia) -> often start at the tail leading to "rat tail": apperance
2) obesity - reduced metabolic rate
3) anaemic
4) lethargic or listless - reduced metabolic rate
5) brittle or dry coat
6) cold intolerance - reduced metabolic rate
97
What age is hypothyroidism common in and heritability
develops in middle aged or elderly dogs.
○ Breeds with definite predisposition to develop hypothyroidism include: the Doberman pinscher, the Golden retriever, the Irish Setter, the Great Dane, the Dachshund, and the Boxer.
98
What are the 4 main ways of testing for hypothyroidism and treatment
1. Serum total T4 (snap T4 test kit)
2. Free T4 measured by equilibrium dialysis
3. TSH concentrations
4. TSH/TRH response test (measurement of T4 after administration)
Treatment
- T4 replacement (thyroxine oral replacement) or iodine
99
Hyperthyroidism what also known as, most common in what species and age, what generally caused by
- Also known as thyroidtoxicosis.
- Most common endocrine disorder in cats, average age of onset 12-13 years.
- Excess circulation of T3 & T4 usually caused by a thyroid tumour (benign adenoma)
100
What are 7 clinical signs of hyperthyroidism
1) Poor tolerance to heat & excessive perspiration (Elevated basal rate increased heat production).
2) Loss of body weight despite polyphagia (increased metabolic demands)
3) Weakness (loss of skeletal muscle protein)
4) Polydipsia/polyuria (renal perfusion enhanced by circulatory dynamics)
5) Skin changes eg alopecia (related to heat intolerance)
6) Goiter an enlarged thyroid gland is usually palpable
7) hypermotility, vomiting
101
What are 4 treatments for hyperthyroidism, advantages and disadvantages
1) Surgery
○ Disadvantages: anaesthetic, local injury, loss of parathyroid function, miss affected tissue
2) administration of radioactive thyroid,
3) thioureylene anti-thyroid drugs eg. methimazole & carbimazole (inhibition of thyroid peroxidase catalysed reactions), thiouracils (stops coupling of iodide to thyroglobulin)
○ Advantage: -> inexpensive, effects gradual and reversible, pre surgery stabilisation
○ Disadvantage: -> administration, ongoing monitoring, side effects
4) Iodide deficient diet -> Hill diet
DVM 2 - 2
flashcards
Decks in class (27)
# Cards
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Nervous 199
-
RAD pictures 1101
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Nervous/Endocrine define77
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Parasitology NEM99
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Parasitology names103
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Nervous 296
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Nervous 3102
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Nervous 448
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Parasitology TREM56
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Repro 199
-
Repro 2106
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Repro 394
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EPI 1.099
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EPI 269
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AHPS - extra34
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Endocrine 1102
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Endocrine 2101
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Endocrine 346
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Parasitology names 277
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Parasitology CEST55
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Parasitology PROTIST98
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Parasitology PROTIST 251
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Para HOST/LOCATION37
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Repro 491
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Repro 596
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Repro 647
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RAD 140
