TBL4 Pancreas Flashcards
Insulin has 2 categories of action
- Metabolic
2. Mitogenic (growth and development)
What general effects does insulin have on glucose, protein and lipid metabolism?
- Decrease glucose output
- Decrease proteolysis
- Decrease lipolysis
=> Overall, insulin has anabolic effects.
Glucose is stored in _______ and ________ as glycogen.
Liver and muscle cells
Insulin stimulates ________ to be recruited to the plasma membrane to allow extracellular glucose to be taken up by the cell via its hydrophilic pore.
GLUT-4 transporter
- particularly muscles and adipose tissue
- increases uptake of glucose into cells to decrease blood glucose levels
Muscle cells contain a large amount of _______.
proteins
Insulin effects on muscle cells:
- Inhibits proteolysis
- Inhibits oxidation of amino acids
- Stimulates protein synthesis (stimulate transport of AA into the muscles)
- Increase GLUT-4 to increase uptake of glucose into muscle cells
Insulin effects on hepatocytes:
- Inhibits gluconeogenesis
- Stimulates glycogenesis
- Increased protein synthesis
Insulin effects on adipocytes:
- Activates (enzyme) to breakdown triglycerides in the blood to glycerol and NEFA
- Activates endothelial lipoprotein lipase to breakdown triglycerides into NEFA and glycerol
- Increased glucose uptake by GLUT-4
- Inhibits lipolysis
- Stimulates combination of glycerol and NEFA back into triglycerides
_______ is a good measure of CV risk.
Waist circumference
- adipocytes in the gut are more metabolically active as their products drain into the liver directly
- omental circulation
The brain can only utilise ______ and ______ as energy substrates.
glucose and ketones
cannot use fatty acids!
Ketogenesis occurs in the ________. It is (stimulated/inhibited) by insulin.
Ketogenesis
- occurs in liver cells
- inhibited by insulin (in the fed state, no need for ketones as energy substrates)
Ketone bodies released from the liver cells include
FA –> acyl-CoA –> acetyl-CoA –> acetone and 3-hydroxybutyrate
Fasted state:
- (Low/High) insulin to glucagon ratio
- (Decreased/Increased) concentration of fatty acids
- (Decreased/increased) concentration of amino acids
- (Decreased/increased) proteolysis, lipolysis and hepatic glucose output from __________ and _________
- (increased/decreased) ketogenesis when fasting is prolonged
Fasted state:
- Low insulin to glucagon ratio
- Increased fatty acids due to lipolysis
- Decreased amino acid concentration when prolonged due to gluconeogenesis
- Increased proteolysis, lipolysis and hepatic glucose output from gluconeogenesis and glycogenolysis
- increased ketogenesis when prolonged fasting
________ DM is characterised by absolute insulin deficiency.
Type 1 DM
- autoimmune destruction of B cells
- leading to increased hepatic glucose output, proteolysis and lipolysis, ketone output
=> continued release of nutrients even in the fed state
In a hypoglycemic event due to insulin, hepatic glucose output is switched off, and patients may be treated with
oral glucose
or
intramuscular glucagon (to mobilise glycogen stores)
_______ DM is characterised by insulin resistance and a relative insulin deficiency.
Type 2
Biochemical pathways of insulin
- Mitogenic
- Metabolic
- Mitogenic: Ras-MAPK pathway (cellular proliferation and growth)
- Metabolic: PI3K-Akt pathway (insulin resistance)
In type 2 DM, the growth pathway becomes amplified due to ___________.
compensatory hyperinsulinaemia
- pancreas responds to the high blood glucose by producing more insulin to allow to glucose to remain normal for many years
________ occurs in type 2 DM due to changes in the lipid metabolism that results from amplified mitogenic pathway.
Dyslipidaemia
- low HDL, high LDL
- risk factor for many macrovascular complications
What is the gastrointestinal incretin effect?
- demonstrated by differences between response to oral and intravenous glucose
- higher insulin response to oral glucose which passes through the gut due to GLP-1 secreted by the gut to stimulate insulin and suppress glucagon.
____________ (PPARy agonists) target the hormone response element within DNA and act as insulin sensitisers in peripheral tissues.
Thiazolidinediones
DPPG-4 inhibitors, also known as _______, can be used to treat DM by preventing the degradation of GLP-1 by DPPG-4.
Gliptins
_______ is the only hormone that decreases blood glucose.
Insulin
Hormones that increase blood glucose
Glucagon, somatotrophin (growth hormones), stress hormones (e.g. cortisol, adrenaline)
Most cells produce ________ secretions which travel via the pancreatic ducts to the small intestine.
exocrine secretions (pancreatic enzymes)
___________ of the pancreas secrete hormones (endocrine) directly into the bloodstream to control blood glucose.
islets of Langerhans
3 types of cells in the islets of Langerhans and its relative positions:
- a-cells secreting glucagon (at the peripheries)
- B-cells secreting insulin (at the middle)
- d-cells secreting somatostatin (scattered)
Cell junctions present between cells in the islets of Langerhans
- Gap junctions
- small molecules to pass directly between cells - Tight junctions
- form small intercellular spaces which trap fluid to allow hormones to be accumulated in high concentrations
Insulin is synthesised as ________. In the (organelle), the linking C-peptide is cleaved, resulting in the insulin made of A and B chain linked by 2 _______.
Insulin:
- synthesised as proinsulin
- in the GA, C-peptide is cleaved and insulin is released as A chain and B chain linked by 2 disulphide bridges.
B-cells have ______ transporters present on the cell surface to allow glucose to move down its concentration gradient into the cell.
GLUT-2 transporter
Insulin production by B-cells:
- Glucose enters the B-cell via _____ transporters.
- (Enzyme) converts glucose to glucose-6-phosphate.
- Glucose-6-phosphate participates in metabolic pathways to produce ____.
- ____ deactivates the K+ channel, preventing K+ efflux from the cell, resulting in depolarisation of cell membrane.
- The depolarisation activates and opens voltage-gated ___ channels, which allows ___ ion influx to stimulate migration of insulin-containing vesicles to the membrane.
Insulin production:
- Glucose enters cell by GLUT-2.
- Glucose converted to glucose-6-phosphate by glucokinase.
- Glucokinase forms ATP.
- ATP deactivates K+ channels and prevents K+ efflux, causing depolarisation.
- Depolarisation activates voltage-gated Ca2+ channels that stimulate the migration of insulin-containing vesicles.
Insulin response to an increase in glucose concentration occurs in ___ phases.
2 phases (biphasic)
- Initial immediate release of pre-synthesised and stored insulin
- Newly-synthesised insulin
Somatostatin released by ___ cells act on
Somatostatin
- released by delta cells
- inhibit both a and B cells
- inhibit secretion of both insulin and glucagon
Sympathetic activation via a receptors will (inhibit/promote) insulin secretion.
inhibit insulin secretion (to increase blood glucose levels during sympathetic activity)
a receptors - inhibit insulin
B receptors - promote insulin (B cells, B B)
Parasympathetic activation will result in (increased/decreased) insulin secretion.
Parasympathetic - increases insulin secretion ( to decrease blood glucose)
Main effects of insulin work to
increase energy storage (anabolism)
decrease energy formation (catabolism)
Insulin receptor is a _______ receptor.
RTK
- upon binding of insulin to RTK receptor, they dimerise and activate the intracellular tyrosine kinase domains
- autophosphorylation and cross-phosphorylation of receptors
=> phosphorylation of cell protein substrates
Why are the effects of insulin on hepatocyte glucose metabolism direct?
The movement of glucose into the cells is insulin-independent because it is GLUT-2 mediated, not GLUT-4.
Glucagon is released in the (Fasted/fed) state to (increase/decrease) blood glucose.
Glucagon
- released during the fasted state
- to increase blood glucose
Glucagon receptor
GPCR
- Gs protein
- adenylyl cyclase activation
- cAMP
Glucagon (stimulates/inhibits) insulin production, whereas insulin (stimulates/inhibits) glucagon production.
Glucagon stimulates insulin production; insulin inhibits glucagon production
Pathophysiology of Type 1 DM
- viral infection
- coupled with genetic predisposition
=> abnormal antigen presentation and recognition by the immune system - islet B-cell destruction
Type 1 DM is known to be _____ and _____ associated. (genetic)
HLA-DR3 and DR4 associated
- Th cells with surface HLA-DR4 can recognise the viral antigen to activate the immune system
HLA-____ is known to be protective against diabetes.
HLA-DR2
Viral trigger for type 1 DM
- direct infection of B cells
- molecular mimicry
- viral proteins incorporated into B cell membrane => B-cell altered expression
Immune mechanisms for type I DM against islet B cells
- Cytotoxic T cells
- Th cells
- Antibodies
Why does weight loss occur in type 1 DM?
Proteolysis and lipolysis
- due to the absence of insulin to prevent these from happening
- wastage of proteins and fats (not stored)
Typical symptoms of T1DM
Osmotic symptoms
- polyuria
- polydipsia
- nocturia
- blurring of vision
- thrush
- weight loss
- fatigue
- glycosuria
- ketonuria
Why does hyperventilation occur in type 1 DM?
type 1 DM
- insulin deficiency
- ketogenesis => ketones
- ketoacidosis
=> compensatory hyperventilation to remove excess CO2
Diet changes in diabetes
- increase complex carbohydrates and soluble fibers
- reduce fat and refined carbs
- regular meals and snacks
Soluble insulin is (short-/intermediate) acting.
NPH is (short/intermediate-) acting.
soluble insulin: short-acting
NPH - intermediate
Background regime of insulin treatment for DM
Insulin taken twice daily via mixed soluble and NPH insulin
- not very physiological => not effective
Basal bolus regime of insulin treatment for DM
NPH insulin at bedtime and soluble insulin with meals
Actrapid is a (short/long)-acting insulin.
short-acting
Lispro/novorapid are examples of ___________.
insulin analogues
- shorter peaks to prevent hypoglycemic events
What is HbA1c?
- shows amount of glucose bound to Hb over the lifespan of a RBC
- ideal measure of long-term glycemic control
- related to the risk of complications (particularly microvascular)
- alternatively, fructoasmine can be used for pregnant/patients with haemoglobinopathy instead.
Hyperglycemia can be caused by insulin deficiency or _________.
stress hormones (cortisol, catecholamines)
How does metabolic acidosis occur in DM?
- Production of acidic ketone bodies
- Polyuria results in low circulating volume in the kidneys => reduced hydrogen ion excretion in the distal convoluted tubule => acidosis of blood
In DKA, the main cause is the drop in bicarbonate concentration.
Dealing with _________ can improve DKA.
dehydration
- patient needs fluid to allow their circulating volume to return to normal
- kidneys can be perfused and have filtrate to excrete H+ ions
Why are recurrent hypoglycemias especially dangerous?
recurrent hypoglycemias result in the loss of warning signs before onset
Alcohol can lead to (hypo/hyper)glycemia.
Alcohol
- hypoglycemia
- use up glycogen stores
How to treat hypoglycemia?
oral glucose or IM glucagon (to liberate glucose from glycogen stores)
LADA
Type 1-like
- insulin-deficient
- ketosis-prone
- but presents older and not as acutely
MODY (Maturity onset diabetes of the young)
Type 2 diabetes
- but occurs younger
- patients less likely to be obese
Diagnosis for diabetes
- Fasting glucose
- 2h 75g Oral glucose tolerance test
- Random glucose test
- Fasting glucose > 7.0mM
- OGTT > 11.1mM
- Random glucose > 11.1 (least ideal)
T2DM is a combination of ___________, intrauterine environment and adult envrionment.
- genetic predisposition
- intrauterine environment
- adult environment
Insulin resistance is affected by genes and _________.
omental fat
- abnormalities in the fatty acid mechanism which contribute to insulin resistance
Why does gradual islet B cell failure occur over time in type 2 DM?
Insulin resistance => B cells try to secrete more insulin => eventually worn out and destroyed => absolute B cell failure (requires insulin)
There is a greater genetic basis for (Type 1/Type 2) DM.
Type 2 DM
Unfortunately, weight gain is a common side effect of most diabetic treatments. ________ is the only treatment which does not cause weight gain.
Metformin
Orlistat
- gastrointestinal lipase inhibitor
- reduce fat absorption to help with obesity
- associated with an improvement in glycemic control
Metformin
- insulin sensitiser
Sulfonylureas
e.g. Glibenclamide
- insulin secretagogue
prevents insulin secretion by closing the Katp channel
Acarbose
- a-glucosidase inhibitor
- prolongs absorption of oligosacchrides
Thiazolidinediones
- PPARy agonists
- peripheral insulin sensitisers
GLP-1
- gut hormone
- stimulates insulin and suppress glucagon
DDP4-inhibitors
- gliptins
- inhibit DDP4 to prolong the action of GLP-1
Microvascular complications of diabetes are related to _______, hypertension.
severity of hyperglycemia
Glucose can cause tissue damage via various pathways, which are all related to ___________.
mitochondrial superoxide over-production
__________ is a chronic complication of diabetes, and it is primarily a disorder of retinal circulation, caused by compromising delivery of oxygen and nutrients to the retina.
Diabetic retinopathy
Diabetic retinopathy: The inner layer of endothelial cells in retinal blood vessels are connected with ___________, and _________ lie outside to control vessel calibre and blood flow.
Endothelial cells in retinal blood vessels connected with tight junctions; contractile pericytes lie outside to control blood flow.
Diabetic retinopathy: Hyperglycemia is associated with damage to _________ and _________ of retinal blood vessels.
Hyperglycemia is associated with damage to endothelial and pericyte damage of retinal blood vessels.
Diabetic retinopathy: Intracellular glucose activates ________, causing the release of _________ upon endothelial damage and causes the release of _____ which induces new vessel formation.
Intracellular glucose activates protein kinase C, causing release of endothelin-1 upon endothelial damage and causes the release of VEGF which induces new vessel formation.
Background diabetic retinopathy (reversible early changes)
- Hard exudates
- Microaneurysms
- Blot haemorrhages
- no cause to visual field
Proliferative diabetic retinopathy
- new vessels as a compensatory mechanism to correct retinal ischemia
- vessels are growing into the vitreous humor => minimal injury can cause blood vessel to shear off and bleed into the humour => vision loss
Diabetic retinopathy: Maculopathy
- hard exudates present near the macula
- similar to background retinopathy but in the macula
- threaten vision
In diabetic nephropathy, __________ is a particularly important contributing factor.
hypertension (resulting in increased GFR)
_______ is a hallmark of diabetic nephropathy.
Proteinuria
Early nephropathy effects on:
- glomerular capillary pressure
- fenestrae size
- charge on membrane
- increased glomerular capillary pressure
- slightly larger fenestrae
- less negative charge on membrane
=> increased microalbumin loss
Late nephropathy effects on:
- fenestrae size
- charge on membrane
- glomerular capillary pressure
- bigger fenestrae
- less negative charge on membrane
- glomerular capillary pressure remains elevated
=> macroalbuminuria
________ can be used to control blood pressure and reduce progression of proteinuria in diabetic nephropathy.
ACE inhibitors
____________ occurs when small vessels supplying nerves (_________) become blocked, causing nerve dysfunction.
Diabetic neuropathy
- small vessels supplying nerves (vasa nervorum) become blocked
The most common diabetic neuropathy is ________, where the longest sensory nerves that supply the feet cause numbness.
diabetic peripheral neuropathy
- affects longest nerves e.g. sensory nerves to feet
Macrovascular complications with diabetes is associated with the metabolic syndrome.
Insulin resistance
- causing hyperinsulinemia (compensatory)
- leading to smooth muscle hypertrophy (mitogenic effect of insulin)
- worsening of atheroma (necrotic lipid core)
Dyslipidemia (due to alterations of lipids and lipoproteins as a result of diabetes) is also associated with lipid accumulation in early atheroma.
-
What are the main differences between microvascular and macrovascular complications of diabetes?
Microvascular
- related to glycemic control mainly
- hardly seen outside DM
Macrovascular
- related to lipids, BP, weight, etc. beyond glycemic control
- seen outside DM
2 most common ways of measuring body mass - indication of nutritional status
- BMI
2. waist circumference
In growing children, BMI may not be a reliable indicator of nutrition. What indicator should we use?
Growth chart
- normal if they grow along certain percentile lines in a growth chart
- abnormal (faltering growth) if their growth cuts across percentile lines
Using body weight measurements in assessment of undernutrition is often not reliable, so _________ is used instead.
arm circumference
- midpoint of the upper arm
- measured after raising skin folds and subcutaneous fat
Dietary reference values reflect the nutritional needs of a (individual/population) and is a way of assessing nutritional adequacy.
Dietary reference values
- nutritional needs of a population
____________ refers to the amount of each nutrient needed, which are different across nutrients and varies between individuals and life stages.
nutritional requirement
_____________ refers to the mean requirement of a nutrient. It is the daily intake value that is estimated to meet the nutrient requirement of half the healthy individuals in a population.
Estimate Average requirement (EAR)
Calculation of nutrient requirement takes into account 2 aspects.
- Metabolic demand
2. Efficiency of utilisation
3 types of energy expenditure
- Obligatory energy expenditure
- basal metabolic rate - Physical activity
- Adaptive thermogenesis
- thermic effect of food
- keep warm/digest food
2 methods to measure energy expenditure
- Measures rate of O2 consumption and CO2 production to calculate RQ
- 2H2 eliminated as water; O eliminated as water and CO2
- Indirect calorimetry
- measures respiratory quotient which represents the ratio between oxidation of sugars and lipids - Doubly labelled water (DLW)
Taking in nutrients is feeding 3 biochemical pathways which converge at _________.
acetyl-CoA molecule
- glucose => acetyl-CoA (glycolysis, link)
- Fatty acids => acetyl-CoA (B-oxidation)
- Amino acids => acetyl-CoA (deamination, oxidation)
_______ cannot be stored in the body, hence it must be used/oxidised as a priority for fuel.
Alcohol
=> perfect auto-regulation
Obese people have (lower/higher) percentage of water in their bodies.
lower
Different signals are integrated in the __________ of the brain to regulate feeding in humans, in order to maintain body weight.
hypothalamus
_________ is a collection of neural cell bodies in the hypothalamus which constitutes an external environment. It is the key brain area involved in the regulation of food intake.
Arcuate nucleus - possess an incomplete blood-brain barrier to integrate hormonal and central feeding signals
2 neuronal populations exist in the arcuate nucleus of the hypothalamus
- Stimulatory: NPY/AgRP
2. Inhibitory: POMC/CART neurones
POMC deficiency and MC4-R mutations have been found to cause ________.
morbid obesity
POMC neurons are present in the arcuate nucleus as inhibitory
Satiety centre in hypothalamus:
Feeding centre in hypothalamus:
Satiety centre: ventromedial hypothalamus (VMH)
Feeding centre: lateral hypothalamus (LH)
Neurotransmitters: AgRP, GABA, GHRH, MCH, NPY
Orexigenic action (feeding, stimulatory)
Neurotransmitters: POMC, a-MSH, GLP-1/2, Leptin, Insulin
Anorexigenic action (satiation, inhibitory)
Adipostat mechanism
circulating hormone produced by fat cells which is sensed by hypothalamus to cause hypothalamus to alter neuropeptides in order to increase/decrease food intake
PYY is released from the ____ into circulation and acts as a (satiety/feeding) factor.
PYY
- released from the gut
- satiety factor
- inhibits NPY release and stimulates POMC neurons to decrease appetite
_______ is a gastric hormone which directly modulates neurons in the arcuate nucleus by stimulating _______ neurones and inhibiting _____ neurones to increase appetite.
ghrelin
- gastric hormone
- stimulates NPY/AGRP and inhibits POMC
- increases appetite (feeding factor)
Leptin is made by _________ in white adipose tissue, which signals to hypothalamus about the fat status of the body.
It triggers thermogenesis, reduced food take and nutrient levels and is therefore (orexigenic/anorexigenic).
Leptin
- orexigenic
Leptin regulatory loop can potentially lead to obesity in 3 ways:
Which one is the main pathophysiological mechanism?
- Leptin deficiency
- Regulatory defects => low stimulation of hypothalamus
- Leptin resistance develops in the hypothalamus
* MAIN mechanism*
Developmental defect:
___________ occurs when the right and left sides of the ventral pancreatic bud migrate in opposite directions, resulting in a ring of pancreatic tissue around the duodenum.
Annular pancreas
- may cause stenosis and even complete obstruction (atresia), blocking the passage of food
___________ is an endocrine marker used to stain islet cells in immunohistochemical staining methods.
Synaptophysin
- Positive (islet) cells appear brown
