Week 1 Flashcards
what are the basic hormone subtypes
protein and peptide hromones, steroid hormoones and tyrosine derivatives
what are the hormones receptors
G-protein coupled receptors
Receptor Tyrosine Kinase (RTK) Families
Receptors associated with tyrosine kinase activity
Steroid hormone receptors
what are the major endocrine glands?
hypothalamus, PG, 4Parathyroid and thyroid, 2 adrenal glands and pancreas, ovaries/testes, adipose tissue
where do most clinical problems from endocrine come from?
hypo/hypersecretion
what are the principles of endocrine testing?
If too little hormone – try and stimulate it
If too much hormone – try and suppress it
what type of glands make up the endocrine system
ductless glands
how is communication (long distance between glands and other tissues) done in endocrine system?
via hormones in bloodstream
how are hormones are specific at signalling?(3 reasons)
- chemically distinct hormones
- specific receptor for each hormone
- distinct distribution of receptors across target cells
what is the chemical nature and deriviative of Adrenaline + thyroid hormones (T3 and T4)?
modifed Amino Acids (from tyrosine)
what is the chemical nature and derivative of Cortisol, progesterone, testosterone?
steroid (from cholesterol)
what is the chemical nature and derivative of Adrenocorticotropic hormone ACTH), antidiuretic hormone (ADH), oxytocin?
(insulin)
peptide (from larger precursor proteins)
proteins
what are the three ways of chemical signally hormones can do?
autocrine, paracrine, endocrine
autocrine signalling definition
cell secretes a hormone or chemical messenger (called the autocrine agent) that binds to autocrine receptors on that same cell, leading to changes in the cell/INTRACELLULAR
paracrine signalling definition
signalling molecule affects surrounding target cells (diffusion in ECF)
endocrine definiton
signalling molecule enters circulation and affects cells at a different site.
not all hormones act in one way. Somatostatin acts via which two signalling methods?
paracrine and endocrine
one hormone can affect many targets and several H may act on one target. T or F?
T
why does a very small change in the concentration of H lead to changes?
due to specific receptors with high efficacy
how long does it take H to act? What can occur when H attaches to receptor?
seconds to days.
Amplification - cascade of events
how are H eliminated?
terminated by enzyme-mediated metabolic inactivation in the liver.
or at sites of action.
What two ways can hormones interact? (Give example of each)
complementary (together - adrenaline, glucagon and cortisol allow enhances physical activity and inc energy while preventing hypokalaemia and hypoglycaemia prophylactically)
antagonistically (in opposition - insulin and glucagon)
Amines: synthesis, storage, release and transport
pre-synthesised from tyrosine, storage in vesicle by adrenaline, release due to external factor causing inc extracellular Ca2+ - release on demand, always reserve.
as amines are small, soluble and hydrophilic they are transported ‘freely’ in bloodstream.
peptide H: synthesis, storage, release and transport
pre-synthesised by long processes (by CONVERTASES), storage in vesicles, release due to external factor causing inc extracellular Ca2+ - release on demand, always reserve.
peptide H are hydrophilic so they are transported/dissolve ‘freely’ in plasma
Steroid H: synthesis, storage, release and transport
synthesised and secreted on demand (no storage)
pathways irrelevant but all via PREGNENOLONE.
hydrophobic so transported by carrier proteins in plasma(CP)
what are the rate limiting steps in Steroid H synthesis? (what inc steroid H synthesis)
(high) conc of cholesterol
(high) rate of conversion of cholesterol into pregnenolone
when are steroid H biologically active?
when ‘free’/when not bound to plasma proteins
what H are relatively insoluble in plasma?
steroids, T3, T4
T3 is what?
Triiodothyronine
T4 is what?
Thyroxine
what is the function of CPs? (give 3)
inc conc of H in blood
provide reservoir of H
to extend the T1/2 of H
give examples of common CP
CBG - cortisol binding globulin (binds cortisol, some aldosterone)
TBG - binds T4, some T3.
SSBG - testosterone + oestradiol
what are two important general CP and what do they carry?
albumin – binds many steroids and thyroxine
transthyretin – binds thyroxine and some steroids
how does CP regulate levels of steroid H?
acts as both buffer and reservoir (equilibrium between CP bonded and non-bonded). If too much or too little steered body can cope.
what state do H have to be to cross capillary wall (and nuclear membrane?)
free (unbonded)
how is H plasma conc levels maintained?
negative feedback system (both short range and long range)
[note that nervous and endocrine systems work together]
what is plasma concentration determined by?
rate of secretion vs rate of elimination
neuroendocrine in negative feedback system?
Elicits a sudden burst in secretion in response to a specific stimulus
what is diurnal/circadian rhythm?
fluctuation thoughtout day [dependant on external factors e.g:night/day]
what are the two main route of H elimination?
excretion by kidneys
metabolism by liver
what are the half life (approx) of amines, peptides and steroid H?
amine - secs
peptides-min
steroid-hours/days
3 types of H receptors?
G-protein coupled (GPCR)
Receptor kinases
Nuclear receptors
G-protein receptors: are found where, which H use them?
found on cell surface as hydrophilic H
amine H and some peptide H
receptor kinases: are found where, which H use them?
found on cell surface as hydrophilic H
activated by some protein/peptide H
nuclear receptors: classes, are found where, which H use them?
receptor on nucleus as lipophilic H (can diffuse across PM)
Class 1 - many steered H; located in cytoplasm and move to nucleus when activated Class 2 - mostly lipids; constitutively present in the nucleus Hybrid - activated by thyroid hormone (T3) and other substances; similar in function to class 1
what is the difference between type 1 and 2 diabetes?
1- absolute insulin deficiency
2-relative insulin deficiency
what is the definition of DM?
a group of metabolic diseases characterised by hyperglycemia resulting from defects in insulin secretion, insulin action, or both
how is diabetes diagnosed?
HbA1c > 48m/m/6.5% (type 2)
fasting glucose >7mmol/L
2hr glucose in OGTT > 11.1mmol/L (after 2hrs)
random glucose>11.1mmol/L (=symptoms)
[slightly lower values can indicate pre-diabetes /impaired function]
type 1 DM PC
Pre-school and peri-puberty Small peak in late 30’s Usually lean Acute Onset severe symptoms severe weight loss ketonuria metabolic acidosis no evidence of microvascular disease at diagnosis immediate and permanent requirement for insulin
what signs to look out for in type 1 DM?
4T’s
toilet, thirsty, tired, thinner
type 2 DM PC
middle-aged/elderly
usually obese
pre-diagnosis duration of probably 6-10 years
insidious onset over weeks to years
ketonuria minimal or absent
evidence of microvascular disease at diagnosis in 20 %
managed initially with diet/ lifestyle +tablets
risk factors for type 2 DM
Obesity (central) Family History Gestational Diabetes Age Ethnicity (Asian, African, Afro-Caribbean) PHx of MI/ Stroke Medications e.g. antipsychotics IGT/ IFG
what is mostly likely cause of DM in children under 1?
neonatal or genetic diabetes
rarely type 1 (even if looks like it)
type 1 DM is what kind of disease? what occurs? what does this allow to help in diagnosis?
AID, insulitis (lymphocytic inflitrate). Antibodies can be used to diagnoses as AID.
PC of type 2 DM
Thirst Polyuria Thrush Weakness Fatigue Blurred Vision Infections (Weight Loss) T2DM- Signs of complications- neuropathy, retinopathy
what are useful discriminatory tests (tell you which type of diabetes is present)?
GAD/ Anti-Islet Cell antibodies
Ketones
C-peptide (plasma)
what is LADA?
Latent autoimmune diabetes (type 1 occuring in adults).
lots of patients with LADA are assumed to have type 2 DM. how is LADA different?
ketosis = type 1 diabetes
type 3 diabetes causes are what?
pancreatic disease, endocrine disease, drug-induced, Abnormalities of insulin and its receptor,
Genetic diseases
what pancreatic conditions cause type 3 diabetes?
Chronic or recurrent pancreatitis (alcoholism mainly)
Haemochromatosis
Cystic Fibrosis
what endocrine conditions cause type 3 diabetes?
Cushing’s syndrome
Acromegaly
Phaechromocytoma
glucagonoma
what drugs
cause type 3 diabetes?
Glucocorticoids
Diuretics
B-blockers
what genetic disease cause type 3 diabetes?
Cystic fibrosis
Myotonic dystrophy
Turner’s syndrome
Down’s syndrome
what are signs of monogenic diabetes (not polygenic)?
Strong Family History Associated Features (renal cysts etc) Young Onset GAD-negative C-peptide positive
what is type 4 DM?
Gestational diabetes - Any degree of glucose intolerance arising or diagnosed during pregnancy
what is HbA1c? what is its use?
Glycated haemoglobin.
Provides a measure of glucose control over past 2-3 months.
complication of DM
Macro-vascular: Heart Disease and Stroke (70% of people with diabetes die from cardiovascular disease)
Micro-vascular: Retinopathy(blindness), Nephropathy (RF), Neuropathy,
Psychiatry/ Psychology
Peripheral vascular disease - ulcers/amputation
DKA
what is DAFNE?
dose adjustment for normal eating (type 1DM)
[educates people on estimating carbohydrate per meal and injecting the right does of insulin]
which DM has stronger genetic competent?
type 2 (twin studies and risk factor for type 2 development greater if parents have than type 1 - weird)- extra info
what is a normal blood glucose level?
5mmol/L
what are the cells of the pancreatic islets, watch percentage and what do they produce?
β cells - secrete insulin (70%)
α cells - secrete glucagon (15%)
δ cells - secrete somatostatin (5%)
PP cells - secrete pancreatic polypeptide (<1%)
how is insulin made? (?→?+?→?+?)
preproinsulin→ proinsulin +singalling petpide →insulin + C-peptide (cleaved to form insulin)
where is preproinsulin made?
Synthesized in the rough endoplasmic reticulum of pancreatic β cells [as a larger single chain preprohormone]
how fast can insulin preparations work?
ultra-short acting to ultra-long acting
ultra-short acting insulin called what? taken when?
lispro.
Injected within 15 minutes of beginning a meal
short duration of action- must be used in
combination with longer-acting preparation for Type 1 diabetes unless used for continuous infusion
(it is monomeric and not antigenic)
ultra-long acting insulin called what? when is it given?
glargine
Recombinant insulin analog that precipitates in the neutral environment of subcutaneous tissue
Peakless- prolonged action
Administered as single bedtime dose
how does glucose enter the Beta-cells?
GLUT2 glucose transporter
what happens to glucose once it enters the beta-cell?
it is phosphorylated by glucokinase (glucokinase is the glucose-sensor)
what can lead to dramatic change in glucokinase captivity?
(small) change in glucose conc
what is the process for excreting insulin?
inc metabolism of glucose→ inc intracelluar ATP conc →inhibition of ATP-sensitive K+ channels Katp → depolarisation of cell membrane → opening of voltage- gated Ca2+ channels → inc intracellular Ca2+ → fusion of secretory vesicles with the cell membrane and release of insulin
how many cells make and secrete insulin?
ONLY B-cells make and secrete
when should insulin be secreted?
ONLY once conc > 5mmol/L
What is the problem in Type 1DM, …type 2 DM?
B-cells are lost -1
cells lose ability to sense change in glucose. - 2
what is the release of insulin? Why?
biphasic → readily released pool (immediate ) and reserve pool (preparation reaction must occur)
what happens to the insulin secretion curve in Type 2 DM?
it flattens and weakens (due to down regulation of sensory process)
what drugs can mimic the action of ATP to depolarise beta cells?
sulphonylurea drugs [SUR’s]
what do Katp channels consist of which two proteins?
Kir6 (An inward rectifier subunit (Kir) - pore subunit )
SUR1 (A sulphonylurea receptor - regulatory subunit) - need both to form functional Katp channel
what is the structure of Katp channel?
octomeric structure
how to SUR’s work?
directly inhibit Katp
give some example of SUR’s, when can they be used?
tolbutamide or glibenclamide
2nd line for type 2 DM)
how is Katp regulated?
inhibited by SUR’s (stimulates insulin secretion)
stimulated by diazoxide (inhibits insulin secretion)
what mutation give neonatal diabetes?
Kir6.2 mutations
why does neonatal diabetes occur? treatment?
Due to constitutively activated KATP channels or an increase in KATP numbers
In some of these patients the β cells are usually responsive to SURs, such as tolbutamide; recover euglyceamia fairly quickly on SURs.
what does euglyceamia mean?
normal blood glucose (normoglycemia)
what mutations lead to congenital hyperinsulinism?
some Kir6.2 or SUR1 mutations
why does congenital hyperinsulinism occur? treatment?
trafficking or inhibiting mutations
diazoxide can help inhibit insulin secretion if channels are still getting to the membrane
MODY: what is it? who does it occur?
Maturity-onset diabetes of the young
Monogenic diabetes with genetic defect in β cell function; Familial form of early-onset type II diabetes, primary defects in insulin secretion
Mutations in at least 6 different genes can cause MODY
why is it important to differentiate MODY from type 1 DM? how is this done?
treatment with sulphonylurea rather than insulin (as MODY patients usually have some b-cell function available).
robust genetic screening
what occurs in type 1, 2 and MODY?
Type 1 Diabetes – Loss of insulin secreting beta cells.
what occurs in type 2 DM
Type 2 Diabetes- Initially hyperglycemia with hyperinsulinemia so primary problem is reduced insulin sensitivity in tissues
what occurs in MODY?
MODY- defective glucose sensing in the pancreas and/or loss of insulin secretion
what is insulin’s biological effect
anabolic
what does insulin promote?
- Amino acid uptake in muscle
- DNA synthesis
- Protein synthesis
- Growth responses
- Glucose uptake in muscle and adipose tissue
- Lipogenesis in adipose tissue and liver
- Glycogen synthesis in liver and muscle
what does insulin inhibit?
lipolysis
gluconeogenesis in liver
what receptor does insulin bind to?
receptor tyrosine kinases
what does insulin cause to happen at the tyrosine kinase receptor?
insulin binds to α subunits → β subunits to dimerise → β + phosphorylate themselves/autophosphorylation → activates catalytic activity of the receptor
how does glucose get transported into the cell?
GLUT 4 receptor (then glycogen synthesis occurs as does cell growth)
what is insulin resistance?
reduced ability to respond to ‘physiological’ insulin levels - due to reduced insulin sensing and/or signalling.
what is the effect of obesity/adipose tissue on insulin resistance?
direct correlation with obesity
[however complete absence of adipose also results in insulin resistance] (therefore adipose tissue is key mediator of insulin sensitivity)
what is leprechaunism/Donoghue syndrome? why does it occur?
Rare autosomal recessive condition, mutations in the gene for the insulin receptor causes severe insulin resistance. [defects in insulin binding or insulin receptor signalling]
what type of condition is type 2 DM? (genetically)
polygenic, [with a large input from environmental influence]
leprechaunism/Donoghue syndrome signs?
Developmental abnormalities (elfin facial appearance,
growth retardation,
absence of subcutaneous fat, decreased muscle mass) - death < 1yearold.