Biochemistry-insulin production Flashcards
what type of hormone is insulin?
Peptide Hormone
what does loss of glucose homeostasis lead to?
Hyperglycaemia
what is the blood sugar threshold for diabetes
> 7mM at fasting level
what is a healthy blood sugar level
4-6mM
In the pancreatic islet, what do beta cells secrete?
insulin
in the pancreatic islet, what do gamma cells secrete?
somatostatin
in the pancreatic islet, what do PP cells secrete?
secrete pancreatic polypeptide
what is insulin initially synthesized as?
preproinsulin (before being cleaved into insulin)
what do pancreatic alpha cells secrete
glucagon
can the brain make its own glucose?
No
what are the risks of hypoglycemia?
Danger of coma
what is the pre diabetic blood sugar range?
6-7mM
does insulin increase or decrease blood sugar levels?
decrease
what is the proportion of cells in the pancreatic islet?
Alpha: 10-20%
beta: 60-80%
gamma: about 5%
PP cells: <1%
what is the formation of insulin?
2 polypeptide chains linked by disulphide bonds
proinsulin is made up of?
3 chains (ABC)
which chains does active insulin have?
A chain and B chain
which synthetic insulin is ultra short acting?
lispro
which synthetic insulin is short acting
Regular
which synthetic insulin is intermediate acting?
NPH
which synthetic insulin is long acting?
ultralente
which synthetic insulin is ultra long acting
glargine
lispro features
– monomeric
– not antigenic
– the most rapidly acting insulin
– 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
glargine features
Recombinant insulin analog that precipitates in the neutral environment of
subcutaneous tissue
– Peakless- prolonged action
– Administered as single bedtime dose
is there a suitable synthetic alternative to the beta cell?
No
through what receptor does glucose enter beta cells
GLUT 2
what phosphorylates glucose?
glucokinase
what does increased metabolism of glucose lead to?
an increase in intracellular ATP conc
what is glucokinase
the blood glucose sensor
how many ATP are produced per glucose?
36
what does ATP do?
inhibits the ATP sensitive K+ channel
what does inhibition of KATP lead to?
depolarisation of membrane
what does depolarisation of the cell membrane lead to?
opening of voltage gated Ca2+ channels
what does an increase in internal Ca+ conc lead to?
fusion of secretory vesicles with the cell membrane and release of insulin
how does the secretion of insulin work?
- Beta cell is only cell in body that makes and secretes
insulin (insulin used as marker of beta cell). - It should only do this in response to blood glucose rising
above 5 mM. - In T1DM the beta cells are mostly lost.
- In other forms of diabetes the beta cells lose the ability to sense changes in glucose
why are there 2 phases of insulin release?
About 5% of insulin granules are instantly ready of release
Reserve pool must undergo preparatory reactions to become mobilised and available for release
* In poorly controlled T2DM insulin secretion weakens and flattens.
how does pharmacological regulation of insulin secretion work?
sulphonylurea drugs mimic the action of ATP to depolarise beta cells.
Incretins induce a glucose-dependent insulin release
what is Type 1 diabetes caused by?
autoimmune destruction of the pancreatic beta cells.
a definitive T1 diabetes diagnosis need what?
evidence of the presence of specific autoantibodies, combined with declining C-peptide production.
how does T2 diabetes usually present?
hyperinsulinemia, as the beta cells try to compensate for the hyperglycemia caused by insulin resistance.
diagnostic criteria in gestational diabetes?
lower than for other forms of diabetes (FBG>5.5) as this comes with significant risk of increased weight of offspring at birth.
how is gestational diabetes treated?
lifestyle advice and sometimes metformin to improve insulin sensitivity
is gestational diabetes associated with a high risk for T2 diabetes?
yes
what is maturity onset diabetes of the young
monogenic disease with common clinical features to both type 1 and type 2 diabetes. Beta cell dysfunction but not autoimmune destruction.
which proteins does KATP channel consist of?
An inward rectifier subunit (KIR) - pore subunit – Kir6
* A sulphonylurea receptor - regulatory subunit - SUR1
- Both are required to
form a functional
channel
what mutation can lead to neonatal diabetes?
Kir6.2 mutations
this is due to constitutively activated KATP channels or an increase in KATP numbers
usually responds to SURs
what does a Kir6.2 or SUR1 mutations lead to?
congenital hyperinsulin
when does insulin resistance occur?
through reduced insulin sensing and/or signalling.
why does insulin resistance happen?
most commonly associated with obesity, however near complete absence of adipose also results in insulin resistance. Therefore normal adipose functionality should be considered a key mediator of insulin sensitivity, rather than simply thinking of excess fat as a antagonist of insulin action
what is the best way to combat insulin resistance?
weight loss
Type 2 diabetes is usually monogenic-true or false?
false
polygenic
why does monogenic severe insulin resistance occur?
due to mutation in key signalling pathways
What is leprechaunism- Donohue Syndrome?
Rare autosomal recessive genetic trait
* Mutations in the gene for the insulin receptor
* Severe insulin resistance
* Developmental abnormalities
– elfin facial appearance
– growth retardation
– absence of subcutaneous fat, decreased muscle mass
* Caused by defects in insulin binding or insulin receptor signalling
what is Rabson Mendenhall syndrome?
Rare autosomal recessive genetic trait
* Severe insulin resistance, hyperglycemia and
compensatory hyperinsulinemia
* Developmental abnormalities
* Acanthosis nigricans (hyperpigmentation)
* Fasting hypoglycaemia (due to hyperinsulinemia)
* Diabetic ketoacidosis
* Severe cases linked to mutations in the insulin receptor that reduce sensitivity
what are the symptoms of diabetic ketoacidosis
Vomiting
Dehydration
Increased heart rate
Distinctive smell on breath (acetone smell)
where are ketone bodies formed?
Formed in liver mitochondria
– derived from acetyl-CoA, which is from b oxidation of fats
what are they converted back to in energy metabolism?
acetyl-CoA
what does low levels of insulin inhibit?
inhibit lipolysis and prevent ketone body overload
In T1 diabetes, what causes DKA?
insulin supplementation is
missed
is DKA rarer in T1 or T2?
T2
how does DKA occur in T2?
insulin resistance and deficiency increases, alongside increase in glucagon
what does fatty acid oxidation yield?
acetyl-CoA which enters the TCA cycle if fat and carbohydrate degradation are balanced
what happens if supply of Pyruvate/oxaloacetate is limited?
Acetyl CoA is diverted to ketones.
what is oxaloacetate consumed for?
gluconeogenesis
what does high glucose excretion cause?
dehydration, exacerbates acidosis
Coma, death
