Biochemistry: Insulin Flashcards
What type of hormone is insulin
Peptide
Cells of pancreatic islets (4) and secretions
Beta- cells
- Secrete insulin
alpha-cells
- secrete glucagon
Delta-cells
- Secrete somatostatin
PP cells
- Secrete pancreatic polypeptide
Insulin Prehormone
Synthesized in RER of beta-cells as a larger single chain preprohormone: preproinsulin
Cleaved to form insulin and connecting ( C ) peptide (byproduct of cleavage with no known physiological function
Insulin structure
Two peptide chains ( A and B chains) linked together by two disulphide bonds
Synthetic insulin preparations
Prepared by changing amino acids
Ultrafast/ ultra-short acting insulin
--> Insulin lispro Monomeric Not antigenic Most rapidly acting insulin Injected with 15 mins of meal Must be used in combo with longer acting preparation for T1DM
Ultra-long acting Insulin
–> Insulin glargine
Recombinant insulin analog that precipitates in neutral environment of subcutaneous tissue.
Prolonged action
Administered as single bedtime dose
Biological Effects of Insulin
9
Turns on
- 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
Turns off
- lipolysis
- gluconeoogenesis in liver
Action of glucokinase
Glucokinase= Glucose sensor
Glucose enters beta-cells through GLUT-2 glucose transporter and is phosphorylated by glucokinase
Glucokinase Km for glucose lies in physiological range of concentrations
Mechanism of Glucose Secretion (5)
Beta-cells secrete insulin in response to blood glucose rising >5mM
- Increased metabolism of glucose leads to an increase in intracellular ATP metabolism
- ATP inhibits ATP sensitive K+ channel (Katp)
- Inhibition of Katp leads to depolarisation of cell membrane
- Depolarisation of cell membrane results in opening of voltage-gated Ca2+ channels
- Increase in internal Ca2+ concentration leads to fusion of secretory vesicles with cell membrane
–> Insulin released
Amount released is directly related to amount of glucose.
Time of Insulin Secretion
Biphasic
First Phase
- Prevents sharp increase in blood glucose
Second Phase
- Related to glucose intake (amount and duration)
Involves presence of 2 different pools of insulin granules
- Readily releasable pool (RRP)
- Reserve. pool - must undergo preparatory reactions
Diseases caused by defects in insulin secretion/action (5)
T1DM T2DM Gestational Diabetes (GDM) Maturity Onset Diabetes of the Round (MODY) Neonatal Diabetes
Diseases caused by severe insulin resistance
Rabson Mendenhall Syndrome
Leprechaunism ( Donohue Syndrome)
Type 1 Diabetes
Autoimmune destruction of pancreatic beta cells.
Presence of autoantibodies, combined with declining C-peptide production
Type 2 Diabetes Mellitus
Primary problem is reduced insulin sensitivity in tissues
Usually present with hyperinsulinaemia as beta cells try to compensate for hyperglycaemia caused by insulin resistance
Gestational Diabetes
- Diagnostic Criteria
- Identifies
- Association
- Treatment
Different diagnostic criteria = FG > 5.5mM
Identifies women with declining beta-cell function
Associated with high risk of future T2DM
Treatment: Lifestyle advice and sometimes metformin
Maturity Onset Diabetes of the Young (MODY)
What it is + Detection + Treatment
Defective glucose sensing in pancreas and/or loss of insulin secretion
Monogenic disease
Beta-cell dysfunction but NOT autoimmune destruction
Mutations in at lease 6 different genes (150 mutations) can cause MODY
- GLucokinase (GCK/ MODY 2)
- several transcription factors (–> HNF 1 & 3)
Robust genetic screening to differentiate MODY from T1DM allows treatment with sulphonylurea rather than insulin.
HNF 1 & 3
Transcription Factors
Key role in pancreas foetal development and neogenesis
Regulate beta-cell differentiation and function .
Mutation can result in MODY
Neonatal Diabetes
Rare form of. monogenic diabetes
mainly caused by mutation in glucose sensing mechanisms (ATP sensitive K channels)
Katp Channels Structure
Consist of 2 proteins
Inward rectifier proteins (Kir)
- pore subunit = Kir6
Sulphonylurea Receptor
- regulatory subunit= SUR1
Both required to form a functional channel. Channel exists as an octomeric structure ( 4xKir6 = 4xSUR1)
Kir6.2 Mutations
- Disease
- mechanism
- treatment
Lead to neonatal diabetes
Constituitively activated Katp channels or increase in Katp numbers
In most patients, beta cells are still responsive to SURs, such as tolbutamide
Kir6.2 or SUR1 mutations
- Disease
- Mechanism
- treatment
Lead to congenital hyperinsulinism
Tafficking or inhibiting mutations
Diazoxide can help inhibit insulin secretion is channels are still getting to membrane
Regulation of Katp
- Drugs to inhibit
- Drugs to stimulate
Intracellular ATP inhibits Katp to elicit depolarisation
Katp is directly inhibited by sulphonylurea class of drugs
- tolbutamide
- glibenclamide
Katp is stimulated by diazoxide which inhibits insulin secretion
Severe Insulin Resistance
- Monogenic and Polygenic Examples
Reduced ability to respond to physiological insulin levels
Monogenic can occur due to mutation in key signalling pathways
- Leprechaunism (Donohue Syndrome)
- Rabson Mendenhall Syndrome
Polygenic
- T2DM (large input from environmental influence)
