Biochemistry of glucose and Insulin Flashcards
What is Insulin?
A peptide hormone
Can you live without insulin?
No
What is the therapeutic window of insulin like?
Narrow
Can Insulin kill you?
Yes it can cause a hypoglycaemic coma
- Low blood glucose
- High insulin
- Low C peptide
What are the 4 cells of pancreatic islets?
Beta cells
Alpha cells
Delta cells
PP cells
What do B cells secrete?
Insulin
What do A cells secrete?
Glucagon
What do D cells secrete?
Somatostatin
What do PP cells secrete?
Pancreatic polypeptide
Where is insulin synthesized and how?
Rough endoplasmic reticulum of pancreatic B cells as a larger preprohormone
Cleaved to form insulin
Contains two polypeptide chains linked by disulfide bonds
Connecting peptide has no physiologic function
What are 5 insulin preperations (add examples)?
Ultra-fast/Ultra Short acting - Lispro Short acting - glargine Intermediate acting Long acting Ultra long acting
What are the characteristics of Lispro?
Monomeric Not antigenic The most rapidly acting insulin Injected within 15 minuted of beginning a meal Short duration of action
What are the characteristics of Glargine?
Recombinant insulin analog that precipitates in the neutral environment of subcutaneous tissue
Prolonged action
Single bedtime dose
How does glucose enter the B cells?
GLUT2 glucose transporter
What phosphorylates glucose?
Glucokinase
What happens when the glucose conc changes?
Dramatic change in glucokinase activity
What does increased metabolism of glucode lead to?
Increased intracellular ATP concentration
DIagram on slide 14
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What does an increase in ATP cause?
Inhibition of the ATP sensitive K channel
What does inhibition of Katp cause?
Depolarisation of cell membrane
What does depolarisatiion of the cell membrane cause?
Opening of voltage gated Ca channels
What does an increase in internal Ca2+ conc lead to?
Fusion of secretory vesicles with the cell membrane and release of insulin
What is the only cell that makes insulin?
Beta cell
What is the level of blood glucose that promotes insuling production?
5mM
What is lost in T1DM?
Beta cells
Graph on 20
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What % of insulin granules are immediately availible for release?
RRP
5%
What must happen to the RRP to be availible for release?
Preparatory reactions
What happens to insuling secretion in T2DM?
Weakens and flattens
Why does weakened insulin production occur in T2DM?
Downregulation of the sensing process
What does restoring physiological glucose do to insulin?
Enhance secretion
What are the 2 proteins present in Katp channels?
An inward rectifier subunit - Kir6
A sulphonylurea receptor - SUR1
Both are required
What are second line for T2DM?
SURs
What patients should get SURs?
Those who struggle injecting insulin
What mutations can lead to neonatal diabetes?
KIR6.2
Responsive to SURs
What mutations cause congenital hyperinsulinism?
KIR6.2 SUR1
What is MODY?
Monogenic diabetes with genetic defect in B cell function
Familial form of early onset type 2 diabetes primary defectts in insulin secretion
What happens in MODY2?
Glucokinase activity impaired
Glucose sensing defect
What does HNF transcription factors do?
Play key roles in pancrease foetal development and neogenesis
Regulates B cell differentiation and function
What must be done to differentiate MODY and T1DM?
Robust screening
What type of hormone is insulin (A or C)?
Anabolic
What does insulin switch on?
Amino acid uptake in muscle DNA synthesis Protein synthesis Glucose uptake Lipogenesis Glycogen synthesis in liver
What does insulin switch off?
Lipolysis
Gluconeogenesis
What does binding of insulin to the A subunits cause?
B subunits to dimerise and phosphorylate themselves, activating the catalytic activity of the receptor
Diagram on 39
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What can go wrong with insulin and what is it associated with?
Insulin resistance -Reduced sensitivity to insulin -Reduced signalling Obesity No adipose tissue
What influences T2DM?
Polygenic in nature
Large input frrom environmental factors
Obesity
Insulin resistance
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 -Abscence of subcut fat Caused by defects in insulin binding or insulin receptor signalling
What is Rabson Mendenhall syndrome?
Rare AR genetic trait Sever Insulin resistance Hyperglycaemia Hyperinsulinaemia Developmental abnormalities Acanthosis Nigricans Fasting hypoglycaemia Diabetic ketoacidosis
Where are ketone bodies formed?
Liver mitochondria
Diffuse into the blood stream and to peripheral tissues
Important in metabolism of energy
Whatt do low insulin levels inhibit?
Lipolysis and ketone body overload
What type of DM is diabetic ketoacidosis more common in?
T1DM
What does fatty acid oxidation yeild?
Acetyl-CoA
What is oxaloacetate consumed for?
Gluconeogenesis
What is excess Acetyl-coA converted to?
Ketone bodies
What can high glucose excretion cause?
Dehydration
Exacerbation of acidosis
Coma
Death
