Biochemistry of Glucose and Insulin Flashcards
What are the different cell types present in the pancreatic islets?
Beta cells = 60-80%, secrete insulin
Alpha cells = 10=20%, secrete glucagon
Delta cells = about 5%, secrete somatostatin
PP cells = <1%, secrete pancreatic polypeptide
What is the prehormone form of insulin?
Preproinsulin = cleaved from single large chain to produce insulin
Where is preproinsulin formed?
In the RER of pancreatic beta cells
What is the structure of insulin?
Two polypeptide chains linked by disulphide bonds
What is connecting (C) protein?
Byproduct of cleavage = has no known physiologic function
What are some insulin preparations?
Short acting = regular insulin Intermediate acting = NPH Long acting = ultralente Ultra fast/ultra short acting = lispro Ultra-long acting = glargine
What are some features of lispro?
Lysine (B28) and proline (B29), monomeric, not antigenic, most rapidly acting insulin preparation, injected within 15 mins of beginning a meal
How is lispro used to treat type 1 diabetics?
Used in combination with longer acting preparations unless being used for continuous infusion
What is glargine?
Recombinant insulin analogue that precipitates in the neural environment of subcutaneous tissue
How is glargine used?
Is peakless so has prolonged action
Administered as a single bedtime dose
How does glucose enter beta cells?
Through GLUT 2 transporters
What phosphorylates glucose once it is in the cell?
Glucokinase
What can a change of glucose concentration do to glucokinase?
Causes dramatic change in glucokinase activity
Where does the Km of glucokinase for glucose lie?
in the physiological range of concentration
What does the increased metabolism of glucose cause?
An increase in intracellular ATP concentration
What does ATP inhibit?
The ATP sensitive K+ channel (KATP) = inhibition of KATP leads to depolarisation of the cell membrane
What does the depolarisation of the cell membrane cause?
Opening of voltage gated Ca2+ channels = rise in internal Ca2+ concentration causes fusion of secretory vesicles within the cell membrane and release of insulin
Why can insulin be used as a marker for beta cells?
Beta cells are the only cells in the body that make and secrete insulin
When should beta cells make and secret insulin?
When blood glucose rises above 5mM
What happens to the beta cells of type 1 diabetics?
They are mostly lost
Why do beta cells lose the ability to sense changes in glucose in some forms of diabetes?
Due to hyperglycaemia taking glucose concentration outwith the Km of glucokinase
What kind of process in insulin release?
Biphasic process
What is the readily releasable pool in relation to insulin release?
5% of insulin granules are immediately available for release
What must happen to the reserve pool of insulin granules before they can be used?
It must undergo reactions to become mobilised and available for release
What happens to insulin secretion in poorly controlled type 2 diabetics?
It weakens and flattens = likely due to downregulation of the sensory process
What are the two proteins that make up the KATP channel?
Inward rectifier subunit (KIR) = pore subunit (Kir6)
Sulphonylurea receptor = regulatory subunit (SUR1)
What structure do KATP channels exist as?
Octameric structures
What can inhibit KATP?
Intracellular ATP inhibits KATP to elicit depolarisation
KATP is directly inhibited by sulphonylurea drug class
What can stimulate KATP to inhibit insulin secretion?
Diazoxide
What are SURs used for the therapy of?
Second line therapy for type 2 diabetics
What patients is SURs therapy most effective in?
Patients who have trouble injecting insulin
Patients who have improved their glucose control and lessened the stress on the islet
What can Kir6 mutations cause?
Neonatal diabetes = due to constitutively activated KATP channels or an increase in KATP numbers
What can be used to treat neonatal diabetes?
Some patients may have beta cells responsive to SURs (e.g tolbutamide) = can recover euglycaemia fairly quickly
What can some Kir6 or SUR1 mutations cause?
Congenital hyperinsulinaemia = caused by trafficking or inhibiting mutations
What can be used to treat congenital hyperinsulinaemia?
Diazoxide = can help inhibit secretions if channels are still getting to the membrane
What is maturity-onset diabetes of the young (MODY)?
Monogenic diabetes with genetic defects in beta cell function = familial form of early-onset type 2 diabetes, primary defects in insulin secretion
What type of MODY does mutations in glucokinase cause?
MODY 2 = glucokinase activity is impaired, defect in sensing glucose, blood glucose threshold for insulin secretion is increased
What type of MODY does mutations in HNF transcription factors cause?
MODY 1 and 3
What do HNF transcription factors do?
Play key role in pancreas foetal development and neogenesis, also regulate beta cell differentiation and function
Why is there robust genetic screening to differentiate MODY from type 1 diabetes?
Allows treatment of MODY with sulphonylurea instead of glucose
What causes type 1 diabetes?
Loss of insulin secreting beta cells
What causes type 2 diabetes?
Reduced insulin sensitivity
What does insulin cause in the body when activated?
Amino acid uptake in muscle, DNA/protein synthesis, growth receptors, glucose uptake in muscles/adipose tissue, lipogenesis in adipose tissue/liver, glycogen synthesis in liver/muscle
What does insulin cause in the body when inactivated?
Lipolysis, gluconeogenesis in the liver
How does insulin signalling occur?
Via a cascade
What is the insulin receptor?
Receptor tyrosine kinases
What does binding of insulin to alpha subunits cause?
Causes beta subunits to dimerise and to phosphorylate themselves, thus activating the catalytic activity of the receptor
What is severe insulin resistance associated with?
Obesity (type 2 diabetes) and complete loss of adipose tissues
What causes monogenic severe insulin resistance?
Mutations in key signalling pathways
What is leprechaunism (Donohue syndrome)?
Rare autosomal recessive genetic trait = mutations in gene for insulin receptor cause severe insulin resistance
What are some features of leprechaunism (Donohue syndrome)?
Elfin facial appearance, growth retardation, absence of subcutaneous tissue and decreased muscle mass
What is Robson Mendenhall syndrome?
Rare autosomal recessive genetic trait = severe cases are linked to mutations in the insulin receptor that reduce sensitivity
What are some features of Robson Mendenhall syndrome?
Severe insulin resistance, hyperglycaemia, compensatory hyperinsulinaemia, developmental abnormalities, acanthosis nigricans, fasting hypoglycaemia, diabetic ketoacidosis
What are the symptoms of diabetic ketoacidosis?
Vomiting, dehydration, increased heart rate, smell on breath
Where are ketone bodies formed?
In the liver = derived from acetyl-CoA from the beta oxidation of fats
Where do ketone bodies spread to?
Diffuse into bloodstream and to peripheral tissues = important molecules of energy metabolism for the heart muscle and renal cortex
What do low levels of insulin do in the body?
Inhibit lipolysis and prevent ketone body overload
When can diabetic ketoacidosis occur?
In type 1 = if insulin supplementation is missed
In type 2 = more uncommon, occurs as insulin resistance and deficiency increases
When is acetyl-CoA diverted to ketones?
If the supply of oxaloacetate is limited
When is oxaloacetate consumed for gluconeogenesis?
When ketosis is occurring in glucose limiting states (starvation and diabetes)
What is oxidised when there is no glucose to breakdown to produce energy?
Fatty acids = causes excess acetyl-CoA which is then converted to ketone bodies
What causes dehydration in diabetic ketoacidosis?
High glucose excretion = dehydration exacerbates acidosis and can lead to coma or death
How is diabetic ketoacidosis treated?
Insulin and dehydration
