Diabetes Flashcards
Describe the different cells making up the Islet of Langerhans and their function
A cells = glucagon
B cells = insulin
D cells = somatostatin
PP cells = pancreatic polypeptide
What are the main modulators of blood glucose?
Insulin
Glucagon
Describe the role of insulin in blood glucose control
Decreases blood glucose concentration
Metabolism of carbohydrates, fats and proteins
Synthesises enzymes involved in glucose metabolism
Activation of RAS -> activation of MAP kinases -> DNA transcription -> RNA production -> enzyme synthesis
What activates insulin release?
Glucose
Increases ATP concentration inside B cells
Describe the role of glucagon in glucose control
Increases concentration of glucose in the blood
What processes do glucagon trigger that increase blood glucose concentration?
Glycogenolysis
Gluconeogenesis
Inhibition of glycogen synthesis
What are the two types of diabetes?
Type I
Type II
Pathogenesis of type I diabetes
B cells are destroyed in an autoimmune process
Insulin replacement therapy is essential
Pathogenesis of type II diabetes
Individuals are resistant to insulin
Fails to secrete sufficient hormone
Symptoms of type II diabetes
Wasting due to increased protein breakdown
Ketoacidosis due to increased fat metabolism
Osmotic diuresis due to decreased utilisation of glucose
Damage to blood vesels
Neuropathy
Conditions caused by damage to blood vessels due to diabetes mellitus
Retinopathy
Nephropathy
How does glycosuria and osmotic diuresis present?
Thirst
Polydypsia
What causes death in diabetes?
Ketoacidosis
How does ketoacidosis cause death?
Lipid metabolism causes the formation of ketones which decreases the pH
Leads to heart failure
What is the half-life of insulin following intravenous injection?
10 minutes
Why is the intravenous route of insulin administration inconvenient?
Short half-life
Constant injections are required to maintain a relatively high concentration in the body
What are ways to prolong the half-life of insulin?
Subcutaneous injection
Insulin hexamer
Protamine
Insulin glargine
Insulin analogues
Why can’t insulin be given by mouth?
Due to the proteolytic action of digestive enzymes
How much longer is the half-life of insulin following subcutaneous injection instead of intravenous injection?
From 10 minutes to 2-4 hours
Travels into the blood slower
How can an insulin hexamer be produced?
Bind insulin to zinc/other ionic metals
Why does insulin hexamer have a longer half-life?
Cannot diffuse as easily into the bloodstream
The molecule has to break down into simpler monomers to allow for appropriate diffusion
The breakdown prolongs the half-life of insulin
Who came up with the idea of using protamine to modify insulin’s half-life?
Hans
What is protamine?
Postively charged nuclear protein
How does protamine increase the half-life of insulin?
Clusters hexamers together
How long is the half-life of insulin using protamine?
8-9 hours
What is the name of protamine insulin?
NPH
Nuclear protamine Hans
What was the importance of NPH?
Meant the patient would survive the night
What technology allows for insulin glargine to be formed?
Recombinant technology
What are the distinguishing features of insulin glargine?
Long acting form
Peak-less
How does insulin glargine synthesis not lead to changes in insulin action?
Changing the amino acids in the insulin structure changes its activity
But insulin glargine is formed through changing the ends
Describe the process of making insulin glargine
One aspargine and two arginine molecules are added to the ends
This makes it less soluble
How does insulin glargine have a longer half-life?
Less soluble in physiologic pH
Through changing the pKa
The insulin therefore acts as a crystal in the body and does not dissolve
Injected once a day
What are insulin analogues?
Changes the structure of insulin
Two insulin analogues
Insulin detemir
Insulin lispro
How is insulin determir formed?
Fatty acid is bound to the lysine amino acid at position B29
How does insulin detemir increase the half-life of insulin?
B29 amino acid binds to albumin
Insulin slowly dissociates from this complex
How is insulin lispro formed?
Lysine and proline residues on the C-terminal end of the B-chain are reversed
When is insulin lispro used?
When insulin is required quickly
Through blocking the formation of insulin dimers and hexamers
Prevents hypoglycemia
Insulin forms used for long-term action
Insulin glargine
Insulin detemir
Insulin form used for quick effect
Insulin lispro
What are the two main targets of therapy for diabetes?
Increasing insulin concentration
Increasing insulin secretion
Drugs increasing insulin secretion
Sulphonylureas
Metformin
Acarbose
On which patients are sulphonylureas effective?
Patients with some functioning B cells
How do sulphonylureas work?
Mimics the action of glucose
- Glucose enters beta cells
- Converts into ATP
- ATP blocks K-ATP channels
- Calcium enters and causes insulin release
Blocks K-ATP channels
How does metformin work?
Increases glucose uptake into tissues
Inhibits gluconeogenesis
How does acarbose work?
Inhibits a-glucosidase
Delaying the carbohydrate absorption and reducing the rise in blood glucose that follows a meal
What is the best treatment for type II diabetes?
Exercise
Reversible condition
Why does ingestion of glucose cause increased insulin release than intravenous injection of glucose?
Autonomic system activation following smell and chewing activates neuroendocrine cells
Secrete peptide GLP1
GLP1 blocks K-ATP channels and increases insulin secretion
What are newer hypoglycemic drugs like?
Oral forms
Examples of newer oral hypoglycemic drugs
Meglitinides - block KATP
Thiozolidines - slow decrease in glucose by binding to transcription factor receptor
