Diabetes: insulin secretion and intermediary metabolism Flashcards
What are the hormones involved in regulating blood glucose?
- Insulin- reduces blood glucose
- glucagon, catecholamines, somatotrophin and cortisol can increase blood glucose
How do you define type 1 diabetes mellitus
It is defined by elevated glucose where insulin is required to prevent ketoacidosis
What is type 2 diabetes mellitus?
More common and a more considerable health burden. It is defined in terms of glucose but is also related to hypertension and dyslipidaemia.
What is MODY?
Maturity onset diabetes of the young
Patients are not insulin requiring but they develop it young. Range of single gene disorders causing diabetes. It allows us to understand more about t2 diabetes.
What are some complications of diabetes?
Diabetic retinopathy
Heart attack
Stroke
Nephropathy
Why is glucose important?
It is an important energy substrate, particularly for the CNS which relies on it almost entirely under normal conditions.
Normal blood glucose levels are 4-5 mM
If it falls below this, it is hypoglycaemia, the brain function is increasingly impaired.
if the concentration falls below 2mM, unconsciousness, coma and death can result
What is the composition of the pancreas?
98% of the pancreas is associated with exocrine secretion via duct to small intestine
2%- small clumps of cells within pancreatic tissue called Islets of Langerhans
What cells make up the islets of langerhans?
Alpha- glucagon
beta- insulin (insulin stimulates growth and development)
gamma- somatostatin (reduces production of insulin and glucagon)
Cells in the pancreas have gap junctions that allow small molecules to pass directly between cells- so the paracrine effect can occur.
Tight junctions- small collections of fluid with high hormone concentration
What happens when the blood glucose is high (and factors that affect insulin secretion?)
Beta cells produce insulin. Insulin causes increased glycogenesis and glycolysis. There is increased transport into cells via GLUT4 transporter, and there is decreased blood glucose.
- Insulin causes decreased lipolysis and increases lipogenesis
- Insulin prevents the breakdown of proteins, increased amino acid transport and proteinsynthesis
There are several factors that can control secretion of insulin:
- Some gastrointestinal hormones and amino acids increase insulin secretion, this ensures that there are stores of glucose. In particular glucagon like peptide makes us produce insulin.
- Control of insulin involves sympathetic stimulation (switch off insulin to increase blood glucose concentration- alpha cells) and parasympathetic stimulation (increase insulin stimuation- Beta cells)
- Gamma cells produce somatostatin which suppresses insulin and glucagon production.
What happens when blood glucose is decreased?
glucagon is secreted from alpha cells in the islets of langerhans.
- This means that there is increased amino acid transport into the liver, increased gluconeogenesis
- There is increased lipolysis, increased gluconeogenesis
- The main effect is increased hepatic glycogenolysis
- All of these physiological changes will increase blood glucose
What is the importance of glucokinase? I.e. how does the pancreas know how much insulin to make?
It is known as the glucose sensor= it is the rate determining step that regulates insulin secretion
Glut 2 receptors allows glucose to enter Beta cells. Glut 2 is not insulin regulated.
Glucose is converted to glucose-6-phosphate by glucokinase which is important for sensing glucose concentration and insulin synthesis
What is the structure of insulin?
Insulin is originallyu constructed as pre-proinsulin.
Pre-proinsulin consists of 3 chains forming one long chain with a signal sequence. (2 chains and a connecting one)
The c peptide is removed.
Insulin released from the pancreas is released with the C peptide along side
Clinical importance of the C peptide
The molar ratio between insulin and c peptide is 1:1 so you can measure endogenous insulin production to see if beta cells are working
C peptide stays a long time in the blood so you can measure it in patients to see if their pancreas is working. High levels in the blood can be pancreatic tumour too.
How is insulin released?
Glucose taken up by glut 2. ATP from metabolism of the glucose means potassium channels open. Voltage change means that ca channels open. Insulin In vesicles are released.
WHat is the incretin effect?
When there is food in our intestine, we start to produce insulin. In this particular exp, someone is given 50g oral glucose load and a matched intravenous infusion of glucose to cuase exactly the same glucose profile.
When given the oral glucose, he makes considerably more insulin- this is the incretin effect- food stimulates more insulin secretion if given orally rather than intravenously
What is first phase insulin release? (FPIR)
A person with T2DM has next to no first phase insulin (no store)- it is produced after glucose intake. First phase insulin release is important in switching off liver glucose production. If someone has an oral glucose load, you don’t see the first phase because its over 30 minutes.
How does the insulin receptor work?
Mostly in muscle but on liver too. Abnormalities in the receptor is not responsible for type 2 diabetes.
insulin is a protein/polypeptide hormone which does not cross membranes. The alpha subunit of the insulin receptor recognises the 3D shape of insulin. This causes a conformational change in the beta subunits. They cross the membrane and this has a metabolic effect on glucose, amino acids and fatty acids.
It also has an effect on growth (mitogenic pathway)
Insulin resistance is not caused by the receptor not being able to recognise the insulin protein or due to the transmembrane portion of the receptor not working.
Insulin resistance lies in the post receptor cytoplasmic elements of insulin function.
