Insulin Secretion and Intermediary Metabolism (4) Flashcards
what hormones are involved in increasing blood glucose levels
glucagon. catecholamines. somatotrophin. cortisol
what is T1DM
defined as elevated glucose where insulin is required to prevent ketoacidosis
what is T2DM
more common than T1DM and is a considerable health burden. It is defined in terms of glucose but is also related to hypertension and dyslipidaemia
What are the complications of diabetes
Diabetic retinopathy. Nephropathy. Heart attacks. Stroke
why is glucose important
very important energy substrate, particularly for the CNS which mainly respires glucose under normal conditions.
What happens if blood glucose falls below 4.0-5.5mM (hypoglycaemia)
brain function is increasingly impaired.
what happens if blood glucose falls below 2mM
could lead to unconsciousness, coma and death.
what is most of the pancreas involved in (98%)
exocrine secretions via duct to small intestine
what is the remaining 2% of the pancreas
Islets of Langerhans which are clumps of cells with a specific endocrine function.
what do the beta cells of the islets of Langerhans do
secret insulin
what do the delta cells of the islets of Langerhans do
secrete somatostatin
what does somatostatin do
decrease the production of insulin and glucagon
what does somatostatin do
decrease the production of insulin and glucagon (negative hormone). mainly paracrine effects.
What is paracrine control
Cells in the pancreas have Gap Junctions which allow the hormones to have an effect on adjacent cells - paracrine effect. They allow small molecules to pass directly between cells. There are also small collections of fluid between cells formed by Tight Junctions.
what does insulin do
stimulates growth and development in utero and child. decreases blood glucose (metabolic pathway)
what does glucagon do
increases blood glucose
What factors increase insulin secretion from beta cells
increase in blood glucose. certain amino acids, certain gastrointestinal hormones. glucagon from alpha cells. parasympathetic activity (beta receptors)
what factors inhibit insulin secretion from beta cells
sympathetic activity (alpha cells) and somatostain from delta cells
what are the effects of insulin release
increased aa transport and increased protein synthesis. decreased lipolysis and increased lipogenesis. increased glycogenesis and increased glycolysis. increased glucose transport into cells via GLUT4. decreased blood glucose.
what factors stimulate glucagon secretion from alpha cells.
Certain GI hormones. Certain amino acids. sympathetic nervous activity. decreased blood glucose
what are the effects of glucagon release
increased amino acid transport into liver and increased lipolysis –> increased gluconeogenesis –> increased blood glucose. increased hepatic glycogenolysis
what factors inhibit glucagon secretion from alpha cells
Beta cells secreting insulin. parasympathetic nervous activity (alpha-receptors). Somatostatin
What does glucokinase (aka hexokinase IV/the glucose sensor) do
Glucokinase is the Rate Determining Step that regulates insulin secretion. Glucose is transported into beta cell via GLUT 2. Glucose is converted to glucose-6-phosphate using Glucokinase, synthesising ATP Via metabolic pathways. G6P results in insulin synthesis and release from the beta-islet cell
Synthesis of insulin
Insulin is a two chain (a and b) polypeptide hormone which is synthesised from pre-proinsulin in the ER. Removal of the pre-peptide leads to pro-insulin. Cleaved at amino acid 64 and 32. Cleavage produces c-peptide and the alpha and beta chains of insulin. A and B chains of insulin are held together by disulphide bonds and is transported to the Golgi apparatus. It is packaged into vesicles and proteolysis of the link between A and B chains occurs resulting in Insulin and C-Peptide
How can measurments of c peptide be used to assess pancreatic function
The molar ratio of insulin to C peptide is 1:1 so by measuring C peptide you can measure endogenous insulin production and see if the beta cells are functioning. Insulin being released by the pancreas is always released with C peptide
whow is insulin secreted
Glucose enters through GLUT2. Glucose –> G6P + ATP
ATP inhibits ATP dependent potassium channels causing depolarization. Voltage dependent calcium channels open and calcium enters beta cell. Then a calcium-calmodulin-dependent-kinase causes exocytosis of insulin vesicles
What is the incretin effect
food stimulates more insulin secretion if given orally rather than intravenously
What is glucagon like peptide-1 (GLP-1)
A gut hormone that mimics Glucagon and is secreted in response to specific nutrients in the gut. It stimulates insulin and suppresses glucagon. It also increases satiety. A transcription product of proglucagon gene, mostly from L cell. Short half life due to rapid degredation from dipeptidyl- peptidase 4.
what is first phase insulin
stored insulin which is released directly after a meal. important in switching off liver glucose production
what is second phase insulin
newly synthesised insulin which is released over a couple of hours, and increases food storage (glycogenesis)
describe the insulin receptor
The 2 extracellular alpha subunits- recognise and bind to insulin. 2 transmembrane beta subunits with tyrosine kinase domains. Binding of insulin causes a conformational change in tyrosine kinase domains. Also autophosphorylation
and cross -phosphorylation
of receptors occurs. Conformation change leads to phosphorylation of cell protein substrates
what are the three domains of the beta subunit
Extracellular associated with alpha subunit. Transmembrane. Intracellular with Tyrosine Kinase activity.
