Coordinating metabolism - Insulin and Glucose Transport Flashcards
Describe metabolic homeostasis
The body’s ability to maintain various metabolic processes to ensure molecules essential for life are kept at an optimal level
- requires the interplay of the digestive system, the seining of nutrients, the endocrine system, the nervous system and many different signal transduction events
- disruptions lead to metabolic disorders such as diabetes, obesity and metabolic syndrome
describe fuel utilisation by different tissues
- liver and muscle can use all fuels, except liver can’t use ketones (it makes them but can’t use them)
- brain can’t use FFA’s as they can’t cross the blood brain barrier
- RBCs can’t use FFAs because they don’t have mitochondria
- adipose is specialised in utilising fats
describe the fuels preferred by different tissues (fuel store, preferred fuel, fuels exported)
Brain:
- fuel store: none
- preferred fuel: glucose, ketone bodies (during fasting)
- fuels exported: none
Skeletal muscle (resting):
- fuel store: glycogen
- preferred fuel: fatty acids
- fuels exported: none
Skeletal muscle (excerisise):
- fuel store: none
- preferred fuel: glucose, fatty acids, branched-chain, amino acids
- fuels exported: lactate, alanine
Heart muscle (exercise):
- fuel store: none
- preferred fuel: fatty acids
- fuels exported: none
Adipose tissue:
- fuel store: triacylglycerols
- preferred fuel: fatty acids
- fuels exported: fatty acids, glycerol
Liver:
- fuel store: glycogen
- preferred fuel: amino acids, glucose, fatty acids
- fuels exported: triacylglycerols (VLDL), glucose, ketone bodies
RBCs:
- fuel store: none
- preferred fuel: glucose
- fuels exported: lactate
Describe insulin
- peptide hormone
- synthesised in pancreas by beta cells
- secreted in response to high glucose (after a meal)
- acts on liver, muscle and adipose tissue to promote glucose transport and use
- the body starves without it
5.8 kDa
51AA
describe type I diabetes
Signs of Type I diabetes:
- extreme thirst
- frequent urination
- weight loss
- excessive hunger
- tiredness
- blurry vison
- fruity breath
- poor wound healing
- early onset form of diabetes
- diagnosed by symptoms, blood glucose and glycated haemoglobin
- glycosuria (glucose in urine) and presence of ketones (fruity breath)
- many complications arise from elevated glucose levels (cardiovascular, and kidney complications incl.)
- autoimmune conditions that leads to loss of pancreatic beta cells and therefore no insulin secretion
- in contrast type 2 diabetes where insulin is made but the response to it is poor
describe insulin processing in the pancreatic beta cell
Insulin gene is transcribed in the nucleus and then translated in the rough ER ribosomes. It gets produced as a preproinsulin that has a signal peptide on it and tells it to go to the ER and that it is a secretory molecule. This gets cleaved off in the ER, and folding occurs.
Proinsulin is trafficed to the Golgi where it forms sectory granules, which has a protease in it (pro protein converts enzymes) that cleaves the C-peptide from the alpha and beta chain to give the mature insulin molecule.
Both the C and alpha and beta peptides are secreted.
describe the features of the C-peptide and how this is useful
- has a longer half-life than insulin
- is a marker of insulin secretion and beta cell function ie. high levels are indicative of insulinoma
- levels can be used to detect inappropriate administering of insulin
- can use the ratio of C-peptide to insulin to see if the person had endogenous or exogenous insulin in them
describe how glucose os the main stimulator of insulin secretion
- glucose transpire into pancreatic cell via GLUT-1
- glucose metabolism via glycolysis and TCA cycle increase ATP levels
- an increase in the ATP/ADP ratio closes the ATP-gated K+ channels
- which triggers membrane depolarisation and opening of voltage-gated Ca2+ channels
- the Ca2+ influx induces exocytosis of insulin-containing secretory vesicles
- transcription and translation of the insulin gene gives rise to pre-proinsulin
- after cleavage of the signal peptide in the ER, proinsulin is folded (stabilised by the disulphide bonds), trafficked bia the Golgi and placed in secretory vesicles where it is cleaved into insulin and C-peptide and secreted on stimulation by glucose
what changes do you see in response to eating in the glucose and insulin levels
Glucose goes up, and then you get a delayed spike in insulin levels.
- things that have more carbs spike the glucose levels more, and it also depends on the type of carb
- simple sugar gets into the bloodstream faster because it doesn’t require as much digestion
- whereas complex carbs need to be broken down
describe how other molecules affect insulin signalling
There are many other molecules that can modulate insulin secretion but we are specifically talking about GLP-1.
- something produced in the intestine was potentiating insulin secretion, later discovered to be the glucagon-derived GLP-1 peptide (causes a bigger spike in insulin levels than injected glucose)
- GLP-1 is a product of glucagon processing in the L-cells of the intestine (which is an example of different processing of the same peptide hormone in different cell types) - proglucagon is cleaved by L-cells to get the GLP-1 section out.
- the same proglucagon gene is cleaved by the pancreatic alpha cells to get glucagon out
describe how GLP-1 potentates insulin secretion in beta-cells
- peptide hormone synthesised in the intestine
- synthesised in response to nutrients ie. amino acids
- made from glucagon via convertase enzyme
- acts through its receptor (GPCR receptor) to stimulate insulin secretion (by activating second messengers and signal transduction through the cell, better than the way glucose does it)
- GLP-1 agonists developed to treat type 2 diabetes
describe how GLP-1 agonists have been developed to treat diabetes
- they are only approved for Type-2 diabetes in NZ, but they can also be used for weight loss (they will just be expensive bc not funded of whatever)
- comes with some side effects ie. nausea, diarrhoea, gastroaresis, and depression
describe how GLP-1 has many actions
GLP-1 has an effect on many areas of the body, but the ones we are focusing on are:
- diabetes
- brain: tells it to reduce food intake (reduces your appetite)
- stomach: slows down gastric emptying (which reduces appetite too)
what are the actions of insulin?
STOP:
Gluconeogenesis, ketogenesis, lipolysis, proteolysis, glycogenolysis
GO:
Glucose uptake in muscle and adipose tissue, protein synthesis, glycogen synthesis, TAG uptake and fatty acid synthesis
describe insulin signalling and glucose transport
- GLUT4 in muscle and adipose cells is found in intracellular storage vesicles
- upon insulin binding to its receptor, a phosphorylation cascade is activated that regulates the trafficking of GLUT4 vesicles to the plasma membrane by regulating vesicle trafficking proteins
- insulin receptor is a RTK - so does autophosphorylation and phosphorylation of an adaptor protein (IRS)
- AS160 is the protein that is activated that interacts with RAB10. RAB10 is what usually holds the vesicles with GLUT4 transporters inside them inside the cell, but once RAB10 is activated the vesicles can go to the cell surface
GSV = GLUT4 storage vesicles
AS160 (aka TBC1D4) regulates GTPase protein Reb10 which is involved in the retention and trafficking of vesicles
