regulating and integrating metabolism

insulin

• what is it secreted by

• which nervous sytem

• what does it do

• secreted by pancreas in response to high blood sugar and parasympathetic nervious system

• indicates fed state and stimulate use and storgage of fuels

• decrease hepatic glucose production

• increase glycogensisand glycolysis

• increase protein synthesis

• increase lipogenesis and decrease lipolysis

GLUT 4

• where is it expressed

• where is it seqestered within

• insulin responsive glucose transporter

• expressed is skeletal muscle, apidose tissue, cardiac muscle

• sequestered within specialised storage vesicles within the cytoplasm GSVs

• activation of the PI3K pathway in response to insulin signalling results in phosophorylation of AS160 (an activating protein) which stimulates translocation of GSVs (GLUT4 storage vesicles) to the plasma membrane from the cytoplasm

• GLUT 4 at the plasma membrane permits facilitated diffusion of glucose into cells

• GLUT 4 translocation in skeletal muscle is also stimulated by exercise mediated mechanism

hexokinase

• expressed in most tissues, high affinity for glucose

• active enzyme even when blood glucose is low

glucokinase

• expressed in liver and pancreas, low affinity for glucose

• enzyme active when blood glucose is high

what determines ability of GLUT isoforms to take up glucose

tissue expression patterns

glucagon

• secreted by pancreas in response to low circulating blood sugar levels

• indicates the fasted state and stimulates the release of stored fuels as well as changing fuel usage

• increase hepatic glucose production, glycogenolysis, protein catabolism, lipolysis

liver function in omnivores

buffers large changes in blood glucose

liver function in carnivores and ruminants

continually produces glucose

carnivores-adaptive insulin resistance

• metabolically adapted to a high protein low carb diet

• adaptations such as low expression and activity of heptatic glucokinase

• liver therefore maintains consistent blood glucose through protein metabolism and gluconeogesis using gluconeogenic amino acids

• carnivores tend to be naturally insulin resistant ot conserve glucose for vital tisses

• so suscpetible to periods of fasting hyperglycaemia which can cause compensator hyperinsulinemia. in chronic cases due to obesity or poor diet domestic cats can develop diabetes

ketogenesis

• normal part of the exended fasting response

• low insulin/high glucagon ratio stimulates the breakdown of stores

• fatty acids from triacylglycerol undergo beta oxidaition to produce acetyl coA

• then Aceyl coa is converted to ketone bodies:β-hydroxybutyrate • Acetoacetate • Acetone

• used as fuel by the brain, heart and muscles where they are onverted abck to acetyl coa to enter the tca cycle to produce nadh and fadh2 that are used by the etc and oxidative phosphorylation ot produce atp

ketosis

normal metabolic state where the body predominantly metabolises fat due to insufficient glycogen stores and the accumulted acetyl coa is used to geenrate ketone bodies

ketoacidosis

dangerous, life threatening condition where the blood becomes too acidic due to ketone body accumulation

can cause coma and death

overview of phases of glucose control

• exogenous glucose, blood glucose concentration increases

• insulin is released decreasing plasma glucose conc

• hepatic glycogenolysis occurs

• gluconeogenesis then surpasses glycogenolysis as a result of glycogen store depletion

• free fatty acid concentration increases as a result of lowering insulin concentration allowing for apidose tissue lipolysis

• enters starvation, free fatty acids undergo beta oxidation to increase plasma ketone body concentration

mechanism of the activation of the PI3K pathway in response to insulin signalling

• where doe insulin bind

• what does this phosphorylate and where

• what binds to the new molecule

• what does this catalyse

• what does the reuslting molecule act as and what does it bind to

• what does this phosphorylate

• what does this phosphorylate

• what does this activate

• what does this trigger

1. insulin binds to the insulin receptor, activating it

2. this phosphorylates the IRS-1 proteins on tyrosine residues

3. PI3K binds to the phosphorylated tyrosine residues activating PI3K

4. this catalyses the conversion of PIP2 to PIP3

5. PIP3 acts as a second messenger, and binds to pdk1 causing a conformational change which activates it

6. pdk1 phosphorylates akt

7. this phosphorylates AS160

8. phosphorylated AS160 causes activation of Rab

9. this triggers translocation of GSV

km

• low means a higher affinity for glucose

• high means a lower affinity for glucose