Haematology Metabolism Cheat Sheet
Metabolic Syndrome
Three types of diabetes
o Type one - autoimmune attack
o Type two - Metabolic syndrome
o Gestational Diabetes
Metabolic syndrome is a cluster of medical disorders that increase the risk of type 2 diabetes
and cardiovascular disease
o Factors that contribute include obesity, insulin resistance and hyperglycaemia
Obesity and Diabetes
Obesity causes defective insulin responsiveness leading to insulin resistance
o This results in compensatory beta cell function leading to hyperglycaemia
Obesity causes insulin resistance due to inflammatory, adipocrine and lipid stress
Insulin Signalling Pathway
Insulin > IR > IRS1 > PI3K > AKT2 > GLUT4 > Glucose Uptake
Fatty Acid Oxidation
Fatty acids accumulate due to biosynthesis, storage, transport, catabolism and from dietary
intake
The body performs fatty acid oxidation by
o Mitochondrial beta oxidation
o ATP/ADP ratio
o Energy expenditure
Insulin Resistance
Fatty acids cause beta oxidation however limiting oxidative catabolism causes the build up of
harmful intermediates
o This activates protein kinases and results in decreased glucose uptake
Lipid intermediates are formed from insulin resistance which include
, o GM3
o DAG
o Ceraminde
o Acylcarnitine
Insulin resistance affects mitochondrial activity including glucose uptake, glycogen and
protein synthesis and mitochondrial biogenesis
Holloszy Argument
This states that mitochondrial capacity does not limit fatty acid oxidation in obesity
Pancreatic Beta Cells
Pancreatic beta cells cause glucose stimulated insulin secretion
This occurs due to a rise in ATP from glycolysis, TCA and OXPHOS
o This causes depolarisation of voltage gated Ca2+ channels
o An increase in Ca2+ in the nucleus causes insulin secretion
Pancreatic beta cell failure causes glucolipotoxicity
o This can cause impaired glucose secretion
Sulphonylureas also trigger insulin secretion by binding to SUR1 subunits of K ATP channels
which closes them
Reactive Oxygen Species
ROS have unpaired electrons
The production of free radicals required NADPH
A one electron reduction yields a superoxide anion radical which reacts with anything it
bumps into
o Oxygen + Ie- = superoxide
A two electron reduction yields hydrogen peroxide
A singlet oxygen is formed when one electron is excited to a higher energy level
Transition metals donate or accept free electrons via intracellular reactions to help create
free radicals
SOD is an enzyme that catalyses the dismutation of the superoxide radical into either
molecular oxygen or hydrogen peroxide
In the mitochondria, ROS cause
, o Redox signalling
o Mitochondrial dysfunction
o Apoptosis and necrosis
o Disease and ageing
ROS Measurements
ROS are measured using
o Fluorescent probes
o Mass Spec probes
o ESR probes - spin of unpaired electrons can be detected using ESR spectroscopy
Small fluorescent probes are used to detect superoxide
o These include DCFH and hydroethidine
Hydroethidine can target mitochondria using MitoSOX
Free radicals can be stabilised using spin traps
o Spin traps covalently bind free radicals producing adducts that can be detected by
electron spin resonance
Cellular Respiration
Proton slip is a decrease in pumping efficiency due to partial and variable decoupling of
chemical reaction and proton transfer
Proton leak is when proton return to the matrix independently of ATP synthase
o Uncoupling proteins act as channels to let protons flow
Electron leak is the exit of electrons prior to the reduction of oxygen to water at cytochrome
C oxidase causing a production of superoxide
Electron slip is where electrons are transferred through respiratory complexes without
pumping protons into the intermembrane space
Fenton’s Reaction
In Fenton's reaction, the ferrous and/or ferric cation decomposes catalytically hydrogen
peroxide to generate powerful oxidizing agents
Capable of generating both hydroxyl radicals and higher oxidation states of iron causing free
radical damage
Metabolic Syndrome
Three types of diabetes
o Type one - autoimmune attack
o Type two - Metabolic syndrome
o Gestational Diabetes
Metabolic syndrome is a cluster of medical disorders that increase the risk of type 2 diabetes
and cardiovascular disease
o Factors that contribute include obesity, insulin resistance and hyperglycaemia
Obesity and Diabetes
Obesity causes defective insulin responsiveness leading to insulin resistance
o This results in compensatory beta cell function leading to hyperglycaemia
Obesity causes insulin resistance due to inflammatory, adipocrine and lipid stress
Insulin Signalling Pathway
Insulin > IR > IRS1 > PI3K > AKT2 > GLUT4 > Glucose Uptake
Fatty Acid Oxidation
Fatty acids accumulate due to biosynthesis, storage, transport, catabolism and from dietary
intake
The body performs fatty acid oxidation by
o Mitochondrial beta oxidation
o ATP/ADP ratio
o Energy expenditure
Insulin Resistance
Fatty acids cause beta oxidation however limiting oxidative catabolism causes the build up of
harmful intermediates
o This activates protein kinases and results in decreased glucose uptake
Lipid intermediates are formed from insulin resistance which include
, o GM3
o DAG
o Ceraminde
o Acylcarnitine
Insulin resistance affects mitochondrial activity including glucose uptake, glycogen and
protein synthesis and mitochondrial biogenesis
Holloszy Argument
This states that mitochondrial capacity does not limit fatty acid oxidation in obesity
Pancreatic Beta Cells
Pancreatic beta cells cause glucose stimulated insulin secretion
This occurs due to a rise in ATP from glycolysis, TCA and OXPHOS
o This causes depolarisation of voltage gated Ca2+ channels
o An increase in Ca2+ in the nucleus causes insulin secretion
Pancreatic beta cell failure causes glucolipotoxicity
o This can cause impaired glucose secretion
Sulphonylureas also trigger insulin secretion by binding to SUR1 subunits of K ATP channels
which closes them
Reactive Oxygen Species
ROS have unpaired electrons
The production of free radicals required NADPH
A one electron reduction yields a superoxide anion radical which reacts with anything it
bumps into
o Oxygen + Ie- = superoxide
A two electron reduction yields hydrogen peroxide
A singlet oxygen is formed when one electron is excited to a higher energy level
Transition metals donate or accept free electrons via intracellular reactions to help create
free radicals
SOD is an enzyme that catalyses the dismutation of the superoxide radical into either
molecular oxygen or hydrogen peroxide
In the mitochondria, ROS cause
, o Redox signalling
o Mitochondrial dysfunction
o Apoptosis and necrosis
o Disease and ageing
ROS Measurements
ROS are measured using
o Fluorescent probes
o Mass Spec probes
o ESR probes - spin of unpaired electrons can be detected using ESR spectroscopy
Small fluorescent probes are used to detect superoxide
o These include DCFH and hydroethidine
Hydroethidine can target mitochondria using MitoSOX
Free radicals can be stabilised using spin traps
o Spin traps covalently bind free radicals producing adducts that can be detected by
electron spin resonance
Cellular Respiration
Proton slip is a decrease in pumping efficiency due to partial and variable decoupling of
chemical reaction and proton transfer
Proton leak is when proton return to the matrix independently of ATP synthase
o Uncoupling proteins act as channels to let protons flow
Electron leak is the exit of electrons prior to the reduction of oxygen to water at cytochrome
C oxidase causing a production of superoxide
Electron slip is where electrons are transferred through respiratory complexes without
pumping protons into the intermembrane space
Fenton’s Reaction
In Fenton's reaction, the ferrous and/or ferric cation decomposes catalytically hydrogen
peroxide to generate powerful oxidizing agents
Capable of generating both hydroxyl radicals and higher oxidation states of iron causing free
radical damage
