Carbohydrate metabolism (gluconeogenesis and glycogen metabolism) Flashcards
Regulation of blood glucose
Maintenance of blood glucose levels essential
Too high: release of water from tissues due to osmotic pressure –> dehydration, death
Too low: lack of fuel to produce ATP –> coma –> death
Blood glucose too low
Lack of fuel to produce ATP
- brain depends on glucose as fuel –> coma
- RBCs low on ATP; can’t provide oxygen to tissues –> death
Hormones play critical role
Insulin
Glucagon
Others (adrenaline)
Glucagon: insulin ratio critical
> (more G, less I) causes release of glucose
< (more I, less G) causes uptake and storage of glucose (glycogen)
Three main sources of glucose
1. Diet 2 Glycogen degradation 3. Gluconeogenesis -2 and 3 critical during fasting Fatty acid oxidation provides energy but not glucose
Glycogen
Storage form of carbohydrates in humans
Major stores in liver and muscle
Fate different in these organs
Glycogen structure
Branched chains of glucose
Joined by α1-4 linkages with branching created by α1-6 linkages
One C joined to protein - glycogenin
Forms huge polymers
Glycogen function
Major storage form of carbohydrate
Acts as source of glucose for ATP generation
Serves different function in muscle and liver
Glycogen synthesis requires
Requires energy in form of UTP
Glycogen synthesis
- Glucose transferred from UDP glucose to glycogenin
- Glycogen synthase transfers glucose from UDP glucose to growing chain
- This forms α1-4 linkages
- When 11 residues reached, 6-8 are cleaved off and rejoined by α1-6 linkages by branching enzyme
Glycogen degradation
Carried out by 2 enzymes:
- Glycogen phosphorylase
- removes glucose molecules at end of chains - Debranching enzyme
- acts as transferase, removing glucose molecules near branch point
- also cleaves branch point
Regulation of metabolism: glycogen
Different in liver and muscle due to different requirements
In liver, glycogen metabolism regulates blood glucose levels
In muscle it responds to changes in energy (ATP) needs
Glycogen: regulation of metabolism (liver)
Regulated by hormones involved in blood glucose homeostasis
- insulin degradation
- glucagon >: > degradation
- adrenaline >: > degradation
Glycogen: regulation of metabolism (muscle)
Glycogen supplies glucose for ATP generation
Low ATP (=high AMP) stimulates glycogen degradation
Calcium and adrenaline also stimulate glycogen degradation
Glycogen: disorders of metabolsim
Can be caused by mutations in number of enzymes
May only effect liver enzymes or muscle enzymes
Differing severity
What happens when glycogen stores are exhausted?
Gluconeogenesis
Gluconeogenesis
Produces glucose from non-carbohydrate sources
Occurs only in liver except in extreme starvation
Important in maintaining availability of glucose:
-fasting/starvation
-intense exercise
Gluconeogenesis precursors
Non carb sources of glucose:
- aas: mainly alanine but other (aas –> pyruvate or aas –> TCA cycle)
- lactate: produced during intense exercise (lactate –> pyruvate)
- glycerol: derived from traicylgerols (fats) (glycerol –> glycerol 3-phosphate)
- propionate: derived from fermentation of fibre
Gluconeogenesis regulation
Two main regulatory factors:
- Substrate availability
- Activity of key enzymes
- energy required provided by fatty acid oxidation
Substrate availability (Gluconeogenesis regulation)
Gluconeogenesis promoted by higher substrate levels ie:
- when blood glucose low, low insulin/ high glucagon stimulates release of: glycerol from adipose tissue, amino acids from muscle
- intense exercise releases lactate from muscle
Enzyme activity (Gluconeogenesis regulation)
Three key regulatory steps:
i) Pyruvate –> phosphoenolpyruvate
ii) Fructose 1,6-bisphosphate –> Fructose 6-phosphate (opposite to glycolysis, fructose 2,6-bisphosphate is an inhibitor)
iii) Glucose 6-phosphate –> glucose
Can be allosteric or at level of gene expression
Ketone bodies
Produced from acetyl coA in liver
Only produced when gluconeogenesis taking place
Can be converted back into acetyl coA in tissues other than liver
Brain in particular can use (up to 70%) in absence of glucose - can cross blood-brain barries (fatty acids can’t)
Excessive production (e.g. starvation) –> ketosis –> smell of acetone on breath
Hormone changes after glucose meal
Glucose increases
Insulin increases dramatically
Glucagon spikes upward slightly then decreases
Beta-oxidation
Catabolic process in mitochondria
-fatty acid molecules broken down to generate acetyl-CoA (enters citric acid cycle) and NADH & FADH2 (co-enzymes used in e- transport chain)
Produces energy but not glucose
Fatty acyl CoA –> energy (beta-oxidation, ketogenesis); membrane lipids (phospholipids, sphingolipids); storage (tricylglycerols)
Journey of dietary carbohydrates
Starch/ lactose/ sucrose –> salivary alpha-amylase in mouth –> stomach (alpha-dextrins break down to sucrose and lactose) –> pancreas (alpha-amylase HCO3- to tri-and oligosaccharides maltose, isomaltose) –> small intestine (maltase and isomaltase to glucose; sucrose via sucrase to glucose and fructose; lactose via lactase to glucose and galactose)
Fiber (short chain fatty acids) via colon –> feces
Glycogen pathway in muscle
Glycogen –> glucose 1-phosphate glucose 6-phosphate –glycolysis–> ATP, Lactate, CO2
Glycogen pathway in liver
Glycogen –> glucose 1-phosphate glucose 6-phosphate –glucose 6-phosphatase–> glucose –> blood glucose
Gluconeogenesis –> Glucose 6-phosphate
Glycogen disorders of metabolism examplese
Type 0 (glycogen synthase affected)
-affects liver
-hypoglycaemia, hyperketonemia, failure to thrive, early death
Type Ib (glucose 6-phosphatase affected): von Gierkes disease
-affects liver
-enlarged liver and kidney, growth failure, fasting hypoglycaemia, acidosis, lipemia, thrombocyte
Type II (lysosomal alpha-glucosidase): Pompe disease
-affects all organs with lysosomes
-infantile form: early-onset progressive muscle hypotonia, cardiac failure, death before 2 years
-juvenile form: later-onset myopathy with variable cardiac involvement
-adult form: limb-girdle muscular dystrophy-like features; glucogen depoits accumulate in lysosomes
Fasting timeline
0-3 hours: glycogen and fatty acid synthesis
3-30 hours: glycogen degradation, fatty acid oxidation, gluconeogenesis
30+ hours: gluconeogenesis
Gluconeogenesis vs glycolysis
Glycolysis: breakdown of glucose into pyruvate
Gluconeogenesis: creation of glucose from pyruvate, lactate or Krebs cycle intermediaries
Pathway differences in 1 way arrows:
-glucose 6-phosphate –glucose 6-phosphatase–> glucose
-fructose 1,6-bisphosphate –fructose 1,6-bisphosphatase–> fructose 6-phosphate
-pyruvate –pyruvate carboxylase and phosphoenolpyruvate carboxykinase–> phosphoenolpyruvate
Fasting
- Blood: < glucose, < insulin, > glucagon
- Glycogen –> glucose in liver
- Glucose to acetyl CoA in brain
- Glucose to lactate in RBC
- Triglycerol–> fatty acid in adipose
- Fatty acid –> acetyl CoA in muscle
- Acetyl CoA –> [ATP] or ketone bodies in liver
- ketone bodies –> acetyl CoA in muscle
- AA –> glucose in liver
- Urea –> urine via kidney
- Lactate –> glucose in liver
- Glycerol –> glucose in liver