the starved state Flashcards
food restriction
- fasting state 2-4h after meal
- > blood glucose falls to basal levels
- > insulin declines, glucagon rises
- triggers fuel release- TAG breakdown, glycogen mobilization.
- the fasting state is catabolic- breaking down.
- after 3 or more days we are in the starved state
starvation
survival time depends on amount of adipose tissue and protein levels.
proteins will be concerted to glucose. protein depletion can lead to vital organs malfunctioning or infection.
deprived of vitamins and minerals- precursors of coenzymes.
death occurs when 30-50% of body protein, 70-95% of fat has been used.
2 main priorities:
1) maintain adequate blood glucose
2) mobilise FAs and synthesise/ release ketone bodies
body stores
Body stores:
Body fuels are readily oxidizable
Carbohydrates are stored as glycogen [75g in liver, 400g in muscle]
- Fluctuates during the day
- Binds water as polar molecule so not practical to store all ‘energy’ as glycogen
70kg male has ~15kg fat
- Can fast as long as 90 days in extreme cases
- Triaglycerols contains more calorie per gram than carbohydrate or protein
9 kCal/g vs. 4 kCal/g
Not much water (∴ 15 kg = 18 kg)
The same energy content in the form of glycogen would weigh 34kg, due to water
- Body protein [particularly muscle mass] can also be used
the brain- fuel use
- glucose is primary fuel [except during starvation]
- ketones used in starvation.
- FAs can’t cross BBB as bound to albumin
muscle fuel use
- Fuel- glucose, FA, and ketone bodies
- Glycogen store can be converted to glucose by glucose-6-phosphate for contraction
- FAs are used by resting muscle [85%] of needs
- Glucose prioritized for contraction
heart- fuel use
- FAs, ketone bodies, lactate
- no glycogen reserves
adipose tissue fuel use
- needs glycerol 3-phosphate to create triacylglycerols
- So will need glucose for glycolytic intermediate- Dihydroxyacetone phosphate
- Reduction = G-3-P
liver fuel use
- Myriad of roles and responsibilities
- Provides fuel to brain, muscle and peripheral organs
Metabolises carbohydrates [~2/3rds of it glucose] to form glycogen
Turns fatty acids into ketone bodies
Utilizes amino acids carbon skeletons [alpha-ketoacids] as its own energy source
carbohydrate metabolism
Carbohydrate metabolism:
- In the starving state, the livers main role is to produce glucose by glycogenolysis and gluconeogenesis. Also, ketone bodies are produced are produced for non-glucose dependent tissues.
Rates of glycogenolysis and gluconeogenesis will drop as usage by rest of tissues drops during prolonged starvation
- Glycogen degradation occurs first, followed by gluconeogenesis
Increased glucagon-to-insulin ratio= PKA-mediated phosphorylation of glycogen phosphorylase kinase -> increased phosphorylation of glycogen phosphorylase -> glycogen breaking down
amino acids used for biosynthetic functions
E.g. haem synthesis, neurotransmitters formation
- The breaking down of AAs in gluconeogenesis results in increased nitrogen which is converted to urea [output decreases as starvation continues]
fat metabolism
- Fatty acid oxidation is the major energy source in liver tissue
These originate in TAGs from adipose tissue
Malonyl CoA drop permitting CPT-1 to activate and beta-oxidation occurs
NADH produced inhibits the TCA cycle
Acetyl CoA produced activates pyruvate carboxylase and inhibits pyruvate dehydrogenase
- gluconeogenesis is increased - Increased ketone body synthesis occurs [acetoacetate and 3-hydroxybutyrate]
These will be transported- not used by liver, as lacking thioporase enzyme
Favoured when acetyl CoA exceeds TCA cycle capacity
adipose tissue- carbohydrate metabolism
- Glucose transport is depressed as GLUT-4 is insulin sensitive [and insulin is decreased]
- Reduction in insulin means less glucose entering the cell so decreasing glycolysis and decreased TAG synthesis
adipose tissue: fat metabolism
- Adipose triaglycerols are mobilized by lipolysis
Releases FAs and glycerol-glycerol used by liver for gluconeogenesis
Mediated by HSL
HSL enhanced by elevated catecholamines e.g. adrenaline
FA usage increases with length of fast - Increased release of fatty acids
Hydrolysis of TAGs release FAs
Bound to albumin they act as fuel for a variety of tissues
Glycerol can also be used as a gluconeogenic precursor in the liver - Decreased uptake of fatty acids in adipose tissue
Because adipose LPL activity is low
resting skeletal muscle
- During fasting, resting muscle moves even further from using glucose to using FAs and ketone bodies
For contraction: as glycogen depleted, FAs mobilized from TAG [adipose tissue] become the dominant energy source - Carbohydrate metabolism
Glucose transported is depressed as GLUT-4 is insulin sensitive [insulin is low in the starved state]
Reduced glycolysis etc. - Lipid metabolism
During the first 2 weeks, muscles use FA from adipose tissue and ketone bodies from liver
After 3 weeks, muscle reduces use of ketone bodies [save for the brain, as the brain cannot use FAs] - Protein metabolism
During the early fast: rapid breakdown of muscle protein [increased liver gluconeogenesis]
Pattern of AAs released by skeletal muscle during starvation is not reflective of the composition of muscle protein
Alanine and glutamine account for over 50% of AAs released
This is initiated by a fall in insulin
the brain in starvation
- During the early days, the brain uses glucose
- In prolonged fasting [beyond 2-3 weeks] plasma ketone levels rise significantly, largely replacing glucose
Some glucose still needed to provide precursors for neurotransmitter synthesis - As glucose isn’t required, protein catabolism for gluconeogenesis isn’t required:
Protein degradation can be reduced
the kidney in starvation
- As starvation continues, the kidneys role gets more important
- Site of gluconeogenesis- releases the enzymes of gluconeogenesis
In late fasting 50% of gluconeogenesis occurs here
Uses self generated glucose
Compensates for acidosis by ketone bodies- by excretion
diabetes mellitus
A heterogeneous metabolic disease group
- Multifactorial, polygenic diseases
Characterized by
- Hyperglycemia
- Relative or absolute deficiency in insulin
Relatively common
- 4.7million people in the UK have diabetes
- The number of people diagnosed with diabetes has more than doubled in 20 years
- Estimated 5 million in the UK by 2025
- Complications include adult blindness, amputation, renal failure
- ~90% of all patients have type 2 diabetes, formerly called ‘non-insulin dependent’, secrete insulin but resistant
- ~8% of all patients have type 1 diabetes- formerly called ‘insulin-dependent’
- ~2% rarer forms of diabetes
type 1 diabetes
Insulin deficiency caused by autoimmune attack on beta-cells
- Islets infiltrated by activated T lymphocytes
- Failure to respond to glucose
Hyperglycemia and ketoacidosis
- Elevated blood glucose and ketone levels
- Increased gluconeogenesis and reduced peripheral utilization [GLUT-4]
- Increased mobilization of FA, and oxidation by liver
- Increased 3-hydroxybutyrate and acetoacetate
Hypertriacylglycerolemia
- Excess FA (not oxidised or used for ketone bodies), converted to TAG
- Also, low lipoprotein degradation by lipoprotein lipase
- Enzyme production is decreased
- Excess chylomicrons & VLDL
type 2 diabetes
- cased by a combination of insulin resistance and dysfunctional beta-cells- insulin is not always required but can be used to control hyperglycemia.
hyperglycemia:
- increased hepatic production and reduced peripheral use of glucose
- ketosis is minimal or absent in patient as insulin is usually present
dyslipidemia:
- in liver, FAs converted to TAG and secreted as VLDL
- chylomicrons are synthesised from dietary lipids in intestine
- but, lipoprotein lipase is low, so VLDL and chylomicrons
