whole body integration of metabolism Flashcards
what ketogenic amino acids cant be converted to glucose
only leucine and lysine cannot be converted into glucose via gluconeogenesis.
ketogenic AAs
- AAs that can be metabolised to acetyl CoA
- all except leucine and lysine can also form glucose [glucogenic]
- phe, tyr, trp, and ile can all be converted to other intermediates of gluconeogenesis.
humans must meet several metabolic requirements:
- Molecules not obtained in diet
- Adapt to changing external conditions and protect from toxins
the 4 basic types of metabolic pathway
- Oxidative pathways [fuel generation]
- Fuel storage and mobilization
- Biosynthetic pathways
- Detoxification/ waste-disposal pathways
anabolic pathways
synthesis large molecules e.g. biosynthetic and fuel storage
catabolic pathways
break down large molecules e.g. oxidation pathways
metabolic homeostasis must balance:
- Intake of fats, carbs, proteins
- Oxidation [catabolic] rates
- De novo synthesis
- Mobilization to/from storage
Balancing these pathways [i.e. anabolic vs catabolic] results in metabolic homeostasis
In eukaryotes this frequently involves interactions between different tissues and organs - Liver, adipose tissue, muscle brain etc have different roles, reflected in different enzyme pathways
glucose requirements
Many body tissues require glucose:
- Blood glucose levels: 80 to 100 mg/dL (~5 mM)
- Maintenance requires careful regulation of carbohydrate, lipid and amino acid metabolism
- Significant decreases [<60 mg/dL; <3.3 mM] limit brain metabolism
Hypoglycemia
Glucose influx is lower due to Km of blood-brain barrier transporters
too much glucose [hyperosmolar hyperglycaemic state]:
- neurologic deficits and coma
- [glucose] rises above renal tubular threshold
- non-enzymatic glycosylation of proteins
inter-tissue integration
This balance is achieved in 3 ways:
- Blood [nutrients]
- Hormones
- Nervous system control
- • e.g. [fatty acids]blood
- determines whether skeletal muscle uses fatty acids or glucose
- • e.g. adrenaline (epinephrine)
- signals immediate need for energy
- released by sympathetic nervous system
the major metabolic hormones
insulin:
- promotes mobilization.
levels of these hormones fluctuate continuously in response to eating patterns
insulin
The major anabolic hormone
- 52 aa polypeptide synthesised as a ‘preprohormone’ [proinsulin]
- Release threshold at 80 mg/dL glucose, then levels rise in proportion
- Degraded by liver, kidney and skeletal muscle
Insulin acts on 3 main tissues: liver, muscle and adipose
It promotes:
- Glycogen formation in liver and muscle
- Conversion of glucose to TAGs in liver
- TAG storage [adipose]
- Glucose uptake by muscle and adipose
- AA uptake and protein synthesis in muscle and liver
insulin release
Insulin is produced in pancreatic beta-cells
- Glucose enters beta-cell through GLUT-2 transporter
- This is phosphorylated by glucokinase to glucose 6-phosphate
- Metabolized via glycolysis, TCA cycle, oxidative phosphorylation [1]
- Increasing ATP levels inhibit ATP-dependent potassium channels [2]
- This depolarizes the membrane [3], leading to calcium influx through voltage-sensitive Ca++ channels [4]
- This results in exocytosis [export] of insulin-containing vesicles [5]
High blood glucose levels trigger insulins release, not synthesis.
glucagon, a counterregulatory hormone
- Produced in pancreatic alpha cells
- Glucagon secreted in response to:
- ↓ [glucose]plasma
- ↑ [insulin]plasma
- Release also promoted by:
- catecholamines [e.g. adrenaline]
- AAs
Catecholamines are a class of transmitter molecules that are formed via the same synthetic pathway from tyrosine. In addition to adrenaline [and noradrenaline] the class includes dopamine] - Glucagon is a 29 amino acid polypeptide
- Produced as preprohormone in rough endoplasmic reticulum
- It acts to maintain glucose levels in liver and adipose tissue- no action at muscles [no receptors]
- Degraded by liver and kidneys with very short half life (t½ ~5min)
glucagon actions
- increases glycogenolysis and reduces glycogen synthesis
- Stimulates gluconeogenesis and ketogenesis
- Mobilizes fatty acids from TAGs
- ‘glucose is gone’
