Endocrine Control of Metabolism Flashcards
(23 cards)
What are the 2 key sources of plasma glucose?
- Diet - Absorption from gut following carb digestion
- Organs that can export glucose into circulation (e.g. liver) - ~This will stop the concentration dropping below the constant 5mmol per litre b/w meals, or for as long as they can in the case of starvation
What are the metabolic pathways serving energy storage?
- Glycogenesis
- Lipogenesis
- TG synthesis
What is glycogenesis?
Synthesis glycogen from glucose
What happens when glycogen stores are full?
Glucose enters glycolysis, converted to acetyl CoA, fed into lipogenesis (rather than enter TCA)
What is lipogenesis?
Synthesis of FA from acetyl CoA. For the means of serving energy storage, rather than being oxidised for energy release, FAs are converted to TG for energy storage. This is how excess carbs are converted into fat
What is TG synthesis?
Esterification of FA for storage as TG
Describe the metabolic pathways serving energy release
- Glycogenolysis - Release of glucose from glycogen stores
- Gluconeogenesis - De novo synthesis from non-carb substrates (principally amino acids)
- Lipolysis - Release of FFA from TG breakdown
- Beta-oxidation - FFA to acetyl CoA
- Ketogenesis - Production of ketone bodies from acetyl CoA
Describe the importance of ketogenesis
Ketone bodies exported from liver freely transported in circulation, reconverted back to acetyl CoA, in brain and other tissues, and metabolised in TCA cycle for energy (sparing glucose)
Outline the pathophysiology of diabetic ketoacidosis
DKA - Terminal event in uncontrolled Type I diabetes
In absence of insulin, gluconeogenesis and B-oxidation running unopposed. In liver, oxidation of FAs and gluconeogenesis can compete for substrates
- B-oxidation produces acetyl CoA, combines with OAA to form citrate, enters TCA for complete oxidative phosphorylation
- However, OAA also used in gluconeogenesis, OAA is used to synthesise phosphoenol pyruvate
- In absence sufficient OAA, acetyl CoA builds and is funnelled into ketogenesis
- Ketone bodies are acids: excess in circulation overwhelm buffering capacity in blood, leading to metabolic acidosis
What is the constant figure of plasma glucose concentration?
5mmol per litre, this is a concentration. Glucose cannot cross cell membrane w/o special transporters, so concentration present in ECF. Glucose can diffuse through capillary membrane, so enters interstitial fluid. (ECF = Plasma + interstitial fluid)
The average 70kg male has approx 60% body water = 42L
- 14 L = Extracellular
- Total glucose = 14 x 5 = 70 mmol
For a 54kg female, 50% body water = 27L
- 9L is extracellular water
- Total glucose is 9 x 5 = 45mmol
The brain consumes approx 30mmol per hour, skeletal muscle consumes approx 300 mmol per hour, so glucose needs to be constantly replenished to maintain blood glucose concentrations
- Hypoglycemia: ultimately coma and death. < ~2.5 mmol per litre is critical
- Hyperglycemia: chronic exposure to raised glucose concentrations leads to protein damage via non-enzymatic glycation reactions. Hence when in excess, glucose needs to be removed from circulation and converted to form which can be safely stored.
What are 2 metabolic pathways that export glucose to circulation?
- From liver glycogen stores - Glycogenolysis
- Gluconeogenesis - Normally occurs in tandem with glycogenolysis. Using lactate, glycerol and amino acids as substrates. During starvation, amino acids are only substrates, have to be provided by breakdown of muscle protein
Describe the 2 phases of metabolism and hormones involved
- Absorptive phase - Storage of nutrients, promoted by insulin. When plasma glucose rises, insulin released, acts to decrease plasma glucose by promoting uptake and metabolism of glucose by tissue cells. It’s an anabolic hormone, a signal of the fed state, also promotes uptake and storage of fats + uptake of amino acids for protein synthesis
- Post-absorptive phase - Release of nutrients, counter-regulatory hormones released: glucagon, adrenaline, cortisol and GH are hormones that promote nutrient release, raise plasma glucose
Describe the role of insulin in uptake of glucose
- Via GLUT, may be insulin-dependent (GLUT 4: muscle, adipose tissue) or insulin-independent (GLUT1/2: liver, pancreas, brain, RBCs). When GLUTs present, glucose will flow across membrane, down concentration gradient e.g. high glucose to lower glucose concentration - this gradient is maintained by conversion of glucose into G6P. In liver cells (when insulin low) production of glucose from glycogenolysis and gluconeogenesis would raise intracellular concentration, would diffuse out, down conc gradient
- Energy, glycoloysis, TCA (all cell types)
- Beyond energy needs, glycogenesis
- Glycogen stores full, lipogenesis (liver, adipose tissue). In liver, FFs formed via lipogenesis are esterified into TGs, packwaged into lipoproteins (VLDLs) for export and storage in adipose tissue
Explain the body’s defences against hypoglycaemia
In the short term:
- Increase hepatic glucose output (glucagon, adrenaline, SNS)
- Fall in plasma glucose detected in pancreas, response is to increase glucagon secretion from pancreatic alpha cells.
- Glucose also sensed in brainstem and hypothalamus, fall increases sympathetic outflow, which directly and indirectly stimulates hepatic glucose output
In medium term:
- Gluconeogenesis - Only source of glucose (no glycogen left)
- Lipolysis
- FA B-oxidation
- Ketogenesis - Ketone bodies from fat reserces can provide a partial substitute for glucose, sparing muscle tissue from destruction
In long term:
- Proteolysis - Body fat stores exhausted, break down proteins (mainly muscles) to release amino acids. Cortisol stimulates proteolysis
Outline the flexible uses of glucose
Glucose can be converted to G6P, which can then be used to synthesise glycogen via glycogenesis. Reverse happens in glycogenolysis
Pyruvate can be converted into G6P and this into glucose is gluconeogenesis
G6P converted into pyruvate via glycolysis
Acetyl CoA converted into fat via lipogenesis
Fat can be broken down into acetyl CoA via lipolysis
What is the first action of insulin?
Acts on insulin receptors on liver to inhibit glucose production (as well as lipolysis and proteolysis)
What are TGs transported in? Describe the major metabolic pathways in adipose tissue
Lipoprotein molecules - Chylomicrons, if absorbed from gut, or VLDLs if exported from liver
In positive energy balance, insulin = uptake (lipoprotein lipase, GLUT 4). LPL, found on capillary endothelium hydrolyses TGs in to FFAs, so they can enter apidocyte. Then re-esterified to TGs for storage. Glucose will diffuse into apidocyte via GLUT4 channel, then converted into FA via lipogenesis
In negative energy balance, counter-regulatory hormones (mainly adrenaline) stimulate lipolysis and release of FFA to circulation, from where, bound to plasma proteins (mainly albumin), can be distributed to tissues for uptake and energy metabolism
Describe the major metabolic pathways in muscle
Skeletal muscle - Largest tissue mass, most important for absorbing glucose from circulation to maintain appropriate plasma glucose
Glucose diffuses into muscles via GLUT4 , only present at low density in basal conditions (lowest lvl of activity). GLUT 4 density can be increased by insulin and muscle contraction (i.e. exercise). In resting muscle, most glucose stored as glycgogen, and this can be used for later energy use in muscle fibre, as muscle lacks phsphatase enzyme to convert G6P back to glucose for export into circulation
Muscle can also oxidise FFAs for energy. Can be plasma albumin bound FAs follwoing release from adipose TG stores, or circulating TGs in lipoproteins. In latter, LPL releases FFA from Tg for uptake. Ability of muscle to oxidise FFA allows for endurance and prolonged fasting, spares glucose for the brain
Describe glucose and amino acid metabolism in the liver
High insulin/low glucagon = Higher ratio = glycogen storage; when this is full, glucose enters glycolysis, forms pyruvate, pyruvate forms acetyl CoA, fed into lipogenesis
Low insulin/high glucagon = lower ratio = Amino aids diverted away from protein synthesis into glconeogenesis. Few amino acids can be directly converted to acetyl CoA (ketogenic AAs) - Fed into ketogenesis. Acetyl CoA beyond that oxidised in citric acid cycle, funnelled into lipogenesis when insulin: glucagon ratio high (absorptive phase), but ketogenesis when insulin: glucagon low
Describe fatty acid metabolism in the liver
Beta oxidation - FA converted to fatty acyl-CoA (in mitochondria). Acetyl CoA can be used to generate ATP via TCA. If acetyl CoA in excess, instead goes into ketogenesis.
Glucose converted into acetyl CoA. If in excess and in presence of insulin, acetyl CoA goes instead into lipogenesis, back to FAs:
- First intermediate = Malonyl CoA - Has inhibiting effect on CPT (carnitine-palmitoyl transferase), which is required to get fatty acyl CoA into mitochondria or oxidation (or ketogenesis). Hence, insulin indirectly inhibits B-oxidation (and ketogenesis)
- Further intermediates then go on to produce FAs
Insulin and glucagon therefore partition liver FA metabolism b/w lipogenesis and ketogenesis. Stimulation of lipogenesis (insulin) prevents FA entry to mitochondria, inhibiting B-oxidation. In absence of insulin, acetyl CoA not converted to malonyl coA, FA can enter mitochondria and acetyl CoA shuttled into ketogenesis.
Compare the actions of insulin and glucagon on metabolism
Insulin stimulates the uptake and storage of gluocse into glycogen, when this becomes saturated, glucose enters glycolysis to form acetyl CoA which is then used for FA synthesis. FA are then converted into TGs which can be stored in adipose tissue etc.
Glucagon stimulates the mobilisation of TGs out of adipose tissue for breakdown to form glucose and increase ATP lvls via FA B oxidation etc.
Describe the inhibitory effects of insulin
Inhibits nutrient release:
- Inhibits release of glucose from liver (hepatic glucose production)
- Inhibits fat and protein breakdown (lipolysis and proteolysis)
Describe the stimulatory effects of insulin
Promotes nutrient storage:
- Stimulates liver glycogenesis
- Stimulates liver lipogenesis
- Glucose uptake in muscle and adipose tissue
