Lecture 12 Regulation of Carbohydrate Metabolism in the Postprandial Phase Flashcards
Role of glucose
both a substrate & a regulator of metabolic pathways:
* acts as a signalling molecule to control glucose & energy homeostasis
* Regulates gene transcription, enzyme activity, hormone secretion & glucoregulatory neuron activity
What is the postprandial phase
the period after a meal
What is the fate of postprandial glucose?
Glucose is dispersed to:
* brain for energy
* adipose tissue for triacylgylcerol storage
* liver for glycogen storage
* muscle for glycogen storage and energy
also 2 to 3 g of glucose is additionally required by the obligatory glycolytic cells
What part of circulation do monosaccharide get absorbed into from the SI?
hepatic portal vein
Where do monosaccharides first go to once in the portal vein?
Liver
Glc uptake in the liver
- 1st pass metabolism of monosaccharides & insulin
- Removes Glc & most fructose & galactose
- Insulin stimulates use of Glc, fructose & galactose for energy & Glc for glycogen synthesis
- Expresses high GLUT2 +glucokinase
Glc uptake in the skeletal muscle
- insulin promotes translocation of GLUT4 to plasma membrane leading to ↑Glc uptake 10-20 fold
- Glc taken up for energy & glycogen synthesis
- Some uptake of fructose for energy
Glc uptake in adipose tissue
- Insulin promotes translocation of GLUT4 to plasma membrane
- Glc taken up for energy and FA, glycerol & TG synthesis
- Excess Glc stored as TG
Glc uptake in cardiac muscle
- Insulin promotes translocation of GLUT4 to plasma membrane
- Glc taken up for energy & some glycogen synthesis
Glc uptake in other tissues
- Glc taken up via other GLUTs (1 & 3) based on energy needs of the cell
What helps to regulate Glc in the liver?
Pancreas
What amount of Glc goes into liver vs. periphery?
~ 1/3 taken up by glucose and the rest ~2/3 goes to periphery
Does insulin increase Glc uptake in hepatocytes?
Liver is generally considered insulin-INDEPENDANT
some level of response
Which cells/ tissues are dependant on insulin for Glc transport?
adipose and muscle
How does glucose get into portal blood?
From the GI tract it goes into the portal vein via active symport with Na+ by SGLT1 + facilitated diffusion by GLUT2
How does glucose move into the cells?
Glc moves into cells via facilitated diffusion via the GLUT family of membrane transport proteins
* 14 GLUT expressed in humans, but only GLUTs 1-4 have distinct regulatory &/or kinetic properties that reflect roles in cellular/ whole body Glc homeostasis
What does rate of glucose uptake into cells depend on?
- # of transporters
- rate of transport
- type of transporters and how they are regulated
- phosphorylation & utilization of glucose (rate/fate of G6P)
GLUT1
- monosaccharide substrates
- sites
- affinity
- capacity
- properties/ functions
- monosaccharide substrates: glucose, galactose, mannose
- sites: CNS, blood-brain barrier (BBB), RBCs, placenta, fetal tissues, most tissues (in low amount.
- affinity: high
- capacity: low
- properties/ functions: basal Glc transport (low levels in most tissues), increase GLUT4 in muscle, adipose at low Ins concentrations
GLUT2
- monosaccharide substrates
- sites
- affinity
- capacity
- properties/ functions
- monosaccharide substrates: glucose, galactose, mannose, fructose
- sites: Liver, β-cells, SI (basolateral), kidney
- affinity: low
- capacity: high (helps control [blood Glc]
- properties/ functions: dependant on Glc concentrations (not insulin); Glc sensor in pancreas; absorption/ reabsorption; bi-directional transport
GLUT3
- monosaccharide substrates
- sites
- affinity
- capacity
- properties/ functions
- monosaccharide substrates: glucose, galactose, mannose
- sites: high in brain (neurons), high in placenta, also in skeletal muscle, spermatozoa
- affinity: low
- capacity: high
- properties/ functions: basal Glc transport
GLUT4
- monosaccharide substrates
- sites
- affinity
- capacity
- properties/ functions
- monosaccharide substrates: glucose
- sites: skeletal/ cardiac muscle, adipose
- affinity: ?
- capacity: high
- properties/ functions: insulin-dependant, role in Glc homeostasis; exercise stimulated in muscle
GLUT5
- monosaccharide substrates
- sites
- affinity
- capacity
- properties/ functions
- monosaccharide substrates: fructose
- sites: SI (brush border), kidney, brain, skeletal muscle, adipose tissue, spermatozoa (not in liver or kidney)
- affinity: med?
- capacity: med?
- properties/ functions: weakest isoform similarity to other GLUTs, does not contribute to [Ins] response
Regulatory properties of insulin
- synthesized and released by β-cells in pancreas
- gut hormones, innvervation & activity regulate its secretion
- Stimulate hepatic uptake & storage of Glc (activates glucokinase)
- anabolic (conditions in fed state)
Regulatory properties of glucagon
- released by 𝝰-cells in pancreas, inhibited in insulin
- main actions in the ↑ hepatic glucose output but can also be catabolic (↑proteolysis, AA catabolism & urea synthesis)
Where are the β-cells and 𝝰-cells found?
islets of langerhans in the pancreas
What do insulin and glucagon respond to?
- insulin: fed state ↑rising blood glucose levels
- glucagon: starvation state ↓blood glucose levels
How does glucagon promote the mobilization of stored energy?
It is released from the pancreas in responce to declining blood glucose levels and promotes breakdown of liver glycogen, adipose tissue, and muscle protein, and the synthesis of ketones and glucose from noncarbohydrate sources.
How does insulin promote energy storage?
Insulin is released from plancreas is response to rising blood Glc levels and stimulate glucose transport into cells. Insulin also promotes energy storage , glycogen synthesis, protein synthesis (muscle), and fat synthesis (adipose tissue)
* Anabolic effects
Role of insulin in cellular uptake of Glc
- insulin released by β-cells in response to ↑ [blood Glc]
- insulin binds to membrane bound receptor
- Glc transporters signalled to move from cytoplasm to membrane
- Glc transporter enable Glc to move from extracellula space into cytoplasm
Role of insulin in cellular uptake of Glc
- insulin released by β-cells in response to ↑ [blood Glc]
- insulin binds to membrane bound receptor
- Glc transporters signalled to move from cytoplasm to membrane
- Glc transporter enable Glc to move from extracellula space into cytoplasm
How does GLUT4 translocate to the membrane in response to Ins?
via targeted exocytosis + GLUT4 endocytosis is reduced
What does the rate of Glc transport into fat and muscle cells depend on?
- [GLUT4] at cell surface from the given pool
- duration at the cell surface
- mechanism working properly
What is the mechanism of insulin secretion?
- glucose enters β-cells via facilitated diffusion by GLUT2
- once in the β-cells, Glc is phosphorylated by glucokinase trapping it in the cell (forms G6P)
- Goes through glycolysis to form pyruvate
- pyruvate goes the mito through the PDH to become Acetyl CoA and complete oxidation
- The increased ↑ATP to ADP ratio depolarizes the cell opening Ca2+ channels
- insulin vesicles can fuse with the cell releasing insulin
Why is pyruvate from glycolysis in pancreas unlikely to become lactate?
Low lactate dehydrogenase enzyme
Efficiency of complete oxidation in the pancreas
very efficient
* hydorgen shuttles are very active so >90% of glucose Cs converted to CO2
What is insulin secretion coupled to?
ATP production in mitochondria drive insulin secretion ‘coupling’ Glc metabolism to insulin secretion
What are other stimulus for insulin secretion?
- Glc most potent
- some AAs
- incretin hormones (secreted by gut like GLP1)
- parasympathetic stimulation (via vagus nerve)
Does fructose stimulate insulin release?
fructose requires GLUT5 for uptake and this is not present in the pancreas
does not stimulate leptin either
History of fructose intake
- ~16-24 g mostly from fruits and honey from foraging and agriculture in past
- ~8-100g (avg ~80g/day) mostly from refined or processed fructose currently
What is high fructose a health concern?
Increases in obesity, T2D and insulin resistance syndromes
* most fructose is taken up by the liver which does not have GLUT5 and hexoses do not enter until lower in glycolysis the the postprandial response does not count fructose and body cannot manage it into storage
normal serum fructose vs. high fructose diet
serum fructose is low at ~0.008 mmol/L but high fructose diets can elevate it to ~0.2-0.5 mmol.L
* results from lower rates of intestinal absorption + efficient clearance of blood fructose (50-70% by liver, 20% by kidneys)
What are the differences in homeostasis Glc level in the liver vs. the pancreas?
- liver: energy storage and regulation of blood Glc
- pancreas: glucose sensor and insulin release
What action ‘senses’ blood Glc levels?
combined action of GLUT2 transport of Glc and rate of glycolysis (glucokinase)
What is similar in the liver and pancreas with Glc homeostasis?
When blood glucose levels are high, the GLUT2/glucokinase system is very active in both tissues
* glucose sensor mechanism adjusts glycolytic flux to plasma [Glc] in β-cells and hepatocytes
what is the range of blood glucose homeostasis?
4 to 6 mmol (70-100mg/dL)
Homeostasis with increased and decreased plasma glucose levels
- ingest CHO: ↑ blood [Glc] above homeostatic range. Results in ↑insulin and ↓glucagon secretion by the pancreas, ↑Glc uptake and utilization by tissues, and ↓ hepatic glucose production, which return plasma glucose to homeostatic range
- lack of food intake: ↓ blood [Glc] below homeostatic range. Results in ↓insulin and ↑glucagon secretion by the pancreas, ↓Glc uptake and utilization by tissues, and ↑hepatic glucose production, which return plasma glucose to homeostatic range
draw
postprandial glucose metabolism curve
needs to be maintained between 4-6 mmol/L
Draw
postprandial insulin metabolism curve
Draw
postprandial glucagon metabolism curve
Insulin resistance
The pancreas gets challenged over a long period of time with high glucose spikes and need for increased insulin release fatigueing the system and requiring them to eventually put out far more insulin to get same uptake rate as someone without resistance (action of insulin via receptor is diminished)
Insulin resistance in T2D
The pancreas is unable to compensate for insulin resistance by secreting more insulin (β-cell ‘fatigue’)
* Glucose transport affected, but many downstream effects of insulin still intact (at a higher rate due to high insulin!) - not a receptor problem but a signalling problem
What does insulin resistance lead to?
- hyperglycemia
- hyperinsulinemia
- T2D
catecholamine actions on Glc regulation
Secreted by adrenal medulla (i.e. adrenaline/epinephrine), stimulates adrenergic receptors (α & β), β-receptors
* ↑ glycogenolysis and gluconeogenesis
How do cathcholamines effect blood glucose?
released during stress states contribute to the development of hyperglycemia by directly stimulating glucose production and interfering with tissue disposal of glucose.
How do glucocorticoids effect blood Glc?
Steroid hormones secreted by adrenal cortex (i.e. cortisol), ↑ hepatic glucose output & expression of gluconeogenic genes
How do Tri-iodothyronine (T3) effect blood Glc?
Can modulate or amplify many other hormones & actions, increases gene expression for enzymes to regulate metabolism (both anabolic & catabolic systems; ↑ BMR)
Draw
Starvation insulin metabolism curve
Draw
starvation glucose metabolism curve
Draw
starvation glucagon metabolism curve
role of insulin and glucagon in starvation
Relative ⇩insulin & ⇧glucagon stimulates liver to break down glycogen & ⇧gluconeogenesis from other substrates → Glucose released into plasma
role of insulin and glucagon in starvation
Relative ⇩insulin & ⇧glucagon stimulates liver to break down glycogen & ⇧gluconeogenesis from other substrates → Glucose released into plasma
What is the glucose sparing effect?
Glucose uptake by muscle & adipose are ⇩
* switch to lipid fuels
define
Glycemic Index
The incremental area under the blood glucose response curve of a 50 g carbohydrate portion of a test food expressed as a percent of the response to the same amount of carbohydrate from a standard food taken by the same subject.
What are the ratings of food for GI based on?
magnitude and duration of glucose rise in blood after ingestion
* low GI: foods digested slowly
* high GI: foods digested more rapidly
Impact of low vs. high GI
- low GI cause a gradual and more moderate response to blood Glc
- High come with lots of energy but then a crash where it goes below normal levels which brain does not like
Intrinsic factors that reduce the GI
- high amylose:amylopectin ratio
- intact grain/large particle size
- intact starch granules
- raw, ungelatinized or unhydrated starch (indigestable)
- physical interaction with fat or protein
extrinsic factors that reduce the GI
- protective insoluble fiber seed coar as in whole intact grains
- viscous fibers
- enzyme inhibitors
- raw foods (vs. cooked foods)
- minimal food processing
- reduced ripeness in fruit
- minimal storage (compared to extended)
Glycemic load
Takes into account both the amount of carbohydrate in a portion of food together with how quickly it raises blood glucose levels.
* GL = GI/ 100 x (g of CHO/serving)
* accounts for quality and quantity
* GI alone does not account for ‘serving size’, calculated for 50 g CHO only
