Carbohydrate metabolism

FNN200

Carbohydrate oxidation

• Chemical energy in nutrients stored and released through metabolic reactions 

• cellular oxidation of 1mol glucose releases net DeltaG of 280 kcal/mol

ATP

• converted to adp results in deltaG of -12kcal/mol

Different pathways of carb metabolism

• Glucose → glycolysis + fructose → pyruvate → 

  • TCA cycle 

  • Lactate 

  • + non carbs → Gluconeogenesis 

• Glucose + galactose → Glycogenesis → glycogen → glycogenolysis +galactose →glucose 

Covalent modification 

• activates/inactivates enzymes 

  • removal/addition of phosphate to or from enzyme 

    • phosphorylaze b to a in glycogenolysis 

Reversibility of enzymes 

• most reactions are reversible with the same enzyme 

• unidirectional may be able to make the same thing but it would require a new enzyme for that 

  • may be because of energy requierments

  • concentration gradients etc

Compartmentalization

• enzyme within a cell and is only active within that cell 

• brings enzymes into close proximity 

• controls metabolic pathways 

  • krebs 

Induction in enzymes

• changes in concentration of inductible enzymes

• increased activity

• often occurs through the action of hormones

Allosteric regulation - main enzyme regulator

• may be positive or negative 

• can either allow or prevent the binding of a substrate to an active site 

• Common ones 

  • ATP (-), ADP (+), AMP (+)

  • reaction metabolites (substrates or products)

  • other substances 

3 key regulatory steps and enzymes

• step 1: HK and GK

  • hexokinase (muscle/adipose) and glucokinase (liver and pancreas)

• Step 3: PFK 

  • Phosphofructokinase

  • committed step 

• Step 10: PK 

  • Pyruvate kinase

1st phase of glycolysis

• Glucose is acted on by either HK or GK depending on where in the body 

  • HK in muscle and adipose 

  • GK in liver and pancreas

• The glucose is phosphorylated in a process which uses an ATP 

  • this is non reversible and traps the glucose in the cel 

  • allosteric regulation to inhibit the kinase to stop taking in when it is full 

• Converted into Glucose-6-phosphate

• Fructose-6-kinase is then acted on by PFK to create fructose-1,6-bisphosphate

  • this is the committed step of glycolysis

GK vs HK

• GK (Glucokinase is found in liver and pancreas)

  • this has a higher Km because there must be a higher regulation of blood glucose 

• HK - hexokinase is in the muscle and adipose tissue 

  • lower Km because it does not need to have the same level fo regulation and they want more glucose in them 

PFK-1

• Phosphofructokinase

  • converts fructose -6-phosphate into Fructose-1,6-bisphosphate

• Committed step of glycolysis

• irreversible so it tells the cell that it is going to do glycolysis

• Allosteric regulation

  • negative: atp, Citrate

  • Positive: AMP, fructose-2,6 bisphosphate/PFK-2

Kinase

• catalyzes transfer of phosphate group

Hexokinase

• located in muscle, brain and adipose itssue

• allosteric inhibition by glucose 6- phosphate (product)

• Low Km function at max velocity at fasting blood glucose

• not induced by insulin at normal individuals

• not induced by insulin in insulin resistant individuals

Glucokinase

• liver and pancreas

• not inhibited by product (glucose-6-phosphate)

• High Km: functions at max only when glucose levels are high like followign a high carb meal

• Induced by insulin in normal inidviduals 

• not induced by insulin in insulin-resistant individuasl

PFK1 vs PFK2

• PFK 1 is responsible for the conversion of Fructose-6-phosphate into fructose-1,6-bisphosphate 

  • positive regulation from fructose -2,6-bisphosphate 

• PFK2 is respobsible for conversion of Fructose-2,6-bisphosphate into fructose-6-phosphate 

  • this is positively regulated by Glucagon 

• PFK 2 is also responsible for the active change of Fructose-6-phosphate into fructose -2,6-bisphosphate 

  • this is positively regulated by insulin 

Energy yield of glycolysis

• 2NADH + 4 ATP 

• then some are used so the ent is actually 

  • 2 ATP and 2 NADH

  • one is used by HK or GK and the other by PFK

2nd phase of glycolysis

• NAD+ is converted to NADH (x2)

• ADP converted to ATP (x2)

• Phosphoenolypyruvate (x2) is acted on by pyruvate kinase (PK)

  • creates pyruvate (x2) 

  • also makes ATP (x2)

Pyruvate kinase (PK)

• irrevertible 

• allosteric regulators 

  • negative: ATP 

  • Positive: AMP and fructose-1,6-bisphosphate 

• Hormonal regulators 

  • negative: glucagon cause it wants body making glucose 

  • Positive= insulin cause it wanst glucose in so it wants glycolysis to occur 

Fate of pyruvate in anaerobic

• skeletal muscles during exercise 

• tissues with no mitochondria or vascularization 

  • rbcs, cornea, lens of eye

• Lactate dehydrogenase acts to turin it into 2 lactate and then it will become lactic acid and leave the cell 

  • the acid will return to the liver where it will be converted to pyruvate 

Fate of pyruvate aerobic

• 2x pyruvate will enter the mitochondria and go through the krebs cycle with 2 acetyl-CoA

Fructose and metabolism 

• always committed to glycolysis because it enters the cycle after PFK

  • all will be oxidized and may be stored in fat more

• Acted on by fructokinase 

  • uses ATP 

• creates Fructose-1-phosphate 

• then will become Fructose-1,6-bisphosphate 

Galactose in glycolysis

• Galactokinase 

  • Uses atp 

  • creates galactose-1-phosphate

• becomes glucose-1-phosphate

  • glycogen synthase can make it into glycogen which is where most galactose is stored

• Some will go to become Glucose-6-phosphate to go through glycolysis

  • depends on the energy state of the cell

Glycogenesis

• Glucokinase is used to convert glucose → glucose-6-phosphate 

• then glycogen synthase is used to create glycogen 

• Glucose-6-phosphate 

  • removes P

  • absent in muscle 

  • liver glycogen contributes to blood glucose in times of need 

  • muscle only produces glucose for the tissue 

• Occurs in the liver 

Gluconeogenesis 

• stimualted by glucagon and epinephrine 

• occurs in the liver

• phosphorylase glycogen, makes glucose-1phosphate whthen phosphotase makes glucose to go to blood glucose

Major sites of glycogen storage

• liver (7% weight)

• Muscle (1% weight)

Different sites pyruvate can go to

• acetyl CoA 

• Oxaloacetate

• lactic acid 

• glucose (comes from glycolysis but can go through gluconeogenesis)

• alanine (muscles)

• amino acids can become pyruvate

Krebs cycle/TCA Cycle

• Step 1 Involves: 

  • Oxaloacetate + Acetyl CoA 

  • undergoes citrate synthase 

  • creates citrate 

• Energy Yield per pyruvate (x2)

  • 3 NADH

  • 1 FADH2

  • 1 ATP 

  • 2 CO2

• TOTAL = 

  • 6NADH

  • 2 FADH

  • 2 ATP 

  • 4 CO2

Krebs regulators

• ADP = positive

• NAD = positive 

• ATP = negative 

• NADH = Negative

Electron transport chain

• this is aerobic oxidation 

• O2 is the final electron accepter 

• each thing fuels the next 

• NADH gives up hydrogen to FADH 

• The final step is a ATP synthase which allows H+ back through creating the change from ADP to ATP 

• PRODUCTS 

  • 1 NADH produces 3 ATP 

  • 1 FADH Produces 2 ATP 

Total ATP calculations

• one carb gets 36-38 atp + heat 

• 10 NADH x 3 ATP = 30 ATP

• 2FADH x 2 ATP = 4 ATP

• + 4 ATP from glycolysis + TCA cycle

• Total becomes 38 ATP/ mol of glucose 

  • sometimes they are lost in the transport of NADH into mitochondria so sometimes there is 36

Concersion of cellular energy into kCal

• 1 mol of carb → 36/38 ATP (40% of potential energy) + heat (60% of potential energy)

• 1 mol of glucose is equivilent to 180gm 

  • ATP = 7.3kcal/mol 

  • 38 ATP = 280kcal (38×7.3) 

  • 280 kcal/180gm = 1.55 kcal/gm (40% of potential enery)

  • remaining 60% is released as heat 

• TOTAL POTENTIAL ENERGY PER GRAM 

  • 1.55 × 100)/40 = 3.89 kcal/g 

    • roung up to 4kcal/g

Lipogenesis

• creates triglycerides when there is excessive carb intake

• when the cells have enough energy there will not be the krebs cycle and therefore fatty acid syntehsis will occur instead 

• it will also activate carb response elment binding protein 

Phosphorylase

• Phosphorylase B must become phosphorylase a in order to convertn glycogen into glucose -1-phosphate which is required to increase blood glucose 

• works with glucose -6-phosphotase 

Phosphorylase induction and covalent modification

• hormonal 

  • epi and glucagon increase the conversion b-a (activates)

  • insuling increases a-b (inactive)

• Metabolic regulators 

  • p is the required substrate for phosphorylase 

  • Ca++ increases the activity of phosphorylase kinase 

  • AMP and IMP can increase the activity of phosphorylase b independent of the conversion to a 

• Protein phosphotase is what inactivates (a→b)

Importance of blood glucose regulation

• energy source

• RBC exclusively use glucose 

• brain and neurons need fuel nonstop and they prefer carbs 

  • no fuel can be stored 

  • ketones are alternative fuels which require only small amounts of glucose 

• Hyperglycaemia 

  • blood vessel damage, glycation (proteins which should not have glucose but do), tissue damage

• Hypoglycaemia 

  • potentially irreversible brain damage, confusion dizziness, seizures, loss of consciousness

TCA cycle glucose

• glucose is essential for energy to be obtained from all macronutrients 

  • pyruvate → acetyl CoA → citrate and oxaloacetate 

Oxaloacetate

• first step of TCA cycle 

  • Oxaloacetate + Acetyl CoA → citrate

• Cannot occur without a constant supply of oxaloacetate

• also a part of gluconeogenesis

• Can be made from pyruvate independent of TCA cycle as well

Pyruvate creation of Oxaloacetate

• can be done independent 

• uses a different enzyme 

• ensures that the TCA cycle can continue to operate

Gluconeogenesis

• mainly occurs in liver 

• Lactate: Cori Cycle 

  • lactic acid in blood 

  • liver → pyruvate 

• Glycerol 

  • triglycerides 

  • Free Fatty Acids do not make glucose 

  • Glycerol does make a small amount of lgucose 

• Glucogenic amino acids 

  • there contribute to pyruvate or oxaloacetate production 

Low dietary CHO

• Glucogenic amino acids will make oxaloacetate and pyruvate 

• Ketogenic and fatty acids will not 

Ketone formation - absence of glucose

• Produced in liver

• can be used for energy

• brain can adapt to use them 

• low oxaloacetate so itll use acetyl-CoA 

  • this is in fatty acids 

Ketosis

• accumulation of ketones in the blood 

• excreted via kidney in urine 

  • require increased water intake to prevent 

• Mild → elevated levels 

  • headaches, dry mouth, lack of appetite 

• Severe → blood acidity, coma and death 

Allulose

• fructose epimer

  • one carbon has a different orientation which changes how the body will respond to it

• 10% of the calories as regular sugar

• occurs naturally in wheat, figs, raisins, maple syrup an dmolasses 

• absorbed similar to fructose (GLUT5) but is not recognisedd by fructokinase

  • GLUT5 into the endothelial cel and GLUT2 out

Fructokinase

• responsible for the changing of fructose into fructose-1-phosphate 

• but does not recognize allulose so allulose is not going to be committed to glycolysis 

Allulose

• reduced glucose release from CHO

  • stimulated in vetro by bellisimo 

• Possible  that it inhibits the a-amylases and therfore results in a lower spike in glucose when consumed with rice 

Blood glucose - Hormonal regulation

• B-cells

  • insulin

  • moves glucose into muscles, liver and into fat cells 

    • immediately after a meal to bring down the blood glucose levels 

    • anabolic to build glycogen stores 

• a-cells 

  • glucagon 

  • moves glucose from glycogen stores and gluconeogenesis back into the blood stream 

    • occurs several hours after a meal so that blood glucose stays normal

    • Catabolic process

Stress and growth hormones

• Raise blood glucose

• Epi and norepi 

• thyroid hormones 

• glucocorticoids 

• growth hormones 

Diabetes

• most common disease associated with CHO metabolism

• characterized by high blood glucose levels 

• inability of body to produce enough insulin or respond to insulin or both 

Types of diabetes

• gestational

  • during pregnancy 

  • if untreated it can pass to baby with high birth reight → delivery complications 

  • risk of obesity and type 2 diabetes in life 

• Type 1 (10%)

  • auto immune disease that destroys the pancreas 

  • treated with insulin injections 

  • the body is unable to produce insulin 

• Type 2 (90%)

  • cells have a decreased sensitivity to insulin

  • decreased insulin production (B-cell dysfunction) or response to insulin (insulin resistance)

Normal blood glucose levels

• fasting : 4.5-5.5mmol/L

• Fed: up to 7.8 mmol/L

Diabetes

• Diagnosis: Fasting blood glucose >7.0mmol/L

• Glycosuria: 10mm/L 

  • glucose in urine cause it was so high in the blood 

Pre-diabetes

• impared glucose tolerance or glucose intolerance

Fasting glucose levels

• Normal: <6

• Prediabetes: 6.1-6.9

• Diabetes: >7

2 hours post eating glucose levels 

• Normal <7.8

• prediabetes 7.8-11

• diabetes >11

Type 2 diabetes

• Step 1: Increased insulin secretion but it is still conpensating 

  • there is a decreased sensitivity to insulin which is why more is being produced 

  • Blood glucose is normal but hyperinsulinemia 

• Step 2: Prediabetes 

  • increased insulin secretion but only partial compensation 

  • Blood glucose is increased and stil hyperinsulinemia 

• Step 3: Beta-cell exhaustion 

  • increased blood glucose and either hyper or hyopinsulinemia 

  • there may be increased or decrease in the insulin secretion depending on insulin functions

Diabetes risk factors

• obesity, age, lifestyle, genetics, ancestory, very complex

Diabetes treatments

• weight loss

• exercise

• diet

• medication 

Grains and starches examples of 3 categories

• Low GI (55 or less)

  • carrots - cooked

  • green peas

  • Winter squash 

• Medium GI (56-69)

  • corn

  • parsnip

  • pumpkin 

• High GI (70+)

  • corn starch 

  • gnocci 

  • rice crackers

Fruits in the 3 categories

• Low GI (55 or less)

  • apple 

  • apricots 

  • berries 

• Medium GI (56-69)

  • ripe bananas 

  • cherries 

  • grapes 

• High GI (70+)

  • overripe banannas 

  • breadfruit 

Dairy in the 3 categories

• Low GI (55 or less)

  •  almond milk

  • cottage cheese

  • cows milk

• Medium GI (56-69)

  • oat milk 

  • processed cheese 

• High GI (70+)

  • rice milk

Proteins in the three categories

• Low GI (55 or less)

  •  Black beans 

  • chickpeas 

  • hummus 

• Medium GI (56-69)

  • Lentil soup 

  • split pea soup 

• High GI (70+)

  • broad beans

Differences in the CFG plate and the Diabetes canada plate

• diabetes has starchy veg grouped in with the whole grain portion 

• it includes more plant protein sources 

• uses more greens 

Genetic screening of newborns for errors in metabolism

• protein metabolism disorders 

• fatty acid oxidation disorders 

• carbohydrate metabolism 

Galactosemia

• all newborns screened

• Deficiency of Galactokinase or Galactose-1-phosphate urdiyltransferase (GALT) 

  • converts galactose-1-phosphate to glucose-1-phosphate 

• Galactose accumulates in blood and tissues 

• failure to thrive, liver damage, sepsis, death 

• Treatment 

  • galactose restricted diet for life

GALT

• enzyme responsible for the conversion of Galactose-1-phosphate into glucose -1-phosphate 

mcardle disease

• type 5 glycogen storage disease

  • onset in childhood in skeletal muscles 

  • deficiency in muscle glycogen phosphorylase: cant break down glycogen to release glucose so glycogen accumulates 

• Results in 

  • fatigue, exercise intolerance 

  • muscle weakness, soreness, cramps 

  • higher in protein (low carb, keto may help-

    • can prevent glycogen breakdown 

  • Goal is to prevent hypoglycemia or muscle symptoms

GLP-1 agonists

• mimic the natural affects of GLP 

  • inhibit motility in the intesting so that your body tell sthe brain that you are full 

• Wegovy 

  • increases satiety 

• Type 2 diabetes targets are 

  • Semaglutide

  • Ozempic - not actually approved by weightloss 

    • cardiosystem 

    • increasing insulin synthesis ans ecretion 

      • B-cell proliferation - cannot get levels back to normal but might be able to get some function back 

    • decrease glucagon synthesis and secretion 

• Increase glucose uptake by fats 

• incake lipolysis 

• increase uptake in muscles and more synthesis of glycogen 

• lower gluconeogenesis 

Exercise training impacts glucose metabolic pathways

• higher GLUT4 density and signaling in muscle 

  • translocation to take in glucose and increase uptake 

  • insulin and muscle contraction 

  • exercise and can take in more glucose form blood 

• increased glycogen synthase activity 

  • glycogen storage → glucose -1-phosphate to glycogen 

  • better in insulin signaling 

  • more translocation 

• Increased number and size of mitochondria 

  • more fat for fuel → spares glucose 

  • all burn in Kreb 

• lower overall fat through increased fat consumption 

Carb Loading

• Goal → to maximise muscle and liver glycogen stores prior to prolonged endurance and exercise 

• phase 1 → deplete the glycogen from muscles 

• phase 2 → CHO load to increase the glycogen storage