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Metabolism Block > Glucose Metabolism > Flashcards

Glucose Metabolism Flashcards

1
Q

What is ATP?

A

Adenosine Triphosphate is relatively low intermediate in metabolism; responsible for providing chemical energy for cellular process.

_The (delta)G’° for ATP hydrolysis to ADP = -30.5kJ/mol _

This means that 30.5 kJ of energy is released fro every mol of ATP hydrolysed

Mg-ATP is always the cellular substrate utilised by cells and enzymes; Mg stabilises the phosphate tale of ATP so that it be chemically modfied.

Enzymes that utilise ATP are ATPases and they have an active ‘lock and key’ site that binds ATP molecules

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2
Q

From what series of reactions is the (delta)G’° of ATP production derived?

A

PEP + H20 -> Pyruvate + Pi (-61.9kJ)

ADP + Pi -> ATP + H20 (+30.5kJ)

The energy released by the conversion of PEP to pyruvate provides the energy to synthesis ATP from ADP -> allows the building of chemical energy bonds which can be broken at a later stage to trelease this energy

PEP + ADP -> Pyruvate + ATP (-31.4 kJ)

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3
Q

What is NAD+ / NADH?

A

Nicotinamide adenine dinucleotide (NAD) is a high energy intermediate of metabolism

HADH is the high energy form that is oxidised to NAD+ to release energy

NADH + H+-> NAD+ + 2H (delta G’° = -220kJ/mol)

NADH is the storage molecule for most of the electrons in the glycolysis/krebs/respiratory chain

NADP+is produced from NAD+ via esterification of the carbon 2 hydroxyl group to phosphate ; this is relevant in the process of cholesterol synthesis

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4
Q

What are carbohydrates?

What are aldehyde sugars?

A

Carbohydrates have the general formula Cn(H20)n ; possibly with conjugated N, P or S moleucles in certain instances.

Mono- and di-saccharides end in “ose” ; monsaccharides have 3-7 carbons

D-carbohydrates have hydroxyl groups on the right hand side (fisher projections) or down (hawthorne projection) at the highest chiral carbon in the molecule.

Aldehyde sugars are aldose sugars demonstrating a CHO group at carbon 1

Aldehyde sugars include Glyceraldehyde (the most simple - 3 carbon), Ribose (DNA sugar - 5 carbons), Glucose (metabolism substrate - 6 carbon) and Galactose (milk sugar - 6 carbon)

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5
Q

What occurs to amino groups in the presence of glucose?

What consequences does this have for disease condition?

A

Glucose is an extremely reactive aldehyde and glycalation of amino groups (particularly in proteins) underlies several disease processes in diabetes.

All amino acids, mostly in protein, are prone to spontaneous glycation when in the presence of glucose.

Glucose + H2N-R -> fructosamine

Glycylated blood vessels become brittle and prone to clots that stop circulation - commonly leading to blindness or gangrene in diabetic patients.

The turnover of enzymes (3 days) and RBCs (120 days) ensure that proteins cumulatively damaged by glucose are replaced

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6
Q

What is the glucose tolerance test?

A

The glucose tolerance test profiles the blood response to an oral dose of 100g glucose

Blood glucose levels in excess of 10mM result in glucose detection in the urine

  • reabsorptive glucose transport in the kidney tubules are inundated at Vmax and unable to reabsorb all of the glucose present in filtrate.
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7
Q

What is the use of measuring haemoglobin-A1C?

A

Haemoglobin-A1C is oneparameter tested by glycohaemoglobin testing systems

The beta-subunits of Hb are particularly prone to glycation of the N-termini ; and levels of this haemoglobin-A1C acts as a diagnostic marker of uncontrolled high blood pressure levels.

Normally HB-A1C is ~3-5% of Hb but can rise to 15% in uncontrolled diabetes

Other parameters tested include fructosamine derivatives of serum albumin

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8
Q

What are GLUTs?

A

Glucose Transporters (GLUTs) are a family of 12 transmembrane receptors responsible for the passage of glucose accross cellular membranes

GLUT 1 = Ubiquitous

**GLUT 2 = **Liver, pancreatic islets

**GLUT 4 = ** Muscles, fat and heart

**GLUT 12 **= Skeletal muscle, adipose and small intestine

Note: GLUT 4 is upregulated to the cell surface membrane in response to downstream signalling pathways from the insulin-insulin receptor interactions.

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9
Q

Discuss the process of glycolysis

A

Glycolysis is an anaerobic process (can occur in the absence of O2) that produces energy rich NADH and ATP

It has two phases: prepatory and payoff

(view previous years notes for specifics)

Every metabolite between glucose and pyruvate is phosphorylated

  • The phosphate group provides a negative charge that prevents the escape of metabolites through the cell membrane
  • Two compounds, 1-3 bisphosphoglycerate and phophoenolpyruvate, have sufficiently high free energy of hydrolyisis to couple to ATP synthesis
  • The phosphate metabolites of glucose form Mg complexes (just like Mg-ATP) which are the true substrates of metabolic enzymes
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10
Q

What are three important steps of glycolysis?

(That we need to know for MD1)

A
  1. Glucose —–(hexokinase)—–> Glucose-6-phosphate (-16.7 kJ)
  2. Glucose-6-phosphate —-(phosphohexose isomerate)—-> Fructose-6-phosphate
  3. Fructose-6-phosphate —-(phosphofructokinase-1)—-> Fructose-1,6-phosphate
  • Phosphofructokinase is only active when cells have low ATP
  • The high negative free energy change makes it a functionally irreversible step and commits metabolism to the glycolytic pathway
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11
Q

Discuss the outcomes of anaerobic metabolism in humans

A

The glycolysis pathway produces pyruvate - can occur with or without the presence

This pyruvate is reduced to lactate **by lactate dehydrogenase - this reaction also results in the oxidation of **NADH + H+to NAD+ **

This replenishement of NAD+ allows ANAEROBIC GLYCOLYSIS to continue

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12
Q

How does phosphocreatine (natural and supplemental) produce ATP?

A

Phosphocreatine + ADP ——-> ATP + Creatine

Involves simple kinase activity moving the sole phosphate from creatine to ADP

Is an importantant sports supplement

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13
Q

Illustrate and explain the Cori Cycle

A

(add the image)

Lactate is linked to acidosis and muscle cramps. Humans recover more quickly from lactic acidosis than crocodiles.

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14
Q

Name two organs in the human body that primarily rely on anaerobic glycolysis for ATP production!

A

Retina

  • No/very few mitochondria in the retina to prevent the mitochondria absorbing and obstructing light from the photoreceptos
  • Few blood vessels in the fovea - so as to not obstruct central vision

Red Blood Cells

  • Anaerobic glycolysis is essential to maintain RBC membrane integrity - the failure of this system leads to haemolysis of the cells
  • No mitochondria - lost in RBC maturation
  • Anaerobic glycolysis of RBCs contribute to constant lactate present in the blood.
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15
Q

What is gluconeogenesis?

What precursors lead to glucose production?

What steps are different in gluconeogenesis vs glycolysis?

A

Gluconeogenesis is the synthesis of glucose from a range of precursors (as opposed to dietary glucose)

Carbon sources for gluconeogenesis includes:

  1. Lactate (after exercise or from anaerobically respiring tissues like RBC’s)
  2. Amino Acids from protein breakdown
  3. Glycerol from the mobilisation of TAGs in adipose tissue (major source after prolonged starvation)

Gluconeogenesis is largely the reverse of glycolysis; except for three bypass reactions:

  1. Pyruvate –(pyruvate carboxylase)–> Oxaloacetate –(PEP carboxylase)–> Phophoenolpyruvate
  2. Fructose –(fructose 1,6-bisphosphatase)–> Fructose 6 phosphate
  3. Glucose-6-phosphate –(glucose 6 phosphatase)–>Glucose
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16
Q

Compare the yields in energy between aerobic and anaerobic respiration

A

Aerobic respiration produces 32 ATP per glucose molecule

whereas

Anaerobic respiration produces 2 ATP per glucose molecule

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17
Q

What is galactosaemia?

A

Galactosaemia is a genetic disease due to defects in any three of the enzymes responsible for the conversion of galactose to glucose.

Galactose is a 4-epimer of glucose and is found in sphingolipid membrane structures, saccharide tags, structural polymers and most importantly as the milk disaccharide lactose.

Utilisation of the human body requires epimerisation back to glucose - a process that fails in galactosaemia

Clinical symtoms: infants with brain damage, cataracts, jaundice and liver + kidney damage

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18
Q

What are ketose sugars?

A

Ketose sugars are CHO sugars with a _ketone group on the carbon-2 _

The most important ketose sugar is fructose

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19
Q

What is the metabolism of fructose?

A

Fructose metabolism involves the liver converting fructose –> fructose-1-phosphate –> DHAP + Glyceraldehyde-3-phosphate

These metabolites, when derived from fructose, preferentially form glycerol that create the bakbone of TAGS in the liver

Fructose does not elicit insulin release from the pancreas, leptin release from adipose cells or suppress production of ghrelin

Fructose is 2-3 times sweeter than glucose

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20
Q

What is aspartame?

A

Aspartame is an amino acid that is used an artificial sweetener.
It is an aspartyl-phenylalanine methyl ester

It is 200x sweeter than sucrose

Is increasingly replacing fructose in the U.S.A

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21
Q

Discuss the chemical structure of Glucose

A

Glucose C6H12O6

The Fisher Projection shows stereochemistry in linear glucose molecule; the Hawthorne projection shows closed ring glucose

Glucose in the human body is the alpha conformation (forming glycogen); whereas the glucose that forms cellulose in plants is in the beta conformation

alpha glucose has a hydroxl group down at highest anomeric carbon

22
Q

What pathways does glucose normally undertake in the body as a source of energy

A
23
Q

Discuss the processes involved in the formation of glycogen

A

Glycogen is the storgae form of glucose and is stored in hepatocytes of the liver.

Glucose is uptaken in the fed state and released in the fasting state.

The ratio between insulin : glucagon determine whether glycogenesis or glycogenolysis occurs

Only the liver and kidneys have glucose-6-phosphatase to release free glucose

Occurs via GLUT-2 receptors

When the liver is saturated with glycogen, glucose is shunted to fatty acids

IGF-1 and GH have similar functions

24
Q

Discuss molecular glycogen

A

Glycogen is the instant energy store form of glucose in animals.

Glycogen is chemically inert, unlike the dangerous monomer glucose

The many ends of this branched molecule can be rapidly converted to glucose. The glycogen in
liver, rather than fat, is used to keep the body supplied with energy in short fasts such as
overnight before breakfast

Glycogen molecules can grow to
55,000 glucose units

A single glycogen complex has the same osmotic effect as a single glucose molecule -> alot more difficult to store 100 glucose molecules compared to storing 100 unit single glycogen

When glucose is needed each end of a branch
can be rapidly digested e.g. in response to adrenaline. Fat stores cannot respond so
rapidly

25
Q

What are some glycogen storage disorders?

A

Pompes Disease

Lack of alpha-1,4-glucosidase enzyme leads to an inability to release glucose molecules from the glycogen complex.

Results in engorgement of lysosomes with glycogen due an inabilty to reduce glycogen size.

Respiratory failure often results due to loss of ability to provide sufficient energy in fasting

26
Q

What steps are involved in the breakdown of glycogen?

A

Glycogen is utilised in the fasting state (in response to glucagon in the liver) or in a ‘fight or flight’ response in response to adrenaline (muscles only)

Both glucagon and glycogen utilise the same pathway to affect glycogenolysis.

cAMP is the second messenger of both of these hormones which starts a cascade amplification to cause the breakdown of glycogen

Liver cells and kidneys are the only cells that release free glucose into the blood ; the breakdown of glycogen in muscle cells produces glucose-1-phosphate which then undergoes glycolysis

27
Q

What is fibre?

A

**Fibre is the term given to complex carbohydrates that the human body cannot digest **

The most common fibre is cellulose

Fibre assists the GIT function by providing strucutre to bowel movements/boluses. The fibre provides extra bulk in water, explained by fibre being highly hydrophilic. It makes peristalsis more efficient.

High fibre diets result in shorter gut transit times and larger stool volumes.

**High fibre diets reduces the risk of haemorrhoids and diverticulums **

but

probably doesn’t reduce the risk of gut cancers as originally thought

28
Q

What archaeological evidence links the development of the human diet and evolution?

A

Humans are omnivores and demonstrate differnt teeth suited to either shearing meat or grinding vegetable matter.

It is proposed that humans may have developed intelligence and communication to better find fruits in season -> monkeys that eat leaves are dumb, monkeys that eat meat + fruit diet are smart

Cooking food may have lead to human intelligence. Cooking could have made fibrous fruits, along with the tubers and tough, raw meat that chimps also eat, much more easily digestible, so that they could be consumed quickly and digested with less energy. This would have allowed human ancestor guts to shrink over time. The energy that would have supported a larger gut was instead invested in a larger brain

29
Q

What are the differences between the modern diet and the diet of neanderthals?

A
30
Q

Discuss the differences in hypertension between modern diet people and primitive peoples who follow a preagricultural hunter-gatherer lifestyle

A

Hypertension is virtually nonexistent in primitive peoples who follow a preagricultural hunter-gatherer lifestyle.

This lifestyle involves significant daily physical activity and a diet rich in potassium and low in fat and sodium. Obesity is uncommon. Dietary patterns involve periods of feasting interspersed with long periods with minimal food.

Modern societies are characterized by a low
level of physical activityand constant availability ofabundant food that is rich in refined sugars, sodium and fat and low in potassium

31
Q

Describe the process involved in the digestion of carbohydrates

A
32
Q

What is the glycaemic index?

A

The glycaemic index is a ranking of carbohydrates based on their immediate effect on blood glucose (blood sugar) levels.

It compares foods gram for gram of carbohydrate

Low glycaemic index diets are justified by avoiding the high peak glucose levels that can lead to insulin resistance

Carbohydrates that breakdown quickly
during digestion have the highest glycaemic indexes. The blood glucose response is fast and high.

Carbohydrates that breakdown slowly, releasing glucose gradually into the blood stream, have low glycaemic indexes

33
Q

What is a glycaemic load?

A

Glycaemic load =

GI (%) x grams of carbohydrate per serving

34
Q

What proportions of the pancreas are dedicated to endocrine functions as opposed to exocrine functions?

A

98% of the pancreas weight is specialised for exocrine functions like the production and secretion of bicarbonate, amylase, trypsin and other digestive enzymes.

2% of pancreas weight are Islets of Langerhan are they dedicated to endocrine function:

35
Q

Discuss the general structure and function of Islets of Langerhans?

A

Islets of Langerhans comprise ~ 2% of pancreatic weight

Each islet is comprised of 50-300 cells

Have a spherical shape -> core mainly consists of beta cells; surrounding mantle is the other cell types.

There are four different cell types that make up each islet in different proportions:

beta cells

  • 80% of islet population
  • insulin + amylin

alpha cells

  • 10% of islet population
  • glucagon

delta cells

  • <5% of islet population
  • somatostatin

epsilon cells

  • <5% of cells
  • pancreatic polypeptide
36
Q

Discuss the biological synthesis of insulin

A

Insulin is synthesised as a **preprohormone **

The pre and pro portions of the hormone are required for the processing and secretion of the insulin protein.

The preprohormone is cleaved by prohormone convertases:

  • Prohormone Convertase 2 removes pre-peptide
  • Prohormone Convertase 1 removed pro-peptide

The mature insulin protein contains two inter-chain disulphide bones and one intra-chain disulphide bond

There is extreme conservation of the insulin gene over the animal kingdom (due to importance) - but mutations occur most often in the c-protein region as it has less effect on insulin function

37
Q

Discuss the two phases of insulin secretion

A

Insulin is secreted in response to nutrient stimulation (glucose and amino acids) in two phases:

  1. 1st Phase
  • sharp rise in secretion
  • lasts for 2-5 minutes
  1. 2nd phase
  • prolonged secretion phase
  • lasts for the duration of stimulus
38
Q

What cellular events are involved in glucose-induced insulin secretion?

A
39
Q

Describe the cellular events that lead to amino acid dependent insulin secretion

A

Is similar to glucose dependent insulin secretion except:

  1. Amino acids enter the beta cells via amino acid transporters
  2. Amino acids enter the TCA cycle
  3. Increased ATP production from TCA
  4. ATP gated K+ channels closed by excess ATP
  5. Depolarisation of the cell activates Voltage gated Ca2+channel
  6. Ca2+influx facilitate exocytosis of insulin vesicles out of cell
40
Q

How does fatty acid dependent insulin secretion occur?

A
  1. mobilised fatty acids are burned in beta cells
  2. This increases the concentration of Malonyl CoA
  3. Malonyl CoA inhibits CPT-1
  4. This causes insulin secretion
41
Q

Is there greater insulin secretion in response to orally administed glucose or IV glucose?

A

Orally administered glucose

This is a result of the _incretin effect _

42
Q

What are incretins?

A

Incretins are gut derived hormones that are excreted in response to nutrient interactions.

There are two main incretin hormones:

  1. Glucagon-like peptide 1 (GLP-1)
  2. Glucose-induced insulinotropic peptide (GIP)

These hormones are derived from differential post-translational processing of proglucagon in the gut

43
Q

Discuss the structure and function of glucagon-like peptide-1 (GLP-1)

A

GLP-1 is the most potent incretin

It is secreted from L-cells of the small intestine in response to glucose and fatty acids

It circulates to bind specific receptors on beta-cells of the pancreas to **upregulate proinsulin biosynthesis **- only does this if blood glucose is also high.

In addition, GLP-1:

  • inhibits glucagon secretion
  • stimulates insulin synthesis
  • promote beta cell proliferation, differentiation and maturation

Is a potential therapeutic agent for T2DM - but has a **very short half life of 2 minutes **due to being degraded by DDP-4

44
Q

How could incretin based therapies contribute to the greater release of insulin in diabetes treatment?

A

GLP-1 agonists (incretin mimetics) could be used as an exogenous source of GLP-1

  • Exenatide is GLP-1 agonist derived from the Gila Monster and shares 50% homology with human GLP-1.
    • Causes a small amount of weight loss (1.5kg)
    • Causes nausea that progressively gets better over course of treatment
  • The growth factor effects of GLP-1 on beta islet cells demonstrates potential as a therapy to prevent the loss of beta cells in T2 diabetes (rat models so far)
    • Growth affects by increase risk of cancer
    • Unfortunately, GF effects don’t appear to translate to humans

DDP-4 inhibitors inhibit the DPP-4 enzyme that degrades GLP-1. This elevates the levels of GLP-1 to function

45
Q

Discuss the structure and function of glucose-dependent Insulinotropic Polypeptide (GIP)

A

GIP is released from K cells of the duodenum in response to glucose and fatty acids.

Binds to specific beta-cell receptors to activate lipoprotein lipase -> leading to increased insulin secretion

46
Q

Discuss the structure and function of glucagon

A

Glucagon is secreted from the alpha islet cells of the pancreas in response to low blood glucose.

It stimulates the liver to release glucose and thhus restore normal blood glucose levels

47
Q

Describe the structure and function of Amylin

A

Amylin is co-stored and secreted with insulin from the beta cells of the pancreas.

Amylin inhibits glucagon secretion, gastric emptying and food intake

There is a deficiency in T1DM

48
Q

Discuss the structure and function of pancreatic polypeptide

A

Pancreatic polypeptide is released after a meal to inhibit food intake and increase energy expenditure.

It also increases inhibits secretion of exocrine enzymes from the pancreas and blocks contraction of gall bladder

49
Q

Discuss the structure and function of somatostatin

A

Somatostatin is released following a mixed meal and inhibits insulin and glucagon signalling

It also inhibits pancreatic exocrine function

Its role is to prevent exaggerated responses to a meal

50
Q

Illustrate the cellular pathways that occur as a result of insulin binding its receptor

A
51
Q
A

Metabolism Block (9 decks)

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