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104: Theme 2 > Applied Biochemistry > Flashcards

Applied Biochemistry Flashcards

Lectures 11-13

1
Q

What are anaerobic systems for producing ATP for muscle contraction?

A
  • ATP-PC system using Phosphocreatine: fastest method but limited
  • The Lactic acid system using glycogen: fast method but limited
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2
Q

How is the Creatine phosphate or phosphocreatine used in muscle contraction?

A
  • Creatine phosphate+ ADP –(Creatine kinase)–> ATP + creatine
  • a contraction restores the ADP for another reaction to take place
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3
Q

How is skeletal muscle blood flow controlled?

A
  • when vascular B2-adrenoreceptors are stimulated by the agonist adrenaline it causes vasodilation
  • blood flow regulated by tissue and endothelial factors: tissue hypoxia, adenosine, K+, CO2, H+, NO
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4
Q

What is the role of Ca2+ in muscle contraction?

A
  • stimulates muscle contraction
  • increases glycogen breakdown by activating glycogen phosphorylase
  • stimulates the production of NO, causing vasodilation (for aerobic respiration)
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5
Q

What is the action of phosphorylase and what are its controls?

A

Phosphorylates glucose to G-6-P

  • Allosterically activated by AMP, - activated by phosphorylation in response to stress hormones, increased cytoplasmic Ca2+
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6
Q

What is the action of glycogen phosphorylase and what are its controls?

A

Converts glycogen to G-1-P

  • allosterically activated by G-6-P
  • inactivated by phosphorylation in response to stress hormones, increased cytoplasmic Ca2+
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7
Q

What is the action of Phosphofructokinase-1 (PFK-1) and what are its controls?

A

The enzyme that converts F-6-P to F-1,6-BP

  • Allosterically inhibited by ATP
  • Activated by AMP and Fru-2,6-P2 it is an important sensor of energy availability and needs during exercise
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8
Q

Explain the Cori Cycle

A
  • Lactate is used by the liver to regenerate glucose, utilises 6ATP to form G-6-P
  • insufficient blood flow in the muscle, leads to lactic acid build up in the muscle
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9
Q

During exercise what is the hormonal control of glucose?

A
  • Adrenaline increased ( acts on a B2- adrenoreceptor to increase vasodilation)
  • Insulin decreases and glucagon increases
  • glucagon upregulates gluconeogenesis whilst insulin would inhibit this process
  • insulin isn’t needed for the uptake of glucose in the muscle because Glut 4 channels are activated by muscle contraction even in insulins absence
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10
Q

What is fatigue?

A
  • inability to produce the desired power output
  • ATP use > ATP production
  • Accumulation of pyruvate and lactic acid in the contracting muscle results in a decline in the force generated
  • glycolysis inhibited by the H+ from lactic acid
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11
Q

What is the metabolism like in resting muscle?

A
  • glycogen stores are maintained/ replenished
  • oxidative metabolism of fatty acids provides energy for the muscle
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12
Q

Describe metabolism in muscles during Sprints

A
  • Fuel ATP and Phosphocreatine
  • blood vessels are compressed so anaerobic energy is required from glycogen
  • large amounts of lactic acid produced ( converted to glucose in the liver via gluconeogenesis)
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13
Q

Describe metabolism in muscles during Middle Distance runs

A
  • aerobic oxidation of glycogen makes up 30% of ATP required
  • some oxygen may come from oxymyoglobin in the muscle
  • lactate is still produced in large quantities
  • 65% of ATP comes from glycogen metabolism
  • CP contributes increasingly less only 5% at 800m
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14
Q

Describe metabolism in muscles during a Marathon

A
  • glycogen stores in muscle are depleted after 20 miles, 90% of liver glycogen is used
  • insulin levels fall and glucagon is secreted
  • fatty acids become ain source of energy, only generate 50% of maximum power output
  • hitting the wall
  • ketone bodies may also be used by a muscle
  • fatty acid catabolism is dependent on sufficient oxaloacetate levels for the Kreb’s cycle
  • this is dependent on pyruvate formation therefore there needs to be a base glycogen metabolism
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15
Q

Explain the cause of Type 1 Insulin-dependent diabetes Mellitus

A
  • patients who cannot survive without insulin
  • autoimmune destruction of ß-cells of the islets of Langerhans
  • sometimes this is following viral infections i.e MMR
  • mainly juvenile onset but increasingly observed in later life
  • no feedback from insulin on alpha-cells glucagon levels remain high, therefore also a disease of glucagon excess
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16
Q

What are the classical symptoms of Type 1 diabetes? What is the treatment?

A
  • Thirst,
  • Tiredness
  • Weight loss
  • Polyuria
  • Hyperglycaemic coma
  • Treatment: insulin injections
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17
Q

Explain the metabolic consequences of Type 1 diabetes

A
  • there is low insulin: glucagon ratio
  • blood glucose is high but cell and tissue glucose is low
  • this leads to induction of catabolic enzymes and repression of anabolic enzymes
  • Weight loss, weakness and fatigue ( increased protein breakdown)
  • Hyperglycemia -> dehydration (osmotic diuresis)
  • Ketoacidosis
  • Hypertriglyceridemia
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18
Q

Explain IDDM diabetic state in the Liver

A
  • Liver remains gluconeogenic due to high glucagon, even though there is a high blood glucose
  • glycogen synthesis and glycolysis inhibited: liver can not buffer blood glucose
  • fatty acids used to provide energy to support gluconeogenesis, the excess is converted to TAGs and VLDL
  • Excess acetyl CoA from fatty acid oxidation converted to ketone bodies
  • if not used fast enough can lead to ketoacidosis due to accumulation and H+ ions in the blood
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19
Q

How are ketone bodies formed?

A
  • the formation is through condensation reaction between 2 molecules of acetyl CoA
  • they can be converted back to acetyl CoA in peripheral tissues for use in the TCA cycle
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20
Q

Explain IDDM diabetic state in Muscles

A
  • little glucose entry due to lack of insulin
  • fatty acid and ketone body oxidation used as fuel
  • proteolysis occurs to provide C-skeleton for gluconeogenesis
  • this leads to muscle wasting
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21
Q

Explain IDDM diabetic state in Adipose tissue

A
  • diminished uptake in glucose
  • low insulin: glucagon ratio increases lipolysis
  • lead to a continuous breakdown of triacylglycerol and release of fatty acids and glycerol into the bloodstream for energy production in peripheral tissue and gluconeogenesis in the Liver
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22
Q

Explain the IDDM diabetic state in Plasma and urine

A
  • hyperglycaemia, due to greater production than utilisation of glucose
  • glycosuria occurs as glucose exceeds the renal threshold for glucose reabsorption
  • results in loss of water and development of thirst
  • fatty acid synthesis is greatly diminished as the expression of lipoprotein lipase is regulated by insulin
  • results in hypertriglyceridemia and hyperchylomicronaemia: susceptible to cardiovascular events
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23
Q

What are the possible short term life-threatening consequences of diabetes?

A
  • Hyperglycaemia and ketoacidosis (typical in Type 1)
  • Hyperosmolar (osmolarity) hyperglycaemia state (typical in Type 2)
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24
Q

What are the possible long term life-threatening consequences of diabetes?

A
  • Predisposition to CV disease and organ damage
  • Retinopathy- cataracts, glaucoma and blindness
  • Nephropathy
  • Neuropathy
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25
Q

What is the impact of high glucose concentrations>

A
  • generation of ROS
  • osmotic damage to cells
  • glycosylation (CHO bound to another molecule or functional group) leading to alterations in protein function
  • formation of advanced glycation end proteins (AGE) which increase ROS and inflammatory proteins
26
Q

What two major tests are used to diagnose diabetes?

A
  • Fasting blood glucose levels: 126mg/dL or above on two occasions = diabetes
  • Glucose tolerance test: performed in the morning after an overnight fast, fasting blood sample is removed and the subject drinks a glucola drink containing 75g of glucose, blood glucose sampled at 20min, 1 hr and 2 hr
27
Q

What is the use of HbA1c- glycated haemoglobin in monitoring diabetes?

A
  • the lifespan of RBCs is 8-12 week, can measure blood glucose over that duration
  • Normal: below 42 mmol/mol : below 6%
  • Prediabetes: 42-47 mmol/mol : 6-6.4%
  • Diabetes: 48 mmol/mol or over : 6.5% or over
28
Q

Give examples of Fast, Intermediate and Long-acting Insulin

A

Fast: , Lyspro/ Aspart/ Glulisine,Regular

Intermediate: NPH (has the longest peak time 6-10hrs)

Long: Detemir, Glargine

(this is in order of their duration)

29
Q

Explain 3 types of insulin treatment regimes

A
  • Premixed intermediate insulin 2/d: less injecting, timing of meals may be critical
  • long/intermediate-acting 3/d: greater flexibility for those doing shift work, potential nocturnal hypoglycaemia
  • rapid-acting with long-acting: reduces the potential for nocturnal hypoglycemia, more expensive
30
Q

What is the cause of Type 2 diabetes?

A
  • a disease where there is not enough insulin

It is a combination of:

  • impaired insulin secretion
  • Increased peripheral insulin resistance
  • increased hepatic glucose output
31
Q

What is the cause of peripheral insulin resistance?

A
  • presence of excess fatty acids: inhibit peripheral glucose disposal and increases hepatic glucose output via gluconeogenesis
  • dysregulated adipokine from adipose tissue
  • defects in cellular translocation of Glut-4 and glucose uptake: observed in adipocytes in both obesity and diabetes
32
Q

What are some features and associated groups in NIDDM?

A
  • develops over many years 2-6% of adults
  • patients can survive long term without insulin usually older and obese (increasing prevalence in adolescence)
  • associated Smith microvascular disease, stroke and atherosclerosis
  • maybe asymptomatic, but many have hyperglycaemic symptoms: thirst, polyuria, weight loss
  • Ketone bodies present in low conc.
33
Q

What are the metabolic process like in NIDDM (Type 2 diabetes)?

A
  • no raised glucagon levels, insulin is present to suppress it
  • as glucagon isn’t very high there isn’t uncontrolled lipolysis (less acetyl CoA) therefore ketone body formation isn’t excessive
  • glycogen is stored normally in the lover, and it continues to produce VLDL from glucose and amino acids
  • this is the cause of hypertriglyceridemia and macrovascular disease, as VLDL production is increased in the Liver
34
Q

How can NIDDM be treated?

A
  • Diet and exercise (effect on Glut4)

Oral hypoglycaemic agents

  • Insulin secretion: Sulphonylureas (hypoglycaemia is a side effect)
  • Tissue insulin sensitivity: Biguanides- Metformin or Thiazolidinediones- Pioglitazone
  • Absorption and digestion carbohydrates: glucosidase inhibitors-Acarbose
35
Q

What is the use and action of Sulphonylureas (Gliclazide)?

A
  • increases insulin secretion and cause hypoglycaemia as a byproduct
  • Inhibits K+ channels, simulating the action of ATP-dependent closing of K+ channels
  • this depolarises the membrane of Beta cells causing Ca+ to move into the cytoplasm causing insulin secretion
36
Q

What is the use and action of Metformin (Biguanides)?

  • overall
  • in the brain
  • in the intestines
A
  • 1st choice hypoglycaemic agent
  • suppresses appetite in the brain
  • decreases glucose absorption in the intestines
  • only effective in the presence of insulin; increases insulin sensitivity
  • reduces LDL and VLDL and CV risk
37
Q

What is the use and action of Metformin (Biguanides)?

  • in adipocytes
  • the liver
  • in muscle?
A

Adipocytes

  • increases glucose uptake
  • increase glucose utilisation

Liver

  • decrease gluconeogenesis, glycogenolysis,
  • decrease glucose output
  • decrease lactate uptake

Muscle

  • increase glucose uptake
  • increase glucose utilisation
38
Q

What is the use and action of Thiazolidinediones (Pioglitazone)

A
  • slow onset
  • reduces hepatic glucose output
  • increases glucose uptake into muscle
  • increases effectiveness of endogenous insulin, it reduces the amount of exogenous insulin needed
  • may also come with reduction in circulating insulin, free fatty acids, triglycerides and small dense LDL
  • bind to PPAR-gamma, regulating gene expression particularly in adipose tissue
39
Q

What is the action of Targeting Glucagon-like Peptide (GLP-1)?

  • what alternatives are there for it?
A
  • GLP-1 and GIP (glucose-dependent insulinotropic peptide) are produced by endocrine cells of the intestine following ingestion of food: they stimulate insulin secretion
  • they have a very short half-life in vivo
  • Exendin-4: powerful stimulator of GLP-1 receptor (saliva of poisonous Gila monster)
  • Exenatide (Byetta): the synthetic version of exendin-4 with a longer half-life in vivo
  • can be used in conjunction with other oral hypoglycemic agents
40
Q

Define Hypoglycaemia and give the immediate response after an initial drop in blood glucose.

A
  • blood glucose level below 4mmol/L (72mg/dL)
  • symptoms may develop at higher levels if there was a rapid fall from previously high levels

Symptoms (phase of the following)

  • sweating
  • tachycardia
  • agitation

the sympathetic nervous system is activated, there is the release of adrenaline and glucagon

41
Q

What are the symptoms of Hypoglycaemia?

A

they are equivalent to cerebral anoxia, - moodiness

  • numbness in arm and hands
  • blurred vision
  • confusion, memory loss
  • faintness, dizziness or lethargy: may progress to a coma

the most serious consequences related to the effects on the brain

  • loss of cognitive function, seizures, and coma
  • loss of consciousness at 2.5mmol/L (45mg/dL)
  • rapid restoration of blood glucose (i.v glucose or injection of glucagon), prolonged or repeated hypoglycemia may result in permanent brain damage
42
Q

What are potential causes of Hypoglycaemia?

A
  • exercise, fasting
  • excess exogenous insulin
  • insulinoma: excess endogenous insulin
  • alcohol (inhibits endogenous glucose production)
  • hypernatremia (diabetes insipidus)
  • hypovolaemia from vomiting, dehydration
  • pathologies such as adrenal insufficiency
43
Q

Explain how Alcohol induces hypoglycaemia

A
  • occurs several hours after alcohol ingestion: occurs on depletion of glycogen stores when blood glucose is reliant on hepatic gluconeogenesis
  • additional stress is placed on gluconeogenesis as, alcohol is metabolised in the liver by an unregulated process
  • ethanol – (alcohol dehydrogenase)–> acetaldehyde
  • acetaldehyde –(aldehyde dehydrogenase)–> acetic acid
  • results in a high NADH:NAD+ ration in the mitochondria: this shifts the equilibrium which involves these cofactors
  • reduces the availability of substrates for entry into the gluconeogenesis, private and oxaloacetate
44
Q

What is the physiological response to alcohol-induced hypoglycaemia?

A
  • leads to stress response: rapid heartbeat, clammy skin
  • rapid breathing in response to metabolic acidosis: brought on by excess lactic acid
45
Q

What are the biochemical consequences of long-term alcohol consumption?

A
  • high levels of NADH (from alcohol synthesis) inhibit fatty acid oxidation; however, in this case, it signals for fatty acid synthesis
  • TGs accumulate in the liver causing ‘fatty liver’: they are exported as VLDL
  • acetate produced from etOH –> acetyl CoA however
  • acetyl-CoA processing in the TCA is prevented because high levels of NADH inhibits both isocitrate dehydrogenase and alpha-ketoglutarate dehydrogenase
46
Q

What are the consequences of the accumulation of Acetyl-CoA

A
  • production of ketone bodies: exacerbates the already acidic conditions from high lactate levels
  • processing of acetate in the liver becomes inefficient leading to a build-up of acetaldehyde
  • acetaldehyde is the direct product of alcohol metabolism DNA is highly toxic
47
Q

Review this diagram of the consequences of alcohol metabolism on hypoglycaemia

A

MEOS – ethanol-inducible microsomal ethanol-oxidising system. This is a second pathway by which ethanol can be converted to acetaldehyde.

ROS- Reactive Oxygen Species: contributes to oxidative stress in the cells

48
Q

How can Alcohol cause Hepatomegaly?

A
  • alcohol consumption decreases the activity of proteosomes
  • accumulation of protein, which causes enlargement of the liver
  • decreased proteosomes activity also increases oxidative stress
49
Q

What is Thiamine deficiency and what are its causes?

A
  • deficiency in thiamine (Vitamine B1)

Causes:

  • Malnourishment
  • Ethanol interferes with GI absorption
  • Hepatic dysfunction, which hinders storage and activation to thiamine pyrophosphate
50
Q

What is the significance of Thiamine deficiency?

A
  • it acts as a cofactor for many enzymes in central energy-yielding pathways
  • Glycolysis, TCA and Pentose phosphate pathway
  • it has a half-life of 10-20 days, therefore deficiency can occur rapidly during depletion
51
Q

What is glycogen storage disease?

A
  • An Inherited disease, which affects the stores of glycogen, defects in either the synthesis or degradation of glycogen

There are 10 different types of disease presentation depending on the impacted enzyme

  • they are all autosomal recessive apart from type IX which is sex-linked
  • all result in an abnormal amount or type of glycogen
52
Q

What are the five types of Glycogen storage disease involved in glycogen synthesis and breakdown?

(what enzyme is affected)

A
  • Type 0: Glycogen Synthase
  • Type I: G-6-Pase
  • Type III: Debranching enzyme
  • Type IV: Branching Enzyme
  • Type V Glycogen Phosphorylase
53
Q

Explain this glycogen storage disease: Type I von Gierke’s disease

A
  • Affects mainly the liver and kidneys, (and intestines)
  • Most common glycogen storage disease: 25%
  • Caused by a deficiency in glucose 6-phosphatase (hydrolysis of G-6-P liberates glucose into the blood): G-6-P —> Glucose +Pi
  • This enzyme catalysts the terminal reaction of glycogenolysis and gluconeogenesis
  • Hypoglycaemia caused by the inability to release glucose during fasting between meals as the two pathways
  • results in excess storage of glucose-6-phosphate and eventually an enlarged liver
54
Q

Explain this glycogen storage disease: Type II Pompe’s disease

A
  • A deficiency of a-1,4 glucosidase activity in the lysosomes.
  • Can be one of the most devastating of the glycogen storage diseases.
  • Causes death by cardiorespiratory failure
55
Q

Explain this glycogen storage disease: Type III Cori’s disease

A
  • The amylo 1,6 glucosidase (de-branching enzyme) is deficient
  • Unable to break down glycogen, resulting in hypoglycaemia.
  • Strangely, symptoms often disappear at puberty.
56
Q

Explain this glycogen storage disease: Type IV Andersen’s disease

A
  • Liver glycogen in normal amounts but comprises long unbranched chains that have low solubility.
  • Sufferers seldom live beyond four years.
  • One of the most severe of these diseases.
57
Q

Explain this glycogen storage disease: Type V McArdle’s syndrome

A
  • Affects muscle glycogen phosphorylase (liver enzyme is normal).
  • Muscle cannot break down glycogen (which accumulates)
  • Sufferers have a low tolerance to exercise and fatigue easily, with painful muscle cramps after exercise. Otherwise, they have a normal life-span
58
Q

What is the bodies response to Type 1 Glycogen storage disease: Von Gierke’s disease?

A

The body attempts to compensate for hypoglycaemia by:

  • releasing glucagon (hyperglucagonaemia) and adrenaline
  • resulting in mobilisation of fat stores and release of fatty acids
  • Conversion of fatty acids to TAGs and VLDL in the liver resulting in accumulation of fat in liver and hyperlipidaemia.
  • May lead to hepatomas - accumulation of fat in cheeks and buttocks.
59
Q

What is the treatment for Type one Glycogen storage disease (GSD): Von Gierke’s disease

A
  • Young infants are fed glucose through nasogastric tubes
  • Older children are fed glucose drinks at 2-3 hour intervals night and day to prevent fall in blood glucose and cerebral damage.
  • Uncooked cornstarch may be used to prolong the period between feeds: cornstarch is digested slowly providing a steady release of glucose
60
Q

What are the results of high levels of G-6-P and what disease would cause this?

A
  • Type 1 glycogen storage disease- von Gierke’s disease
  • abnormal levels of glycogen accumulate in the liver and kidney
  • increased glycolysis leading to lactic acidosis
  • increased fatty acids, TAG and VLDL synthesis and excretion
61
Q

What are other dysfunctions that occur with Type 1 Von Gierke’s disease?

A

Patients suffer with:

  • hepatomegaly/ renomegaly,
  • stunted growth,
  • severe tendencies to hypoglycaemia (convulsions),
  • hyperlactatemia and hyperlipidemia.
  • May also show hyperuricaemia and neutropenia the latter being associated with recurrent bacterial infections.
  • Symptoms of neutropenia appear when intervals between feeds increases and the infant sleep through the night, or when an illness prevents normal feeding routine.

104: Theme 2 (7 decks)

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