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104 Liver and regulation metabolism > Lisa Mullen MTT2 > Flashcards

Lisa Mullen MTT2 Flashcards

1
Q

causes of hypoglycaemia

A
  • fasting
  • exercise
  • hypernatraemia (eg diabetes insipidus)
  • hypovolaemia eg from vomiting, dehydration
  • alcohol ingestion
  • adrenal insufficiency (lack of hormone to counteract insulin)
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2
Q

In alcohol induced hypoglycaemia, NADH is increased. what effects does this have

A
  • shifts equilibrium of reactions reducing availability of OAA and pyruvate for gluconeogenesis, and causing lactic acid build up leading to metabolic acidosis. (Pyruvate —> lactate, OAA—>malate and DHAP —> glyc-3-P

> inc NADH leads to inhibition of fatty acid oxidation, signalling fatty acid synthesis instead. TG’s accumulate in liver = fatty liver

> Excess NADH inhibits isocitrate dehydrogenase and alpha-ketoglutarate dehydrogenase, inhibiting TCA cycle, leading to acetyl CoA build up (see separate card as to why this is bad)

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3
Q

In alcohol induced hypoglycaemia, why is a build up of acetyl CoA bad?

A

> production of ketone bodies which are released into blood, exacerbating already acidic conditions caused by lactic acid

> processing of acetate becomes inefficient, leading to build up of acetaldehyde which is highly toxic

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4
Q

50% of alcholics have thiamine deficiency. Thiamine is a cofactor for many enzymes. What are potential causes

A

> malnourishment

> ethanol interferes with GI absorption

> Hepatic dysfunction: hinders storage and activation of thiamine pyrophosphate

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5
Q

Name 5 glycogen storage diseases

A 
Type I: Von Gierke's disease
Type II: Pompe's disease
Type III: Cori's disease
Type IV: Andersen's disease
Type V: McArdle's syndrome
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6
Q

short and long term possible life-threatening consequences of diabetes

A

Short term: hyperglycaemia and ketoacidosis (type 1)
Hyperosmolar hyperglycaemic state (type 2)

Long term: -predisposition to CV disease and organ damage

  • retinopathy
  • nephropathy
  • neuropathy
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7
Q

High conc of glucose is toxic, what are 4 things it can lead to

A

> generation of ROS
osmotic damage to cells
glycosylation leading to altered protein function eg Hb causing anoxia
formation of advanaced glycation end products (AGE) which inc ROS and inflammatory proteins

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8
Q

2 tests to diagnose diabetes

A

> fasting blood glucose levels test: if blood glucose is higher than normal range after overnight fasting on at least two occasions

> glucose tolerance test: performed after overnight fast. Fasting blood sample removed and pt drinks glucola containing 75g glucose. Blood glucose is sampled after 20 min, 1 hour and 2 hours. Pt diabetic if blood glucose is greater than 11.1mM

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9
Q

What can be used as an indicator of long term glucose control and why

A

HbA1c (glycosylated Hb) as RBC’s lifespan is 8-12 weeks

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10
Q

Types of fast, intermediate and long acting insulin

A

Fast: Regular insulin, Lyspro/aspart/glulisine

Intermediate: NPH

Long: Detemir, Glargine

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11
Q

In NIDDM (Type 2) what is peripheral insulin resistance induced by

A

> presence of fatty acids - inhibits peripheral glucose disposal and enhances hepatic glucose output

> dysregulated adipokines from adipose tissue

> defects in translocation of Glut-4 eg this has been observed in adipocytes in obesity and diabetes

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12
Q

Treatment of NIDDM

A

1) Diet and exercise
2) Oral hypoglycaemia agents
eg Sulphonylueas (Gliclazide), Metformin (Biguanides), Thiazolidediones (Pioglitazone)
3) Targetting GLP-1
eg Exendin-4, Exenatide, Vildagliptin

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13
Q

Brain: fed, early fasting and starved state

A

Fed: glucose> glycolysis>TCA cycle (both produce ATP)

Early fasting: continues to use glucose (fatty acids cannot cross bb barrier)

starved: ketone bodies used. AND continues to take up glucose for glycolysis

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14
Q

Liver in fed, early fasting and starved state

A 
fed: .glucose> glycogen
.glucose>glycolysis>TCA cycle
.glucose>TGs>secreted as VLDL
.glycerol from peripheral tissues>TGs
.excess aa from gut>TG
.excess aa from gut>pyruvate>TCA cycle

early fasting: .reduced insulin leads to glycogenolysis and gluconeogenesis due to glucagon (cAMP)
.TGs via lipolysis become fatty acids, which undergo beta oxidation to become acetyl CoA & citrate, which inhibits glycolysis and activates gluconeogenesis

starved: .glycogen depletes after 24 hours
.fat/protein breakdown into lactate, alanine and glycerol which via gluconeogenesis increase plasma glucose
. urea synthesis to cope with aa’s entering liver
. fatty acids enter liver provide energy to support gluconeogenesis
.fatty acids enter liver, excess acetyl CoA produces ketone bodies which are released to be used by brain/muscle

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15
Q

Muscle in fed, early fasting and starved state

A

fed: .glucose>glycolysis>TCA cycle
. aa>protein
. fatty acids enter from chylomicrons and VLDL, go through beta oxidation > acteyl CoA>energy for contraction

early fasting:
.no glycogenolysis as no glucagon receptors
.fatty acid oxidation used as energy> inhibits glycolysis
.proteins>aa>carbon skeletons used for energy, and transported to liver in form of alanine

starved: .switch to fatty acids for fuel>beta oxidation>acetyl CoA>citrate>inhibits PFK-1>build up of G-6-P>inhibits Hk> preserves glucose
.take up ketone bodies as alt source of fuel
.NA/cortisol> causes proteolysis> alanine used for glucose synthesis (in liver)

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16
Q

Adipose tissue in fed, early fasting and starved state

A

fed: .glucose via glycolysis>acetyl CoA>gives us fatty acids via lipogenesis>TG
.fatty acids from chylomicrons/VLDL>TG

early fasting: .inhibition of glycolysis
.breakdown of TGs into glycerol>liver for gluconeogenesis
.breakdown of TGs into fatty acids> used in tissue for energy, and released into blood to support other glucose independent energy production

starved: .greater lipolysis (TG>fatty acid for energy, and glycerol exportation to liver)

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17
Q

Name the enzymes for:

1) pyruvate>oxaloacetate
2) OAA>PEP
3) F-1,6-P2>f-6-P
4) G-6-P>glucose

A

1) pyruvate carboxylase
2) PEP carboxykinase
3) Fructose-1,6-bisphosphatase
4) G-6-Pase

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18
Q

What is PFK-1 allosterically regulated by

A

1) ATP inhibits
2) AMP activates
3) H+ inhibits
4a) Fru-6-phos activates
4b) Fru-2,6-P2 activates
4c) citrate inhibits

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19
Q

what activates gluconeogenesis short term, and what activates it long term?

A

short term: glucagon, adrenaline and acetyl coa

long term: glucagon, glucocorticoids and thyroid hormones

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20
Q

How does urea cycle lead to gluconeogenesis

A

aa first transaminated to lose ammonia> converted to urea and fumarate> fumarate converted to OAA (starting substrate for gluconeogenesis)

21
Q

3 systems for ATP production in muscle

A

Anaerobic: ATP-PC, Lactic acid

Aerobic: oxygen-system

22
Q

What is glycogen phosphorylase activated by?

A

AMP allosterically

phosphorylation in response to stress hormones and increased cytoplasmic ca2+

23
Q

What is glycogen synthase activated and inactivated by

A

activated allosterically by G-6-P which is low during exercise

inactivated by phosphorylation in response to stress hormones and increased cytoplasmic ca2+

24
Q

what is PFK-1 inhibited and activated by

A

inhibited allosterically by ATP

activated by AMP and Fru-2,6-P2

25
Q

effect of adrenaline during exercise

A

decreases insulin and increases glucagon which promotes gluconeogenesis

26
Q

describe metabolism whilst sprinting

A

.50%: catecholamines stimulate glycogen breakdown which is anaerobically converted to lactate (large quantities of lactic acid converted to glucose via gluconeogenesis in liver)

.50%: PC converted to creatine, releasing ATP

27
Q

describe metabolism for middle distance

A

30%: aerobic oxidation of glycogen

65%: glycogen breakdown into lactate

5% is use of PC (Use of PC decreases with distance)

28
Q

briefly describe 4 stages of marathon

A

stage 1: resting muscle and liver: glycogen stores maintained, aerobic oxidation of fatty acids to provide energy

stage 2: 10 minutes: muscle glycogen/glucose from liver used to power muscles, mainly via glycolysis. Release of adrenaline causes mobilisation of fatty acids to provide energy.

stage 3: 2 hours: 90% glycogen depletion, switch to fatty acids for energy source. ketone bodies may also be used. lactate, glycerol and aa used for gluconeogenesis in liver

stage 4: the finish: muscle/liver glycogen depleted. hypoglycaemia symptoms.

29
Q

a) what does glucagon stimulate in the liver, what is second messenger
b) what does adrenaline stimulate in liver and muscle, what is receptor/receptors for each and what is second messenger for each

A

a) glycogenolysis, cAMP
b) glycogenolysis, in liver/muscle bets-adrenergic receptors 2nd messenger cAMP
in liver alpha1-adrenergic receptors 2nd messenger is ca2+

30
Q

Describe reciprocal regulation of glycogen phosphorylase and glycogen synthase

A

See notability lecture 9

31
Q

Glucagon leads to cAMP cascade and activation of cAMPPK. What effect does this have on F-2,6-BPase and PFK-2, and the implications of this

A

cAMPPK phosphorylates F-2,6-BPase into ‘a’ form and phosphorylates PFK-2 into ‘b’ form. Ultimately leads to gluconeogenesis

32
Q

Fatty acid oxidation leads to formation of acetyl coa, how does an increase in acetyl coa favour gluconeogenesis (what does it activate and inhibit)

A

Activates pyruvate carboxylase and inhibits pyruvate dehydrogenase

33
Q

3 Roles of ca2+ during exercise

A

1) signal for muscle contraction
2) activates glycogenolysis by activating glycogen phosphorylase
3) stimulates production of NO, leads to vasodilation which leads to inc blood flow

34
Q

What is hormonal control during exercise

A

Adrenaline increases blood flow to muscles via beta adrenoreceptors

Decreased insulin: no need for insulin for muscle intake of glucose, as muscle contraction activates glut 4 even in absence of insulin

Increased glucagon promotes gluconeogenesis

35
Q

What is fatigue

What is effect of accumulation of pyruvate and lactic acid on muscle

A

Rate of ATP utilisation exceeds synthesis rate
Accumulation leads to decreased force of muscle contraction due to dec muscle pH
Glycolysis inhibited from H+ from lactic acid

36
Q

Type 1 diabetes
Onset?
Aetiology?
Sometimes follows viral infections such as

A

Young onset
Autoimmune destruction of islet of langerhans
Mumps measles rubella

37
Q

What’s type II diabetes caused by

A

1) insensitivity or target cells to insulin (defects in receptors and cell signalling)
2) impaired insulin secretion (amyloid deposits reducing beta cell mass)

38
Q

Mechanism of action sulphonylureas (eg gliclazide)

A

Inhibits k+ channels in beta cells. This depolarises membrane opening voltage -dependent ca2+ channels. Increase in intracellular calcium stimulates insulin secretion from cell

39
Q

Mech of action for metformin (a biguanide)

A

Only effective in presence of insulin. Inc insulin sensitivity. Reduces LDL and VLDL dec CV risk. Supresses appetite - useful if overweight

40
Q

Mech of action of thiazolidediones eg pioglitazone

A

Slow onset. Achieved after 1-2 months treatment.
Reduction in hepatic glucose output inc effectiveness of insulin.
Bind to PPARgamma regulating gene expression in adipose tissue for things such as glut 4 and lipoprotein lipase

41
Q 
Regarding drugs that target GLP-1
A) what does glp-1 do
B) what does exendin-4 do
C) what does exenatide do
D) what does vildagliptin do
A

A) stimulates secretion if insulin. It’s produced by endocrine cells of intestine following ingestion
B) hormone that stimulates GLP-1 receptor
C) synthetic version of exendin-4, longer half life, stimulates insulin secretion, inhibits glucagon secretion and glucose production by liver.
D) inhibits inactivation of GLP-1

42
Q

What is hypoglycaemia defined as
What are symptoms
When does loss of consciousness occur

A

Blood glucose less than 4mM
symptoms: lethargy, memory loss, confusion, blurred vision, coma, numbness arms hands, faintness,seizures, moodiness

Loss of consciousness occurs at less than 2.5mM/L

43
Q

Describe how ethanol is converted into acetate in liver

A

Ethanol ——> acetaldehyde via alcohol dehydrogenase,and NAD+ to NADH . = high NADH:NAD+ ratio in cytosine

Acetaldehyde transported to mitochondria where it is converted to acetate via enzyme aldehyde dehydrogenase and another NAD+ to NADH.= high NADH:NAD+ in mitochondria

44
Q

How does alcohol consumption cause hepatomegaly

A

Decreases activity of the proteosome leading to accumulation of protein in liver = enlargement

45
Q

Describe Von Gierkes disease

A

Most common glycogen storage disease
Affects mainly liver and kidney . Deficiency in G-6-Pase.
High levels of G-6-P leads to abnormal accumulation of glycogen in liver and kidney, inc glycolysis leads to lactic acidosis, inc fatty acids, TG and VLDL synthesis and excretion
Body tries to compensate for dec glucose by releasing glucagon and adrenaline which leads to breakdown of fat stores, release of fatty acids, conversion to TGs and VLDL in liver which leads to hyperlipidaemia which leads to hepatomas

Pts may also show hypouricaemia and neutropenia

46
Q

Describe pompe’s disease

Describe cori’s disease

A

Can be most devastating glycogen storage disease
A deficiency of alpha -1,4 glucosidase activity in lysosomes. Causes death by cardiorespiratory failure

Coris: the amylo -1,6 glucosidase (debranching enzyme) is deficient. Unable to break down glycogen

47
Q

Describe Andersen’s disease

A

Glycogen in normal amounts but has long unbranded chains with low solubility. Sufferers rarely live past four years. Issue with branching enzyme

48
Q

Describe McCardles syndrome

A

Affects glycogen phosphorylase (liver enzyme is normal) muscle cannot breakdown glycogen therefore accumulation
Sufferers have low tolerance to exercise they fatigue easily and have muscle cramps after

104 Liver and regulation metabolism (5 decks)

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