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Biochemistry (MPAS) > Tutorial: Diabetes and integrated glucose metbaolism > Flashcards

Tutorial: Diabetes and integrated glucose metbaolism Flashcards

1
Q

Normal glucose level in body

A

4-6 mM

normoglycemia

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2
Q

What happens in a well fed state?

A

aka postprandial state

Ample nutrients (glucose, amino acids, fatty acids)

Insulin is secreted, causing a high insulin/glucagon ratio

Ratio activates pathways to store excess nutrients

Insulin lowers glucose levels in blood and promotes synthesis of glycogen, amino acid uptake, lipogenesis and inhibits lipolysis

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3
Q

What happens after the body has been fasting for more than 8 hours?

A

Glucagon secretion is increased, insulin is decreased

Ratio of insulin to glucagon activates the generation of energy from stored molecules

Glycogenolysis in liver, protein breakdown, lipid breakdown

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4
Q

Sensitivity of lipase to insulin

A

Very sensitive!!

Only a small amount is necessary to prevent uncontrolled breakdown of lipids

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5
Q

Prolonged fasting and starvation

A

Further decrease in insulin/glucagon ratio

Causes changes in energy metabolism to maintain the constant supply of glucose required as an energy source by the brain and RBC

Glycogen supplies become exhausted and glucose must be synthesized from amino acids, glycerol and lactate

Lipolysis increases and ketone bodies are formed. Can be used by the brain to decrease body’s demand for glucose

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6
Q

Major anabolic and catabolic pathways

A

See figure

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7
Q

Where is insulin synthesized?

A

As a preprohormone in the beta cells of the islet of langerhans

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8
Q

When is insulin released into blood?

A

In response to high glucose

In response to high amino acids

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9
Q

Pathway of insulin release

A

Increased uptake of glucose by pancreatic beta cells leads to increased glucose oxidation

Elevation in ATP/ADP ratio

High ATP inhibits ATP sensitive potassium channel, which depolarizes the cell

This leads to Ca2+ influx and insulin secretion

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10
Q

What route of glucose administration has a greater effect on insulin secretion?

A

Oral glucose has greater effect than injected glucose

Probably because there is secretion of gut incretin hormones (glucagon-like peptide 1 and gastric inhibitory peptide)

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11
Q

What does glucagon-like peptide 1 do?

A

GLP-1

Increases insulin secretion only in the presence of elevated plasma glucose levels

Avoids inappropriately high insulin during fasting

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12
Q

On what organs does insulin have its effects?

A

On tissues that have abundant insulin receptors

Liver

Adipose

Skeletal muscle

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13
Q

What happens when insulin binds insulin receptor?

A

Autophosphorylation of insulin receptor on several kinase residues

Activates the receptor as a kinase toward downstream binding partners and substrates

Secondary messengers activate most anabolic pathways (except gluconeogenesis)

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14
Q

What are the main counter-regulatory hormones that act in opposition to insulin?

A

Glucagon

Epinephrine

Cortisol

Growth hormone

Raise glucose level in bloodstream

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15
Q

Glucagon - where is it secreted and why?

A

Fast acting

Secreted by pancreatic alpha cells

In response to low blood glucose

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16
Q

What does glucagon act on?

A

Receptors in the liver

Works to increase cAMP and activate protein kinase A

This leads to activation of enzymes that release glucose into blood stream

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17
Q

How does epinephrine increase blood glucose?

A

Short acting

Activates hepatic glycogenolysis and gluconeogenesis via beta-adrenergic receptors

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18
Q

Action of cortisol and growth hormones

A

Longer acting

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19
Q

How to glucocorticoids work?

A

ex: cortisol

Elevate blood glucose by decreasing glucose uptake and stimulating transcription of phosphoenolpyruvate carboxykinase (key enzyme in gluconeogenesis)

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20
Q

How does growth hormone work to increase blood glucose?

A

Primarily by decreasing glucose uptake in peripheral tissues

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21
Q

How does type 1 diabetes arise?

A

Destruction of pancreatic beta cells, which synthesize insulin

Often due to production of autoantibodies against beta cells, but initiating event is unclear

Insulin deficiency results. Relative high glucagon levels.

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22
Q

What is type 1 diabetes often referred to as?

A

Juvenile diabetes

Majority of cases present before 18 years of age

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23
Q

What happens if someone with type 1 diabetes goes untreated?

A

Catabolic state

High glucose levels due to glycogen breakdown and gluconeogenesis

High ketone levels due to uncontrolled lipolysis

Protein is degraded

Fatty acids are used as source of energy and glucose is not used

Leads to weight loss, hyperglycaemia and ketonuria

24
Q

What are the symptoms of uncontrolled type 1 diabetes?

A

Extreme thirst (polydipsia)

High urine output (polyuria)

During the early stages when there is still a small amount of insulin produced, the individual may have high blood glucose level without ketones because only a small amount of insulin is required to inhibit lipolysis

25
Q

Symptoms of later stages of uncontrolled type 1 diabetes

A

Complete insulin deficiency

Hyperglycemia and ketonuria will lead to hyper osmotic ketoacidosis and eventually death

Inflammtory response can lead to increase in counter regulatory hormones

26
Q

What are most cases of diabetic ketoacidosis caused by?

A

Non compliance

Infection

27
Q

Other names for type 2 diabetes

A

Non-insulin dependent

Adult onset

28
Q

Causes of type 2 diabetes

A

Multifactorial

Genetic and environmental contributions

29
Q

Characterization of type 2 diabetes

A

Elevated circulating insulin but a resistance to insulin, leading to hyperglycaemia

30
Q

Why is hyper osmotic ketoacidosis infrequent in type 2 diabetes?

A

Levels of insulin are often still adequate to prevent uncontrolled breakdown of lipid

31
Q

Short term consequences of hyperglycemia

A

Blurred vision

Frequent urination

Thirst

32
Q

Longterm consequences of hyperglycaemia

A

Damage to vessels that leads to retinopathy, nephropathy, cardiovascular disease, neurological dysfunction

33
Q

How can long term control of glucose be monitored?

A

Hemoglobin A1C

34
Q

Signs of hypoglycemia

A

Sweating, pallot, shaking, confusion

If untreated, can lead to seizures, unconsciousness and death

35
Q

How to treat modest hypoglycaemia?

A

Fast acting carbohydrate

36
Q

How to treat severe hypoglycaemia?

A

Administration of glucagon

37
Q

How is type 1 diabetes managed?

A

Providing basal insulin

Supplemented with insulin boluses (around meal time)) to match carbohydrate consumption and exercise

38
Q

How is insulin administered

A

Recombinant human insulin

Subcutaneous injection

Subcutaneous catheter connected to an insulin pump

39
Q

How are synthetic forms of insulin differentiated from endogenous insulin?

A

Synthetic forms do not contain internal C-peptide that must be removed by processing

40
Q

Onset and duration of rapid acting insulin

A

Very fast onset

Short duration (3-5 hrs)

41
Q

Formulation of rapid acting insulin

A

monomers or molecules that quickly dissociate into monomers

Can be rapidly absorbed from the site of injection

Useful for prandial insulin replacement

42
Q

Which form of insulin has the lowest variability of absorption?

A

Rapid acting (<5% variability of absorption)

43
Q

Onset of short acting insulin

A

Rapid onset (30 min)

5-8 hour duration

44
Q

When is short acting insulin injected?

A

Injected 30-45 minutes before meal to more closely match insulin levels with glucose levels

45
Q

What is regular insulin?

A

Short acting

46
Q

How does short acting insulin behave after administration

A

Can form dimers that stabilize around zinc ions to form hexameters.

Slow dilution of the insulin depot by interstitial fluids allows hexameters to break down into dimers and then monomers (3 absorption rates)

47
Q

Intermediate acting insulin name

A

NPH = neutral protamine hagendom

48
Q

How is intermediate insulin prepared?

A

Mix protamine : insulin (1:10 by mass)

After injection, tissue proteases degrade the protamine, which allows absorption of insulin

49
Q

Onset of intermediate acting insulin? Peak effect? duration?

A

Onset: 2 hours

Peak effect: 4-8 hours

Duration: 12-24 hours

50
Q

Onset, peak effect and duration of long acting insulin

A

Onset: 4 hours

Peak effect: 8-24 hours

Duration: 24-36

51
Q

How does long acting insulin work?

A

Crystalline insulin analog

Precipitates at neutral body pH after subcutaneous injection

Insulin monomers slowly dissolve from crystal

52
Q

Management of type II diabetes

A

Sometimes diet and exercise changes can help manage

However, in many cases, insulin secretagogues and/or insulin sensitizing agents are needed

53
Q

What is Glyburide?

A

A sulfonylurea

Stimulates endogenous insulin secretion by closing K+ channels on pancreatic beta cells causing depolarization

54
Q

What is metformin?

A

Synthetic analogue of guanidine

Activates the AMP-activated protein kinase (AMPK)

Does not increase in secretion of insulin

Effective as mono therapy

55
Q

How is metformin effective as a monotherapy?

A

Reduces HbA1C levels

Decreases hepatic and renal gluconeogenesis

Reduces intestinal absorption of glucose

Increases peripheral glucose uptake and utilization (increase glucose transporters in skeletal muscle/adipose tissue)

Reduction of plasma glucagon levels

56
Q

Why do insulin injections carry a risk for hypoglycaemia?

A

One may inject more insulin than necessary, and counter regulatory hormones may not be able to response quickly or adequately to avoid hypoglycaemia

Biochemistry (MPAS) (10 decks)

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