Lecture 8

Glucose Disposal

Post-Prandial Glucose Rise

• Blood glucose goes up after a carbohydrate meal– Uptake and disposal mediated by insulin

• Glucose challenge– 1 g/kg body weight, or 50 g or 70 g– Measure blood glucose changes

• “Normal” is 5 mM at time zero• rises to a peak at about 30 min• back down to basal by 60 min

– Glucose intolerance• glucose peak is higher and time to return to basal is longer• Glucose is not being taken up properly

Glucose responses

BloodGlucose(mM)

5

10

Time (h)

0 1 2

Intolerant

Tolerant

Consequences of Intolerance

• Post-prandial hyperglycemia is a problem– If occurs after each meal and persists for several

hours then there will be problems• The person will rarely be euglycemic!• Leads to complications of hyperglycemia

– Root cause may be insulin resistance• Impaired ability of tissues to respond to insulin• Underlies Type II Diabetes

• Control of glucose intolerance– Insulin injections– Consumption of slowly absorbed starches

Starch Digestion

BloodGlucose(mM)

5

10

Time (h)

0 1 2

Amylose

Amylopectin

Different Glycemic Responses

The Glycemic Index

• Describes the post-prandial glucose response– Area under the ‘test’ food glucose curve divided by– Area under a ‘reference’ food glucose curve

• Reference food is normally 50 g gluocse• Test food given in an amount that will give 50 g digestible

carbohydrate– Expressed as a %– GI of modern, processed, amylopectin foods >80– GI of legumes < 30

• Useful knowledge for controlling blood glucose – Especial relevance to diabetes– QUALITY of carbohydrate (GI) as important as total

amount of carbohydrate

GI critics say..• Area under slowly absorbed may be the same as quickly

absorbed– Look closely at previous figure

• The GI should not apply to foods other than starches– Sugary foods are low GI

• Because half the carbohydrate is fructose• Similarly, fructose containing foods are low GI

– Dairy foods are low GI• Because half the carbohydrate is galactose

• Claims of “slow burning energy” debatable– What regulates energy expenditure and what determines ‘supply’

of substrates– Even if supply was important, the classic “persistently but subtly”

raised post-prandial glucose response is hardly ever seen• Some Low GI values may be more related to inaccurate

estimation of digestible carbohydrate portions

Glucose Disposalglucose

glucose G6P

Glycogen

F16BP

pyruvate

pyruvate acetyl-CoA

acetyl-CoA

Fatty Acids

CO2

GLUTs

GLYCOGENESIS

GLYCOLYSIS

KREBS CYCLE

LIPOGENESIS

Fat

Glucose Transporters

• GLUT-1– Present in all cells at all times in constant amounts– Catalyze basal transport

• GLUT-4– Insulin dependent– Present in muscle and WAT only– Translocation and fusion – in response to insulin, vesicles

that contain GLUT-4 move from Golgi Apparatus and fuse with cell membrane

– Translocation is stimulated when insulin binds to its receptor or in response to exercise

glucose

glucose G6P

GLUTs GLYCOGENESIS

GLYCOLYSIS

glucose

insulin

Translocation

Vesicles in Golgi

PFK – phosphofructo kinase

GS – glycogen synthase

Muscle Glucose Uptake

Rate Limiting Enzymes• The slowest enzyme in the metabolic pathway determines the

overall speed – Rate-limiting step – Flux generating step

• Properties of these enzymes– Irreversible

• Need alternative enzymes to ‘go back’• Not ‘equilibrium’ under physiological conditions• Committed steps

– Saturated with substrate• Low Km or [S] >> Km• Working at Vmax

• Key points of regulation

Enzyme kinetics

• At high [substrate], minor changes in [substrate] will not affect the rate of reaction

• Doubling or halving the [S] isn’t even going to affect the rate

[substrate]

Rate

Vmax

½ Vmax

Km S1 S2

Redfern Station Analogy• Imagine a railway station at peak hour with just one barrier operating

– This step will soon become ‘saturated’ with people– It is the ‘rate limiting’ step– The point of regulation of the rate of the people moving pathway!

• There are 3 major ways to regulate this (and metabolic!) pathways– Change the intrinsic activity of the step

• Make ticket-reading & gate-opening happen faster• Akin to Allostery

– molecules bind to allosteric site of an enzyme and influence the activity of the active site

– Make more gates open• Switch them from being ‘off’ to ‘on’• Or change the direction from ‘in’ to out• Akin to Covalent Modification and reversible phosphorylation

– transporters working more activated enzymes

– Make and destroy gates according to need • Akin to making more enzymes (and then degrading them later!)• This very energy consuming and seemingly inefficient, involving

– Transcription of genes– Translation of mRNA