1. Lecture 8 Glucose Disposal

2. 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

3. Glucose responses Blood Glucose (mM) 5 10 Time (h) 012 Intolerant Tolerant

4. 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

5. Starch Digestion Blood Glucose (mM) 5 10 Time (h) 012 Amylose Amylopectin Different Glycemic Responses

6. 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

7. 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

8. Glucose Disposal glucose G6P Glycogen F16BP pyruvate acetyl-CoA Fatty Acids CO 2 GLUTs GLYCOGENESIS GLYCOLYSIS KREBS CYCLE LIPOGENESIS Fat

9. 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

10. glucose G6P GLUTsGLYCOGENESIS GLYCOLYSIS glucose insulin Translocation Vesicles in Golgi PFK – phosphofructo kinase GS – glycogen synthase Muscle Glucose Uptake

11. 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

12. 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 V max ½ V max KmKm S1S1 S2S2

13. 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