Lecture 9: Glycemic Responses and Glycogenesis

Learning Outcomes:

• Dynamics of post-prandial glucose disposal and the key hormones involved

• Understand the post-prandial glucose responses for subjects with glucose intolerance, insulin resistance and diabetes

• Understand what glycemic index is, how it is measured and how it is clinically useful

• Appreciate the role of different glucose transporters in different tissues and how these function

• Review the chemical structure of glycogen and the chemical strategy for its synthesis

• Understand how increased glycogen synthesis stimulates glycolysis

• Explain the consequences of the different activities of hexokinase and glucokinase

• Summarise the similarities and differences in glycogenesis in different tissues (liver vs muscle)

• Building glycogen = glycogenisis

• Glucose is toxic and can react with every protein in our body

  • No enzymes required

  • Glycation = no enzymes for glucose and protein reaction

    • Glycation is bad – leaves proteins sugar coated and impacts their function

    • The rate this occurs in proportional to blood glucose concentration

    • Even happens at 4-5mM – but out brain requires 4-5mM

    • Time of exposure is also important

      • Want to return blood glucose levels to normal asap after eating, or damage to proteins is at risk

• Determining risk of diabetes:

  • Don’t consume food 8-12 hours, measure BG concentration – fasting blood glucose

  • HbA1c test – measures how many haemoglobin molecule in the blood are glycated (have glucose attached) – indicator of [blood glucose] over the last 3 months

Post-Prandial Glucose Disposal:

• Oral glucose tolerance test

  • Patient consumes a standard glucose load

  • Monitor BG concentration over 2 hours

Accomplished by:

• Insulin secretion

• Liver sponging up lots of glucose

Glucose Tolerant – you are able to return to fasting blood glucose by 2 hours after consumption

Glucose Intolerant – Normal fasting blood glucose but slow clearance; doesn’t return to fasting concentration within 2 hours

Diabetic – Fasting hyperglycaemia, doesn’t return to fasting concentration within 2 hours, relentless exposure to high [glucose]

• The more glucose exposure, the more the damage

Insulin Production:

• Released by the beta cells of the pancreas when [glucose] > 5mM

• Small amount of insulin can also be released in response to amino acids

• Each time a meal is consumed, insulin spiked

• Insulin stimulates glucose uptake upregulating GLUT-4 recetptors in the muscle and adipose tissue

• Cells won’t keep bringing in glucose if they aren’t doing anything with it – glycogenesis or lipogenesis

Insulin Resistance:

Normal, Tolerant, Insulin Sensitive: Insulin spikes in response to food intake and then lowers within 2 hours

Tolerant Insulin Resistant: Need to secrete more insulin to get rid of glucose

Intolerant (pre-diabetic): Secreting more insulin but not enought o overcome resistance, constant hyperinsulinemia

T2 Diabetes: Beta-cells exhausted, unable to respond dynamically, unable to maintain basal euglycemia (normal blood sugar)

Starch:

• Main source of dietary carbohydrate

  • A polymer of glucose

• Two major forms:

  • Amylose

    • Linear, forms helices

    • Difficult to digest – digestive enzymes can only act on one end of the chain

    • Difficult for amylases to penetrate

    • Makes itself all the way to the lower bowel before it is digested, causes Flatulence

    • Low GI foods

  • Amylopectin

    • Branched

    • Easy hydrolysis/digestion

    • Easy and quickly to digest

    • Lots of digestive enzymes can work on the many branches at the same time

    • Faster spike in [glucose]

    • Processed foods

    • High GI

Glycemic Index:

• Invented to try and help us chose foods that didn’t expose our body to very high [glucose] or great fluctuations – which are linked to the development of T2 diabetes

• Describes post-prandial glucose response

• Area under the test food curve divided by area under the reference curve

  • Reference food is usually 50g glucose

  • Test food given in an amount that will give 50g digestible carbohydrate

    • E.g. the amount of food that will provide 50g of digestible carbs – 2 apples

  • Measure ration of area under each curve = GI index (as a %)

  • GI of amylopectin foods (modern grains) have a high GI >80

  • GI of legumes <30

Notes:

• Area under slowly absorbed may be the same as area under quickly absorbed

• Should GI apply to non-starches?

  • Fructose can sweetened foods but your body doesn’t respond with insulin production when you consume it

  • Fructose is a non-glycemic sugar

  • Sucrose (table sugar) is only half glucose

    • Using sucrose to sweeten foods = only consuming half as much glucose

  • Dairy foods are low GI

    • Lactose is glucose and galactose

      • only half glucose

      • GI is reduced

    • e.g. yogurt is low GI because of the galactose but it will eventually be converted anyway

• Low GI is considered healthier, generally

• Spikes tend to predispose people to T2 diabetes rather than slow release

• Claims of “slow burning energy”

  • Not supply driven – we burn energy at the rate we use it

Glucose Disposal:

• Every cell has GLUT1 transported to transport blood glucose to your tissues

• First blood in your body to look at the sugar you consume if in the hepatic portal vein (liver) – liver gets the first look at food

  • Liver has GLUT2 transporters – takes a lot of blood glucose out of the blood – insulin independet

    • GLUT2 are wide open doors (don’t need insulin)

• Muscle – GLUT4

  • Strongly dependent on insulin

  • Very high capacity to get rid of glucose – muscle requiring energy to do things

  • Has more GLUT4

• White adipose tissue – GLUT4

  • Strongly dependent on insulin

  • Used glucose to build fat and store it for later

  • We have lots of white adipose tissue

• Need to do something with the blood glucose

• High glucose levels inhibits hexokinase

In Muscles:

• Glycogen synthase is used to turn glucose 6 phosphate into glycogen – glycogenesis

• GLUT4 live in Golgi apparatus and translocate to the membrane with insulin stimulation

Glucose in the Muscle:

• Glucose comes in and it phosphorylated by hexokinase

  • Could go down glycolysis

• Or it gets converted to glucose-1-phosphate via isomerisation reaction

• UTP comes, gets rid of 2 phosphates (PP), becomes UMP, and attaches to glucose-1-phosphate to make UDP glucose (Activated Glucose)

• This prepares it to add on to the end of the glycogen chains – the end specifically

• UDP is left over and needs to be converted back to UTP to be used again

• This uses ATP

• UDP + ATP = UTP + ADP

Activate glucose by turning it into UDP glucose so it can be added onto a glycogen chain and that costs 1 ATP

Branching:

• Need branching in glycogen or it will be entirely linear

• Glycogen branching enzyme takes some glycogen chain, cuts it, and joins it to form a branch.

Glycogen Synthase:

• Regulated by reversible phosphorylation

  • Has a kinase and a phosphatase that can regulate it

• Insulin can stimulate phosphatase I that will remove the phosphate from glycogen synthase to make it active to add glucose to glycogen

• Kinase removes adds the phosphate groups – makes it inactive

• Insulin stimulated the building of new glycogen molecules

Phosphofructokinase

• Rate limiting step of glycolysis

• Not directly stimulated by insulin

• Regulated allosterically

  • Especially by AMP which is stimulates by low energy charge

Stimulation of glycolysis by insulin creates an energy demand

• Glycogenesis drops cellular ATP and increases ADP and AMD

• This drop in energy stimulates PFK and glucose oxidation

• The anabolic pathway requires and stimulates the catabolic pathway – coupling

• Signals to store fuels also causes fuels to be burn

Liver Glucose Disposal

• GLUT2 used to take up glucose

• Glucokinase

  • Keeps trapping glucose-6-phosphate

  • Won’t be inhibited by glucose-6-phosphate build up

  • High Km (10mM) for glucose – not saturated by high levels of liver glucose

  • [GP6] rapidly increases as blood [glucose] rises

• GP6 can stimulate inactive glycogen synthase in the liver

  • Don’t need insulin

• Glycogen synthase needs to see protein at the core (glycogenin) of the glycogen molecule to keep adding glucoses

  • Makes glycogen granules

  • Each glycogen is only 12 to 14 residues

• 2 ATPs are required for the incorporation of a glucose into the glycogen chain

  • G to G6P and UDP to UTP