L24 Blood glucose homeostasis and insulin action

what is the concentration of blood glucose

~5 mM

what is the total blood volume

~5 litres

Glucose molar weight

180>900 mg/l (~90mg/dl)

what is the total mass of glucose in the blood

<5g

what is the daily intake of glucose

~300g

after a meal what is the rise in glucose concentration

>5-7 mM (could rise to 60 mM in disease states like diabetes)

what does hyperglycaemia stimulate

insulin secretion

what does hyperglycaemia inhibit

glucagon secretion

describe the role of insulin

• secreted in conditions of increased blood glucose

• insulin decreases blood glucose concentration

describe the role of glucagon

• secreted in conditions of decreased blood glucose

• glucagon increases blood glucose concentration

describe pancreatic islets (islets of langerhans)

• make up 1-2% of pancreatic tissue

• comprise alpha, beta and delta cells that secrete hormones

• <0.5mm in diameter

what percentage of beta cells (insulin) is in human islets

60%

what percentage of alpha cells (glucagon) is in human islets

30%

what percentage of delta cells (somatostatin) is in human islets

8-10%

what is the major regulator of insulin release

glucose

what are the minor regulators of insulin release

• amino acids

• neural input (cholinergic)

• gut hormones (GLP1, GIP)

• adrenaline

• somatostatin

what are the major regulators of glucagon relase

• glucose

• insulin

• amino acids

what are the minor regulators of glucagon release

• neural input (stress)

• adrenaline

• gut hormones (GLP1/GIP)

• cortisol

where is insulin produced

in islet beta-cell as pre-proinsulin

how long is pro insulin

single chain of 86 amino acids

what residues is proinsulin cleaved at

31 to 65

what does proinsulin form

• C-peptide (inactive)

• Insulin

how many amino acids does insulin have from proinsulin

51 amino acids in 2 chains

insulin has 1 to 30 amino acids and 66 to 86 amino acid chains (1-21) joined by what

disulphide bonds (~6 kDa)

what form is insulin stored in

hexatrimeric form complexed with zinc

what releases insulin

pancreatic beta cells in response to elevated [glucose]

how long is insulins A chain

21 AAs

how long is insulins B chain

30 AAs

what is the half life like of insulin

active and short

what is the stability of C-peptide

inactive and stable

• diagnostic value

what is the glucose sensor

glucokinase

what occurs at basal glucose concentration at 5mM

• K_ATP channel open

• K+ flux

what happens when the membrane is hyperpolarised from low basal glucose concentration~-60mV

Ca2+ channel closed

• low insulin secretion

what happens when glucose concentration is raised

• raised ATP closes the K_ATP channel

• membrane depolarised ~-40mV

• Ca2+ channels open

• High cytoplasmic Ca2+

• High insulin secretion

what is the fed state called

postprandial

what are the insulin sensitive tissues

liver, muscle and adipose tissue

glucose absorbed from the gut is converted to…

liver glycogen

liver glucose is the first line of defence against…

declining blood glucose concentration

hepatic glycogen is degraded between meals to…

maintain blood glucose concentrations

how is glucose produced during fasting

• glycogenolysis

• gluconeogenesis

what is gluconeogenesis

synthesis of glucose from non-carbohydrate carbon substrates (i.e. protein, lactate)

during fasting, glucose usage is much lower than during glucose ingestion and…

decreases progressively

glucose is also converted to lipid in the adipose tissue where…

it is stored as TG

describe insulin action on the liver (what does it increase)

• glycogen synthesis

• fatty acid/TG synthesis

• protein synthesis

describe insulin action on the liver (what does it decrease)

• glycogen degradation

• gluconeogenesis

describe insulin action on the muscle (what does it increase)

• glucose transport

• glycogen synthesis

• glucose oxidation

• protein synthesis

describe insulin action on the adipose tissue (what does it increase)

• glucose transport

• triacylglycerol synthesis

describe insulin action on the adipose tissue (what does it decrease)

triacylglycerol breakdown release of fatty acids

describe insulin action in the muscle - stimulation of glut4 translocation and glucose metabolism

translocation of GLUT4 (glucose transporter) from intracellular vesicular site to plasma membrane

• activation of glycogen synthase (dephosphorylation)

• activation of pyruvate dehydrogenase (dephosphorylation)

summarise insulin action in adipose tissue

• stimulation of Glut4 translocation and fatty acid synthesis

• inhibition of TAG breakdown (lipolysis)

• stimulation of TAG uptake

TAG

triacylglycerol

DAG

diacylglycerol

MAG

monoacylglycerol

describe the action of insulin in adipose tissue

translocation of GLUT 4 (glucose transporter) from intracellular vesicular site to plasma membrane

• increased fatty acid synthesis: increased transcription of acetyl-CoA carboxylase and fatty acid synthase

• decreased fatty acid release: decreased activity of hormone sensitive lipase (HSL) (covalent modification)

describe the activity of LPL (lipoprotein lipase) enzyme

• originates from adipose

• translocates to capillary lumen

• activated by insulin

• resynthesised within the adipocyte

describe insulin action in the liver

• increased glucose metabolism

• increased glycogen formation

  • stimulation of glycogen synthesis

  • inhibition of glycogen breakdown

• increased fatty acid synthesis

• decreased gluconeogenesis

glucose transport by Glut2 is near-equilibrium and…

is not regulated by insulin

what occurs in insulin covalent modification

serine. threonine phosphorylation-dephosphorylation

what activates insulin covalent modification

• glycogen synthase (+ve)

• acetyl-CoA carboxylase (+ve)

what inactivates insulin covalent modification

phosphorylase (-ve)

what is insulin gene transcription

chronic

what causes induction in insulin gene transcription

• glucokinase (GCK)

• acetyl-CoA carboxylase

• fatty acid synthase (FAS)

what causes repression in insulin gene transcription

• glucose 6-phosphatase (G6PC or G6Pase)

• PEPCK (phosphoenolpyruvate carboxykinase)