PSC2002/L24 Glucose Homeostasis & Insulin Action Flashcards
What is normal blood glucose concentration and how much does this rise after a meal?
5mM (90mg/dl)
Rises to 5-7mM
Can be 60mM in disease states
What is a normal amount of blood glucose and daily intake of glucose?
Blood: <5g
Intake: 300g
What effect does hyperglycaemia have on insulin and glucagon secretion?
Stimulates insulin secretion
Inhibits glucagon secretion
When is insulin secreted?
High blood glucose
When is glucagon secreted?
Low blood glucose
Describe pancreatic islets (islets of Langerhans). (3)
1-2% of pancreatic tissue
Comprise a, B and d cells that secrete hormones
<0.5mm diameter
Describe B-cells.
Secrete insulin
60% of human islets
Describe a-cells.
Secrete glucagon
30% of human islets
Describe d-cells.
Secrete somatostatin
8-10% of human islets
Give 3 minor regulators of insulin release.
+Amino acids
+Neural input (cholinergic)
+Gut hormones (GLP1, GIP, incretins)
-Adrenaline
-Somatostatin
Give the 3 major regulators of glucagon release.
-Glucose
-Insulin
+Amino acids
Give 3 minor regulators of glucagon release.
+Neural input (stress)
+Adrenaline
-Gut hormones
+Cortisol
What 3 structure occur before insulin production?
Insulin gene
Preproinsulin
Proinsulin
Describe the formation of proinsulin from preproinsulin.
Cleavage of the signal peptide
How is insulin produced from proinsulin?
C peptide cleavage
Describe the formation of insulin. (4)
Pre-proinsulin-> proinsulin (86aa) through signal peptide cleavage
Proinsulin packaged in vesicles from Golgi
Proinsulin -> insulin (51aa in 2 chains) through C peptide cleavage
1-30 and 66-86 (1-21) joined by disulphide bonds
Stored in heaxtrimeric complex with zinc and released from B cells
What length are the A and B-chains in insulin?
A-chain 21aa
B-chain 30aa
Active, short half-life
Describe type 1 diabetes.
B-cells become damaged/defective and cannot produce insulin
Take insulin injections
Describe beta cell activity at basal glucose levels. (5)
K(ATP) channel open
K+ flux out of cell
Membrane hyperpolarised at -60mV
Ca2+ channel closed
Low insulin secretion
What senses glucose levels in B cells?
Glucokinase
Describe beta cell activity during raised glucose concentration. (6)
Raised ATP
K(ATP) channel closed
Membrane depolarised at -40mV
Ca2+ channels open
High cytoplasmic Ca2+
High insulin secretion
Which glucose transporter is present in B-cells?
GLUT1 or 2 dependent on species
In other cells types (not Islets), what is glucose to G-6-P regulated by?
Hexakinases
Describe the affinity of glucokinase for glucose.
Low-affinity (S(0.5) ~ 8mM)
Describe monogenic diabetes.
Glucokinase gene mutation
Activating - hypoglycaemia (PHHI)
Deactivating - Diabetes (GCK-MODY/PNDM)
Describe how a KCNJ11 mutation might cause diabetes.
Encodes K(ir) 6.2 subunit of K(ATP) channel
Need to inherit 2 alleles
Activating - diabetes (PDNM)
inactivating - hypoglycaemia (PHHI)
K(ATP) closed when it shouldn’t be; high-insulin, low-glucose phenotype
What is glucose converted into in the liver in a postprandial state?
Glycogen, triglyceride (TG)
What is glucose converted to in muscle in a postprandial state?
Glycogen
Metabolised by glycolysis/oxidation
What is glucose converted into in adipose tissue in a postprandial state?
Triglyceride (TG)
Describe the structure and formation of glycogen.
Branched polymer of glucose residues
Glucose absorbed from gut converted to liver glycogen
First line of defence against declining blood glucose conc.
Hepatic glycogen degraded between meals to maintain blood glucose conc.
Give 2 key enzymes in conversion of glucose to glycogen.
Glycogen synthase - 1,4
Glycogen synthase - 1,6
Give 2 key enzymes in breakdown of glycogen.
Glycogen phosphorylase
Debranching enzymes
What happens to dietary glucose when liver glycogen stores are full? (5)
Liver converts glycogen to fat
Metabolises and enters TCA cycle - leaves as citrate
Converted to acetyl CoA
Acetyl CoA -> Malonyl CoA by acetyl CoA carboxylase
Malonyl CoA -> Palmitate by fatty acid synthase
TG packaged into vesicles and exocytosed into blood
What is glucose converted into in the liver in a fasted state?
Produce ketone bodies for energy
What is converted in muscle in a fasted state?
Protein to amino acids
Metabolise fatty acids for fuel
What is converted in adipose tissue in a fasted state?
Triglyceride to fatty acids and glycerol
Describe glucose usage after ingestion of 100g of glucose.
During fasting, glucose produced by glycogenolysis, gluconeogenesis
What is the effect of insulin action on the liver?
+Glycogen synthesis
+Fatty acid/TG synthesis
+Protein synthesis
-Glycogen degradation
-Gluconeogenesis
What is the effect of insulin action on muscle?
+Glucose transport
+Glycogen synthesis
+Glucose oxidation
+Protein synthesis
What is the effect of insulin action on adipose tissue?
+Glucose transport
+Triacylglycerol synthesis
-Triacylglycerol breakdown release of fatty acids
Describe the stimulation of GLUT4 translocation and glucose metabolism in muscle.
Insulin action triggers:
Translocation of GLUT4 from intracellular vesicular site to plasma membrane
Activation of glycogen synthase (dephosphorylation)
Activation of pyruvate dehydrogenase (dephosphorylation)
Describe insulin action in adipose tissue.
Stimulation of GLUT4 translocation and fatty acid synthesis - increased acetyl-CoA carboxylase and fatty acid synthase transcription
Inhibition of TAG breakdown
Decreased hormone sensitive lipase (HSL): covalent modification
Describe stimulation of TAG uptake in adipose tissue. (3)
Insulin activates lipoprotein lipase
Breaks down triacylglycerol which crosses capillary wall
Can then be resynthesised and neutralised
Describe insulin action in the liver (covalent modification).
Serine, threonine phosphorylation-dephosphorylation
Activation: glycogen synthase (+ve); acetyl CoA carboxylase (+ve)
Inactivation: phosphorylation (-ve)
Describe enzymes involved in insulin action in the liver (insulin gene transcription (chronic)).
Induction: glucokinase (GCK), acetyl-CoA carboxylase, fatty acid synthase (FAS)
Repression: glucose-6-phosphatase (G6PC or G6Pase; PEPCK (phosphoenolpyruvate carboxykinase)
Which form of glycogen synthase is active?
Dephosphorylated
Which form of glycogen phosphorylase is active?
Phosphorylated
What is the effect of increased G6P and glucose in the liver?
Moves glycogen synthase/phosphorylase to unphosphorylated form
What is the role of glucagon in the liver?
Activates Ph-kinase which phosphorylates glycogen phosphorylase (active form)
