Lecture 5 - Glucose Control in Health and Disease

Question 1

Normal blood glucose level

Answer 1

~4.5mmol/L

Question 2

Parts of a meal that are soluble in the blood

Answer 2

Glucose, amino acids

Question 3

Parts of a meal that are insoluble in blood

Answer 3

Lipids

Question 4

How do lipids enter the blood?

Answer 4

Packaged into chylomicrons. Enter blood via lymphatics

Question 5

Insulin release after a meal stimulates:

Answer 5

Glucose uptake Amino acid uptake into muscles, protein synthesis

Question 6

Insulin precursor activation into insulin 1) 2) 3)

Answer 6

1) Prepro insulin has A, B, C subunits, curled into a paperclip shape 2) NH3-terminal signal sequence is cleaved, two disulphide bonds form between A and B subunits, one disulphide bond forms on B subunit. This forms pro insulin. 3) C subunit is removed. Insulin formed.

Question 7

Answer 7

Question 8

Answer 8

a

Question 9

Stages of insulin formation (picture)

Answer 9

Question 10

What are GLUT proteins?

Answer 10

Membrane-bound proteins that mediate glucose movement across animal cell plasma membranes

Question 11

How can GLUT isoforms differ? 1) 2) 3) 4)

Answer 11

1) Tissue expression 2) Substrate specificity 3) Kinetic characteristics 4) Functions

Question 12

Generic shape of a GLUT protein 1) 2) 3) 4) 5)

Answer 12

1) Single polypeptide. 2) 12-pass transmembrane. 3) Both C and N termini are in the cytoplasm. 4) ~500aa 5) Mostly hydrophobic residues in transmembrane regions. Polar residues in the membrane form a polar pore

Question 13

Where are GLUT4 found?

Answer 13

Myocytes

Question 14

GLUT4 regulation in myocytes 1) 2) 3) 4) 5) 6)

Answer 14

1) Regulated exocytosis 2) GLUT4 stored in cytoplasmic vesicles 3) When insulin binds insulin receptor, vesicle fuses with plasma membrane, depositing GLUT on cell surface 4) When insulin levels drop, GLUT are removed from the plasma membrane by endocytosis 5) Smaller vesicles fuse with endosome 6) Small, GLUT-rich parts of endosome bud off to form GLUT vesicles

Question 15

What is the rate-limiting step in glucose use by a cell?

Answer 15

Glucose uptake

Question 16

Proportion of insulin-stimulated glucose uptake that occurs in muscle

Answer 16

90%

Question 17

Early feature of insulin resistance

Answer 17

Failure of GLUT4 transport

Question 18

How are pancreatic beta cells induced to release insulin? 1) 2) 3) 4)

Answer 18

1) Increased extracellular glucose leads to increased glucose uptake through GLUT2 into beta cell 2) This increases intracellular ATP levels 3) ATP inhibits ATP-gated K+ channel, which depolarises plasma membrane 4) Voltage-gated Ca2+ channel brings Ca2+ into cell. This leads to insulin release from vesicles into extracellular environment

Question 19

Primary targets of insulin (organs)

Answer 19

Liver Adipose tissue Muscle

Question 20

Broad outcomes of insulin release 1) 2) 3) 4)

Answer 20

1) Increased glucose uptake from blood into tissues 2) Increased glucose storage as glycogen 3) Increased metabolism of glucose for energy 4) Increased synthesis of triacyl glycerides (TAGs)

Question 21

Product of glucose metabolism that leads to TAG synthesis

Answer 21

Acetyl coenzyme A (from pyruvate)

Question 22

VLDL

Answer 22

Very low density lipoprotein

Question 23

How is glucagon release stimulated? 1) 2) 3)

Answer 23

1) Hypothalamus monitors blood glucose 2) When blood glucose drops too low, K+-gated ATP channels depolarise cell. 3) Autonomic nerve signalling stimulates alpha cells to release glucagon

Question 24

Targets of glucagon

Answer 24

Mainly the liver Adipose tissue

Question 25

Enzymes upregulated by glucagon 1) 2) 3)

Answer 25

1) Glycogen phosphorylase 2) Fructose 1,6-bisphosphatase 3) Triacylglycerol lipase

Question 26

Enzymes downregulated by glucagon 1) 2) 3)

Answer 26

1) Glycogen synthase 2) Pyruvate kinase 3) Phosphofructokinase 1

Question 27

Effect of downregulating glycogen synthase

Answer 27

Reduction in liver synthesis of glycogen

Question 28

Effect of increasing glycogen phosphorylase

Answer 28

Increased liver breakdown of glycogen

Question 29

Effect of reducing pyruvate kinase

Answer 29

Increased gluconeogenesis in liver.

Stops glycolysis.

Question 30

Effect of increasing fructose 1,6-bisphosphatase

Answer 30

Increased gluconeogenesis in liver

Question 31

Effect of decreasing phosphofructokinase 1

Answer 31

Reduced glycolysis

Question 32

Effect of increasing triacylglycerol lipase

Answer 32

Increased mobilisation of fatty acids

Question 33

Symptoms of uncontrolled type 1 diabetes 1) 2) 3) 4) 5) 6)

Answer 33

1) Frequent urination 2) Extreme thirst, dry mouth 3) Hunger 4) Sudden weight loss 5) Lack of energy 6) Blurred vision

Question 34

Mechanism behind type 1 diabetes

Answer 34

Autoimmune destruction of beta cells in pancreas. Particularly inflammatory cytokines

Question 35

Relative loss of beta cells in type 1 and 2 diabetes

Answer 35

Greater loss of beta cells in type 1

Question 36

Characteristics of type 2 diabetes 1) 2) 3) 4)

Answer 36

1) Heterogenous levels of insulin production and release 2) Varying levels of insulin resistance in tissue 3) Increasing levels of beta cell destruction as disease progresses 4) Symptoms are similar to type 1 diabetes

Question 37

Effect of type 1 diabetes on muscle glucose uptake 1) 2) 3) 4)

Answer 37

1) Lack of insulin binding to insulin receptor leads to little GLUT4 transport to cell surface 2) This limits the amount of glucose entering a cell 3) Glycogen synthesis is inhibited 4) Glycogen stores are depleted

Question 38

Effect of type 1 diabetes on muscle

Answer 38

1) Uptake of amino acids and muscle synthesis is inhibited 2) Normal inhibition of protein degradation is lost 3) Muscle degradation

Question 39

Consequence of muscle degradation in type 1 diabetes

Answer 39

Increased transport of nitrogen to the liver in the form of alanine. This leads to gluconeogenesis, worsening hyperglycaemia

Question 40

Effect of type 1 diabetes on adipose tissue 1) 2) 3) 4) 5)

Answer 40

1) Glucose uptake failure by GLUTs 2) Increased lipolysis of TAGs leads to increased levels of circulating free fatty acids 3) Transfer of lipids to liver for metabolism 4) Fatty acid oxidation leads to excess ketone body formation 5) Excess ketone bodies lead to diabetic ketoacidosis

Question 41

Why is glycogenolysis favoured in type 1 diabetes?

Answer 41

Loss of activation of glycogen synthase by insulin Loss of inhibition of glycogen phosphorylase

Question 42

What leads to diabetic ketoacidosis? 1) 2) 3) 4)

Answer 42

1) Lack of insulin leads to excess glucagon, stress hormone release. 2) Muscle broken down into amino acids, TAGs in adipose tissue lipolysed into fatty acids 3) Blood glucose exceeds ability of kidneys to remove glucose. Urine becomes hypertonic, drawing more water out of the body. Increased urination. 4) Liver produces increased numbers of ketone bodies

Question 43

What might lead to insulin resistance?

Answer 43

Defective insulin receptor

Question 44

When does type 2 diabetes occur?

Answer 44

When there is both insulin resistance in target tissues, and death of beta cells in pancreas

Question 45

Stages of type 2 diabetes 1) 2) 3)

Answer 45

1) Insulin resistance in tissues. Pancreas releases more insulin to compensate (hyperinsulinaemia) 2) Hyperglycaemia despite elevated insulin. Glucose tolerance impaired 3) Insulin secretion declines from death of beta cells. High fasting blood glucose (diabetes)

Question 46

Lipotoxicity model of insulin resistance 1) 2) 3) 4)

Answer 46

1) With positive caloric balance, adipocytes enlarge (store TAGs). Excessively large adipocytes release MCP-1 (macrophage chemotaxis protein). 2) MCP-1 attracts macrophages, which release TNFa 3) TNFa favours TAG export. Adipocytes export TAGs, which deposit on muscle cells 4) Ectopic lipids form on muscles, which interfere with GLUT4 transport.

Question 47

Structure of insulin receptor

Answer 47

Preformed heterotetrameric receptor Alpha and beta subunits. Insulin binds alpha subunit, beta subunit is transmembrane, autophosphorylates in response to insulin binding. Alpha and beta are joined by disulphide bridges

Question 48

Protein tyrosine kinases

Answer 48

1) Transfer gamma-phosphate of ATP to target tyrosine residue on substrate