Metabolism and insulin

Question 1

What is the cellular structure of an Islet of Langerhans?

Answer 1

70% Insulin secreting β cells
Glucagon secreting α cells
Somatostatin secreting δ cells
Tight junctions between cells to produce extracellular regions of high hormone concentration for paracrine signalling

Question 2

What is the purpose of somatostatin in the release of pancreatic hormones?

Answer 2

Paracrine effect to inhibit release of pancreatic hormones

Question 3

What is the purpose of glucagon?

Answer 3

Increases transport of amino acids to the liver
Lipolysis
Hepatic glycogenolysis and gluconeogenesis

Question 4

What stimulates glucagon secretion?

Answer 4

Sympathetic and parasympathetic activity
GI hormones
Certain amino acids

Question 5

What inhibits glucagon secretion?

Answer 5

Insulin

Somatostatin

Question 6

What is the purpose of insulin?

Answer 6

Increase glycogenesis and decrease glycogenolysis in muscle and liver
Decrease gluconeogenesis in liver
Incrase glycolysis in liver and adipose tissue
Decrease breakdown of amino acids in liver
Increased amino acid uptake and protein synthesis in muscle, liver and adipose tissue
Decreased lipolysis
Increased lipogenesis and esterification of fatty acids in liver and adipose tissue
Inhibits production of ketone bodies from NEFA
Increased GLUT4 transport to increase glucose uptake into cells

Question 7

What stimulates insulin secretion?

Answer 7

Parasympathetic activity via β receptor
GI hormones
Certain amino acids

Question 8

Which cell produces insulin?

Answer 8

β cells in the Islet of Langerhans

Question 9

Which cell produces glucagon?

Answer 9

α cells in the Islet of Langerhans

Question 10

What inhibits insulin secretion?

Answer 10

Sympathetic activity via the α receptor

Somatostatins

Question 11

How is insulin synthesised?

Answer 11

Insulin translated to preproinsulin which has a signal sequence
Converted to proinsulin in the ER/Golgi with signal sequence removed
Disulfide bonds are formed to hold A and B chains together
When stimulated to be secreted, C Chain cleaved upon cell exit to release the C peptide

Question 12

What can be studied to monitor insulin production?

Answer 12

C peptide concentration - it has no glucose-lowering effect but is released with every insulin synthesised

Question 13

Where is insulin stored?

Answer 13

In vesicles as proinsulin in β cells

Question 14

How is insulin secreted?

Answer 14

1) Glucose binds to GLUT2 receptor on β cell
2) Glucose→glucose6phosphate by glucokinase (RATE LIMITING STEP)
3) Glycolysis occurs - ATP produced
4) ATP binds to ATP sensitive K+ channels, closing them
5) This allows Ca2+ influx
6) Influx of C2+ causes release of insulin vesicles

Question 15

How is exocrine and endocrine function divided in the pancreas?

Answer 15

98% exocrine function

2% endocrine function - Islets of Langerhans

Question 16

Where are insulin receptors found and how are they activated?

Answer 16

Found on cell membranes of liver, adipose and skeletal muscle tissues
Insulin binds to α subunit causing auto-phosphorylation of receptors to activate β subunit tyrosine kinases
These phosphorylate cell protein substrates

Question 17

What is the structure and purpose of GLUT4?

Answer 17

Muscular insulin transporter
hydrophilic pore and hydrophobic outside
Causes 7 fold increase in glucose uptake when fused with cell membrane
Normally stored in vesicles

Question 18

What is the effect of insulin on GLUT4?

Answer 18

Causes increased GLUT4 synthesis

Causes exisiting GLUT4 vesicles to fuse w the membrane to increase glucose uptake

Question 19

What is glycogenolysis?

Answer 19

Breakdown of glycogen to produce Glucose-6-phosphate

Question 20

What is the role of insulin in the liver?

Answer 20

Stimulates storage of glucose as glycogen
Inhibits gluconeogenesis and increases protein synthesis, reducing concentration of free AAs
Decreases ketone production by decreasing the production of acetoacetate from fatty acyl CoAs

Question 21

What is the role of insulin in muscle?

Answer 21

Stimulates GLUT4 vesicle fusion with membrane to increase glucose uptake for aerobic respiration and storage as glycogen
Inhibits proteolysis and increases protein synthesis, reducing the concentration of free AAs

Question 22

What is the role of catecholamines in the liver and muscle?

Answer 22

Stinmulates glycogenolysis in liver

Inhibits GLUT4 glucose uptake in muscle

Question 23

What is the role of growth hormone in muscle?

Answer 23

Inhibits GLUT4 glucose uptake to promote glycogenolysis

Increases protein synthesis to build proteins for growth

Question 24

What is the role of glucagon in the liver?

Answer 24

Stimulates glycogenolysis to increase hepatic glucose output
Causes transporter channels to open and allow gluconeogenic amino acids to enter liver
Stimulates proteolysis and gluconeogenesis
Increases production of ketone bodies by increasing production of acetoacetate as blood glucose is low

Question 25

What is the role of cortisol in muscle?

Answer 25

Inhibits GLUT4 glucose uptake to promote glycogenolysis Increases proteolysis when stressed to release gluconeogenic amino acids into circulation to enter liver for gluconeogenesis

Question 26

Why must triglycerides be converted to ketones and glucose?

Answer 26

Brain cannot metabolise fatty acids but can metabolise ketones and glucose fatty acids → ketones glycerol → glucose

Question 27

What are adipocytes?

Answer 27

Specialised cells that store fat as triglycerides

Question 28

How are triglycerides modified in order for them to be able to enter adipocytes?

Answer 28

Those in blood are too large to enter directly | Lipoprotein lipase hydrolyses triglycerides that are too large so they can enter the cell

Question 29

What is the effect of insulin on adipocytes?

Answer 29

Insulin increases formation of triglycerides in adipocytes Activates lipoprotein lipase to increase concentration of non-esterified fatty acids Activates GLUT4 to increase glucose which is converted to NEFAs NEFAs condensed with glycerol-3-phosphate to form triglycerides

Question 30

What is the effect of growth hormone and cortisol on adipocytes?

Answer 30

Increase hydrolysis of triglycerides to release NEFAs for growth

Question 31

What is gluconeogenesis and where does it happen?

Answer 31

Occurs in liver uses glycerol-3-phosphate to produce glucose 25% of hepatic glucose output after 10 hour fast

Question 32

How are ketones produced and where?

Answer 32

Occurs in liver Converts NEFAs to fatty acyl CoAs These combine with acetyl CoA to form acetoacetate Acetoacetate converted to ketone bodies that can be used by brain

Question 33

What would suggest an insulin deficiency?

Answer 33

High ketones and high glucose | No inhibition of ketone production, yet blood glucose high

Question 34

What are omental adipocytes?

Answer 34

More metabolically and endocrinolically active adipocytes | More omental fat leads to higher risk of coronary heart disease

Question 35

What is glycosuria?

Answer 35

Presence of glucose in the urine

Question 36

What is osmotic diuresis?

Answer 36

Osmotically active glucose pulls water into urine by osmosis

Question 37

What is the renal reabsorptive capacity?

Answer 37

Amount of glucose that can be reabsorbed by the kidneys - if exceeded leads to glycosuria

Question 38

How does T1D present?

Answer 38

Months after onset without complications | Polyuria and polydipsia secondary to absolute insulin deficiency

Question 39

What is the regular age of onset for T1D?

Answer 39

Young usually

Question 40

What is the mechanism of T1D?

Answer 40

Unabated proteolysis = muscle loss Continual lipolysis of triglycerides High hepatic glucose output leads to glycosuria and ketonuria

Question 41

What is the treatment available for T1D?

Answer 41

Insulin injections

Question 42

What is a potential complication of insulin injections?

Answer 42

May produce insulin induced hypoglycaemia because level of insulin not reduced as it is not endogenous ∴ keeps causing entry to muscle even at low blood glucose levels and in the face of high glucagon

Question 43

How does T2D typically present?

Answer 43

After years of onset without complications Fewer osmotic symptoms Results from end organ resitstance to insulin 60-80% obese dyslipidaemia common

Question 44

What is the normal age of onset of T2D?

Answer 44

Older usually

Question 45

What is the mechanism of T2D?

Answer 45

Liver, muscle and adipose tissue resistant to insulin Usually enough to suppress ketogenesis and proteolysis so no muscle loss Not enough insulin to stop other effects

Question 46

What is the treatment available for T2D?

Answer 46

Diet and exercise Control of total calories reduction in number of fats and refined carbs and sodium Increase in number of complex carbohydrates and soluble fibre

Question 47

What two pathways does insulin binding activate and what do they do?

Answer 47

MAP Kinase pathway - growth in utero and children | PI3K-Akt pathway - leads to metabolic actions such as GLIT4 production

Question 48

How does insulin resistance arise and what does it affect?

Answer 48

Arises in all organs at the same time affects PI3K-Akt pathway Prevents glucose from being taken up from blood fasting glucose >6mmol

Question 49

What are the features of insulin resistance?

Answer 49

``` hypertension high blood concentration of triglycerides and LDLs Low HDL concentration Fasting glucose >6mmol High omental fat ```

Question 50

What is compensatory hyperinsulaemia and what does it cause?

Answer 50

Because blood glucose doesn't fall when insulin is secreted, mitogenic MAPK pathway is over activated Produces hypertension and dyslipidaemia see in in diabetes Abnormal lipid carriage leading to isachemic heart disease

Question 51

What does dyslipidaemia cause?

Answer 51

Higher LDL and NEFA/triglyceride concentration in blood due to MAPK pathway Causes damage to blood vessels and hypertension Lower lipoprotein lipase activity Causes isachemic heart disease