Control of Blood Glucose + Pancreas

Question 1

How does glucose enter cells?

Answer 1

Sodium-glucose cotransporters (SGLTs) :
SGLT1: glucose absorption from gut
SGLT1, SGLT2: glucose reabsorption from kidney (PCT)

Question 2

What’s GLUT 1?

Answer 2

brain, erythrocytes

high affinity for glucose: constant uptake of glucose at 2-6 mM

Question 3

What’s GLUT 2?

Answer 3

liver, kidney, pancreas, gut
low affinity: glucose equilibrates across membrane
Glucose-dependent insulin release in pancreas

Question 4

What’s GLUT 3?

Answer 4

brain – high affinity

Question 5

What’s GLUT 4?

Answer 5

muscle, adipose tissue
medium affinity : insulin recruits transporters
Insulin-dependent uptake of glucose into cells

Question 6

What’s Islets of Langerhans?

Answer 6

Clusters of endocrine cells surrounded by exocrine pancreas

Question 7

Hormone of α-cells?

Answer 7

glucagon

Question 8

Hormone of β-cells?

Answer 8

insulin

Question 9

Hormone of δ-cells?

Answer 9

somatostatin

Question 10

Describe synthesis of insulin?

Answer 10

• original transcript: pre-pro insulin
• signal seq removed: proinsulin (in RER)
• transfer to Golgi
• peptidases break off C peptide leaving an A + B chain linked by disulphide bonds
• 1 mole of C-peptide is secreted for each mole of insulin

Question 11

Importance of C-peptide?

Answer 11

inert so good index of insulin secretion

Question 12

What’s the pancreas supplied by?

Answer 12

branches of coeliac, superior mesenteric, splenic arteries

Question 13

Venous drainage of the pancreas?

Answer 13

into the portal system

Question 14

How’s insulin metabolised?

Answer 14

• half of secreted insulin is metabolized by liver in it’s first pass
• remainder is diluted in the peripheral circulation

Question 15

Why’s C-peptide more accurate index of insulin secretion in peripheral circulation?

Answer 15

not metabolized by liver

Question 16

Why are insulin levels in peripheral circulation much diluted?

Answer 16

Hepatic portal vein is only a fraction of the CO

Question 17

Which factors stimulate insulin release from β-cells?

Answer 17

Plasma glucose
AA 
Glucagon - locally via paracrine actions
Parasympathetic 
Incretin hormones - amplify glucose release

Question 18

Which factors inhibit insulin release from β-cells?

Answer 18

α-adrenergic

Somatostatin - paracrine effect from neighbouring δ-cells via negative feedback

Question 19

Which factors stimulate glucagon release from α-cells?

Answer 19

AA - arginine
β-adrenergic
Parasympathetic

Question 20

Which factors inhibit glucagon release from α-cells?

Answer 20

Insulin
Plasma glucose
Somatostatin

Question 21

Why does AA stimulate both insulin + glucagon?

Answer 21

meal high in protein low in carbohydrate

Question 22

How does insulin:glucagon ratio vary?

Answer 22

over physiologically significant range of glucose concentrations

Question 23

How do β-cells sense rise in glucose?

Answer 23

• plasma glucose rises
• glucose enters via GLUT2
• GLUT2 has low affinity so rate of entry low
• glucose -> G6P by glucokinase
• G6P goes full oxidative phosphorylation via TCA using ATP
• ATP binds to ATP-sensitive K+ channel
• channel closes
• K+ can’t leave
• cell is less hyperpolarised (more depolarised)
• vgcc open
• intracellular Ca triggers insulin exocytosis

Question 24

Effect of metformins

Answer 24

common class of insulin-potentiating drugs, directly closes K/ATP channel --> increasing insulin release by-passing the normal mechanisms
Decreases gluconeogenesis

Question 25

How parasympathetic stimulation can increase insulin release?

Answer 25

due to muscarinic R activation, which via intracellular signalling, leads to Ca release from intracellular stores

Question 26

How sympathetic stimulation can decrease insulin release?

Answer 26

- via α receptors - reduced sensitivity of the channel - reduced likelihood of closure - decreased inuslin release

Question 27

Effect of insulin binding to its receptor

Answer 27

- Activates cascade of protein phosphorylation, which stimulate or inhibit specific metabolic enzymes by modulating enzyme phosphorylation - Modulates activity of metabolic enzymes by regulating gene transcription

Question 28

Describe insulin receptor

Answer 28

disulfide-linked tetramer with β-subunits spanning the membrane + α-subunits on exterior

Question 29

What's acetyl-CoA carboxylase (ACC)?

Answer 29

enzyme that starts off lipogenesis converts acetyl CoA -> malonly CoA under inhibitory control by PKA, which depends on cAMP for its activity

Question 30

What's phosphatidylinositol-3-kinase?

Answer 30

phosphorylates membrane phospholipids | major product = phosphatidylinositol-3,4,5-trisphosphate

Question 31

How insulin binding promotes lipogenesis?

Answer 31

- insulin binding - decrease in cAMP levels - reducing PKA activity - releasing ACC from inhibition - promoting lipogenesis

Question 32

Describe glucagon receptor

Answer 32

Gs protein acting via PKA - coupled to adenylate cyclase - generates cAMP - activates PKA - phosphorylates key enzymes

Question 33

DM1?

Answer 33

absolute insulin deficiency (due to destruction of insulin-producing pancreatic beta cells)

Question 34

DM2?

Answer 34

variable combination of insulin resistance+insufficiency

Question 35

Diabetes random + fasting glucose conc?

Answer 35

Random plasma glucose ≥ 11.1 mmol L-1 | Fasting plasma glucose ≥ 7.0 mmol L-1

Question 36

What's oral glucose tolerance test (OGT) + diabetic value?

Answer 36

drink 75g glucose in solution and monitor plasma glucose every 30 min for 2hrs ≥ 11.1 mmol L-1

Question 37

Importance of glycaemic control?

Answer 37

Reduce macro- and microvascular complications

Question 38

Macrovascular complications?

Answer 38

stroke, other CV diseases

Question 39

Microvascular complications?

Answer 39

Diabetic nephropathy=damage to capillary beds in kidney Retinopathy Neuropathy=other peripheral tissues resulting in local nerve damage

Question 40

Indicator of glycaemic control?

Answer 40

Glycosylated Hb (A1C) levels

Question 41

Values of glycosylated Hb (A1C) levels

Answer 41

Less than 6.5% is good | Every 1% fall in A1C results in 20-30% relative risk reduction in microvascular complications

Question 42

What's the incretin effect?

Answer 42

Evidence for its impairment in T2DM | Major target for new drug development

Question 43

Describe how to measure incretin effect?

Answer 43

- continuous monitoring of plasma glucose+insulin - 2 sets of measurements - give an oral glucose load + monitor plasma glucose over 2-3 hrs - track the time-course + amount of this rise - repeat, but no oral glucose but copy as closely as possible previously-measured change in plasma glucose by iv infusion of glucose - track insulin response - greater insulin response via the oral route

Question 44

Why's there greater insulin response via oral vs iv?

Answer 44

Something in GI tract must potentiate insulin release in response to glucose, since insulin release is lower when you by-pass the gut.

Question 45

What are the incretins?

Answer 45

glucagon-like peptide-1 (GLP-1) + GIP | released in response to nutrients in gut

Question 46

Effect of sulfonylureas?

Answer 46

bind + close KATP channels, depolarize B cell releasing insulin : : :

Question 47

Effect of thiazolidinediones?

Answer 47

activate PPARγ receptor (controller of lipid metabolism), which (somehow) reduces insulin resistance

Question 48

Effect of SGLT2 inhibitors?

Answer 48

promote glucose excretion via kidney

Question 49

Effect of incretin targeting drugs + eg?

Answer 49

potentiate insulin release in response to rising plasma glucose - DPP-4 inhibitors : (prevent breakdown of natural incretins) - Synthetic GLP-1 analogues