case 6 - glucose and insulin physiology

Question 1

where is delivery of glucose critical to

Answer 1

the CNS - it cannot substitute glucose

Question 2

what is the stored reservoir of glucose

Answer 2

glycogen

Question 3

what is normoglycaemia

Answer 3

4-6mmol/L
8mmol/L post-prandial (2 hrs after eating)

Question 4

what is hypoglycaemia

Answer 4

<3mmol/L

Question 5

what is hyperglycaemia

Answer 5

> 10mmol/L

Question 6

what decreases blood glucose

Answer 6

glucose utilisation
energy expenditure
glucose loss <0.3g/day

Question 7

what increases blood glucose

Answer 7

food intake - 160g/day
glucose uptake
glucose production
glucose reabsorption

Question 8

what is insulin secreted by

Answer 8

the beta cells which are situated in the islets of Langerhans in the endocrine pancreas

Question 9

what does insulin serve to do

Answer 9

decrease blood glucose levelds

Question 10

what is glucagon secreted by

Answer 10

the alpha cells in the islets of langerhans

Question 11

what is glucagon secreted in response to

Answer 11

low glucose levels and increase blood glucose levels

Question 12

what are the glucagon sensitive tissues

Answer 12

liver
fat (adipocytes)
muscle

Question 13

what are the insulin sensitive tissues

Answer 13

liver
fat (adipocytes)
muscle

Question 14

what happens to our glucose levels when we have fasted

Answer 14

they are often quite low

Question 15

what does low glucose levels trigger

Answer 15

the release of glucagon from the alpha cells

Question 16

what also happens at low glucose levels

Answer 16

beta cells are not stimulated

Question 17

what happens once the glucagon is released

Answer 17

it will act upon the liver to stimulate endogenous glucose production from its glycogen stores

Question 18

where does this glucose go

Answer 18

into the blood stream

Question 19

what are glucose levels like in the fed state and what does this stimulate

Answer 19

relatively high glucose levels, this stimulates the beta cells

Question 20

what do these beta cells do

Answer 20

they secrete insulin

Question 21

what does this insulin do

Answer 21

turns off glucagon production

acts on muscle and fat to increase their uptake of glucose - thus lowering blood glucose levels

it also acts upon the liver to switch of endogenous glucose production

Question 22

what else happens when we are in the fed state

Answer 22

there are endocrine cells located within the small and large intestine called enteroednocrine cells and they are stimulated to produce hormones

Question 23

what is the main hormone they produce and wha does it do

Answer 23

they produce GLP1. it is secreted in response to glucose load. it is an incretin hormone. GLP1 receptors are on the beta cells and this stimulated insulin secretion

Question 24

what is T1DM

Answer 24

autoimmune destruction of beta cells

Question 25

what is T2DM

Answer 25

defects in insulin release, sensing and/or signalling

Question 26

what is common in patients with diabetes receiving insulin

Answer 26

hypoglycaemia is common and there is a huge lack of awareness of it

Question 27

what is hyperinsulinism caused by

Answer 27

congenital defects in insulin release or insulin signalling insulinoma pancreatic tumours can produce too much insulin too - insulinomas

Question 28

what are the main transporters in glucose homeostasis

Answer 28

passive glucose transporters - GLUTs sodium coupled/linked transporters - SGLTs

Question 29

what are the SGLTs

Answer 29

family of insulin insensitive transporters

Question 30

what are the two important SGLTs

Answer 30

Two are important: - SGLT1 (SLC5A1) (2 sodiums per 1 glucose molecule per transport) - SGLT2 (SLC5A2) (uniporter)

Question 31

what transporter has the highest affinity for glucose

Answer 31

SLGT2

Question 32

can SGLT inhibitors be used to treat diabetes

Answer 32

are approved for mono- and combination therapy of T2DM

Question 33

what mutations cause glucose-galactose malabsorption

Answer 33

SLC5A1

Question 34

what mutations cause familial glucosuria

Answer 34

SLC5A2

Question 35

what passive transporters have major functional roles

Answer 35

GLUT1, GLUT2, GLUT4

Question 36

which of these are insulin insensitive

Answer 36

GLUT1 and GLUT2 are insulin insensitive ; critical to glucose absorption and glucose signalling

Question 37

what are some features of GLUT4

Answer 37

it is insulin sensitive found in adipose tissues, striated muscle and heart

Question 38

what are the Km values of the GLUTs

Answer 38

GLUT 4 and GLUT1 have similar Km for glucose (approx 5mM), lower than GLUT2 (17mM)

Question 39

how many transporters are in the GLUT family

Answer 39

13

Question 40

what do the GLUTs do

Answer 40

not only take glucose into the cell but also out of it aswell

Question 41

how does SGLT1 take glucose into the cell

Answer 41

takes glucose into the cells across the membrane by using 2 sodium ions

Question 42

how does glucose leave the enterocyte

Answer 42

via the passive transporters GLUT2

Question 43

what happens next to the glucose

Answer 43

it goes into the blood stream and goes into erythrocytes using the GLUT1 transporters

Question 44

what happens in the early primal tubule

Answer 44

in the early primal tubule >90% of glucose is absorbed by SGLT2

Question 45

what happens in the late proximal tubule

Answer 45

In the late proximal tubule, almost all of the remaining glucose os absorbed by SGLT1

Question 46

in healthy conditions, how much filtered glucose is reabsorbed

Answer 46

>99%

Question 47

what happens in people with diabetes to this level

Answer 47

the absorptive capacity of glucose transporters is overwhelmed in people with diabetes

Question 48

what do SGLT2 inhibitors promote

Answer 48

insulin loss and are used as diabetes therapy, pass out much more glucose in the urine

Question 49

what are two different diabetes therapy

Answer 49

K channel inhibitor enhance insulin secreiton

Question 50

describe the uptake of glucose into the beta cells

Answer 50

Uptake via the GLUT1 and GLUT2 Metabolism Leads to generation of signalling molecules such as ATP which stimulates the closure of potassium channels - located within the cell membrane When these potassium channels are closed, this leads to depolarisation of the beta cell which leads to an influx of sodium and calcium into the cell via calcium channels This influx of calcium leads to exocytosis - insulin release from the beta cell and into the blood stream

Question 51

what is the class of drugs used to counteract this

Answer 51

sulphinurias

Question 52

describe the GLP-1 mediated insulin release cascade

Answer 52

Activation of GLP-1 receptor G protein stimulation Stimulation of adenylate cyclase Elevation of cAMP Exocytosis Activation of PKA and Epac2

Question 53

what diabetes therapies are used for this

Answer 53

incretin minetics enhance insulin secretion

Question 54

what is the mechanism of action of the beta cells

Answer 54

Uptake Metabolism K ATP channel closure Activation of GLP1 receptor G protein stimulation Stimulation of adenylate cyclase Elevation of cAMP Exocytosis Activation of PKA and Epac2 Insulin release

Question 55

describe the process of insulin sensitive glucose transport

Answer 55

GLUT 4 : Insulin binding to receptors Tyrosine kinase actiivation Signalling molecules: PRS, P13K, PDK1, AKT, AS160 etc Translocate GLUT4 transporters Glucose uptake

Question 56

what therapies are given for this signalling pathway

Answer 56

enhance insulin signalling e.g metformin

Question 57

where are the immediate effects of insulin

Answer 57

in the cytoplasm

Question 58

what does lower insulin lead to

Answer 58

increase glucose production and lowered peripheral glucose uptake this leads to hyperglycaemia

Question 59

what is the short term complications of hyperglycaemia

Answer 59

Glucosuria leading to dehydration, polydipsia, osmotic diuresis This short term problem leads to ketoacidosis

Question 60

what are the long term effects of hyperglycaemia

Answer 60

leads to diabetes complications

Question 61

where does glucotoxicity take place

Answer 61

capillary endothelial cells; mesangial cells; neurones and Schwann cells in peripheral nerve