Glucose Regulation, Pancreas, Glucagon, GLP-1 and GIP

Question 1

amount of glucose in blood provides the body with energy for how long

Answer 1

•With normal glucose levels the total amount of glucose in the blood at any given moment is only enough to provide energy to the body for 20-30 minutes and so glucose levels must be precisely maintained

Question 2

3 main hormones from pancreas which regulate blood glucose

Answer 2

•insulin, glucagon an somatostatin

Question 3

where are glucagon receptors mainly and what do they do

Answer 3

•Glucagon receptors are mainly expressed in the liver and kidney causing an increase in blood glucose when there are low blood glucose levels

Question 4

where are insulin receptors found and when is it realsed

Answer 4

•Insulin receptors are on ALL cell types and signals glucose storage – main cells we focus on are liver, muscle and adipose and it is released when blood glucose levels are high

Question 5

what does the pancreas contain (in terms of cell type)

Answer 5

The Pancreas contains Islets of Langerhans (Endocrine Tissue):
•Beta cells = insulin & mostly in center
•Alpha cells = glucagon, delta cells (which secretes somatostatin) and are both around the periphery

Question 6

what do pancreatic hormones do in general

Answer 6

work together to regulate blood glucose after and between meals

Question 7

function of insulin (activates what)

Answer 7

activates beta cells (insulin producers) and inhibits alpha cells (glucagon producers)

Question 8

function of glucagon (activates what)

Answer 8

activates alpha cells (glucagon producers) and activates beta cells (insulin producers) and activates delta cells (somatostatin producers)

Question 9

function of somatostatin (inhibits what)

Answer 9

inhibits alpha cells and inhibits beta cells

Question 10

function of Glucagon-like Peptide 1 (GLP-1) and where is it made

Answer 10

•is made in the intestine from the same precursor as glucagon but has a very different function
-acts on the pancreas as a potent stimulator of insulin transcription and release after meals, decreases glucagon secretion and acts on other tissues as well as the pancreas

Question 11

GLP-1 is a _____ which is a protein that amplifies insulin effects

Answer 11

incretin

Question 12

what is another incretin aside from GLP-1

Answer 12

•Gastric inhibitory peptide (GIP) also known as glucose-dependent insulinotropic peptide is also an incretin and is secreted by the cells of the small intestine

Question 13

what are incretins defined as

Answer 13

hormones that stimulate insulin secretion in response to meals

Question 14

GLP-1 and GIP

1. where are they made
2. what do they signal via
3. what do they amplify
4. they’re _____ dependant

Answer 14

1. GLP-1 and GIP are made in the small intestine
2. GLP-1 and GIP signal via their specific G-protein coupled receptors and increases cAMP
3. GLP-1 and GIP amplify insulin secretion and release
4. GLP-1 and GIP are glucose-dependant, postprandial (meaning after eating)

Question 15

GLP-1 role in glucose homeostasis
Brain:
Stomach:
Liver:
Pancreas:

Answer 15

• Brain: decrease in appetite
• Stomach: decrease in gastric emptying
• Liver: decrease in glucose production by inhibiting glucagon
• Pancreas: increase insulin secretion, decrease glucagon secretion, increase insulin biosynthesis, increase B-cell proliferation and decrease B-cell apoptosis

Question 16

what is glucagon produced by and what does it do

Answer 16

• Glucagon is a peptide hormone produced by alpha cells of the pancreas
• Raises the concentration of glucose and fatty acids in the bloodstream – considered to be the main catabolic hormone of the body

Question 17

what receptor does glucagon bind to and what effects does this have

Answer 17

•Glucagon binds to the glucagon receptor, a G protein, seven transmembrane receptors, locate in the plasma membrane of many tissues but especially in the liver where it generates glucose production through first glycogenolysis (for about 3 hours) then both glycogenolysis and gluconeogenesis

Question 18

what is gluconeogenesis

Answer 18

•is the production of glucose from non-carbohydrate sources and requires energy whereas glycogenolysis is the process of glycogen breakdown

Question 19

what two things inhibit glucagon

Answer 19

insulin and somatostatin

Question 20

Hypoglycemia what is it and what are some symptoms

Answer 20

•Hypoglycemia: if blood sugar levels drop too low, a potentially fatal condition
-Hypoglycemic symptoms include loss of consciousness – brain damage and even a lethal coma is possible

Question 21

Hyperglycemia

-short and long term symptoms (& associated with what disease)

Answer 21

short term symptoms appetite is supressed, long-term hyperglycemia causes many of the chronic health problems associated with diabetes mellitus: includes eye, kidney, heart disease and nerve damage

Question 22

what is diabetes mellitus and what is the difference between type 1 and 2

Answer 22

•deficiency in secretion of action of insulin – type 1 often is young onset and one needs injections of insulin otherwise they won’t survive (no insulin produced) and type 2 is insulin resistant and is much more common

Question 23

Cell Surface Receptors Control Gene Expression via MAPK, PKC and PI3K Pathways
Insulin secretion stimulated by _____ (2 things)
Insulin synthesis stimulated by ______

Answer 23

• Insulin secretion stimulated by calcium at voltage gated calcium channel (VGCC)
• Insulin secretion stimulated by GLP-1 acting on G protein coupled receptor (GPCR)
• Insulin synthesis stimulated by insulin at receptor tyrosine kinase (RTK) plus glucose sensor that transports glucose into the cell

Question 24

what type of granules release insulin

Answer 24

•Secretory granules release insulin, require calcium and stimulated by glucose (v low basal)

Question 25

control of insulin secretion (what mechanism?)

Answer 25

* a glucose sensor mechanism, a metabolic coupling to potassium channels to control plasma membrane potential and a voltage dependant calcium channel are required to link blood glucose levels to insulin secretion * Insulin containing granules are found in a reserve pool and “readily released” pool

Question 26

what factors mediate insulin release

Answer 26

•AA from food, glucose from food, other hormones: GLP-1 and GIP are both incretins which are proteins that amplify insulin effects

Question 27

once released how long does insulin last in circulation

Answer 27

•Once released, insulin lasts 3-5 minutes in circulation; mostly degraded by insulinases in the liver, kidney and placenta

Question 28

insulin release from B cell (6 steps)

Answer 28

1. Glucose from meal 2. GIP and GLP-1 (incretins) act on the same cell to increase cAMP & PKA potentiating other steps 3. ATP increase and cAMP/PKA signalling blocks K+ channel = cell depolarization (positive charge trapped) 4. Voltage-sensitive calcium channel opens and there is an increase in intracellular calcium 5. Intracellular calcium increase opens K+ -Ca2+ channel = cell repolarization 6. Intracellular calcium and cAMP/PKA increases causes insulin release

Question 29

IGF-1 and IGF-2

Answer 29

* IGF-1: major player in growth hormone axis; especially produced in liver, negative feedback on GH, protein synthesis, cell proliferation etc.; insulin family and same type receptor * IGF-2: fetal growth hormone especially in liver; mediates GH effect; insulin family too

Question 30

insulin uses a growth factor receptor _____

Answer 30

dimer | -disulphide bridge already formed between two cysteines so it doesn't need to dimerize upon binding

Question 31

insulin receptor structure Insulin binding domain: transmembrane domain: tyrosine kinase domain:

Answer 31

* Insulin binding Domain: extracellular; binds insulin; regulates kinase domain – keeps inactive until insulin binds; if defective then kinases stays on * Transmembrane Domain: holds receptor in place and transmits conformation signal when insulin is bound (alpha helix change) * Tyrosine Kinase Domain: intracellular; autophosphorylates across to neighbor kinase domain plus recruits and phosphorylates substrates like Insulin Receptor Substrate (IRS) to start phosphorylation cascade

Question 32

difference between alpha and beta subunit (insulin receptor structure) 1. how many domains each 2. which types of binding domains each

Answer 32

* Alpha subunit has 3 major domains whereas beta subunit has 2 major domains * Alpha subunit has the insulin binding domain an it regulates the kinase domain – keeps insulin off until it binds but if kinase remains on then cancer can occur * Beta subunit has a transmembrane domain

Question 33

Insulin and IGF evolution

Answer 33

* You share hormone ancestry with sea squirts * Evolution of insulin and IGF-1 and IGF-2 from a common ancestor; see how the genes double via gene duplication = new genes because once split can mutate one gene without messing up the organism and can acquire new function = evolve

Question 34

Endocrine effects of insulin (4 effects)

Answer 34

1. Insulin most potent metabolic storage hormone: glycogenesis to store glucose; triglycerides store fat; protein synthesis to store amino acids 2. Increase cell growth (via growth factor receptor aka tyrosine kinase receptor) 3. Critical for fetal growth 4. Directly suppresses glucagon transcription since glucagon gene has an insulin response element; recall glucagon increases blood glucose so opposite action from insulin; insulin also upregulates self

Question 35

Insulin signalling can go through 2 diff pathways 1. mitogenic (via MAPK) and 2. metabolic (PI3K/PKB) what do each pathways lead to

Answer 35

mitogenic functions trigger MAPK pathway - MAPK: cell growth and gene expression metabolic functions trigger PI-3K pathway : synthesis and cell survival / proliferation

Question 36

``` insulin effects in cell types via PI3K/PKB (AKT) pathway Liver: Pancreas: Muscle: Adipocyte: ```

Answer 36

•Liver: Decrease gluconeogenesis, increase glycogenesis and decrease glycogenolysis •Pancreas: increase B-cell growth and increase insulin secretion – note cell growth is mitogenic so not 100% MAPK action •Muscle: increase glucose transport, increase glycogenesis and increase protein synthesis •Adipocyte: increase glucose transport, increase protein synthesis, increase lipogenesis and decrease lipolysis -These effects are metabolic and the mitogenic effect is through MAPK pathway

Question 37

Signalling by growth factor receptors: insulin specific (6 steps)

Answer 37

1. Insulin receptor is synthesized as a dimer already (dimers form upon ligand binding for many other growth factors) 2. Autophosphorylation 3. Recruitment of accessory proteins: first is insulin receptor substrate (IRS) that is docking protein with more phosphorylation sites to recruit more protein; SH2 domains recognize phosphorylated tyrosines – for insulin e.g. GRB2 (growth factor receptor binding protein 2) and PI3K (phosphoinositide-3 kinase) 4. SH3 proteins recognize pro-rich regions – for insulin e.g. Grb2 has SH3 domain an binds other proteins 5. Formation of large complexes 6. Biological effects here for insulin will be via MAPK path and cell growth or via PI3K/PKB path for glucose and aa transport or glycogen/triglyceride synthesis; this is in any cell with insulin receptor (all cells have IR)

Question 38

Stopping Insulin Signalling (4 steps)

Answer 38

1. Receptor desensitized by internalization once insulin bound. First, some activity at the cell membrane (uses ATP to phosphorylate) then a bit more phosphorylation seen in endosomes 2. Then endosomes fuse with lysosomes and insulin-receptor complex undergoes acidification and degradation to turn off the phosphorylation capability of the hormone/receptor complex 3. Receptor can be downregulated (less insulin receptor transcription) if chronic insulin e.g. obese 4. Insulin gets degraded by insulinases within minutes