Insulin

Question 1

Islets of Langerhans

Answer 1

Cell clusters alpha, beta, delta and P cells within the pancreas, that secretes hormones.

Question 2

Hyperglycemia

Answer 2

A condition of excess glucose circulation in the plasma

Question 3

SGLT1

Answer 3

This is responsible for glucose absorption in the small intestine, reabsorbing 3% of filtered glucose in the renal proximal tubule

Question 4

SLT2

Answer 4

Responsible for reabsorption in the small intestines proximal tubule, reabsorbing 90%

Question 5

cAMP

Answer 5

Cyclic Adenosine Monophosphate is a second messenger used for intracellular signal transduction

Question 6

Protein Kinase A

Answer 6

A family on enzmyes with activity dependent on cellular levles of cAMP

Question 7

Insulin

Answer 7

A pancreatic hormone that regulates blood glucose levles by stimulating the conversion of glucose to glycogen.

Question 8

Insulin Receptor

Answer 8

A tyrosine kinase receptor that activates on insulin binding, phosphorylating itself and other proteins.

Question 9

Negative Co-operativity

Answer 9

Insulin binding at one sites decreases insulin binding affinity in the other site.

Question 10

Insulin Receptor Substrate Family

Answer 10

A family of proteins phosphorylated by activated insulin receptor, with roles in insulin-stimulated signal transduction pathways.

Question 11

P13K

Answer 11

Phosphoinositide-3 Kinase Heterodimers are lipid kinases, regulating various processes.

Question 12

PDK1

Answer 12

Pyruvate Dehydrogenase Kinase is a major regulator of P13K pathways transmission to downstream kinases.

Question 13

AKT1

Answer 13

An enzyme responsible for regulation of glucose uptake, mediating insulin induced translocation of GLUT4 to the cell surface.

Question 14

What is the structure of Insulin?

Answer 14

A 51 residue anabolic protein secreted by beta cells in the Islets of Langerhans, containing two A/B chains connected by disulfide bonds.

Question 15

GLUT4

Answer 15

A transporter for glucose in insulin-dependent mechanisms

Question 16

What is the mature, functional insulin hormone a product of?

Answer 16

Proinsulin

Question 17

Proinsulin

Answer 17

An insulin precursor, giving rise to the double chained insulin, by removal of the C-peptide

Question 18

What is Diabetes mainly caused by?

Answer 18

Mutations in the insulin gene, being associated with impaired folding of proinsulin, leading to ER stress, beta cell death and diabetes.

Question 19

What is diabetes characterised by?

Answer 19

Decreased glucose tolerance resulting from a relative deficiency of insulin or lack of sensititiy to insulin, with resulting hyperglycemia.

Question 20

What are the associated problems of hyperglycemia?

Answer 20

Long term exposure of tissues to elevated glucose concentrations involving development of macro-microvascular disease, like coronary heary disease.

Question 21

What are the 3 functions of Insulin?

Answer 21

Stimulation of glucose uptake from systemic circulation
Supression of hepatic gluconeogenesis, regulating glucose homeostasis.
Regulation of protein/fat synthesis, RNA/DNA synthesis and cell growth and differentiation.

Question 22

What is glucose movement into cells faciliated by and how do they function?

Answer 22

Membrane transporters that reduce plasma glucose concentrations in response to insulin stimulation.

Question 23

What are the two types of membrane transporters?

Answer 23

Na dependent, like SGLT1/2 and Na independent, like GLUT3

Question 24

Where are SGLT/1/2 found?

Answer 24

Luminal side of the intestinal and kidney cells.

Question 25

What do SGLT1/2 do?

Answer 25

Absorb glucose against concentration gradient by coupling movement of glucose into cells with movement of NA into the cell.

Question 26

What is the mechanism of SGLT glucose absoprtion against its concentration gradient?

Answer 26

Na moving down its electrochemical gradients provides energy used to co-transport glucose.

Question 27

How do Na independent glucose movement mechanisms function?

Answer 27

Facilitate movement of glucose down its concentration gradient, like GLUT4

Question 28

How does GLUT4 function?

Answer 28

Enables cells to increased glucose uptake, lowering circulating concentrations, as intracellular glucose is low due to phsophorylation into G6P.

Question 29

How does GLUT4 membrane translocation work?

Answer 29

Insulin binds INSR, IRS recruit to area like P13K then AKt2, which targets substratse regulating translocation of GLUT4 from storage vesicles via exocytosis.

Question 30

How does GLUT4 relate to TYPE2 DM?

Answer 30

Impaired ability of insulin on binding/activation of the IR to signal GLUT4 translocation.

Question 31

What is the structure of insulin?

Answer 31

Insulin consists of 21 residue alpha chain linked to a 30-residue B chain by two disulfide bonds.

Question 32

Structurually, how does proinsulin relate to insulin?

Answer 32

Contains both the A and B chain of insulin in a continous single chain joined through the C domain, flanked by dibasic residues(Arg-Arg and Lys-Arg)

Question 33

What is the C domain in proinsulin?

Answer 33

A segment joining the alpha and beta chain of proinsulin.

Question 34

How is proinsulin converted into insulin?

Answer 34

Cleavage of dibasic links by trypsin-like enzymes to release insulin and a free C peptide.

Question 35

What is the process of the transcription of insulin?

Answer 35

Its intial mRNA transcript is modified by excision of the C domain, capping of the 5-terminus with polyadenylation of 3; terminus, encoding preproinsulin.

Question 36

What is the process of translation of insulin?

Answer 36

It translocates into RER, where proinsulin undergoes folding and disulfide bond formation, generting its tertiary structure, followed by transport to GA, packaged into secretory granules and conversion into insulin.

Question 37

How is proinsulin converted to insulin?

Answer 37

Endoprotease enzymes cleave after dibasic residues pairs at ends of C-domain, and exopeptidase removes basic residues left after tryptic cleavage.

Question 38

How do elevated glucose concentrations stimulate insulin biosynthesis?

Answer 38

Increase cAMP levels, which exert effects involving PKA, which phosphorylates and activates key proteins.

Question 39

In glucose stimulated insulin biosynthesis, alternatively what does cAMP do?

Answer 39

With glucose, it rapidly increases translation and transcription of insulin mRNA, increasing its half-life by 30 hours threefold.

Question 40

What is the main mechanism of glucose-stimulated insulin secretion?

Answer 40

Calcium dependent exocytosis.

Question 41

What inhibits insulin secretion?

Answer 41

Catecholamines interact with adrenergic receptors on the b cell, and inhibition by somatostatin and amylin.

Question 42

How does insulin exert all of its physiological effects?

Answer 42

Binding to the insulin receptor of PM of target cells.

Question 43

What type of recpetor is the insulin receptor?

Answer 43

Tyrosine Kinase Receptor with two extracellular a subunits that bind insulin, two beta subunits containing tyrosine kinase domain.

Question 44

Why does the insulin receptor have two binding sites?

Answer 44

So it may have negative co-operativity.

Question 45

How is RTK activated?

Answer 45

Binding of a ligand, inducing dimerization, activating intracellular TKD through TM beta domain, TKD is cis-autoinhibited by intramolecular interactions, RTK activation occurs upon relieving of this inhibition, where then transphosphorylation of tyrosine residues are required for activation.

Question 46

What occurs proceeding INSR activation?

Answer 46

Downstream signalling through effector protein recruitment.

Question 47

What happens when INSR is autophosphorylated?

Answer 47

It recruits many substrates like insulin receptor substrate family.

Question 48

What does insulin receptor do to IRSF after INSR autophosphorylation?

Answer 48

Phosphrylate multiple tyrosine residues on the IRS, allowing downstream signalling effectors to propgate/amplify insulin response.

Question 49

What do IRS proteins do upon phosphorylation of their tyrosine residues?

Answer 49

Recruit P13K which contain regulatory/catalytic subunits, important in production of PIP3 from PIP2.

Question 50

What does PIP3 do after IRS activation?

Answer 50

Recruit proteins to the PM, which co-localise downstream signalling efftors like PDK1 and AKT, AKT activated by PDK1.

Question 51

What does activated AKT do?

Answer 51

Phosphorylate many downstream substrates in many pathway, key in insulin signalling.