Insulin Flashcards

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1
Q

Islets of Langerhans

A

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

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2
Q

Hyperglycemia

A

A condition of excess glucose circulation in the plasma

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3
Q

SGLT1

A

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

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4
Q

SLT2

A

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

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5
Q

cAMP

A

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

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6
Q

Protein Kinase A

A

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

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7
Q

Insulin

A

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

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8
Q

Insulin Receptor

A

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

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9
Q

Negative Co-operativity

A

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

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10
Q

Insulin Receptor Substrate Family

A

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

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11
Q

P13K

A

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

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12
Q

PDK1

A

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

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13
Q

AKT1

A

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

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14
Q

What is the structure of Insulin?

A

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

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15
Q

GLUT4

A

A transporter for glucose in insulin-dependent mechanisms

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16
Q

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

A

Proinsulin

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17
Q

Proinsulin

A

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

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18
Q

What is Diabetes mainly caused by?

A

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

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19
Q

What is diabetes characterised by?

A

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

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20
Q

What are the associated problems of hyperglycemia?

A

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

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21
Q

What are the 3 functions of Insulin?

A

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.

22
Q

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

A

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

23
Q

What are the two types of membrane transporters?

A

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

24
Q

Where are SGLT/1/2 found?

A

Luminal side of the intestinal and kidney cells.

25
Q

What do SGLT1/2 do?

A

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

26
Q

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

A

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

27
Q

How do Na independent glucose movement mechanisms function?

A

Facilitate movement of glucose down its concentration gradient, like GLUT4

28
Q

How does GLUT4 function?

A

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

29
Q

How does GLUT4 membrane translocation work?

A

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

30
Q

How does GLUT4 relate to TYPE2 DM?

A

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

31
Q

What is the structure of insulin?

A

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

32
Q

Structurually, how does proinsulin relate to insulin?

A

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)

33
Q

What is the C domain in proinsulin?

A

A segment joining the alpha and beta chain of proinsulin.

34
Q

How is proinsulin converted into insulin?

A

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

35
Q

What is the process of the transcription of insulin?

A

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

36
Q

What is the process of translation of insulin?

A

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.

37
Q

How is proinsulin converted to insulin?

A

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

38
Q

How do elevated glucose concentrations stimulate insulin biosynthesis?

A

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

39
Q

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

A

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

40
Q

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

A

Calcium dependent exocytosis.

41
Q

What inhibits insulin secretion?

A

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

42
Q

How does insulin exert all of its physiological effects?

A

Binding to the insulin receptor of PM of target cells.

43
Q

What type of recpetor is the insulin receptor?

A

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

44
Q

Why does the insulin receptor have two binding sites?

A

So it may have negative co-operativity.

45
Q

How is RTK activated?

A

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.

46
Q

What occurs proceeding INSR activation?

A

Downstream signalling through effector protein recruitment.

47
Q

What happens when INSR is autophosphorylated?

A

It recruits many substrates like insulin receptor substrate family.

48
Q

What does insulin receptor do to IRSF after INSR autophosphorylation?

A

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

49
Q

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

A

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

50
Q

What does PIP3 do after IRS activation?

A

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

51
Q

What does activated AKT do?

A

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