Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Molecular & structural basis of disease > Diabetes > Flashcards

Diabetes Flashcards

1
Q

what does ‘diabetes’ mean?

A

the excessive urination and a persistent thirst

in greek it means ‘a siphon’ because people passed water like a siphon’

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

where does the mellitus of diabetes mellitus come form?

A

tasted the pee and it was sweet
mellitus = honey

Thomas Willis, who rediscovered the connection between diabetes and sweetness by conducting his taste test. He renamed the disease diabetes mellitus; mellitus is Greek for “like honey.”

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

what are the two common types of diabetes?

A
  1. Diabetes mellitus (of or pertaining to honey – sweet tasting) - a disease in which insulin has insuffient function leading to unregulated blood glucose levels
  2. Diabetes insipidus (lacking flavour) – a disease in which the pituitary gland does not secrete sufficient vasopressin (large amounts of urine still)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

what are the three main classifications of diabetes mellitus (DM)?

A
  • Type 1 – “absolute insulin deficiency” - Body attacks cells that make insulin (pancreatic beta cells) if these cells die out can no longer make insuin
  • Type 2 – “insulin resistance” Body becomes resistant to insulin effects
  • Gestational - is a condition in which women without previously diagnosed diabetes exhibit high blood glucose levels during pregnancy (esp. during the third trimester due to changes in renal absorption of glucose).
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

describe the relationship between blood sugar regulation and (bacterial) infection ?

A

Disease states can alter the normal balance of blood glucose
As part of the body’s defence mechanism for fighting illness and infection, more glucose is released into the blood stream.

Bacterial really like to grow on glucose - if there is lots in your blood stream then the bacterial have more food

High blood sugar unleashes destructive molecules that interfere with the body’s natural infection-control defenses.

two dicarbonyls — methylglyoxal (MGO) and glyoxal (GO) — alter the structure of human beta-defensin-2 (hBD-2) peptides, crippling their ability to fight inflammation and infection.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

what two hormones work together to maintain an appropriate blood glucose level?

A

insulin and glucagon

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

breifly describe how your blood glucose levels change throughout the day

A

after breakfast there is a spike of glucose and then after a little while there is a small increase again (as the body have broken donw the starches)
this same thing happens at lunch and dinner
after dinner levels continue to decrease throughout the night until breakfast

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

describe the similarity between blood glucose and insulin levels in the body

A

The insulin levels mirror the blood sugar levels
they go up when the sugar goes up

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

why do the blood glucose levels never fo donw to zero?

A

because cells always need an energy source

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

what ways can glucose be stored?

A

as glycogen or fats

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

describe the function of insulin

A

When glucose levels increase, pancreatic beta cells are sitmulated to release insulin
This causes the
Body cells take up more glucose and Liver to take up glucose and stores it as glycogen
Causing blood glucose levels to fall

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

describe the function of glucagon

A

when glucose levels get low, pancreatic alpha cells are stimulated to release glucagon
this stimulates the liver to break down glycogen and release glucose to the blood
causing blood glucose levels to rise

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

what is the exocrine function of the pancreas?

A

The exocrine pancreas is responsible for secretion of digestive enzymes, ions and water into the duodenum of the gastrointestinal tract.
The digestive enzymes are essential for processing foodstuffs in meals to molecular constituents that can be absorbed across the gastrointestinal surface epithelium.
Acini cells are responsible for producing and secreting these enzymes into the pancreatic duct

End of pancreatic duct is the acini cells with duct in middle, along with lots of capillaries

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

what is diabetic ketoacidosis?

A
  • a serious complication of diabetes that can be life-threatening.
  • DKA develops when your body doesn’t have enough insulin to allow blood sugar into your cells for use as energy. Without enough insulin, the body begins to break down fat as fuel. This causes a buildup of acids in the bloodstream called ketones. If it’s left untreated, the buildup can lead to DKA
  • ## DKA is most common among people with type 1 diabetes. People with type 2 diabetes can also develop DKA.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

what is the endocrine function of the pancreas?

A

The endocrine component of the pancreas consists of islet cells (islets of Langerhans) that create and release important hormones directly into the bloodstream (plasma).
Two of the main pancreatic hormones are insulin (release by beta cells), which acts to lower blood sugar, and glucagon (release by alpha cells), which acts to raise blood sugar.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

what are the four major cells of the Islets of Langerhans?

A

Pancreatic Beta-cells comprise the majority of pancreatic islet cell population; secrete insulin.
Pancreatic Alpha-cells cells in the islet of Langerhans which secrete glucagon.
Pancreatic PP-cells PP cells secrete pancreatic polypeptide.
Pancreatic Delta-cells cells in the islet of Langerhans; known to secrete somatostatin, and vasoactive intestinal peptide.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

describe the cellular role of insulin
what four things does it result in

A

In its monomeric form, insulin will bind to its insulin receptor causing a conformational change
This results in:
- an increase in glucose gransporters (GLUT4)
- glucose conversion to glycogen
- glucose conversion to fatty acids
- glucose channelling into metabolism/conversion to pyruvate

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

how is insulin made?

A

the insulin gene is transcribed and translated into preproinsulin
the signal recognition particle recognises the signal sequence and brings it to a translocon where its inserted into the ER membrane

then the rest of the protein can be made as its forced through the translocon into the ER lumen where it is folded
then the signal sequence is cleaved off (by signal peptidase)
now left with a soluble protein (proinsulin)
this goes through the Golgi where the C peptide is cleaved off by prohormone convertases, PC2 and PC1/3 and Carboxypeptidase to produce mature insulin
final packaging into secretory granules as a zinc bound hexamer (storage form)

from the ER lumen through the golgi to secretory vesicles the pH drops considerably so the protein precipitates

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

what is the pI?

isoelectric point

A

isoelectric point is the overall charge of the protein
(sum of positive and negative side chains of amino acids)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

what happens if the pI of the protein is close to that of the buffer?

A

the protein precipitates

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

what is the isoelectric point of insulin?

A

pi of insulin ~ 5.4

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

what are the pH values of the Er lumen, the golgi and secretory vesicles?

A

ER lumen - pH7.2
Golgi - pH 6.7 -> 6.0
Secretory vesicles - pH5.7

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

why is it important that the isoelectric point of insulin is close to that of the secretory vesicles?

A

if pi is close to that of the buffer then it precipitates
precipitation slows down the release of insulin

meaning its in its storage form in the secretory vesicles

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

what is Znt8?

A

a zinc transporter that channels zinc ions into secretory vesicles for binding with insulin to generate its stored form

it is a genetic risk factor for the development of both type 1 and 2 diabetes

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

describe the stored from of insulin

A

a hexamer of monomeric insulin molecules bound to two zinc ions

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

describe the changes in the quaternary structure of zinc in the body

A

there is a shift in the equilibrium of monomeric (active) to hexameric (sored) forms from one side to the other depending on if we want quick or slow release of insulin

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

describe the primary structure of insulin

A

insulin is made up of two chains the A chain and the B chain
these two chains are connected via 2 disulphide bridges (between cysteines - inter S-S)
the A chain has an additional disulphide bridge on itself (intra S-S)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

what are the two monomeric conformations of insulin?

how can you remember them?

A

R state - looks like a cormant
T state - looks like a parrot

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

why is glycine in the B chain important in the structure of insulin?

A

the conformational changes are based around the glycine
glycine is knwon as a helix breaker - because it has a very small side chain (easy to make it fall apart

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

describe the secondary structure of insulin

A

A chain has two alpha helices
B chain has an alpha helix and a beta sheet

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
31
Q

why is the C chain in insulin needed?

but then cleaved off

A

C chain is required energetically to form the structure of insulin

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
32
Q

how does dimerisation of monomeric insulin occur?

A

occurs between the beta sheets of the B chain (looks like an antiparalele beta sheet ie going in different directions)
hydrogen bonds form between them to hold them together

can be T with an R state, T state with a T state or R state with an Rstate

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
33
Q

how must insulin be taken?

A

must be injected subcutaneouly

cant be swallowed, as it is a protein so it will be broken down

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
34
Q

why do the monomeric and hexmeric froms of insulin have different rates of release/effect?

A

the molecular size dictates how quickly it can get into the blood stream after its injected subcutaneouly

monomeric is 6kDa so can get into bloodstream via capillaries fast hence the rapid absorption
hexameric form is 36kDa or even larger aggregates (72kDa - >50000kDa) slows down the absorption becase ultimately it has to break dwon into the monomeric form before its released into the capilary where it can have its effects

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
35
Q

how do the two monomeric conformational states of insulin differ?

A

the N terminus of the B chain has 8 residues that differ structurally between the states

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
36
Q

insulin hexamers exist in one of three states what are they?

how do they differ?

A

T6, T3R3 or R6

  • The allosteric states differ widely with respect to the physical and chemical stability of the insulin subunits within each hexamer, exhibiting the following stability order: R6&raquo_space;T3R3&raquo_space;T6
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
37
Q

how and why was the R state of insulin discovered?

A

years ago 1960s, when you wanted to analyse the structure of a protein you need lots of protein to from a crystal
this can take hours to weeks to months
if you have a high conc of protein sitting about for weeks - there is a high likelihood of contamination and no protein being left because it is a great food source for bacteria and fungus
phenol was used to kill the bacteria and fungus but then was incorporated into the structure

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
38
Q

what else is included in the preparation of insulin that is injected?

A

zinc
protamines
phenol

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
39
Q

what are protamines and why are they used in the preparation of insulin?

A

protamines come from salmon sperm, they are proteins that protect DNA but have also been shown to slow down release of insulin
protamines hold the hexamers together which then slows the breakdown to monomers

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
40
Q

why are protamines added to insulin preparations?

A

In the insulin crystal, protamine regulated interactions between dimers and hexamers

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
41
Q

why are phenol or metacresol added to insulin preparations?

A

as preservatives

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
42
Q

why is zinc chloride added to insulin preparations?

A

Hexamers, made stable by zinc ions, are the predominant quaternary structure of pharmacological insulin.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
43
Q

what are the three categories of the insulin drug?

A
  1. Fast-acting insulin analogues
  2. Long acting insulin analogues
  3. Very long acting insulin analogues
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
44
Q

Hexameric insulin is an allosteric protein that undergoes ligand-mediated interconversion among three global conformation states designated…

A

T6 , T3R3 and R6.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
45
Q

what are the three categries of insulin drugs?

A
  1. Fast-acting insulin analogues
  2. Long acting insulin analogues
  3. Very long acting insulin analogues
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
46
Q

what category of drug is insulin Lispro?

A

Rapid acting drugs

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
47
Q

what is Humalog?

A

Humalog is a mixture of insulin lispro solution, a rapid-acting blood glucose-lowering agent and insulin lispro protamine suspension, an intermediate-acting blood glucose-lowering agent.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
48
Q

chemically what is insulin lispro?

how does it shift the equlibrium?

how does it differ from human insulin?

A

Chemically, insulin lispro is Lys(B28), Pro(B29) human insulin analog, created when the amino acids at positions 28 and 29 on the insulin B-chain are reversed.

Lysine and proline are swapped around (lispro), so that in the dimer they repel each other destabilising it slightly making it more likely to reside in monomeric form to mimic what the body is doing

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
49
Q

what is Insulin aspart?

NovoLog

how does it differ from human insulin?

A

NovoLog (insulin aspart) is a rapid-acting human insulin analog used to lower blood glucose.
NovoLog is homologous with regular human insulin with the exception of a single substitution of the amino acid proline by aspartic acid in position B28

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
50
Q

describe the chemical action of insulin aspart

A

Proline is mutated to aspartic acid – aspartate has a negative charge, this will repel and destabilize the dimeric interphase

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
51
Q

what is Insulin glulisine

how does it differ from human insulin?

A

APIDRA (insulin glulisine rdna origin inj) ® (insulin glulisine [rDNA origin] injection) is a rapid-acting human insulin analog used to lower blood glucose. Insulin glulisine differs from human insulin in that the amino acid asparagine at position B3 is replaced by lysine and the lysine in position B29 is replaced by glutamic acid.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
52
Q

describe the chemical action of insulin glulisine

A

Two mutations, lysine and glutamate changed, to effect the binding of zinc ions so its less stable as a hexamer making it more likely to break down to a dimer or a monomer

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
53
Q

give three examples of rapid acting insulin drugs

A

Lispro (Humalog) ProB28 ➔ Lys & LysB29 ➔ Pro Impairs dimerization, doesn’t stop just shift toward monomer
Eli Lilly and Co.
**Aspart (NovoLog) ** ProB28 ➔ Asp Charge repulsion at dimer interface, eg breaking down to monomer
Novo-Nordisk
Glulisine (Apidra) AsnB3 ➔ Lys & LysB29 ➔ Glu Decreased zinc-free self-association,
more likely to break down to dimers and monomers
Sanofi-Aventis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
54
Q

give two examples of long acting insulin drugs

A

Glargine (Lantus) ArgB31-ArgB32 tag & AsnA21 ➔ Gly Shift in pI to pH 7 leads to isoelectric precipitation on injection
Sanofi-Aventis

Detemir (Levemir) Modification of LysB29 by a tethered fatty acid Stabilization of hexamer and binding to serum albumin
Novo-Nordisk

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
55
Q

what is insulin glargine?

how does it differ from human insulin?

A

LANTUS® is a sterile solution of insulin glargine for use as an injection.

Insulin glargine is a recombinant human insulin analog that is a long-acting (up to 24-hour duration of action), parenteral blood-glucose-lowering agent.

Insulin glargine differs from human insulin in that the amino acid asparagine at position A21 is replaced by glycine and two arginines are added to the C-terminus of the B-chain

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
56
Q

what is insulin determir?

A

Insulin detemir is a long-acting (up to 24-hour duration of action) recombinant human insulin analog. Insulin detemir differs from human insulin in that the amino acid threonine in position B30 has been omitted, and a C14 myristic fatty acid chain has been attached to the amino acid B29.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
57
Q

chemically what is the action of insulin determir?

A

Remove threonine and attach a fatty acid
fatty acid is hydrophobic, doesn’t like being in solution (albumin carries them around the body, holding on and eventually release, a large protein that protects it, slowing the release down)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
58
Q

give two examples of very long acting insulin drug

A

Insulin Degludec
PEGLisPro Insulin (LY2605541)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
59
Q

what is PEGLisPro Insulin (LY2605541) ?

A

Insulin LY2605541 is a long-acting blood glucose-lowering agent. Chemically, it is PEGylated insulin lispro is Lys(B28), Pro(B29) human insulin analog, created when the amino acids at positions 28 and 29 on the insulin B-chain are reversed.

(lysine and proline swapped)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
60
Q

what does protein PEGylation do?

A

increases solubility
protects against proteolytic degradation
decreases renal clearance

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
61
Q

what carbohydrates are present in the diet?

A

polysaccharides: starch and glycogen
disaccharides: lactose, maltose and sucrose
monosaccharides: glucose, fructose and pentose

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
62
Q

how are polysaccharides broken down for absorption?

A

saliva and pancreatic alpha amylases breaks starch and glycogen down into Maltose, Dextrans and Maltotriose
membrane bound alpha glucosidases then subsequently break these disaccharides down into glucose which is absorped

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
63
Q

how are disaccharides broken down for absorption?

A

Lactose, maltose and sucrose are broken down by membrane bound alpha glucosidase and lactase into glucose fructose or galatose which are absorped

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
64
Q

what breaks down carbs into monosaccharides?

A

alpha glucosidases

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
65
Q

what three locations are amylases released?

A
  1. Saliva
  2. Pancreas (alpha amylase)
  3. Intestinal brush border
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
66
Q

how are monosaccharides absorbed?

A

on the brush border membrane in the intestinal lumen there are trasnporters SGLT1 and GLUT5
glucose/galactose goes through the SGLT1 transporter down a sodium concentration gradient, and fructose through GLUT5
on the basolateral membrane there are GLUT2 transporters to move the glucose/galactose/fructose into the blood, AND Na+/K+ ATPases that maintain the concentration gradient

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
67
Q

where is alpha glucosidase located?

A

on microvilli
they are tethered to the brush border membrane via a transmembrane helix

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
68
Q

what is intestinal alpha glucosidase?

A

a carbohydrate-hydrolase that releases α-glucose
an integral membrane glucosidase located in the brush border of the small intestine that acts upon α(1→4) bonds
with an transmembrane helix and two catalytic domains
Two proposed mechanisms include a nucleophilic displacement and an oxocarbenium ion intermediate

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
69
Q

what are the two prposed mechanism of alpha glucosidase activity

A

Two proposed mechanisms include a nucleophilic displacement and an oxocarbenium ion intermediate

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
70
Q

what is atherosclerosis?

A

Atherosclerosis is the buildup of fats, cholesterol and other substances in and on the artery walls. This buildup is called plaque. The plaque can cause arteries to narrow, blocking blood flow. The plaque can also burst, leading to a blood clot

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
71
Q

what is postprandial hyperglycaemia?

A

postprandial hyperglycemia is characterized by hyperglycemic spikes that induce oxidative stress. Postprandial hyperglycaemia is defined as a plasma glucose level>7.8 mmol/L (140 mg/dL) 1-2 hours after ingestion of food

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
72
Q

describe the pharmacological action of acarbose

A

acarbose working by competitive, reversible inhibition of intestinal brush border alpha-glucoside with a weaker effect on pancreatic alpha-amylase. The overall effect is the reduction in production and absorption of monosaccharides in the small intestine.
In patients with diabetes this results in a decrease in postprandial hyperglycaemia

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
73
Q

what is acarbose?

A

Acarbose is a pseudotetrasaccharide, a natural microbial product derived from culture broths of Actinoplanes strain SE 50. The unsaturated cyclitol component of the molecule has been identified as essential for a-glucosidase inhibitory activity.

Acarbose binds reversibly, competitively and in a dose-dependent manner to the oligosaccharide binding site of a-glucosidase enzymes in the brush border of the small intestinal mucosa. As a consequence, hydrolysis is prevented

74
Q

what is miglitol?

A

Miglitol is an oral anti-diabetic drug that acts by inhibiting the ability of the patient to break down complex carbohydrates into glucose.
consists of a single sugar ring, acting similar to cytlitol system - inhibits glycoside hydrolase enzymes called alpha-glucosidases.
In contrast to acarbose, miglitol is systemically absorbed; however, it is not metabolized and is excreted by the kidneys.

75
Q

why does acarbose have a side effect of flatulence

A

the unhydrolysed glucose ends up in your colon, if there is lots of glucose here then it will feed bacteria - this results in an increase of CO2 production and flatulence

76
Q

whats the difference between the mechanisms of acarbose and miglitol?

A
77
Q

describe the function of miglitol and voglibose

A

The anti-hypoglycaemic action of voglibose and miglitol results from a reversible inhibition of membrane bound intestines α glycosidase hydrolize enzymes which hydrolize oligosaccharides and disaccharides to glucose and other monosaccharides in the brush border of the small intestine (making less sugars available for digestion and reducing postprandial hyperglycemia)

78
Q

why does miglitol only inhibit alpha glucosidase and not other amylases

A

the cytlitol group does not fit into the deep groove that forms the carbohydrate binding site of alpha amylase therefore
Miglitol does not bind and therefore does not inhibit α-amylase

need all four rings of acarbose to create high enough affinity

79
Q

what is the role of alpha amylase?

A

to break down the complex carbohydrates in the gut

80
Q

what is the role of alpha glucosidase?

A

Responsible for final digestion of dietary carbohydrates prior to their absorption.

to break down smaller polysaccharide units to monosaccharides for absorption in the intestinal lumen

81
Q

what is the difference in the functions between acarbose and miglitol/voglibose

A
  • Acarbose inhibits alpha-glucosidase (surface binding site) and alpha-amylase (pocket site)
  • Miglitol and voglibose only inhibit alpha-glucosidase
82
Q

what is membrane potential?

A

An electrical voltage (a charge differential with the potential to do work) across the cell membrane, due to the unequal distribution of ions, primarily the differences in sodium and potassium ion concentrations inside and outside the cell.

83
Q

what is depolarisation?

A

a decrease in the measured voltage potential between the inside and the outside of the cell, i.e., the cell cytoplasm becomes less negative than the resting potential.

84
Q

what are the two important factors for the creation of resting membrane potential?

A

(1) primarily due to the continuous action of the Na+/K+ ATPase pumps using the energy from the hydrolysis of ATP.

(2) The differences in sodium and potassium (and, to a lesser extent, chloride) concentrations inside and outside the cell create the resting membrane potential, approximately -70 mV.

85
Q

what’s the sodium concentration inside the cell at resting potential?

A

15mM

86
Q

what’s the sodium concentration outside the cell at resting potential?

A

150mM

87
Q

what’s the potassium concentration inside the cell at resting potential?

A

150mM

88
Q

what’s the potassium concentration outside the cell at resting potential?

A

5mM

89
Q

describe how glucose levels are detected and trigger insulin release

A
  1. Glucose is taken up by the cells via the Na+-glucose transporter GLUT2
  2. ATP is released from the breakdown of glucose via glycolysis and the mitochondrial TCA cycle.
  3. As this increases, the ATP/ADP ratio also increases resulting in ATP binding to the KATP.
  4. KATP is a channel complex consisting of 4 Kir6.2 subunits and 4 sulphonylurea receptors (SURs). Binding of ATP to the Kir6.2 shuts the channel.
  5. As a result the membrane potential progressively increases (depolarises from a resting potential of -70 mV).
  6. This results in the activation (opening) of voltage-dependent Ca2+-channels.
  7. Calcium ions enter the cell and stimulate the fusion of the insulin-containing secretory vesicles with the membrane thus releasing insulin
90
Q

what happens to ATP and ADP levels when glucose levels rise?

A

ATP goes up and ADP goes down

91
Q

describe the structure of the KATP channel

A

a tetrameric complex of 4 Kir6.2 and 4 SUR1

KATP = (Kir6.2)4 + (SUR1) 4

92
Q

what is the function of the SUR1 subunits in KATP?

A

(four) regulatory subunit .
ATPase activity at the nucleotide-binding domains of SUR results in an increase in KATP channel open probability

that binds SulfonylURea compounds.

Sulfonylureas reduce KATP channel activity by binding to the SUR subunits. They include glibenclamide, tolbutamide, acetohexamide, glipzide, and glimepiride.
Sulfonylureas (decrease KATP activity) compete with the action of Mg2+-ADP on the SUR

93
Q

whats the function of the Kir6.2 subunits in KATP?

A

Binding of ATP to the Kir6.2 shuts the channel.

94
Q

what role do Sulfonylureas have in the release of insulin?

A

Sulfonylureas reduce KATP channel activity by binding to the SUR subunits. They include glibenclamide, tolbutamide, acetohexamide, glipzide, and glimepiride.
Sulfonylureas (decrease KATP activity) compete with the action of Mg2+-ADP on the SUR

95
Q

where are SUR1 found in the body?

A

in pancreatic beta cells

96
Q

where are SUR2 found in the body?

A

in heart and skeletal muscle

97
Q

generally, open K+ channels keep electrically active cells ____

A

quiet

97
Q

generally, open K+ channels keep electrically active cells ____

A

quiet

ie when a K+ channel is open it is electrically quiet (ie the neuron is not signalling)

98
Q

what keeps the KATP channel open?

A

Mg2+-ADP binding on the SUR1 subunit

99
Q

KATP is open when…

A

ADP is bound to Nucleotide binding domains of transmembrane domain 1 and transmembrane domain 2

100
Q

mechanistically what occurs when ADP binds the nucleotide binding domains of KATP

A
  • This opens up a site for the lipid PIP2 to bind between TMD0 and the Kir6.2 channel
    to keep the potassium channel open
101
Q

what happens in the KATP channel after feeding?

A
  • After feeding, ADP levels drop so NBDs are free and ATP levels are high. The resulting conformational change results in the loss of the PIP2 binding site while ATP is able to bind to the Kir6.2 channel locking it in the closed state. This ultimately results in more insulin secretion.
102
Q

what happens in the KATP channel after feeding?

A
  • After feeding, ADP levels drop so NBDs are free and ATP levels are high. The resulting conformational change results in the loss of the PIP2 binding site while ATP is able to bind to the Kir6.2 channel locking it in the closed state. This ultimately results in more insulin secretion.
103
Q

how can GBC close the KATP channel?

A
  • GBC wedges itself between TMD0 and TMD1&2, blocking the PIP2 binding site and mimicking the ATP-bound closed state
104
Q

what/ why is SUR1 around the Kir6.2 channel?

A

regulation

ATP binds to the Kir6.2 channel and causes the channel to close. However it is the ratio of ATP:ADP that defines the state of the channel i.e., whether the channel is in the closed or open state.
This is because the nucleotide binding domains of the SUR bind ADP which results in channel opening.

105
Q

give an easy way to remember the KATP mechanism

A

TIK DOK
ATP inhibits KATP and ADP opens KATP

atp closes channel
adp opens channel

106
Q

what percentage of total insulin is secreted due to the incretin effect

A

50 - 70%

107
Q

if the same amount of glucose is injected or swallowed, why are the subsequent blood glucose levels/ insulin not equivelent?

A

If glucose is the only factor influencing the release of insulin then administration of the same amount of glucose orally or intravenously should be equivalent.
It’s not. 50 – 70 % of the total insulin secreted is due to the incretin effect.

108
Q

whats the differnce in the incretin effect between healthy patients vs type 2 diabetics?

A

type 2 diabetics have a reduced incretin effect
compared to healthy patients

(low insulin levels)

109
Q

what are incretins?

A

hormones that are secreted from the gastrointestinal tract into the circulation in response to nutrient ingestion that enhance glucose-stimulated insulin secretion.

110
Q

what two hormones account for the incretin effect in humans?

A

Gastric Inhibitory Peptide (GIP)
Glucagon-Like Peptide-1 (GLP-1)

111
Q

what is GIP?

derived from, synthesised by

A

Glucose-dependent Insulinotropic Peptide
GIP is derived from a 153-amino acid proprotein encoded by the GIP gene and circulates as a biologically active 42-amino acid peptide.
It is synthesized by K cells, which are found in the mucosa of the duodenum and the jejunum of the gastrointestinal tract.

112
Q

why was GIP originally named so?
what is it now?

A
  • Originally named gastric inhibitory peptide as it was believed to neutralise stomach acid and protect the small intestine from acid damage.
  • Physiologically this role is performed by the hormone secretin.
  • now named glucose dependent insulinotropic peptide
113
Q

what are the similarities and differences between GIP and GLP-1?

A

similarities - both stimulate insulin release from beta cells

differences
GLP-1 released from L cells in ileum and colon and
GIP is release from K cells in duodenum

GLP-1 has potent inhibition of gastric emptying and glucagon secretion
GIP has modest effects on gastric emptying but no significant inhibition of glucagon secretion

GLP-1 reduces food intake and body weight but GIP has no significant effects on food intake and body weight

GLP-1 has significant effects on beta cell growth and survival but GIP only has potential effects on this

GLP-1 insulinotropic action preseved in T2DM but GIP has defective insulinotropic action in T2DM

114
Q

what cells release GLP-1

A

released from L cells in ileum and colon

115
Q

what cells release GIP?

A

released from K cells in duodenum

116
Q

what effect does GLP-1 have on gastric emptying?

A

potent inhibition

117
Q

what effect does GLP-1 have on glucagon secretion?

A

potent inhibition

118
Q

what effect does GLP-1 have on food intake and body weight?

A

reduction of food intake and body weight

119
Q

what effect does GLP-1 have on beta cell growth and survival?

A

significant effects

120
Q

what effect does GIP have on gastric emptying?

A

modest effects

121
Q

what effect does GIP have on food intake and body weight

A

no significant effects

122
Q

what effect does GIP have on beta cell growth and survival?

A

potential effect

123
Q

how does GIP effect insulinotropic actions in T2DM?

A

defective insulinotropic action in T2DM

124
Q

what effect does GIP have on glucagon secretion?

A

no significant inhibition

125
Q

how does GLP-1 effect insulinotropic actions in T2DM?

A

insulinotropic action is preserved in T2DM

126
Q

how is GLP-1 made?

A

processing of pro glucagon in intestinal L cells

127
Q

what are PGDPs?

A

proglucagon derived peptides

glucagon, GLP-1, GLP-2, GRPP, IP-1, IP2

128
Q

what are the effects of GLP-1 in the body?

brain pancreas adipose tissue muscle liver stomach heart

A

brain: neuroprotective function and decreases appetite
pancreas: increase insulin secretion and biosynthesis, increase beta cell proliferation, decreases glucagon secretion and beta cell apoptosis
adipose tissue and muscle: increases glucose uptake and storage
stomach: decreases gastric emptying
liver: decreases glucose production
heart: increases cardioprotection and cardiac function

129
Q

what proteins are made from Proglucagon in the pancreas?

A

glucagon and major proglucagon fragment (MPGF)

130
Q

what PGDPs are made from froglucagon in the GI tract and the brain?

A

GLicentin
Oxyntomodulin
GLP-1
GLP-2
IP-2

131
Q

what protease is used to make GLP1 from proglucagon?

A

prohormone convertase 1

132
Q

how are different proteins made from proglucagon?

A

there are different proteases depending on location in the body

133
Q

what are the similarities between glucagon and GLP-1 structure and why?

A

On the N terminus glucagon is almost homologous to GLP-1

This is the location of the GPCR TM binding, it is where the peptide activates the receptor.
These proteins activate their receptors in a similar way

134
Q

what is the difference between GLP-1 and glucagon structure and why?

primary

A

the C terminus of glucagon and GLP-1 is very different

This is because this is the part that is recognised by the receptor and they bind to different (GPCR) receptors

135
Q

what type of receptor do glucagon and GLP-1 bind to ?

A

GPCRs

136
Q

what are the 6 classes of GPCRs?

A
  • Class A (or 1) (Rhodopsin-like)
  • Class B (or 2) (Secretin receptor family)
  • Class C (or 3) (Metabotropic glutamate/pheromone)
  • Class D (or 4) (Fungal mating pheromone receptors)
  • Class E (or 5) (Cyclic AMP receptors)
  • Class F (or 6) (Frizzled/Smoothened)
137
Q

what class of receptor does GLP-1 bind?

A

class B (or 2) secretin receptor family

138
Q

what are GPCRs?

A

GPCR are integral membrane proteins consisting of 7 TM helices with an extracellular N-terminus and a cytoplasmic C-terminus.
C terminal part as well as some of the loops interacts with the G protein (made up of alpha ceta and gamma)
The N terminus of the peptide will bind in the middle of the helices

139
Q

describe the activation/ signalling of GPCRs

A
  1. ligand binds to and actviated GEF activity of GPRC
  2. GPCR exchanges GTP for GDP on the G protein alpha subunit
  3. the activation G protein alpha subunit dissociates and is free to move into the cytoplasm and signal
140
Q

GPCRs are technically ___

A

GEFs

141
Q

describe the two domain model

A

Peptide ligands are believed to bind to class B receptors according to the “two-domain” model. First, the C-terminal part of the ligand binds the ECD of the receptor, followed by binding of the N-terminal part of the ligand to the transmembrane (7TM) receptor domain.

142
Q

the downstream signally effects of GPCRs depend on what?

A

which G protein types it couples to

(named by the alpha subunit they contain)

143
Q

where does GLP-1 bind in the GPCR?

A

ECD consists of mostly beta sheets and one alpha helix
a groove in the ECD provides a bidning site for the C terminal section of the GLP-1 helix

144
Q

whats the function of Gαs/Gαolf ?

A

activates plasma membrane adenylyl cyclases, increasing cellular cyclic AMP (cAMP), which e.g. stimulates phosphorylation of target proteins by cAMP-dependent protein kinase.

Gαs and its downstream signalling can be covalently activated by cholera toxin.

145
Q

whats the function of Gαi/Gαo

A

inhibit most adenylyl cyclases, decreasing cellular cAMP. Gαo is said to constitute 1% of brain proteins.

Gαi and Gαo can be covalently inactivated and their signalling turned off by Pertussis toxin.

146
Q

whats the function of Gαq/ Gα11 ?

A

activate phospholipase Cβ (PLCβ), which cleaves certain phosphoinositide lipids (PIP2) of the plasma membrane, and generates several second messengers that e.g. release Ca2+ from intracellular stores and activate phosphorylation by protein kinase C.

147
Q

whats the function of Gα12/ Gα13

A

enhance Rho kinase and change expression of some genes and the phosphorylation of myosin

148
Q

whats the function of Gαtransducin, Gαgustducin?

A

activates cyclic GMP (cGMP) phosphodiesterase (transducin) that cleaves and depletes cytoplasmic cGMP (retina only) or cAMP phosphodiesterase (gustducin) that cleaves and depletes cAMP (taste receptors)

149
Q

give some function of the Gβγ subunits

A

They activate G-protein coupled inwardly rectifying K+ (GIRK) channels.
They inhibit opening of voltage-gated Ca2+ channels of the Cav family.
They bind to the SNARE complex of the exocytotic machinery in synapses and reduce exocytosis of neurotransmitters.

(In neurobiology, the latter two signalling actions provide a major component of presynaptic inhibition by reducing Ca2+ entry and by blocking exocytosis of transmitter.)

In addition Gβγ dimers act directly on at least two more downstream effectors, stimulating PLC β and phosphoinositide 3-kinase γ (PI3Kγ).

150
Q

what two pathways can activate intracellular calcium stores?

A

PKA dependent mechanism
PKA independent mechanism

151
Q

describe the PKA dependent mechanism activating intracellular calcium stores

A
  • ER is a major intracellular calcium ion store
  • Binding of GLP to its receptor activates (GDP is replaced with GTP) the Gαs signalling pathway
  • Activated Gαs is released from the trimeric G-protein, binds and activated adenylyl cyclase – increasing cAMP level
  • cAMP activates the Protein Kinase A (PKA) which (1) phosphorylates KATP resulting in channel closure (causing depolarisation and voltage gated calcium channel opening ) and (2) phosphorylates IP3 receptors resulting in channel opening and calcium release from the ER
    (↑intracellular Ca2+)

  • Ca2+ ions cause secretory vesicles to fuse and release their contents
152
Q

describe the PKA independent pathway of activation of intracellular calcium stores

A
  • Binding of GLP to its receptor activates (GDP is replaced with GTP) the Gαs signalling pathway
  • Activated Gαs is released from the trimeric G-protein, binds and activated adenylyl cyclase – increasing cAMP level
  • cAMP binds Epac2 which activates ryanodine receptors resulting in channel opening releasing calcium from ER (↑intracellular Ca2+)

  • Ca2+ ions cause secretory vesicles to fuse and release their contents
153
Q

describe the PKA independent pathway of activation of intracellular calcium stores

A
  • Binding of GLP to its receptor activates (GDP is replaced with GTP) the Gαs signalling pathway
  • Activated Gαs is released from the trimeric G-protein, binds and activated adenylyl cyclase – increasing cAMP level
  • cAMP binds Epac2 which activates ryanodine receptors resulting in channel opening releasing calcium from ER (↑intracellular Ca2+)

  • Ca2+ ions cause secretory vesicles to fuse and release their contents
154
Q

What are the prolonged effects of GLP-1R activation?

A

Reduction in ER stress
Increased insulin biosynthesis
Increased beta cell proliferation and neogenesis
inhibition of apoptosis (of beta cells)

155
Q

What are the prolonged effects of GLP-1R activation?

A

Reduction in ER stress
Increased insulin biosynthesis
Increased beta cell proliferation and neogenesis
inhibition of apoptosis (of beta cells)

156
Q

what is the half life of GLP-1?

A

minutes

157
Q

what is Exenatide?

(Byetta)

A

a synthetic version of the exendin-4 peptide from the Glia monster. Exenatide bears a 50% amino acid homology to GLP-1 and it has a longer half-life in vivo. – binds to GLP1R but has prolonged effects

158
Q

why does Exanatide has prolonged effects compared to GLP-1

A

DPP4 cleaves off the last two peptides (alanine or proline) to breakdown the peptide GLP-1
in exenadin-4, one of its last amino acids is glycine which is not recognised by DPP4 so it can last in the body for a longer period of time

159
Q

what are the substrates of DPP4?

A

GLP-1
GIP
neuropeptide Y
eotaxin

160
Q

what is Taspoglutide?

(why was it taken off the market)

A

the 8-(2-methylalanine)-35-(2-methylalanine)-36-L-argininamide derivative of the amino acid sequence 7–36 of human glucagon-like peptide I.
As of September 2010, Roche had halted Phase III clinical trials due to a incidences of serious hypersensitivity reactions and gastrointestinal side effects

161
Q

what ways can we chemically modfiy GLP-1 to use pharmacologically?

A

artifical amino acid intervention
lipid linkage modification
sequence modificaiton

162
Q

what is semaglutide?

A

an incretin mimetic chemically similar to human GLP-1, with 94% similarity. The only differences are two amino acid substitutions at positions 8 and 34, where alanine and lysine are replaced by 2-aminoisobutyric acid and arginine, respectively.
Amino-acid substitution at position 8 prevents chemical breakdown by dipeptidyl peptidase-4. In addition, the lysine at position 26 is in its derivative form (acylated with stearic diacid).

163
Q

how does semaglutide work?

A

Semaglutide binds to, and activates, the GLP-1 (glucagon-like peptide-1) receptor to increase insulin secretion, suppress glucagon secretion, and slow gastric emptying
Semaglutide forms a series of aggregates that are concentration dependent with the highest concentrations forms branched tree-like aggregates.
Amino-acid substitution at position 8 prevents chemical breakdown by dipeptidyl peptidase-4. In addition, the lysine at position 26 is in its derivative form (acylated with stearic diacid).
The fatty acid moiety and the linking chemistry to GLP-1 were the key features to secure high albumin affinity and GLP-1 receptor potency.

164
Q

how does Semaglutide differ from Liraglutide?

A
165
Q

what diabetic drug has been named a wonder drug for weight loss?

A

semaglutide
because it slows gastric emptying

166
Q

what antibody therapy is there for diabetes?

A

Dulaglutide

167
Q

what are the components of Dulaglutide?

A

Fab domains of (IgG) antibody are replaced with 2 homologies of GLP-1(N terminal GLP-1 analog sequence) (90% amino acid homlog to human GLP-1)

Small peptide linker

Human IgG4 Fc regions

168
Q

why is the half life of GLP-1 so low?

A
  • After secretion, GLP-1 is rapidly metabolized by the enzyme DPP-4 (dipeptidyl peptidase-4) in the liver. The plasma half-life of GLP-1 is ~ 2 minutes
169
Q

what is DPP4?

A

DIpeptidyl peptidase -4
part of the serin protease family
exists as homodimeric and soluble forms
has a diverse range of substrates
plays a major role in glucose metabolism - responsibel for degredation of incretins

170
Q

give some examples fo the effects of DPP4 in the body?

A
  • DPP4 plays a major role in glucose metabolism. It is responsible for the degradation of incretins such as GLP-1.
  • Furthermore, it appears to work as a suppressor in the development of some cancers and tumours

also functions in restricting the inflammatory actions of the chemokine CCL11/eotaxin

171
Q

what possible effects could DPP4 inhibitors have?

A
  • Recent studies indicate that DPP4 inhibition may play a protective role in heart and kidney ischemia-reperfusion injury by antiapoptotic, immunological, and antioxidative changes.
  • DPP4 also functions in restricting the inflammatory actions of the chemokine CCL11/eotaxin, so that inhibiting DPP4 might unleash the recruitment of inflammatory cells.

DPP-IV inhibitors such as sitagliptin inhibit the breakdown of GLP-1 by DPP-4.

  • DPP-IV inhibitors will only produce an effect when blood sugar is elevated, causing the release of GLP-1 from the small intestine.
  • DPP-4 inhibitors do not inhibit gastic emptying, while GLP-1 agonist do. (weight neutral in clinical trials)
  • DPP-4 inhibitors have been observed to increase satiety, decreased food intake.
172
Q

how could DPP4 inhibitors potentiate the incretin effect?

A

DPP4 inhibitors block incretin degredation
so incretins can remain actin to stimulate insulin secretion

173
Q

what are Gliptins?

A
  • Standard small molecular inhibitors.
  • First generation inhibitors were directed against the DPP family.
  • DPP8 & 9 are intracellular – adverse side effects observed in animal models but none in human clinical trials (chemistry v pharmacology).
  • Second generation focused on generating DPP4 specific drugs.
174
Q

give some examples of gliptins for diabetes

A
  • Saxagliptin (OnglyzaTM) and sitagliptin (Januvia®) are DPP4 inhibitors approved in the United States as adjuncts to diet and exercise to improve glycemic control
  • Vildagliptin (Galvus®) is also commercially available but only outside the United States.
175
Q

why were PPAR agonists taken off the market?

A

PPAR agonist were good however had side effects and caused a lot of

176
Q

what are the two forms of intestinal alpha glucosidase?

A

Human maltase-glucoamylase (MGAM) and sucrase-isomaltase (SI)

177
Q

how does acarbose inhibit alpha glucosidase

A

Made of three sugars, in one the oxygen is replaced with nitrogen which stops the catalytic mechanism of alpha glucosidase so its no longer functional
The unsaturated cyclitol component of the molecule has been identified as essential for a-glucosidase inhibitory activity.

Acarbose binds reversibly, competitively and in a dose-dependent manner to the oligosaccharide binding site of a-glucosidase enzymes in the brush border of the small intestinal mucosa. As a consequence, hydrolysis is prevented

178
Q

what is voglibose?

A

is an alpha-glucosidase inhibitor used for lowering postprandial blood glucose levels in people with diabetes mellitus.

179
Q

inaddition to inhibting enzymes what other way can voglibose affect diabetes?

A

Valigobose may also facilitate mobilisotary α endogenous glycogen -like peptide 1 (GLP-1), which has an inhibitory action on glycogen, thus lowering fasting glucose levels too. Voglibose treatment has resulted in an increased release of GLP-1, which is an insulinotrupic hormone and it has also increased release of GLP-1, which is known to enhance insulin secretion and insulin sensitivity

180
Q

compare the effects of glucosidase inhibitors on the release of insulin?

A

Arakawa et al. report that
miglitol affects postprandial GLP-1 secretion more strongly than
acarbose in patients with visceral obesity, and several reports
suggest that miglitol increases GLP-1 and decreases GIP to
greater extents than voglibose after a single or long-term
administration in type 2 diabetes

Molecular & structural basis of disease (6 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions