Diabetes Flashcards
(115 cards)
1
Q
What is metabolic syndrome?
A
a name for the group of risk factors that occur together and increase the risk for coronary artery disease, stroke and type 2 diabetes.
2
Q
What are the two most important risk factors for metabolic syndrome?
A
extra weight around the middle or upper parts of the body- obesity, and insulin resistance.
other factors can include aging, genes that make you more likely to develop this condition, hormaone changes and lack of exersise.
3
Q
what are the 3 main classifications of diabetes?
A
type 1- absolute insulin deficiency
type 2- insulin resistance
gestational - which women without previously diagnosed diabetes exhibit high blood glucose levels during pregnancy
4
Q
What hormones regulate blood sugar levels?
A
Insulin and glucagon.
insluin lowers and glucagon raises
5
Q
what is hypo and hyperglycaemia and what can they lead to?
A
Hypoglycemia – prolonged low blood sugar levels can result in coma and death.
- Hyperglycemia – recurrent infections, cardiac arrhythmia, stupor, coma, seizures, ketoacidosis, death.
6
Q
where is insulin and glucagon produced?
A
insluin is produced in the beta cells of the pancreas
glucagon is produced in the alpha cells of the pancreas.
7
Q
what type of organ is the pancreas?
A
its an endocrine and exocrine organ.
8
Q
What is the exocrine function of the pancreas?
A
The exocrine function of the pancreas is to secrete digestive enzymes, ions and water into the duodenum of the gastrointestinal tract.
9
Q
Which part of the gastrointestinal tract does the pancreas secrete digestive enzymes into?
A
The pancreas secretes digestive enzymes into the duodenum.
10
Q
What are the essential components of digestive enzymes that are secreted by the pancreas?
A
The essential components of digestive enzymes are trypsin, chymotrypsin, pancreatic lipase, and amylase.
11
Q
Which cells in the pancreas produce digestive enzymes?
A
The acini cells in the pancreas produce digestive enzymes.
12
Q
What is the endocrine function of the pancreas?
A
The endocrine function of the pancreas is to create and release important hormones directly into the bloodstream.
13
Q
What are the two main hormones secreted by the endocrine pancreas?
A
The two main hormones secreted by the endocrine pancreas are insulin and glucagon.
14
Q
What is the role of insulin and glucagon in the body?
A
Insulin lowers blood sugar, while glucagon raises blood sugar.
15
Q
Which cells in the pancreas produce insulin and glucagon?
A
Pancreatic Beta-cells produce insulin, while pancreatic Alpha-cells produce glucagon.
16
Q
where are the hormone-producing cells of the pancreas found?
A
islet of langerhans
17
Q
what are the major cells of the islet of langerhans?
A
beta cells
alpha cells
PP- cells (secrete pancreatic polypeptide)
delta cells (known to secrete somatostatin, and vasoactive intestinal peptide.)
18
Q
what is pancreatic polypeptide>
A
regulates pancreatic secretion activities, and also impacts liver glycogen storage and gastrointestinal secretion
19
Q
What changes occur with insulin binding?
A
increase in glucose transporters bringning more glucose into the cells.
puts glucose into storage as glycogen or broken down into pyruvate, or put into fatty acids and then adipose tissue.
20
Q
How is insulin made?
A
the insulin gene is transcribed and translated
- the signal recognition particle recognises signal sequence and brings it to a translocon
- the translocon inserts the signal sequence into the membrane
- then the rest of the protein can be made through the translocon and sent into the ER lumen (forced into the ER lumen as it is being made)
- then the signal sequence is cleaved off
- now left with a soluble protein
- this goes through the golgi and into the secretory vesicles
- here protease cleavage releases the C peptide
- carboxypeptidase produces mature insuin
- final packaging as a zinc bound hexamer
21
Q
What is insulin composed of?
A
Insulin is a peptide hormone composed of two polypeptide chains, an A chain and a B chain, connected by disulfide bonds.
22
Q
What is the first step in the synthesis of insulin?
A
The first step in the synthesis of insulin is the transcription and translation of the insulin gene, which produces a precursor protein called preproinsulin.
23
Q
What is the role of the hydrophobic signal sequence in insulin synthesis?
A
The hydrophobic signal sequence directs preproinsulin to the endoplasmic reticulum (ER), where it is translocated into the ER lumen via a translocon.
24
Q
What happens to the signal sequence once preproinsulin is in the ER lumen?
A
The signal sequence is cleaved off, and the rest of the protein is folded into its native conformation.
25
Where does insulin undergo post-translational modifications?
Insulin undergoes post-translational modifications in the Golgi apparatus, such as glycosylation and proteolytic cleavage.
26
What sorts insulin into secretory vesicles?
The Golgi apparatus sorts insulin into secretory vesicles, which have an acidic environment that promotes the precipitation of insulin.
27
How is insulin stored in secretory vesicles?
Insulin is stored in secretory vesicles as a zinc-bound hexamer, which slows down its release.
28
What happens to insulin when it is released into the bloodstream?
The low pH of the extracellular environment causes insulin to precipitate into the monomeric form, which is then activated by proteolytic cleavage.
29
When was the 3-dimensional structure of insulin first solved?
The 3-dimensional structure of insulin was first solved 50 years ago in 1969.
30
what is the monomeric strucutre of insulin?
Insulin's monomeric structure consists of two polypeptide chains, an A chain and a B chain, which are held together by disulfide bridges. The A chain has two alpha helices, while the B chain has an alpha helix and a beta sheet.
31
What is the significance of the glycine residue in insulin?
The glycine residue in insulin is located at the junction between the A and B chains, and is known as a helix breaker. This is because glycine has a small side chain, which makes it energetically favorable for the helix to break at this point.
32
What are the two main conformations of insulin?
Insulin can exist in two main conformations, the T state and the R state. The T state is the low-affinity conformation, while the R state is the high-affinity conformation.
33
What is the significance of the conformational changes in insulin?
The conformational changes in insulin are important for its function as a hormone. These changes are primarily driven by the movement of the glycine residue, which allows insulin to adopt different conformations and interact with its receptor.
34
Where does dimerisation of insulin occur?
between the beta sheet are antiparallel.
35
Why must insulin be injected?
its a protein so if was swallowed would be broken down so its injected subcutaneously.
36
What are the three states of insulin hexamers?
T6, T3R3, R6.
37
What is the structural difference between the three insulin hexamer states?
The first N-terminal 8 residues of the B chain.
38
What is the structure that the T state of insulin adopts?
An elongated structure.
39
What does the R state of insulin form?
An alpha helix.
40
How are R6 crystals formed in insulin?
In the presence of phenol, which is used in insulin preparation as an antibacterial agent.
41
What type of insulin preparations dissolve slowly?
Prolonged-acting insulin preparations, which can be amorphous or crystalline.
42
How can rapid-acting insulin preparations be achieved?
By introducing mutations at the dimer interface, such as B28
43
What role does the intrinsic flexibility at the ends of the B chain play in insulin stability?
It plays an important role in governing the physical and chemical stability of insulin.
44
What type of protein is hexameric insulin?
It is an allosteric protein that undergoes ligand-mediated interconversion among three global conformation states designated T6, T3R3, and R6.
45
What is the order of insulin subunit stability within each hexamer for the three allosteric states?
R6 > T3R3 >T6.
46
What are protamines and how are they related to insulin release?
Protamines come from salmon sperm and are proteins that protect DNA but also slow down the release of insulin by holding hexamers together.
47
what are some additions to insulin preparations?
Protamine, a protein extracted from the nucleus of fish sperm, where its role is to stabilise DNA. In the insulin crystal, protamine regulates interactions between dimers and hexamers.
2. Phenol or metacresol are added as preservatives.
3. Zinc chloride. Hexamers, made stable by zinc ions, are the predominant quaternary structure of pharmacological insulin
48
what are 3 categories of insulin drugs?
Fast-acting insulin analogues
2. Long acting insulin analogues
3. Very long acting insulin analogues
49
why are combinations of differnt speed acting insulins used?
We use combinations to try to mimic the body, long acting are trying to maintain glucose levels over a long time, fast acting ones are when there are large spikes
50
what are some examples of rapid acting insulin drugs?
All three of these Shift the equilibrium from the storage form to the monomeric form
Lispro (Humalog) ProB28 ➔ Lys Impairs dimerization, doesn’t stop just shift toward monomer
Eli Lilly and Co. LysB29 ➔ Pro
Aspart (NovoLog) ProB28 ➔ Asp Charge repulsion at dimer interface, eg breaking down to monomer
Glulisine (Apidra) AsnB3 ➔ Lys Decreased zinc-free self-association, more likely to break down to dimers Sanofi-Aventis LysB29 ➔ Glu and monomers
51
How are long term acting insulin drugs made? give examples
shifts equlibrium to the heameric storage form by stabilizing monomers or stablising oligomeric state.
Glargine (Lantus) ArgB31-ArgB32 tag Shift in pI to pH 7 leads to isoelectric
Sanofi-Aventis & AsnA21 ➔ Gly precipitation on injection
Detemir (Levemir) Modification of LysB29 Stabilization of hexamer and binding
Novo-Nordisk by a tethered fatty acid to serum albumin
52
how does insulin get to its active form then to storage form as hexamer?
proteases PC2 and PC1/3 cleave and release peptide C and then carboxylpeptidase (CpE) produces mature insulin. two zinc ions enter secretory vesicle by Znt8 and then package as a hexamer.
53
Why is the C chain needed in insluin formation?
needed to allow the correct disulphide bridges to be formed. without it the reformed bridges would be in the wrong places
54
How do ion channels regulate insulin release?
Glucose is taken up by Beta cells by GLUT2
glucose broken down and used to make ATP by mitocondondria
ATP/ADP ratio chages which inhibits KATP channel causing its depolarisation
voltage dependent Ca2+ channels recognise the deoplarisation and cause Ca2+ influx
influx of Ca2+ causes secreteory vesicles of insulin to be released
55
what is the KATP channel made of?
it consits of 4 Kir6.2 subunits and 4 sulphonoyurea receptors (SURs) and binding of ATP to the Kir6.2 shuts the channel.
56
Where are SUR1 and SUR2 (sulphonylurea receptors)
SUR1 present iin the pancreatic beta cells
SUR2 present in the heart and skeletal muscle
57
ATP binding closes KATP while ADP binding opens KATP.
this is for the KATP channel
58
What does the Pi (iosoelectric point) mean if its close to the that off the buffer?
When the Pi is close to the buffers Pi it will preipitate
59
Why when developing insulin for treatment do we change the equlibirum of its qauternary strucutre?
the monomeric strucutre is the active form and its stored form is as hexamers so by moving to either side can change the speed of its activation
60
what are alpha glucosidases ultimately broken down into?
monosaccahrides
61
at the intentional brush boarder what stops movement of glucose between cells?
Tight junctions.
62
how does glucose move from the intestional lumen into the blood>
Glucose goes throgh the SGLT1 transporter over conc gradient under Na co transport
at the basolateral membrane there are GLUT2 and NA/K ATPases that maintain this conc.
63
at the intestinal brush boarder what transports fructose across the membrane?
GLUT5
64
What tethers alpha glucosidase to the intestional brush boarder membrane?
a transmembrane helix
65
What is the alpha glucosidase responsible for?
the final digestion of dietary carbohydrates prior to their absorption.
66
what are alpha glucosidase responsible for?
final digestion of dietary carbohydrates prior to thier absorbstption
67
what are the two forms of intestinal alpha glucosidase:
human maltase-glucoamylase (MGAM) and sucrase-isomaltase (SI)
they each have two catalytic domains
68
What can inhibit the alpha glucoside?
Acarbose competitively reversibly inhibits.
69
What is the overall effect of acarbose?
leads to a reduction in production and absorption of monosaccharides in the small intestine.
70
in paitents with diabetes what does Acarbose do?
leads to a decrease in postprandial hyperglycaemia.
ends up in the colon and if lots of flucose then will feed bacteria and cause CO2 production - flatulence
71
What is Miglitol?
a inhibitor of alpha glucosidases and is absorbed, metabolised and excreted by the kidneys unlike acarbose that goes to the colon
72
what is Voglibose?
an alpha glucosidase inhibitor that competively inhibits
73
what is the role of alpha amylase?
to break down complex carbohydrates in the gut.
74
the the KATP channel what can the lipid PIP2 do?
can keep the channel in the open conformation.
75
what do Glibenclamides (GBC) do to the KATP channel?
is a sulfonylurea that binds in a diff location from that to PIP2 and ATP binding sites, located between TMD 1 and 2 and TM0 of the SUR1. When bound it displaces PIP2 and locks the channel in the closed conformation.
76
in pancreatic alpha amylase where where does acarbose bind and how does it do it
binds in a lilttle cup/cradle and needs all four rings of acarbose to create high enough affinity to bind to pancreatic amylase.
77
what is the incretin effect?
The incretin effect is defined as the increased stimulation of insulin secretion elicited by oral as compared with intravenous administration of glucose under similar plasma glucose levels. (in t2 diabeties see a dampened incretin effect)
78
what are incretins and what are the two hormones that account for the incretin effect in humans?
Incretins are hormones that are secreted from the gastrointestinal tract into the circulation in response to nutrient ingestion that enhance glucose-stimulated insulin secretion.
Gastric Inhibitory Peptide (GIP)
and
Glucagon-Like Peptide 1 (GLP-1)
79
What is GIP (Gastric inhibitory 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.
80
GLP-1 and GIP are inolved in the Incretin effect what occurs to their insulintropic action in T2 diabeties?
only GLP-1 has its insulintropic effect perserved.
81
where and what are GLP-1 and Glucagon derived from?
both derived from a proglucagon in the intestinal L cells.
82
what is the structure of glucagon?
it is a simple alpha helix.
83
there are big differences between the N and C terminus of glucagon why is this?
the N terminus is similar becasue this is what activate the receptor and the c terminus is different because this is what is recognised by the receptor. (bind to different GPCR)
84
how many classes of GPCR are there?
6
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)
85
what are GPCR?
they ar eintegral membrane proteins that consist of 7 TM helices with an extracellular N terminus and cytoplasmic C terminus.
C terminal part as well as some of the loops interacts with the G protein (made up of alpha beta and gamma)
The N terminus of the peptide will bind in the middle of the helices
86
How do GPCRs work as GEFs
can have two forms. when has GTP bound allows them to bind to different proteins to lead to a signalling pathway and have a biological effect. take GTPases from their off GDP form to ON GTP form to cause the signalling
87
where are the incretin hormoes secreted from?
the gastroinstestinal tract into the circulation in respose to nutrient ingestion
88
What cells are GIP produced by?
K cells found in the mucosa of the duodenum and jejunum of the GI tract
89
why does GLP-1 reduced appetite?
can reduce gastric emptying so food occupies the stomach for longer and can also cause the brain to reduce signals of appetite.
90
What is the G alpha s (Gαs) signalling pathway do?
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.
91
What are the two pathways that intracellular calcium stores can be activated to further increase insulin secretion?
PKA dependednt and PKA independent mecahnisism.
PKA dependent:
- GLP1 binds to its receptor, kicks in GEF function and binds to Adenylyl cyclase who converts ATP to cAMP.
increased cAMP activates PKA leading to release of Ca2+ from the ER at IP3R channels.
PKA independent:
cAMP binds to Epac2 that casues release of Ca2+ from RyR channels on ER.
92
Describe the steps involved in activating intracellular calcium stores
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 and (2) phosphorylates IP3 receptors resulting in channel opening (↑intracellular Ca2+)
* cAMP binds Epac2 which activates ryanodine receptors resulting in channel opening (↑intracellular Ca2+)
* Ca2+ ions cause secretory vesicles to fuse and release their contents
93
What are some of the effects of prolonged GLP-1R activation?
decrease ER stress. (reduces missfoldings)
Increase in beta cells proliferation adn neogenesis
inhibiton of apoptosis
94
What is Semaglutide?
Semaglutide is 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).
95
Why is the half life of GLP-1 so low?
it N terminus gets celaved by DDP4 (dipiptidyl peptidase 4)
rapidly degraded within a few minuties
96
What are gliptins and give examples
Gliptins are DPP4 inhibitors used to potentiate the incretin effect by preventing the degredation of GLP-1
examples are:
Saxagliptin
Sitagliptin
Vildagliptin
97
Where can SGLT2 be found and what role does it have in glucose reabsorption?
it is fond in the proximal tubule of the nephron and it is where 90% of glucose reabsorption occurs, its a high capacity low affinity channel
98
Where is SGLT1 found and whats it role in glucose reabsorption?
it is found in the distal end of the proximal tubule and is where the last 10% of reabsorption occurs. its a low capacity high affinity channel.
99
what have epidemiological and nutritional studies shown that excessive consumption of fructose can be linked with?
metabolic abnormalitis including dyslipidemia, diabeites, and CV diseases
100
Where can we find SGLT1 and SGLT2?
SGLT1 is found mostly in the small intestine, and some in the kidney and heart
SGLT2 is found almost exclusively in the kidneys
101
What is Dapaglifozin?
a selective SGLT2 inhibitor.
102
what are some advantages of SGLT2 inhibition in the kidneys?
- glucose ic cleared from circulation without hte need for insulin lowring pancreatic B cell demand
-glucose excretion decreases as blood clucose levels decrease therby limiting risk of hypoglycemia
- urinary glucose excretion (UGE) may lower blood pressure and lead to weight loss
- novel mechanisim is compatible with other glucose lowering therapies
103
why can SGLT2 inhibition lead to increased risk of UTIs?
Glucose entering the urinary system and can feed bacteria leading to infection
104
what side effects to the blood occur with SGLT2 inhibition?
blood becomes thicker due to increased haematocrit hence use of blood thinners required alongside inhibition.
also blood pressure can decrease
105
How does Metformin work?
decreases liver glycogenolysis and gluconeogeneisis and increaes glucose uptake in muscle.
106
Metformin can inhibit a mitochondiral glycerophosphase dehydrogenase (mGPD). what does this do in its mechanisim?
inhibiton leads to a deceleration of the DHAP - G3P shuttle leading to an increase in the G3P to DHAP ratio and NADH to NAD ratio and lactate to pyruvate ratio.
this decreases glucose formation and export. (reductions of gluconeogenesis)
107
What is Amylin?
amylin or islet amyloid polypeptide (IAPP) is a 37 residue peptide hormone that is co secreted with insulin from the Beta cells. (1:100) so a lot less amylin.
plays a role in glycemic regulation by slowing gastric emptying and promoting satiety.
108
Amylin stimulates the accumulation of cAMP via what receptor?
calcitonin/RAMP receptor.
RAMP transports the calcitonin receptor to the plasma membrane.
109
what is the glucose sensitive part of the brain stem?
area postrema
110
amylin and insulin are secreted together and act together in what way?
Insulin controls glucose levels
amylin is to control food intake.
111
What are some of the issues with Amylin?
can cause pancreatic amyloid plaques to be formed in over 95% of T2 diabeites paitents.
abundance of the plaque correlates with the severity of the disease. can ultimately lead to cell death.
112
what is the structure of Amylin fibrils that lead to plaque formation?
cross beta sheet architecture where the strands run perpendicular to the fibril long axis with the inter-strand hydrogen bonds orientated parallel to the long axis.
113
what is Pramlintide (proline amylin peptide) designed for?
it resembles the hormone amylin and was designed to avoid fibril formation.
the residues that cause amyloid formation were replaced with prolines.
114
what is the most frequent and severe sideaffect of pramlintide (proline amylin peptide)
the area postrema detects toxins in the blood and acts as a vomit inducing centre.
so the most common side affect is nausea and can generally occur at the start of treatment but gradually reduces
115
what does it mean when a drug is PEGylated?
the process of both covalent and non-covalent attachment or amalgamation of polyethylene glycol (PEG, in pharmacy called macrogol) polymer chains to molecules and macrostructures, such as a drug, therapeutic protein or vesicle, which is then described as PEGylated
can slows down. a drugs coalescence and degradation as well as elimination in vivo
