Week 1 Flashcards
(167 cards)
1
Q
How can insulin resistance cause hypertension
A
Insulin resistance increases sodium retention hence water = increase in blood volume
Activates the sympathetic nervous system = increased vasoconstriction
2
Q
How can insulin resistance cause atherosclerosis
A
Insulin resistance decreases lipoprotein lipase activity so clearance of VLDL decreases
Increase in VLDL = increase in LDL
3
Q
How can insulin resistance cause steatosis -> steatohepatitis -> cirrhosis
A
Insulin inhibits lipolysis which breaks down fatty acids
= increased fatty acid level in blood
= more fatty acids to liver (steatosis)
fatty liver triggers inflammation -> steatohepatitis
Fibrosis due to chronic inflammation -> cirrhosis
4
Q
Describe the likely insulin level and blood sugar level in early type 2 diabetic patients
A
High insulin
High blood glucose level
5
Q
Why is there high insulin level and high blood sugar level initially in type 2 diabetic patients
A
Insulin resistance; cells in the body does not respond to insulin but beta cells are still producing insulin. This causes beta cells to produce more insulin to try decrease blood glucose level
6
Q
Which hormone stimulates lipolysis
A
Glucagon
7
Q
Which cluster of cells in the pancreas regulate blood sugar level
A
Islet of Langerhans
8
Q
Which cell in the pancreas secretes insulin
A
Beta cells of islets of Langerhans
9
Q
Which cell in the pancreas secretes glucagon
A
Alpha cells of islets of Langerhans
10
Q
Effect of insulin
A
Inhibit hepatic glucose production
Inhibit lipolysis
Stimulate glucose uptake in cells
Stimulate storage of glucose as glycogen in cells
= lowers blood sugar level back to normal
11
Q
Effects of glucagon
A
Stimulate hepatic glucose production
Stimulate Lipolysis
= increases blood sugar level back to normal
12
Q
In mM, what is the fasting blood sugar level considered as diabetes
A
above 7mM
13
Q
In mM what is the fasting blood sugar level considered as pre-diabetes
A
6-7mM
14
Q
Why is it important to recognize pre-diabetics
A
Because they have very high risk of developing into diabetes hence we should start prevention treatment asap
15
Q
What is the likely insulin level and blood sugar level in type 1 diabetics
A
low insulin and high glucose level
16
Q
When can insulin become poisonous
A
When injected to a normal healthy person.
It can cause hypoglycaemic coma
17
Q
What are the cells of islets of Langerhans
A
Beta cells
Alpha cells
Delta cells
PP cells
18
Q
What is the function of delta and PP cells
A
Regulatory cells; they regulate beta and alpha cells
19
Q
What blood glucose level is considered as hypoglycaemia and what is at risk
A
<4mM
Hypoglycaemia coma
20
Q
What hormone does delta cells produce and what is its function
A
Somatostatin
Inhibit release of pancreatic enzymes, hormones (insulin, glucagon)
Inhibit release of gastrin and secretin (when acted on the gut)
Decrease motility of the gut
21
Q
How is insulin formed in beta cells
A
Synthesized in RER as larger chain of polypeptide preprohormone -> cleaved -> proinsulin -> cleaved -> insulin
22
Q
Which chain is cleaved in proinsulin to form active insulin
A
C chain
23
Q
What peptide chains are in proinsulin
A
A, B, C chains
24
Q
What peptide chain is used to measure insulin secretion
A
C peptide chain
25
In relation to the peptide chains of insulin, what data would suggest that the insulin was injected
Cannot detect C peptide chain but can detect insulin
Endogenous insulin came from cleavage of C chain from proinsulin hence C chain must be present if the insulin was made by the body
26
Example of an ultra fast acting synthetic insulin
Lispro
27
Mechanism of lispro
Swaps lysine and proline amino acids in B chain of active insulin to make it faster acting
28
Short action of Lispro means that
Lispro cannot be administered on its own. Needs to be administered with another longer acting insulin
29
Example of a ultra long acting synthetic insulin
Glargine
30
Mechanism of Glargine
Adds 2 argine amino acids at the end of B chain to cause prolonged action
31
When is Lispro usually injected
Within 15 minutes of beginning a meal
32
When is Glargine usually injected
Single bedtime dose
33
Which intracellular enzyme phosphorylates glucose
Glucokinase
34
Which transporter allows glucose to move into beta cell
GLUT2
35
What happens once the glucose enters the beta cell
1) Glucose enters cell through GLUT2
2) Glucose phosphorylated into glucose 6 phosphate by glucokinase
3) glucose 6 phosphate used to produce ATP
36
How is insulin secreted
1) Because presence of ATP closes ATP sensitive K+ channels which stops K+ from leaving the cell
2) Causes cell to become hyperpolarised
3) Activates voltage gated Ca2+ channels
4) Ca2+ move into cell
5) Presence of Ca2+ stimulate release of insulin
37
What happens to beta cells in type 1 diabetes compared to type 2
In type 1, most beta cells are lost
In type 2, beta cells are present but lose their ability to sense changes in blood glucose level
38
How do beta cells lose their sensitivity to blood glucose level in type 2 diabetics
Hyperglycaemia causes blood glucose level to be outside the Km of glucokinase
Outside Km, change in glucose level only leads to small change in activity of glucokinase
= reduced sensitivity
39
What does a definitive diagnosis of Type 1 diabetes require
Presence of specific autoantibodies
Declining C peptide production (=less insulin produced)
40
What happens to beta cells in type 2 diabetics over a period of time
Beta cell mass decreases
Reduction in insulin secretion (secretory failure)
41
Why do beta cells lose their function at late stages of diabetes
Mitochondrial exhaustion
Run out of insulin stores
42
What is gestational diabetes
Diabetes diagnosed for the first time during pregnancy (24-28 weeks)
43
Why is the diagnostic criteria for gestational diabetes lower than other forms of diabetes
Because gestational diabetes comes with significant risk of increased weight of offspring at birth = can be dangerous for the mother and baby during delivery
44
What is the criteria for gestational diabetes
Fasting blood sugar level >5.6
2 hour glucose > 7.8
45
What is the fasting blood glucose criteria for diabetes
Fasting blood sugar level >7
46
What is the 2hr oral glucose tolerance test criteria for diabetes
>11.1
47
What is overt diabetes
Pregnant woman diagnosed with diabetes for the first time at the first antenatal visit (early pregnancy
48
What is the criteria does overt diabetes
Same as other forms of diabetes (not gestational).
>7 FBG
>11.1 2hr OGTT
49
What is the threshold of diabetes based on
The risk of developing retinopathy
50
What is type 1 diabetes
Autoimmune destruction of beta cells resulting in beta cell deficiency
51
What is type 2 diabetes
Insulin resistance + relative insulin deficiency progressing to insulin secretory defect + insulin resistance
52
Risk factors of type 2 diabetes
Obesity
Poor dietary habits
PCOS
Family history
History of gestational / overt diabetes
53
What occurs in skeletal muscle when insulin binds
1) Insulin binds to INSR (insulin's receptor)
2) Stimulates downstream phosphorylation
3) GLUT4 then moves from the cytoplasm up to the cell membrane
4) Enables glucose uptake
5) Glucose phosphorylated by glucokinase into glucose 6 phosphate
6) glucose 6 phosphate can then be used to generate ATP / stored as glycogen
54
What occurs in skeletal muscles in insulin resistance
1) Decreased activity of INSR hence decreased downstream phosphorylation
2) Less GLTU4 transported to cell membrane
3) decreased glucose uptake
55
Mechanism of obesity induced inflammation
1) Obesity triggers JNK and NF alpha B inflammatory cytokines
2) JNK triggers phosphorylation of Ser IRS1
3) this inhibits phosphorylation of Tyr IRS1 which is used to signal insulin
4) JNK and NF alpha B also initiates gene expression of pro inflammatory cytokines
5) pro inflammatory cytokines travel by blood to cause systemic effects
56
What are the sub units of ATP induced K+ channels in beta cells
Kir6
SUR1 (sulphonylurea receptor)
57
Function of ATP sensitive K+ channels
K+ channels are closed to hyperpolarise the beta cell in order to activate the voltage gated Ca2+ channels -> release insulin
58
What conditions are caused by mutations in ATP sensitive K+ channels
Neonatal diabetes
Congenital hyperinsulinism
59
Which drug can allow neonatal diabetics to recover euglycaemia quickly and why
Sulphonylurea because the SUR1 subunit still responds to binding of Sulphonylurea
60
Which drug can inhibit insulin secretion in congenital hyperinsulinism
diazoxide
61
Diabetic ketoacidosis is most commonly seen in which type of diabetes
Type 1
62
How does diabetic ketoacidosis occur
1) Not enough insulin so not enough glucose being transported into cells
2) causes hypergylcaemia
3) Causes the body to use fatty acid oxidation for fuel which produces ketones
4) level of ketones build up and cause acidosis
5) Hyperglycaemia causes osmotic diuresis (increased urination) and hypovolaemia
6) hypovolamia exacerbates acidosis
7) causing severe electrolyte derangement, coma, possibly death
63
Risk factors for diabetic ketoacidosis
Type 1 diabetes
Non-compliance to drugs
Infection
Inappropriate drug dose
64
Symptoms of diabetic ketoacidosis
Polydipsia (extreme thirst)
Polyuria
Hypotension
Ketotic breath (acidic)
Vomiting
Confusion
Kussmaul breathing
65
Management for diabetic ketoacidosis
Fluid resuscitation
Insulin
66
Symptoms of diabetes
Blurred vision
Polyuria
Polydipsia
Fatigue
Weight loss
67
What are the severe conditions diabetes can lead to
Diabetic ketoacidosis
Hyperosmolar hyperglycaemic state
68
What is hyperosmolar hyperglycaemic state
Prolonged elevated blood sugar level making you dehydrated and hyperosmolar (blood has high concentration of glucose)
69
What conditions are at increased risk due to hyperglycaemia, dyslipidaemia and high blood pressure
Myocardial infarction
Atherosclerosis (accelerated)
Acute coronary syndrome
Peripheral vascular disease
70
What is HbA1c
Glycated haemoglobin
Haemoglobin becomes glycated when exposed to glucose so the level of glucose is proportional to the level of glycated haemoglobin
71
What does HbA1c measure
measure of glucose exposure over the last 90 days (haemoglobin survives for 90 days)
72
What conditions may cause HbA1c to be inaccurate
Increased or decreased red blood cell turnover
Haemolytic anaemia
73
Mechanism of metformin
1) binds to complex 1 of resp chain
2) causes reduction in respiration hence fall in ATP
74
What are the consequences of fall in ATP due to metformin
Rise in AMP
Activation of AMP kinase
Rise in ADP/ATP ratio
Reduction in gluconeogenesis (probably due to rise in AMP)
75
Site of action of metformin
Mainly cells in intestines, liver and kidney
76
Why isn't metformin transported into all cells
Because it is highly hydrophilic so it will only enter certain cells that have transporters of metformin
77
Is metformin metabolized
No, it is excreted in its unchanged form in the urine
78
Effects of metformin
Lowers hepatic glucose production (gluconeogenesis)
Enhances uptake of glucose in adipose and skeletal muscle tissues
Enhances glucose uptake and utilization in the gut
Increase GLP-1 secretion
Alters gut microbiome
Decrease lipogenesis
79
What type of hormones is GLP-1
Incretin hormone
80
Overall effect of metformin
Lowers glucose production and increases glucose utilization
Acts like insulin
81
Does metformin affect weight
Can be weight neutral / weight losing
82
Side effects of metformin
GI intolerance
- Diarrhea / bloating / dyspepsia / abdominal pain / metallic taste in mouth
Metformin associated lactic acidosis
83
Why may metformin cause GI side effects
Because it is highly concentrated in enterocytes hence can be toxic and cause side effects
84
What should you do if the patient cannot tolerate metformin
Use modified form of metformin which releases metformin more slowly and distributes throughout the gut
85
What should you do to prevent the side effects of metformin when the patient first started it
Initiate slowly ; use lower dose then increase slowly over time
86
What increases the risk of Metformin associated lactic acidosis
Patient has acute kidney injury / poor renal function
87
Which condition causes acute kidney injury
Sepsis
88
Mechanism of metformin associated lactic acidosis
Metformin increases lactate production because it blocks the resp chain hence increases anaerobic resp
If the patient has acute kidney injuries / poor renal function, all the lactate produced cannot be excreted
-> lactic acidosis
89
Why is metformin preferred over sulphonylureas
Has cardiovascular benefits
Does not cause weight gain
Does not have hypoglycaemia risk
90
First line management for diabetes
Metformin + lifestyle management
91
Examples of sulphonylureas
Gliclazide
Glipizide
Glimepiride
Glibenclamide
92
Mechanism of sulphonylureas
1) Binds to SUR1 subunit of ATP sensitive K+ channels in beta cells
2) Causes closure of K+ channels
3) Depolarisation of the cell causes opening of voltage gated Ca2+ channels
4) Ca2+ move in, causing release of insulin hence uptake and metabolism of glucose
93
Overall mechanism of sulphonylurea
Insulin secretion INDEPENDENT of glucose metabolism
94
What cells do sulphonylureas act on
Pancreatic beta cells
95
Does sulphonylurea affect weight
Yes, it causes weight gain because it increases insulin secretion
96
Why does insulin secretion increase weight
Anabolic effects (e.g. increases storage of fat, glucose uptake)
Stimulates appetite
97
Most common SUR
gliclazide
98
Side effects of SUR
Hypoglycaemia
Weight gain
99
Which group of people are more at risk of hypoglycaemia caused by SUR
Elderly
Those with impaired renal function (cannot excrete SUR)
Over-treated blood sugar level lower than it is supposed to be
Long term diabetics
100
When is SUR used
In less developed countries where cost is the main issue
Because SUR are very cheap
101
Mechanism of TZD
PPARy ligands;
bind to PPARy to initiate transcription of PPARy target genes
Also causes repression of transcription of some genes
102
Which tissue does TZD mostly bind to
Adipose tissue
103
Mechanism of TZD in adipose tissue
1) Bind to PPARy in adipose tissue
2) causes preadipocytes to differentiate into mature adipose tissue which increases subcutanoeus fat mass storage
3) increase fat mass storage = increase uptake of FFA
4) Increase uptake of FFA removes FFA from liver, pancreas and muscles where FFA causes lipotoxicity
5) Removal of fat from muscles causes increase in uptake of glucose
104
How does TZD decrease hepatic glucose production
1) binds to PPARy in adipose tissue
2) Causes release of adiponectin as well
3) Adiponectin binds to adiponectin receptors in the liver
4) activates AMP kinase
5) improves insulin sensitizing in liver and reduce hepatic glucose production
105
Other than adipose tissue, What other tissues / cells can TZD bind to
Macrophages
Arterial wall
Liver
106
TZD takes away fat from the liver, what condition is prevented by this
Steatosis and NAFLD
107
Effect of TZD on arterial wall
Decreases inflammation
Increases cholesterol efflux
= reduces atherosclerosis
108
What is the only available TZD called
Pioglitazone
109
Overall effect of TZD
Reduce blood sugar level
Reduce hepatic glucose production
Reduce lipotoxicity
Reduce blood pressure
110
Side effects of TZD
Weight gain
Fluid retention
Fracture risk
111
How does TZD cause fluid retention
Because TZD affects some of the genes regulating sodium transport in the kidney
112
How does TZD increase fracture risk
Fat accumulation in bone marrow and reduction in bone density
113
Fluid retention caused by TZD increases the risk of which CVD
Heart failure; doubles the risk of HF in elderly patients / those with previous CVD
114
Which group of people will respond well to TZD
Obese, young patients
115
Which insulin resistance drugs can be used where cost is a major issue in the country
Sulphonylurea
TZD
116
What are the 2 incretin hormones
GIP
GLP-1
117
Which cells secrete incretins
Enterocytes
118
Which cell secrete GIP
K cells at duodenum / jejunum
119
Which cell secrete GLP-1
L cells at distal ileum
120
What evokes the secretion of GIP and GLP-1
Ingestion and digestion of glucose, amino acids, fatty acids
121
How does GIP and GLP-1 affect the beta cells
Via Amplifying pathway to increase insulin secretion
122
What needs to happen in order for amplifying pathway to be triggered
The triggering pathway must be triggered first
123
What is the triggering pathway in beta cells
The glucose pathway where the influx of glucose causes subsequent secretion of insulin
124
Mechanism of GIP and GLP-1
1) Bind to GIP / GLP-1 receptors on beta cells
2) Increase cAMP to cause responses such as
- close K+ channels
- Modulate Ca2+ current
3) this will ultimately enhance the insulin secretion induced by the triggering pathway
125
Is GIP and GLP-1 amplifying pathway glucose dependent or independent
Glucose dependent
126
Why wouldn't GIP and GLP-1 cause hypoglycaemia
Because they are glucose dependent; the amplifying pathway does not work unless the triggering pathway induced by glucose works first
127
Overal effects of GIP and GLP-1
Increase insulin secretion -> reduce blood glucose
Reduce glucagon secretion
Reduce hepatic glucose production
Reduce appetite
Reduce gastric emptying
Increase heart rate
128
How does GIP and GLP-1 cause reduction in appetite
Can act on hypothalamus
129
Function of DPP4
breaks down GIP and GLP-1
130
What effect does DPP4i have on GIP and GLP-1
Increase their effect because DPP4i blocks DPP4 which breaks down GIP and GLP-1
131
Examples of DPP4i
Sitagliptin
Alogliptin
Saxagliptin
132
Does DPP4i cause hypoglycaemia
No because they are glucose dependent
133
Effect of DPP4i on weight
Weight neutral because although it increases insulin production, it also reduces appetite
134
Which drugs for diabetes can cause increase in weight
Sulphonylurea
TZD
135
DPP4i may increase the risk of
pancreatitis
136
Why may DPP4i require another drug to be used alongside
because it is not very potent
137
What are GLP-1RA
GLP-1 like molecules that are modified to avoid breakdown by DPP4 and acts on GLP-1 receptors to induce insulin secretion via amplifying pathway
138
Which GLP-1RA are the most commonly used
Exenatide
Liraglutide
139
Why does Liraglutide only need to be injected once daily
Because it has fatty acid binding to albumin, allowing Liraglutide to hang along for longer and exert longer effects
140
Exenatide was a daily injection but it is now made into a weekly injection, how did that happen
Exenatide is modified to be put into microsphere polymers that will sit under the skin when injected then gradually secrete exenatide
141
Which GLP-1RA can be made into an oral tablet
Semaglutide
142
Why can semaglutide be made into an oral tablet
A fatty acid chain derivative is added to protect the GLP-1 from breaking down in the stomach
143
Are there side effect for DPP4i
generally well tolerated
144
Side effects of GLP-1RA
Delayed gastric emptying
Gallstones
Pancreatitis
145
What are the symptoms of delayed gastric emptying
Bloating
Nausea
Loss of appetite
Vomiting
Acid reflux
146
Cardiovascular effects of GLP-1RA
Reduction in mortality for liraglutide and semaglutide (not exenatide)
147
When should you prescribe GLP-1RA
When SGLT2i is not tolerated by patients with HF /CVD
In patients to minimize hypoglycaemia risk
In patients who need weight loss / prevent weight gain
148
Which drugs are used in a diabetic patient with HF
First line: SGLT2i
Second line: SGLT2i + GLP-1RA
149
What are the glucose transporters in the kidney to absorb glucose from urine
SGLT1
SGLT2
150
Which SGLT absorbs the majority of glucose
SGLT2
151
Mechanism of SGLT2i
Blocks a quarter of absorption of glucose so some glucose will be peed out in urine
152
Why is Phlorizin, a SGLT2i, not used anymore
Because it is non-specific: it blocks SGLT1 in the gut causing osmotic diarrhea
153
What are the SGLT2i used now
Dapagliflozin
Canagliflozin
Empagliflozin
154
SGLT2i effect on weight
Weight loss at first but stops after a while due to homeostatic regulations
155
Why is there weight loss due to SGLT2i
Because you are peeing out sugar = peeing out calories
156
Effects of SGLT2i
Reduce risk of heart failure
Renal protection
Reduce blood glucose level
Reduce blood pressure
Reduce insulin
Increase glucagon
Increase lipolysis
157
How does SGLT2i reduce risk of heart failure
Because SGLT2 is a sodium glucose transporter, blocking it means less Na+ reabsorption -> mild diuretic effect
158
How does SGLT2i cause renal protection
Reduces filtration pressure
159
Why does SGLT2i increase the production of ketones
1) Reduce in glucose causes reduction in insulin, increase in lipolysis and glucagon secretion
2) Increase in lipolysis causes increase in FFA
3) Increase in FFA -> more oxidized into ketones
160
Apart from reducing risk of heart failure, how does SGLT2i improve cardiac bioenergetics
It increases FFA and ketone which are good fuel for cardiomyocytes
161
Side effects of SGLT2i
Thrush
Fournier Gangrene
Hypovolaemia and hypotension
Euglycaemic ketoacidosis
162
Why may SGLT2i cause thrush
because you are peeing out glucose, forming an ideal environment for candida and other bacteria to grow in
163
What is fournier gangrene
Necrotic infection occurring in the perineal region
164
What type of patients should avoid SGLT2i
Those on diuretics
Those that are hypotensive
Those that have impaired renal function (makes SGLT2i less potent)
165
Treatment of T2 diabetes in patients with heart disease
Metformin
If the patient doesn't respond -> Metformin + GLP-1A/SGLT2i
166
When do you prefer GLP-1A instead of SGLT2i
When the patient has atheroscleroses; GLP-1A is more effective against atherosclerosis
167
When do you prefer SGLT2i instead of GLP-1A
When the patient has heart failure
