Week 1 Flashcards

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

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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

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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

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4
Q

Describe the likely insulin level and blood sugar level in early type 2 diabetic patients

A

High insulin
High blood glucose level

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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

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6
Q

Which hormone stimulates lipolysis

A

Glucagon

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7
Q

Which cluster of cells in the pancreas regulate blood sugar level

A

Islet of Langerhans

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8
Q

Which cell in the pancreas secretes insulin

A

Beta cells of islets of Langerhans

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9
Q

Which cell in the pancreas secretes glucagon

A

Alpha cells of islets of Langerhans

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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

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11
Q

Effects of glucagon

A

Stimulate hepatic glucose production
Stimulate Lipolysis
= increases blood sugar level back to normal

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12
Q

In mM, what is the fasting blood sugar level considered as diabetes

A

above 7mM

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13
Q

In mM what is the fasting blood sugar level considered as pre-diabetes

A

6-7mM

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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

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15
Q

What is the likely insulin level and blood sugar level in type 1 diabetics

A

low insulin and high glucose level

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16
Q

When can insulin become poisonous

A

When injected to a normal healthy person.
It can cause hypoglycaemic coma

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17
Q

What are the cells of islets of Langerhans

A

Beta cells
Alpha cells
Delta cells
PP cells

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18
Q

What is the function of delta and PP cells

A

Regulatory cells; they regulate beta and alpha cells

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19
Q

What blood glucose level is considered as hypoglycaemia and what is at risk

A

<4mM
Hypoglycaemia coma

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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

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21
Q

How is insulin formed in beta cells

A

Synthesized in RER as larger chain of polypeptide preprohormone -> cleaved -> proinsulin -> cleaved -> insulin

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22
Q

Which chain is cleaved in proinsulin to form active insulin

A

C chain

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23
Q

What peptide chains are in proinsulin

A

A, B, C chains

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24
Q

What peptide chain is used to measure insulin secretion

A

C peptide chain

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25
Q

In relation to the peptide chains of insulin, what data would suggest that the insulin was injected

A

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

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26
Q

Example of an ultra fast acting synthetic insulin

A

Lispro

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27
Q

Mechanism of lispro

A

Swaps lysine and proline amino acids in B chain of active insulin to make it faster acting

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28
Q

Short action of Lispro means that

A

Lispro cannot be administered on its own. Needs to be administered with another longer acting insulin

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29
Q

Example of a ultra long acting synthetic insulin

A

Glargine

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30
Q

Mechanism of Glargine

A

Adds 2 argine amino acids at the end of B chain to cause prolonged action

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31
Q

When is Lispro usually injected

A

Within 15 minutes of beginning a meal

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32
Q

When is Glargine usually injected

A

Single bedtime dose

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33
Q

Which intracellular enzyme phosphorylates glucose

A

Glucokinase

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34
Q

Which transporter allows glucose to move into beta cell

A

GLUT2

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35
Q

What happens once the glucose enters the beta cell

A

1) Glucose enters cell through GLUT2
2) Glucose phosphorylated into glucose 6 phosphate by glucokinase
3) glucose 6 phosphate used to produce ATP

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36
Q

How is insulin secreted

A

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

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37
Q

What happens to beta cells in type 1 diabetes compared to type 2

A

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

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38
Q

How do beta cells lose their sensitivity to blood glucose level in type 2 diabetics

A

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

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39
Q

What does a definitive diagnosis of Type 1 diabetes require

A

Presence of specific autoantibodies

Declining C peptide production (=less insulin produced)

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40
Q

What happens to beta cells in type 2 diabetics over a period of time

A

Beta cell mass decreases
Reduction in insulin secretion (secretory failure)

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41
Q

Why do beta cells lose their function at late stages of diabetes

A

Mitochondrial exhaustion
Run out of insulin stores

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42
Q

What is gestational diabetes

A

Diabetes diagnosed for the first time during pregnancy (24-28 weeks)

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43
Q

Why is the diagnostic criteria for gestational diabetes lower than other forms of diabetes

A

Because gestational diabetes comes with significant risk of increased weight of offspring at birth = can be dangerous for the mother and baby during delivery

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44
Q

What is the criteria for gestational diabetes

A

Fasting blood sugar level >5.6
2 hour glucose > 7.8

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45
Q

What is the fasting blood glucose criteria for diabetes

A

Fasting blood sugar level >7

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46
Q

What is the 2hr oral glucose tolerance test criteria for diabetes

A

> 11.1

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47
Q

What is overt diabetes

A

Pregnant woman diagnosed with diabetes for the first time at the first antenatal visit (early pregnancy

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48
Q

What is the criteria does overt diabetes

A

Same as other forms of diabetes (not gestational).
>7 FBG
>11.1 2hr OGTT

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49
Q

What is the threshold of diabetes based on

A

The risk of developing retinopathy

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50
Q

What is type 1 diabetes

A

Autoimmune destruction of beta cells resulting in beta cell deficiency

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51
Q

What is type 2 diabetes

A

Insulin resistance + relative insulin deficiency progressing to insulin secretory defect + insulin resistance

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52
Q

Risk factors of type 2 diabetes

A

Obesity
Poor dietary habits
PCOS
Family history
History of gestational / overt diabetes

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53
Q

What occurs in skeletal muscle when insulin binds

A

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

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54
Q

What occurs in skeletal muscles in insulin resistance

A

1) Decreased activity of INSR hence decreased downstream phosphorylation
2) Less GLTU4 transported to cell membrane
3) decreased glucose uptake

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55
Q

Mechanism of obesity induced inflammation

A

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

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56
Q

What are the sub units of ATP induced K+ channels in beta cells

A

Kir6

SUR1 (sulphonylurea receptor)

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57
Q

Function of ATP sensitive K+ channels

A

K+ channels are closed to hyperpolarise the beta cell in order to activate the voltage gated Ca2+ channels -> release insulin

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58
Q

What conditions are caused by mutations in ATP sensitive K+ channels

A

Neonatal diabetes

Congenital hyperinsulinism

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59
Q

Which drug can allow neonatal diabetics to recover euglycaemia quickly and why

A

Sulphonylurea because the SUR1 subunit still responds to binding of Sulphonylurea

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60
Q

Which drug can inhibit insulin secretion in congenital hyperinsulinism

A

diazoxide

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61
Q

Diabetic ketoacidosis is most commonly seen in which type of diabetes

A

Type 1

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62
Q

How does diabetic ketoacidosis occur

A

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

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63
Q

Risk factors for diabetic ketoacidosis

A

Type 1 diabetes
Non-compliance to drugs
Infection
Inappropriate drug dose

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64
Q

Symptoms of diabetic ketoacidosis

A

Polydipsia (extreme thirst)
Polyuria
Hypotension
Ketotic breath (acidic)
Vomiting
Confusion
Kussmaul breathing

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65
Q

Management for diabetic ketoacidosis

A

Fluid resuscitation
Insulin

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66
Q

Symptoms of diabetes

A

Blurred vision
Polyuria
Polydipsia
Fatigue
Weight loss

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67
Q

What are the severe conditions diabetes can lead to

A

Diabetic ketoacidosis
Hyperosmolar hyperglycaemic state

68
Q

What is hyperosmolar hyperglycaemic state

A

Prolonged elevated blood sugar level making you dehydrated and hyperosmolar (blood has high concentration of glucose)

69
Q

What conditions are at increased risk due to hyperglycaemia, dyslipidaemia and high blood pressure

A

Myocardial infarction
Atherosclerosis (accelerated)
Acute coronary syndrome
Peripheral vascular disease

70
Q

What is HbA1c

A

Glycated haemoglobin

Haemoglobin becomes glycated when exposed to glucose so the level of glucose is proportional to the level of glycated haemoglobin

71
Q

What does HbA1c measure

A

measure of glucose exposure over the last 90 days (haemoglobin survives for 90 days)

72
Q

What conditions may cause HbA1c to be inaccurate

A

Increased or decreased red blood cell turnover

Haemolytic anaemia

73
Q

Mechanism of metformin

A

1) binds to complex 1 of resp chain
2) causes reduction in respiration hence fall in ATP

74
Q

What are the consequences of fall in ATP due to metformin

A

Rise in AMP
Activation of AMP kinase
Rise in ADP/ATP ratio
Reduction in gluconeogenesis (probably due to rise in AMP)

75
Q

Site of action of metformin

A

Mainly cells in intestines, liver and kidney

76
Q

Why isn’t metformin transported into all cells

A

Because it is highly hydrophilic so it will only enter certain cells that have transporters of metformin

77
Q

Is metformin metabolized

A

No, it is excreted in its unchanged form in the urine

78
Q

Effects of metformin

A

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
Q

What type of hormones is GLP-1

A

Incretin hormone

80
Q

Overall effect of metformin

A

Lowers glucose production and increases glucose utilization

Acts like insulin

81
Q

Does metformin affect weight

A

Can be weight neutral / weight losing

82
Q

Side effects of metformin

A

GI intolerance
- Diarrhea / bloating / dyspepsia / abdominal pain / metallic taste in mouth

Metformin associated lactic acidosis

83
Q

Why may metformin cause GI side effects

A

Because it is highly concentrated in enterocytes hence can be toxic and cause side effects

84
Q

What should you do if the patient cannot tolerate metformin

A

Use modified form of metformin which releases metformin more slowly and distributes throughout the gut

85
Q

What should you do to prevent the side effects of metformin when the patient first started it

A

Initiate slowly ; use lower dose then increase slowly over time

86
Q

What increases the risk of Metformin associated lactic acidosis

A

Patient has acute kidney injury / poor renal function

87
Q

Which condition causes acute kidney injury

A

Sepsis

88
Q

Mechanism of metformin associated lactic acidosis

A

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
Q

Why is metformin preferred over sulphonylureas

A

Has cardiovascular benefits
Does not cause weight gain
Does not have hypoglycaemia risk

90
Q

First line management for diabetes

A

Metformin + lifestyle management

91
Q

Examples of sulphonylureas

A

Gliclazide
Glipizide
Glimepiride
Glibenclamide

92
Q

Mechanism of sulphonylureas

A

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
Q

Overall mechanism of sulphonylurea

A

Insulin secretion INDEPENDENT of glucose metabolism

94
Q

What cells do sulphonylureas act on

A

Pancreatic beta cells

95
Q

Does sulphonylurea affect weight

A

Yes, it causes weight gain because it increases insulin secretion

96
Q

Why does insulin secretion increase weight

A

Anabolic effects (e.g. increases storage of fat, glucose uptake)
Stimulates appetite

97
Q

Most common SUR

A

gliclazide

98
Q

Side effects of SUR

A

Hypoglycaemia
Weight gain

99
Q

Which group of people are more at risk of hypoglycaemia caused by SUR

A

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
Q

When is SUR used

A

In less developed countries where cost is the main issue
Because SUR are very cheap

101
Q

Mechanism of TZD

A

PPARy ligands;
bind to PPARy to initiate transcription of PPARy target genes
Also causes repression of transcription of some genes

102
Q

Which tissue does TZD mostly bind to

A

Adipose tissue

103
Q

Mechanism of TZD in adipose tissue

A

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
Q

How does TZD decrease hepatic glucose production

A

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
Q

Other than adipose tissue, What other tissues / cells can TZD bind to

A

Macrophages
Arterial wall
Liver

106
Q

TZD takes away fat from the liver, what condition is prevented by this

A

Steatosis and NAFLD

107
Q

Effect of TZD on arterial wall

A

Decreases inflammation
Increases cholesterol efflux

= reduces atherosclerosis

108
Q

What is the only available TZD called

A

Pioglitazone

109
Q

Overall effect of TZD

A

Reduce blood sugar level
Reduce hepatic glucose production
Reduce lipotoxicity
Reduce blood pressure

110
Q

Side effects of TZD

A

Weight gain
Fluid retention
Fracture risk

111
Q

How does TZD cause fluid retention

A

Because TZD affects some of the genes regulating sodium transport in the kidney

112
Q

How does TZD increase fracture risk

A

Fat accumulation in bone marrow and reduction in bone density

113
Q

Fluid retention caused by TZD increases the risk of which CVD

A

Heart failure; doubles the risk of HF in elderly patients / those with previous CVD

114
Q

Which group of people will respond well to TZD

A

Obese, young patients

115
Q

Which insulin resistance drugs can be used where cost is a major issue in the country

A

Sulphonylurea
TZD

116
Q

What are the 2 incretin hormones

A

GIP
GLP-1

117
Q

Which cells secrete incretins

A

Enterocytes

118
Q

Which cell secrete GIP

A

K cells at duodenum / jejunum

119
Q

Which cell secrete GLP-1

A

L cells at distal ileum

120
Q

What evokes the secretion of GIP and GLP-1

A

Ingestion and digestion of glucose, amino acids, fatty acids

121
Q

How does GIP and GLP-1 affect the beta cells

A

Via Amplifying pathway to increase insulin secretion

122
Q

What needs to happen in order for amplifying pathway to be triggered

A

The triggering pathway must be triggered first

123
Q

What is the triggering pathway in beta cells

A

The glucose pathway where the influx of glucose causes subsequent secretion of insulin

124
Q

Mechanism of GIP and GLP-1

A

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
Q

Is GIP and GLP-1 amplifying pathway glucose dependent or independent

A

Glucose dependent

126
Q

Why wouldn’t GIP and GLP-1 cause hypoglycaemia

A

Because they are glucose dependent; the amplifying pathway does not work unless the triggering pathway induced by glucose works first

127
Q

Overal effects of GIP and GLP-1

A

Increase insulin secretion -> reduce blood glucose
Reduce glucagon secretion
Reduce hepatic glucose production
Reduce appetite
Reduce gastric emptying
Increase heart rate

128
Q

How does GIP and GLP-1 cause reduction in appetite

A

Can act on hypothalamus

129
Q

Function of DPP4

A

breaks down GIP and GLP-1

130
Q

What effect does DPP4i have on GIP and GLP-1

A

Increase their effect because DPP4i blocks DPP4 which breaks down GIP and GLP-1

131
Q

Examples of DPP4i

A

Sitagliptin
Alogliptin
Saxagliptin

132
Q

Does DPP4i cause hypoglycaemia

A

No because they are glucose dependent

133
Q

Effect of DPP4i on weight

A

Weight neutral because although it increases insulin production, it also reduces appetite

134
Q

Which drugs for diabetes can cause increase in weight

A

Sulphonylurea
TZD

135
Q

DPP4i may increase the risk of

A

pancreatitis

136
Q

Why may DPP4i require another drug to be used alongside

A

because it is not very potent

137
Q

What are GLP-1RA

A

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
Q

Which GLP-1RA are the most commonly used

A

Exenatide
Liraglutide

139
Q

Why does Liraglutide only need to be injected once daily

A

Because it has fatty acid binding to albumin, allowing Liraglutide to hang along for longer and exert longer effects

140
Q

Exenatide was a daily injection but it is now made into a weekly injection, how did that happen

A

Exenatide is modified to be put into microsphere polymers that will sit under the skin when injected then gradually secrete exenatide

141
Q

Which GLP-1RA can be made into an oral tablet

A

Semaglutide

142
Q

Why can semaglutide be made into an oral tablet

A

A fatty acid chain derivative is added to protect the GLP-1 from breaking down in the stomach

143
Q

Are there side effect for DPP4i

A

generally well tolerated

144
Q

Side effects of GLP-1RA

A

Delayed gastric emptying
Gallstones
Pancreatitis

145
Q

What are the symptoms of delayed gastric emptying

A

Bloating
Nausea
Loss of appetite
Vomiting
Acid reflux

146
Q

Cardiovascular effects of GLP-1RA

A

Reduction in mortality for liraglutide and semaglutide (not exenatide)

147
Q

When should you prescribe GLP-1RA

A

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
Q

Which drugs are used in a diabetic patient with HF

A

First line: SGLT2i
Second line: SGLT2i + GLP-1RA

149
Q

What are the glucose transporters in the kidney to absorb glucose from urine

A

SGLT1
SGLT2

150
Q

Which SGLT absorbs the majority of glucose

A

SGLT2

151
Q

Mechanism of SGLT2i

A

Blocks a quarter of absorption of glucose so some glucose will be peed out in urine

152
Q

Why is Phlorizin, a SGLT2i, not used anymore

A

Because it is non-specific: it blocks SGLT1 in the gut causing osmotic diarrhea

153
Q

What are the SGLT2i used now

A

Dapagliflozin
Canagliflozin
Empagliflozin

154
Q

SGLT2i effect on weight

A

Weight loss at first but stops after a while due to homeostatic regulations

155
Q

Why is there weight loss due to SGLT2i

A

Because you are peeing out sugar = peeing out calories

156
Q

Effects of SGLT2i

A

Reduce risk of heart failure
Renal protection
Reduce blood glucose level
Reduce blood pressure
Reduce insulin
Increase glucagon
Increase lipolysis

157
Q

How does SGLT2i reduce risk of heart failure

A

Because SGLT2 is a sodium glucose transporter, blocking it means less Na+ reabsorption -> mild diuretic effect

158
Q

How does SGLT2i cause renal protection

A

Reduces filtration pressure

159
Q

Why does SGLT2i increase the production of ketones

A

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
Q

Apart from reducing risk of heart failure, how does SGLT2i improve cardiac bioenergetics

A

It increases FFA and ketone which are good fuel for cardiomyocytes

161
Q

Side effects of SGLT2i

A

Thrush
Fournier Gangrene
Hypovolaemia and hypotension
Euglycaemic ketoacidosis

162
Q

Why may SGLT2i cause thrush

A

because you are peeing out glucose, forming an ideal environment for candida and other bacteria to grow in

163
Q

What is fournier gangrene

A

Necrotic infection occurring in the perineal region

164
Q

What type of patients should avoid SGLT2i

A

Those on diuretics
Those that are hypotensive
Those that have impaired renal function (makes SGLT2i less potent)

165
Q

Treatment of T2 diabetes in patients with heart disease

A

Metformin
If the patient doesn’t respond -> Metformin + GLP-1A/SGLT2i

166
Q

When do you prefer GLP-1A instead of SGLT2i

A

When the patient has atheroscleroses; GLP-1A is more effective against atherosclerosis

167
Q

When do you prefer SGLT2i instead of GLP-1A

A

When the patient has heart failure