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Flashcards in Endocrine Deck (113):
1

Define diabetes mellitus

A persistent state of hyperglycaemia due to the body’s inability to properly utilise glucose

2

Compare the two different types of diabetes mellitus

T1DM - pancreas does not produce any insulin due to beta-cells in islets of Langerhans being destroyed

T2DM - relative insulin deficiency and/or resistance

3

What is T2DM commonly associated with?

Obesity, physical inactivity, HTN, dyslipidaemia, tendency to develop thrombosis

4

Explain the signs and symptoms of DM

Polyuria, nocturia, polydipsia - osmotic diuresis

Lethargy - inability to utilise glucose to provide energy

Weight loss - breakdown of body protein and fat as alternative energy sources as glucose is unavailable

5

Describe the different types of insulin available

Short acting
Intermediate
Long acting
Ultra long acting

6

When is short acting insulin used and why?

Mimics usual increases of insulin around meal times.
Soluble insulins are injected 15-30mins before meals, onset is 30-60m, peak action is 1-4h and duration is <9h.
Human insulin analogues are injected just before, with or just after a meal, onset is faster, peak action is 0-3h and duration is 2-5h.

7

What is the onset, peak action and duration of intermediate and long acting insulins?

Onset 1-2h, peak 3-12h, duration 11-24h.

Provide baseline

8

What ADRs are associated with insulin?

Local reactions at injection site
Hypoglycaemia
Hypersensitivity

9

What are the risk factors for gestational diabetes?

Obesity
Family history of DM
Unexplained stillbirth or death of a neonate in a previous pregnancy
Very large infant in a previous pregnancy
Previous history of gestational diabetes
Family origin south Asian, black Caribbean or middle eastern

10

What are the glucose targets?

Pre-prandial 4-7mmol/L
Post-prandial <9mmol/L

11

What are the symptoms of hypoglycaemia?

Feeling shaky
Sweating
Hunger
Tiredness
Pallor
Blurred vision
Headaches
Irritability

12

What are the causes of hypoglycaemia?

Too much insulin
Delayed/missed meal or snack
Not eating sufficient carbohydrates
Excess physical activity
Drinking large amounts of alcohol

13

What is the treatment for hypoglycaemia in a conscious patient?

15-20g fast acting carbohydrate
15-20g slower acting carbohydrate to prevent levels dropping low again
Blood glucose retested after 15-20mins and treatment repeated if levels <4mmol/L

14

What is the treatment for hypoglycaemia in an unconscious patient?

Recovery position
Glucagon injection
Ambulance

15

Define hyperglycaemia

Pre-prandial >7.5mmol/L
2h post-prandial >8.5mmol/L

16

What are the symptoms of hyperglycaemia?

Excessive thirst
Passing more urine than usual
Headaches
Tiredness/lethargy

17

What are the causes of hyperglycaemia?

Missing doses of medication
Eating more carbohydrates than the body or medication can cope with
Stress
Concurrent infections
Over treating a hypoglycaemic episode

18

What is the main purpose of energy homeostasis in the fed state?

Store calories

19

What changes does insulin induce?

Glucose stored as glycogen in muscle and liver
Glucose used as fuel in muscle
Glucose carbons and calories sorted in fatty acids
Switched off glycogen degradation and gluconeogenesis

20

What effect does insulin have on lipid metabolism?

Glucose-> fatty acids
Fatty acid storage in adipose

21

Describe protein metabolism by the liver

Fed state - excess amino acids deaminated
Fasting - amino acids a major source of glucose (gluconeogenesis)
Glucagon => increased uptake, deamination and urea cycle activity

22

How is liver glycogen metabolism controlled?

Glycogen - stimulates PKA when blood glucose is scarce. FBPase2 is activated. Glycolysis is inhibited, and gluconeogenesis is stimulated.

High levels of fructose-6-phosphate stimulate phosphoprotein phosphatase. PFK2 is activated. Glycolysis is stimulated and gluconeogenesis is inhibited.

23

What occurs during the well-fed state?

Glucose and amino acids from food enter the blood stream and reach the liver via the portal vein.
Triacylglycerol from food is packed into chylomicrons and absorbed via the lymphatic system.
Insulin is secreted to stimulate the storage of fuels:
Glycogen synthesis occurs in the liver and muscles
Glycolysis occurs in the liver which generates acetyl-CoA for FA synthesis
Triglycerides are stored in adipose tissue

24

What effect does insulin have during the well-fed state?

Liver
- switch off glycogenolysis and gluconeogenesis to reduce glucose output
- switch on glycolysis - increased acetyl CoA to increase FA synthesis

Adipose
- switch off hormone sensitive lipase to reduce FA production and increase fat storage

Muscle
- increase GLUT4 expression - increased glucose uptake to increase use of glucose as fuel and decrease use of FAs

Brain
- decreased appetite

25

What changes occur between meals?

Blood glucose levels drop
Glucagon secreted
- glycogenolysis stimulated to release glucose - glucose taken up primarily by the brain
- FA released from adipose tissue increased, muscle uses FAs as primary fuel source
- gluconeogenesis stimulated

26

What changes occur during the fasting state?

Glucose no longer taken up by muscles - muscles use FAs and ketone bodies
Proteins broken down => atrophy - amino acids, lactate and glycerol all used to maintain a supply of glucose for the brain
Brain begins to rely more upon ketone bodies
Long-term starvation leads to brain malfunction

27

How does encephalopathy occur?

Reduced gluconeogenesis, glycogen storage - inadequate hepatic glucose production

Reduced fatty acid oxidation - inadequate ketone body production, inadequate energy for gluconeogenesis

Brain runs out of energy - toxic metabolites accumulate in brain cells => brain swelling and coma

28

How does T2DM occur?

Resistance to insulin, cannot raise insulin sufficiently to promote glucose uptake in muscle or control glucose production by the liver

Consequence of obesity
Normal increase in fructose 2,6-bisphosphate and down-regulation of phosphoenolpyruvate carboxylase does not occur
Translocation of GLUT4 to plasma membrane is decreased
Ketoacidosis rarely develops, observed increase in VLDL

29

How does T1DM occur?

Complete absence of insulin production by pancreas
Stuck in starved state
- liver is always gluconeogenic and glycogenolytic -> hyperglycaemia
- uncontrolled proteolysis-> muscle wasting and provides substrates for gluconeogenesis
- uncontrolled adipose tissue lipolysis increased plasma [FA] - liver ketone body production, uncontrolled by insulin leading to ketoacidosis

30

Describe normoglycaemia in endothelial cells

Glucose in via GLUT1 -> acetyl CoA -> ATP

31

What changes occur in endothelial cells during hyperglycaemia?

Glucose in via GLUT1 -> acetyl CoA -> ATP, no more ATP or acetyl CoA can be made, glucose takes other pathways:

Glucose -> sorbitol (reduced NADPH leads to oxidative stress, increased sorbitol leads to reduced vasoelasticity)

Glucose -> glycation (AGE) (increased protein stability, altered cellular interactions, altered extracellular matrix)

Glucose -> acetyl CoA -> FAs -> diacyl glycerol (DAG activates protein phosphorylation, altered cellular signalling, multiple effects on vascular cells)

32

Outline the major complications of T1DM

Chronic effects of hyperglycaemia
Hypoglycaemia
Diabetic ketoacidosis

33

How does diabetic ketoacidosis occur?

Uncontrolled lipolysis and beta-oxidation -> over-production of ketone bodies (strong acids) -> overwhelms the buffering capacity of the body -> acidosis -> coma and death

34

What causes insulin resistance?

Genetics
Environment
Ectopic lipid accumulation
Cellular stress-response
Inflammation

35

What are the long-term complications of diabetes?

Microvascular damage => retinopathy, nephropahty, and neuropathy

36

How does diabetes cause peripheral neuropathies?

Endothelial damage -> wall thickening -> ischaemia and neural death

37

Compare the different types of diabetic peripheral neuropathies

Somatic - parasethesias; impaired pain, temperature, light touch, two-point discrimination and vibratory sensation

Autonomic - vasomotor function (postural hypotension), gastrointestinal function (postprandial and nocturnal diarrhoea), genitourinary function (impotence), cranial nerve (impaired pupillary responses)

38

What are the risk factors for diabetic nephropathy?

Genetic and familial predisposition
Elevated BP
Poor glycaemic control
Smoking
Hyperlipidaemia
Microalbuminuria

39

What are the risk factors for diabetic retinopathy?

Poor glycaemic control
Elevated BP
Hyperlipidaemia

40

Describe the pathogenesis for diabetic retinopathy

Endothelial change of vascular wall
- microaneurysms -> burst -> scarring, damage to cellular environment, macular oedema
- ischaemia -> fragile new blood vessels, more prone to aneurysms and bursting

41

What class of drug is metformin?

A biguanide

42

Describe the mechanism of action of metformin

Becomes concentrated in hepatocytes
Inhibit mitochondrial respiratory chain complex I
Alters ATP:AMP
Activates AMPK
Decreased glucose output

43

What ADRs are associated with metformin?

Lactic acidosis
Hypoglycaemia

44

What cautions surround the use of metformin?

Patients receiving radiological contrast agent may suffer temporary renal impairment - withdraw metform for 48h

45

What are the contraindications for the use of metformin?

Renal insufficiency - risk of lactic acidosis

46

What interactions are associated with metformin?

Drugs which impair renal function e.g. NSAIDs (risk of lactic acidosis)

47

Give examples of sulfonylureas

Gliclazide, glibenclamide, glipizide, glimepiride, tolbutamide

48

Describe the mechanism of action of sulfonylureas

Bind SUR1
ATP-sensitive potassium channel closes
Membrane depolarises
Voltage-gated calcium channel opens
Insulin secretion and synthesis triggered

49

What ADRs are associated with sulfonylureas?

Hypoglycaemia
Weight gain
Nausea
Vomiting
Diarrhoea
Constipation

50

What cautions surround the use of sulfonylureas?

Elderly, debilitated and malnourished patients are at greater risk of hypoglycaemia
Hepatic impairment - increased risk of hypoglycaemia

51

What are the contraindications for the use of sulfonylureas?

Acute porphyria
Ketoacidosis

52

What interactions are associated with sulfonylureas?

Corticosteroids (increase expression of enzymes involved in gluconeogenesis)
Thiazides (hypokalaemia causes beta-cell hyperpolarisation so less insulin secretion)
Meglitinides

53

Give examples of meglitinides

Nateglinide and repaglinide

54

Describe the mechanism of action of meglitindes

Close potassium channels
Membrane depolarises
Calcium channels open
Insulin synthesis and secretion triggered

55

What ADRs are associated with meglitinides?

Hypoglycaemia
Weight gain
Nausea
Vomiting
Diarrhoea
Constipation

56

What cautions surround the use of meglitinides?

Elderly, debilitated and malnourished at greater risk of hypoglycaemia
Hepatic impairment - increased risk of hypoglycaemia

57

What interactions are associated with meglitinides?

Corticosteroids - increase expression of enzymes involved in gluconeogenesis
Thiazides - hypokalaemia causes beta-cell hyperpolarisation so less insulin secretion
Sulfonylureas

58

What effect does GLP-1 have on insulin secretion?

Potentiates glucose-stimulated insulin secretion
- increases secretory machinery
- increases insulin biosynthesis
- increases calcium channel activity

59

What is the mechanism of action of DPP-4 inhibitors?

Increases GLP-1 concentration
- increases secretory machinery
- increases insulin biosynthesis
- increases calcium channel activity

60

Give examples of GLP-1 agonists

Liraglutide
Lixisenatide
Exenatide
Albiglutide
Dulaglutide

61

Give examples of DPP-4 inhibitors

Alogliptin
Linagliptin
Saxaglitpin
Sitagliptin
Vildaglitpin

62

What ADRs are associated with GLP-1 agonists?

Nausea and vomiting
Significant weight loss
Pancreatitis and kidney failure

63

What ADRs are associated with DPP-4 inhibitors?

Pancreatitis and kidney failure
Some GI ADRs

64

What class of drug is pioglitazone?

Thiazolidinedione

65

Describe the mechanism of action of pioglitazone

Ligand for transcription factor PPAR-gamma
Decrease ectopic fat storage
Improving insulin resistance

66

What cautions surround the use of pioglitazone?

HF
Increased risk of bladder cancer

67

What are the contraindications for the use of pioglitazone?

Hepatic insufficiency
History of HF
Active bladder cancer
History of bladder cancer or uninvestigated haematuria

68

What interactions are associated with pioglitazone?

Clopidogrel
Oral contraceptives

69

Give examples of SGLT-2 inhibitors

Dapagliflozin
Canagliflozin
Empagliflozin

70

Describe the mechanism of action of SGLT-2 inhibitors

Inhibit SGLT-2 leading to reduced reabsorption and increased loss of glucose in urine

71

What ADRs are associated with SGLT-2 inhibitors?

Increased risk of UTIs
Increased risk of breast and bladder cancer
Minor risk of euglycaemia diabetic ketoacidosis

72

What cautions surround the use of SGLT-2 inhibitors?

Increased urination -> increased risk of hypovolaemia or hypotension
Reduced efficacy in patients with impaired renal function

73

What are the contraindications for the use of SGLT-2 inhibitors?

Hepatic insufficiency
Impaired left ventricular function

74

What interactions are associated with SGLT-2 inhibitors?

Diuretics

75

Describe the action of oestrogen

Oestrogen act as signalling molecules by interacting with specific target cells
- include tissues of the breast, uterus, brain, heart, liver and bone
- ER modulation used in contraception
ER undergoes dimerisation in order for it to have increased affinity for EREs and regulate gene expression

76

What are the targets and uses of progestins?

Physiological target - reproductive tract
- decreases oestrogen-driven endometrial proliferation
- establishment and maintenance of pregnancy

Uses
- oral contraceptives
- HRT
- Uterine bleeding disorders
- premature labour

77

Name a progesterone antagonist

Mifepristone

78

What is mifepristone used for?

Termination of pregnancy
Induction of labour after foetal death

79

Describe the pituitary hormone effects that occur in the early follicular phase

FSH stimulates several follicles to grow, and stimulates estradiol secretion

80

Describe the ovarian hormone effects that occur during the early follicular phase

Follicles produce low levels of estradiol which:
- causes endometrial arteries to constrict, resulting in menstruation
- inhibits LH secretion
- stimulates FSH secretion

81

Describe the pituitary hormone effects that occur during the late follicular phase/ovulation

FSH stimulates one follicle to further develop
LH surge stimulates ovulation from that follicle

82

Describe the ovarian hormone effects that occur during the late follicular phase/ovulation

Follicles produce increasing levels of estradiol which:
- stimulates GnRH secretion by hypothalamus
- with GnRH drives LH levels to spike, causing ovulation
- causes the endometrium to further develop

83

Describe the pituitary hormone effects of the luteal phase

LH stimulates development of a corpus lute up left behind after ovulation

84

Describe the ovarian hormone effects that occur during the luteal phase

The corpus luteum secretes progesterone and estradiol which:
- blocks GnRH secretion by the hypothalamus and LH and FSH secretion by the pituitary
- causes the endometrium to further develop

85

Describe the pituitary hormone effects that occur during menstruation

Low GnRH, LH, FSH

86

Describe the ovarian hormone effects that occur during menstruation

Progesterone and estradiol levels fall:
- causes endometrial arteries to constrict, resulting in menstruation

87

What changes occur to the menstrual cycle during pregnancy?

Implantation - blastocyst produces hCG which supports continued secretion of progesterone by corpus luteum until placenta takes over
Progesterone:
- maintains decidua (lining of uterus)
- promotes blood vessel growth

88

What changes occur to the menstrual cycle during the menopause?

All follicles depleted
Decreased oestrogen and inhibin -> LH, FSH

89

What are the two types of method of contraception?

Mechanical
- condoms, diaphragms, intrauterine devices
- some can be combined with chemical spermicide - essential with a diaphragm, nonoxynol 9 (surfactant)

Hormonal
- p.o, depot formulation for i.m. Injection, transdermal patch, vaginal ring, intrauterine devices

90

What oestrogens are used in hormonal contraception?

Ethinyl estradiol or mestranol

91

What progestins are used in hormonal contraception?

Norethisterone (1st gen)
Norgestrel/levonorgestrel (2nd gen) - agonists at AR
Desogestrel/gestodene/norgestimate (3rd gen) - less androgen activity
Drospirenone (4th gen) - anti-androgenic and anti-mineralocorticoid

92

What is the mechanism of action of COCs?

Suppress GnRH, LH, and FSH release at hypothalamic and pituitary level
Progestin inhibits oestrogen-induced LH “surge” and inhibits ovulation
- oestrogen up-regulates PGR, increasing negative feedback by the progestogen

93

What effects do oestrogen only contraceptives have?

Promote endometrial growth => Endometrial cancer

94

Outline the PK of COCs

Phase 1 - extensive first pass by CYP3A4
Phase 2 - sulfation and glucuronidation followed by biliary secretion

95

Compare monophasic and multiphasic COCs

Monophasic - dose of oestrogen and progestin doesn’t vary

Multiphasic
- biphasic - progestin dose varies
- triphasic - 3 different dose combinations

96

What ADRs are associated with oestrogens?

Fluid retention
HTN
Increased risk of endometrial cancer

97

What ADRs are associated with progestogen?

Headache
Nausea
Vomiting
Lower back pain

98

What ADRs are associated with COCs?

HTN
Thromboembolism
Cancer

99

What are the contraindications for the use of COCs?

Risk of CV, thromboembolic or malignant disease
Pregnancy

100

What interactions are associated with COCs?

CYP3A4 inducers => contraceptive failure
- rifampicin
- phenytoin
- phenobarbital
- st john’ wort

101

What is the mechanism of action of POPs?

Inhibit GnRH release
No menstruation

102

What ADRs are associated with POPs?

Breakthrough bleeding

103

What progestogen only depot injections are available?

Medroxyprogesterone
- t1/2~30h
- aqueous depot formulation for i.m injection every ~12weeks

Norethisterone
- oil depot formulation used for short term contraception
- also used to treat heavy periods

104

What progestogen only subdermal implants are available?

Levonorgestrel
- fertility restored on removal
- irregular and prolong bleeding can occur

105

What progestogen only intrauterine devices are available?

Levonorgestrel
- prevents endometrial thickening
- fertility restored on removal
- irregular and prolonged bleeding can occur
- dysmenorrhoea less than with copper IUD

106

How do copper IUDs work?

Release copper to prevent fertilisation

107

What EHCs are available?

Levonorgestrel
- high single dose
- blocks LH surge
- useful for up to 72h after intercourse

Ulipristal
- useful for up to 120h after intercourse

108

How does tamoxifen work?

ER antagonist in breast tissue (inhibits oestrogen-dependent growth of breast cancer)
Partial ER agonist in endometrium and bone

109

How do SERMs work?

Tissue-specific patterns of oestrogen receptors

Tissue-specific pattern of co-regulator expression
- pattern of genes activated by ER activation regulated by the expression of co-regulator proteins
- co-regulator repertoire varies from tissue to tissue
- co-regulator recruitment may be ligand-dependent, thus a ligand may recruit co-activators specific to one tissue but co-repressors specific to another

Effects on ER stability and degradation

110

Outline the properties of an ideal SERM

Strengthen bones
Lower LDL
Raise HDL
Relieve hot flushes
Reduce breast cancer risk
Reduce uterine cancer risk

111

Outline the good effects of real oxide effects

Strengthens bones
Lowers LDL
Reduces risk for invasive breast cancer
Fewer uterine cancers than tamoxifen
Fewer blood clots than tamoxifen

112

Outline the bad effects of raloxfiene

Hot flushes
Blood clots
Leg cramps
Teratogenic

113

What are the effects of raloxifene?

Antagonist in breast and endometrium
Agonist in bone