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Medicine 1 > Optional module - Diabetes and Obesity > Flashcards

Optional module - Diabetes and Obesity Flashcards

1
Q

When are in-uteros at risk of obesity?

A

Babies that are born smaller than usual

Have + risk of obesity and CVD later in life

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2
Q

When are children at risk of adult obesity?

A

If overweight under 5 years old

+ risk if one or both parents are overweight

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3
Q

When are adolescence at risk of adult obesity?

A

If overweight when adolescence

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4
Q

When are adult females at risk of obesity?

A
  • Pregnancy
  • Oral combined pill
  • Menopause
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5
Q

How does male weight change overtime?

A
  • Progressive increase over the decades until 6th decade
  • Progressive reduction in energy expenditure as age
  • Stabilises between 55-64 then slowly declines
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6
Q

What other factors affect weight?

A
  • Sleep deprivation
  • Smoking cessation (4-5kg on average)
  • Drugs:
    • Antidepressants
    • Antiepileptic drugs
    • Diabetes drugs
    • Beta blockers
    • Glucocorticoids
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7
Q

What illnesses can affect weight?

A
  • Hypothyroidism (low energy expenditure)
  • Polycystic ovarian syndrome (50% obesity rates)
  • Cushing’s syndrome (excess endogenous glucocorticoid)
  • Hypothalamic obesity (severe uncontrolled increase in appetite)
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8
Q

What are general potentiual causes of obesity?

A
  • Excess calorie intake
  • Genetics, intrauterine environment and post-brith environment
  • Ethnic differences
  • Socioeconomic differences
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9
Q

What are problems with melanocortin-4 receptor deficiency?

A

Associated with early onset obesity and taller than average height

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10
Q

What are problems with POMC gene defects?

A
  • Infant adrenal crisis
  • Early onset obesity from hyperphagia caused by ‘alpha’ MSH deficiency
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11
Q

What is the function of leptin?

What are problems with leptin deficiency?

A

Informs brain of extent of fat stores

Deficiency = hyperphagia and obesity

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12
Q

What is Berardinelli Seip syndrome?

A

Leptin deficiency

Leads to no fat storage in body

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13
Q

What is Prader Willi syndrome?

A
  • Genetic abnormalities on long arm of chromosome 15
  • Neonatal hypotonia and cryptorchidism
  • Hypothalamic dysfunction:
  • Hunger with lack of satiety
  • Obesity
  • Low sex hormones and growth hormone
  • Cognitive and behavioural challenges
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14
Q

What is Bardet Beidl syndrome?

A
  • Autosomal recessivie disorder
  • Obesity
  • Intellectual disability
  • Small male testes
  • Retinal dystrophy
  • Polydactyly
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15
Q

Where is the worst place to store fat and why?

What is the waist-to-hip ratio for this?

A

In the abdominal region

  • Associated with + risk of CVD
  • Apple shaped figure

Women = >0.85

Men = >1

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16
Q

What is increased visceral fat associated with?

What does comparision of normal and T2D CT look like?

A

Metabolic syndrome:

    • hypertension risk
    • hyperlipiodaemia risk
    • impaired glucose tolerence progressing to type 2 diabetes risk
  • CVD
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17
Q

Why is visceral fat a problem?

A
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18
Q

What are the main associated health risks with obesity?

A
  1. •Diabetes
  2. •Hyperlipidaemia
  3. •Hypertension
  4. •CVD
  5. •Heart failure
  6. •Atrial fibrillation
  7. •Stroke disease
  8. •Venous thrombosis
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19
Q

What are the musculoskeletal risks with obesity?

A
  • Osteoarthritis
  • Gout
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20
Q

What are the gastrointestinal risks with obesity?

A
  • Hepatic disease
  • NASH
  • Cirrhosis
  • Gall stones (Cholelithiasis)
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21
Q

What are the renal risks with obesity?

A
  • Chronic kidney disease
  • Renal stones
  • Urinary incontinence
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22
Q

What are respiratory risks with obesity?

A

Sleep apnoea

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23
Q

What are the 2 main drugs used for weught loss in EU?

A

Orlistat - 60-120mg / day - Oral - intestinal lipase inhibitor, reducing fat absorption by 30%

Liraglutide - 3mg / day - SC injection - GLP-1 agonist, reducing hunger and delaying gastric emptying

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24
Q

What are the 3 types of surgery fpr weight loss?

A

Gastric bypass

Gastric banding

Duodenal bypass

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25
Q

What should glucose levels be and what are the dangers when out of this range?

A
  • Normal circulating [glucose] is 4-5 mM.
  • [glucose] below ~4 mM causes problems:
  • [glucose] < 1-2 mM and brain cannot sustain activity
  • brain is obligate glucose utilising tissue

•[glucose] above 7-8 mM is also dangerous:

  • glycation of proteins
  • peripheral and CNS neuron damage
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26
Q

What are the 3 main sources of glucose?

A
  • Glycogenolysis
  • Gluconeogenesis
  • Diet
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27
Q

What are the properties of glucose uptake?

A
  • Mediated by series of glucose transporters
  • Glucose transporters = proteins in cell surface
  • Channels form which allow transport across membrane
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28
Q

What is the main GLUT and why is it different from the others?

A

GLUT 4

Is the only insulin-dependent one

1-5 = don’t require ATP

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29
Q

What is the purpose of kinases in cells during glucose sensing?

A

Remove GLUT2 transporter from cell once glucose is in the cell

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30
Q

What is the order of events of glucose sensing in the brain of neonates and adults?

A
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31
Q

What 2 things directly cause insulin release in pancreatic ‘beta’-cells?

A

+ calcium ion concentration

G coupled protein binding

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32
Q

What are the properties of the insulin receptor?

A
  • Is a tetramer (has 4 subunits)
  • Beta subunits are in the membrane
  • Alpha subunits are above membrane
  • Subunits are attached by disulphide bridges
  • Kinase domains phosphorylase other proteins
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33
Q

What are the early events of insulin signalling?

A
  • Insulin binds as a monomer
  • 2 identical binding sites per receptor
  • Receptors are activated by conformational change from insulin binding
  • ‘Beta’-subunit tyrosine kinase domains trans-phosphorylate one-another
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34
Q

What are the second early events of insulin signalling?

A
  • Phosphorylated insulin receptor cytoplasmic domain acts as docking site for various IR effectors
  • IR effects contain specific phosphotyrosine (pY) binding domains
  • PTB and SH2 domains bind pY motifs
  • IR tyrosine phosphorylates IRS, Shc and SH2 proteins
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35
Q

What are the third early events of insulin signalling?

A
  • Phosphorylated IRS proteins recruit critical signallinh protein complex PI3K
  • PI3K = heterodimeric enzyme composed of p85 and p110 subunits
  • p110 = catalytic
  • p85 = alpha and beta isoforms
  • p110 = alpha, beta, gamma and δ isoforms
  • PI3K phosphorylates PIP2, creating PIP3
  • PIP3 acts as docking site for proteins containing PH domains
  • PTEN antagonises PI3K and converts PIP3 back to PIP2
36
Q

What are the fourth early stages of insulin signalling?

A
  • Phosphorylated IRS proteins recruit Grb2
  • SH2 and 3 domains
  • Grb2 recruits and activates SOS
  • GEF interacts with Grb2 SH3 domains
  • SOS stimulates activity of Ras GTPase
37
Q

What are the later events of insulin signalling?

A
  • Kinases relay IR signalling downstream to effectors
  • PKB = + important kinase
    • pH domain
    • Pro-survival/growth
38
Q

What switch off insulin signalling?

A

Phosphotases

Kinases

39
Q

What is GLUT4 and its importance?

A

A high affinity glucose transporter

  • Predominantly expressed in muscle and adipose (muscle = 90% insulin dependent glucose uptake)
  • Mediates insulin-dependent glucose uptake
  • Predominantly intracellular in insulin absence (stored in GLUT4 storage vesicles (GSVs))
  • Re-distributed to plasma membrane in insulin-dependent fashion
40
Q

What are the results of insulin signalling in the liver?

A
  • Gluconeogenesis inhibited by PP1 activation and phosphofructokinase-2 activation
    • glycolysis
    • glycogen synthesis
    • cholesterol synthesis
    • FA and TAG synthesis
    • VLDL synthesis
    • FA oxidation
    • protein synthesis rate
41
Q

What are the results of insulin signalling on muscle?

A
    • GLUT4 in PM
    • glycolysis
    • glycogen synthesis
    • FA oxidation
    • TAG uptake
    • protein synthesis rate
42
Q

What are the results of insulin signalling on adipose?

A
    • GLUT4 in PM
    • lipolysis
    • FA and TAG synthesis
    • plasma TAG clearance
    • protein synthesis rate
43
Q

What does your BMI have to be to class you as obese?

A

> 30

44
Q

How does the body deal with excess energy?

A
  • Converting it to fat and storing it in adipose tissue
  • Burnt by extra exercise
  • Diverting it into heat production (in brown adipose tissue - UCP1)
45
Q

What events occur during body mass homeostasis?

A
  • Adipocyte releases peptides that signal the brain centre that inhibits eating behaviour and increases motor activity
  • Leptin stimulates region that suppresses appetite
    • fatty acid synthesis
    • fatty acid degradation
  • Leptin stimulates sympathetic nervous system
  • Leptin inhibits fatty acid synthesis and activates fatty acid oxidation in liver and muscle
46
Q

What is adiponectin and it’s function?

A

Peptide hormone, produced by adipose tissue

    • insulin sensitivity
  • Anti-inflammatory effect
    • fatty acid uptake and beta-oxidation and muscle and liver
    • fatty acid synthesis and gluconeogenesis
47
Q

What is peroxisome proliferator-activated receptors (PPARs) and their function?

A

Transcriptional factor that responds to dietary lipids

  • Promotes fat storage in adipose tissue
  • Promotes fatty acid oxidation in muscle and liver
  • Promotes adipocyte differentiation from pre-adipocyte
  • Acts by forming heterodimers with another transcripti9nal factor RXR
48
Q

How do the 3 types of PPARs work?

A
49
Q

What factors released by adipocyte affect peripheral tissues and how?

A
  • Resistin - increase insulin resistance
  • TNF(alpha) - increase insulin resistance
  • Free fatty acids - increase insulin resistance
50
Q

What are the effects, molecularly, of fat accumulation?

A
  • Dysregulation of adipokine production (i.e. leptin)
51
Q

What are the effects of obesity on fat storage and what are its consequences?

A
  • Adipocytes are filled with TAGs so no more can be stored in adipose tissue to meet demand
  • Adipocytes are insulin resistant
  • Decreased expression of genes promoting adipocyte development (i.e. PPAR)
  • Increased expression of genes promoting adipocyte development in muscle and liver
    • fat storage in muscle and liver
  • Excess TAG in muscle and liver = TOXIC
52
Q

What is the endocrine signalling from adipose tissue mechanism in obesity?

A
  • Insulin resistance –> + glucose output from liver
    • glucose uptake by muscles
    • adipose
    • blood glucose
53
Q

How does an increase in free fatty acids lead to insulin resistance?

A
  • Lead to inflammation –> + inflammatory cytokines
  • Inflammatory cytokines inhibit insulin signalling
54
Q

What are the basic principles of type 2 diabetes?

A
55
Q

What are the steps leading to type 2 diabetes?

A
  • Increase in insulin resistance
    • fatty acids
  • Beta cell compensation - hyperinsulinemia
  • Beta cells cannot meet insulin demand due to + glucose output and insulin resistance
  • Impaired glucose tolerance and + glucose in blood
  • Decreased insulin secretion due to insulin resistance
  • Diabetes
56
Q

What are the HBA1c values for pre-diabetics?

A

42-47 Mmol/mol

57
Q

What things put people at higher risk of developing type 2 diabetes?

A
  • Relative with it
  • Ethnicity
  • Obesity
  • Previous IGT, IFG or gestational diabetes
  • Dyslipidaemia
  • Sedentary lifestyle
  • Smoker
  • Small birth weight
58
Q

What is the patholhysiology of type 2 diabetes?

A
  • Insulin resistance –> ageing, genetics, obesity
  • Environmental factors –> Improper diet, sedentary lifestyle
  • + fatty acids –> + lipolysis in visceral fat
  • Increased glucose output –> + gluconeogenesis
  • Hyperinsulinemia –> B-cell compensation
  • - insulin secretion
  • B-cell decompensation
  • Impaired glucose tolerance
  • Type 2 diabetes
59
Q

What is the diabetes prevention programme for?

A

Prevent or delay development of type 2 diabetes in someone with IGT

60
Q

How is Metformin used?

A

850mg twice daily

61
Q

What are the pharmacological strategies to prevent type 2 diabetes?

A
  • Reduce endogenous liver glucose production
  • Stimulate insulin secretion
  • Reduce insulin resistance
  • Reduce gut absorption of glucose
  • Suppress appetite
  • Delay gastric emptying
  • Increase urinary glucose secretion
62
Q

What are the functions of Metformin?

A
  • Reduce endogenous liver glucose production
  • Reduce insulin resistance
63
Q

What is the function of sulphonylureas?

A

Stimulate insulin secretion

64
Q

What is the function of DPP4 inhibitors?

A

Stimulate insulin secretion

65
Q

What are the functions of GLP-1 analogues?

A
  • Stimulate insulin secretion
  • Suppress appetite
  • Delay gastric emptying
66
Q

What is the function of glitazones?

A

Reduce insulin resistance

67
Q

What is the function of alpha glucosidase inhibitors?

A

Reduce gut absorption of glucose

68
Q

What is the function of SGLT2 inhibitors?

A

Increase urinary glucose excretion

69
Q

What is the mechanism of metformin?

A

Inhibit electron complex in mitochondria

70
Q

What are the positives of Metformin?

A
  • Inexpensive
  • Weight neutral
  • Effective glucose lowering
  • Probably cardio-protective
  • Possibly cancer-protective
71
Q

What are the negatives of Metformin?

A
  • Not tolerated in up to 20% of patients
  • eGFR < 30 ml/min contraindicated
72
Q

What are the positives of sulphonylureas?

A
  • Cheap
  • Lowers glucose
73
Q

What are the negatives of sulphonylureas?

A
  • Weight gain
  • Hypoglycaemia
  • CVD risk ?
74
Q

How do sulphonylureas work?

A

+ insulin secretion

75
Q

What are the positives of alpha glucosidase inhibitors?

A
  • Lowers glucose
  • No hypoglycaemia
  • CVD risk lowered ?
76
Q

What are the negatives of alpha glucosidase inhibitors?

A
  • Poorly tolerated (GI side effects)
  • Relatively weak
  • Avoid if GFR < 30 ml/min
77
Q

How do alpha glucosidase inhibitors work?

A
78
Q

What are the positives of PPAR gamma activator?

A
  • Lowers glucose
  • Improved CVD risk
  • No hypoglycaemia
  • Ok in renal disease
79
Q

What are the negatives of PPAR gamma activator?

A
  • Weight gain (5-7 kg)
  • Fluid retention
  • Heart faikure
  • Anaemia
  • Increased bone fractures
  • Increased bladder cancer risk
80
Q

How does GLP-1 work on pancreas?

A

Alpha-cells:

  • Reduces post-meal glucagon secretion

Beta-cells:

  • Increases glucose-dependent insulin secretion
81
Q

How does GLP-1 work on liver?

A

Increased insulin and reduced glucagon in portal vein reduces hepatic glucose output

82
Q

How does GLP-1 work on stomach?

A

Slows gastric emptying

83
Q

How does GLP-1 work on hypothalamus?

A

Promotes satiety and reduces appetite

84
Q

What is the overall result of GLP-1 use?

A

Lowers blood sugar and weight loss overtime

85
Q
A

Medicine 1 (28 decks)

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