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LCRS Year 2 - Endocrinology > Type 2 Diabetes Mellitus > Flashcards

Type 2 Diabetes Mellitus Flashcards

1
Q

What is the definition of diabetes mellitus?

A

‘A state of chronic hyperglycaemia sufficient to cause long-term damage to specific tissues, notably the retina, kidney, nerves, and arteries’

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2
Q

What levels of fasted glucose, 2 hours after glucose tolerance test, and random glucose in normal people and diabetic patients?

A

Normal

  • fasted - <6.0mmol/L
  • 2 hour - <7.8mmol/L
  • random - <11.1mmol/L

Diabetic

  • fasted - >7.0mmol/L
  • 2 hour - >11.1mmol/L
  • random - >11.1mmol/L
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3
Q

What are the gaps between fasted glucose 6-7mmol/L and 2 hour glucose 7.8-11.1mmol/L called?

A

Impaired fasting glucose
- fasted glucose between 6.0 and 7.0mmol/L

Impaired glucose tolerance
- 2 hour glucose between 7.8 and 11.1mmol/L

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4
Q

Is diabetes prevalent in today’s society?

A

Yes
Reaches almost 10% at 60yrs +
- mostly T2DM
- prevalence varies enormously but is INCREASING

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5
Q

What is worrying about the age of people diabetes is occurring and being diagnosed in?

A

Occurring and being diagnosed in younger and younger people, now in children for example

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6
Q

Which groups are at most risk of developing diabetes?

A

Greatest risk is in ethnic groups that move from rural to urban lifestyle

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7
Q

What is MODY?

A

Mature onset Diabetes of the Young
- single-gene heretidary condition
- autosomal dominant
Causes ineffective pancreatic Beta cell insulin production

Specific treatment for each type

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8
Q

Where may mutations be found in MODY and what is the family history of this and obesity?

A

Mutations may be in transcription factor genes and the glucokinase gene
- positive family history of this but not of obesity

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9
Q

What is the pathophysiology of T2DM?

A

Insulin resistance

Insulin secretion defects

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10
Q

What hormones modulate insulin resistance?

A

Adipocytokines

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11
Q

What condition are diabetes-predisposing genes involved with and how may it predispose that person to diabetes?

A

IUGR - IntraUterine Growth Restriction

- being born light is associated with later diabetes development

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12
Q

How can certain fatty acids and obesity cause diabetes?

A

Certain fatty acids and obesity cause progression of insulin resistance

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13
Q

What effects can insulin resistance cause?

A

Mitogenic effects
Metabolic dyslipidaemia (basically the ‘bad’ lipids like LDL cholesterol and triglycerides are high in the blood, increases atheroma formation)
- causes macrovascular disease

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14
Q

Which of microvascular and macrovascular disease is found in the elderly generally and which is usually caused specifically by diabetes?

A

Macrovascular (general blood vessel disease like atherosclerosis) is found in the elderly generally

Microvascular (organ specific disease, retinopathy, nephropathy etc) is usually as a result of the diabetes (most of these require the constant hyperglycaemia of diabetes to happen)

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15
Q

What have studies in twins shown about T1/T2DM?

A

Shown that T2D behaves as if it is autosomal dominant (from a rough Punnet square from the results) but we don’t know the specific genes that cause it. MODY is a single-gene disease but T2D has multiple genes involved
- shows T2D is more genetics-based while T1D is more environment-based

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16
Q

How does insulin production change with age and why?

A

Decreases

- beta cell reserve decreases with age so less insulin made

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17
Q

How does insulin resistance change with age and is this inevitable?

A

Resistance increases with age
- fairly inevitable, some individuals have poorer beta cell function or a higher natural insulin resistance and will develop T2D earlier than normal people

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18
Q

What form, on a graph, does the relationship between insulin resistance and insulin release take, why is this important, and when should action take place?

A

Two converging lines

  • insulin secretion starts high and descends with age
  • insulin resistance starts low and ascends with age

Important point is when the two cross over. Once there is a deficit between the two (resistance higher than secretion), you get T2D
- preventative action should take place before the two lines cross over

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19
Q

Where does insulin resistance occur and why is this a problem?

A

POST-RECEPTOR metabolic mechanism
- makes treatment a bit more complex than T1D (just give insulin) since the body is already not responding healthily to the endogenous insulin

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20
Q

What are the 3 insulin-related problems in T2D?

A

Defective insulin secretion - less insulin made for a given glucose challenge than normal

Inability to switch off HGO (hepatic glucose output, insulin normally does this)

Inability to drive glucose into muscle via GLUT-4

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21
Q

What is the metabolism and presentation of T2DM?

A

Heterogeneous (range of conditions with the common ultimate result of hyperglycaemia)
Obesity - 80% of patients
Deficit in insulin resistance and insulin secretion
Hyperglycaemia - impaired glucose disposal, increased hepatic glucose production both contribute to high fasting blood glucose
Dyslipidaemia
Acute and chronic complications (chronic is usually T1D, acute complications like heart attacks and strokes are mainly how T2D presents)

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22
Q

What is the purpose of adipose tissue?

A

Fat produces lots of hormones to communicate with the brain - to tell whether food intake is needed or not
- in this case, fatty acids aren’t just an energy store but also act as a hormone in this pathway

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23
Q

Is obesity just a precipitant or more than that, which molecules are important in obesity, and is central or peripheral obesity/fat more dangerous?

A

Obesity is much more than a precipitant

  • fatty acids and adipocytokines are important
  • central (also known as omental) obesity is the most important form in that it increases your risk of other diseases much more than cutaneous fat
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24
Q

What is centripetal adiposity and what is it an important predictor of?

A

Centripetal adiposity is the fat deposited around your waist

- important predictor of risk of ischaemic heart disease

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25
Q

What role do adipocytokines play in diabetes?

A

MODULATE INSULIN RESISTANCE
- don’t directly cause the diabetes but if they increase insulin resistance then the insulin secretion/resistance deficit obviously closes and diabetes becomes more likely

26
Q

What are the is the main molecule in adipocytes, what two molecules is it broken down into and what is the fate of each metabolite?

A

Triglycerides
- broken down to glycerol and non-esterified fatty acids

Glycerol travels to the liver where it is used to make glucose via gluconeogenesis

The fatty acids go to the liver, are chopped up into 2-carbon segments and CANNOT be used to make glucose - instead used to make very LDL triglycerides which are ATHEROGENIC (contributes to atherogenic profile of insulin resistant patients)

27
Q

Where is the breakdown of triglycerides particularly marked and what does this mean?

A 
Omental adipocytes (centripetal fat)
- reason why waist circumference is predictive of ischaemic heart disease risk
28
Q

Given that obesity is such a strong contributing factor to and is so prevalent in, patients with T2D, what is a good treatment option involving this?

A

Weight reduction

- reduces the omental fat and harmful adipocyte number

29
Q

What problems have perturbation in gut microbiota been associated with?

A
  • Obesity, insulin resistance in T2D
  • Host signalling
  • Bacterial lipopolysaccharides fermentation to short chain fatty acids, bacterial modulation bile acids (various lipopolysaccharides fermented by gut bacteria to short chain fatty acids which enter the circulation and modulate bile acids)
  • Most studies are correlative rather than causative
30
Q

What is a common side of effect of diabetes treatment?

A

Weight gain is a common side effect of diabetes treatment

  • METFORMIN is the only agent that reduces weight)
  • older drugs usually cause some weight gain
31
Q

There is an excellent graph in the presentation which has every factor in developing or altering the course of T2D, what are the 4 stages of T2D development and what are involved in each stage? (see the graph)

A

Early life
- Genes
- Intra-uterine environment
Adult years
- gene and intrauterine effects can be modulated by adipocytokines and microbiota
- exercise and diet are important in effect on insulin resistance
Insulin resistance/secretion interaction
- lines on the graph getting close together, T2D about to develop
- medication can help prevent this
T2D stage
- absolute insulin deficiency (lines have crossed and there is now a clear deficit)

32
Q

How does T2DM present and why do patients not present earlier?

A
  • Osmotic symptoms (high plasma glucose, can leak into the urine, drinking a lot of water, passing a lot of urine)
  • Infections
  • Screening tests
  • At presentation of complication - acute; hyperosmolar coma, chronic; ischaemic heart disease, retinopathy

Presentation is based on how quickly patients come to the doctor. Males particularly bad at going to the doctors about problems, on average 11 years living with T2D before they present. Sometimes patients present with a heart attack which, if they had presented earlier, could’ve been prevented

33
Q

What are the microvascular complications of T2D?

A

Retinopathy
Nephropathy
Neuropathy

34
Q

What are the macrovascular complications of T2D?

A

Atheroma in big arteries and veins that cause

  • Ischaemic heart disease
  • Cerebrovascular (stroke)
  • Renal artery stenosis
  • PVD
35
Q

What are the metabolic complications and how common are they?

A

Lactic acidosis
Hyperosmolar
- a lot rarer than in T1D e.g. ketoacidosis very common in T1D

36
Q

What is a complication of T2D treatment?

A

Hypoglycaemia

37
Q

What are the principles that form the basis of management of T2DM?

A

Education
Diet
Pharmacological treatment
Complication screening (finding them before they start)

38
Q

Why do we treat T2D?

A
  • Help symptoms
  • Reduces chance of acute metabolic complications (although rare in T2DM)
  • Reduce the chance of long-term complications
  • Education - people generally only treat things if they have symptoms so have to be educated about complications of poor management even when they feel fine
39
Q

What are T2D patients advised to eat?

A
  • Control total calories, increase exercise (reduce weight overall)
  • Reduced refined carbohydrate (simple carbs, less sugar)
  • Increase complex carbs (spreads out carbohydrate load so first phase insulin not needed)
  • Reduce fat as proportion of calories
  • Increase unsaturated fat as proportion of fat
  • Increase soluble fibre
40
Q

What is monitored in diabetic clinics in assessment of treatment progress?

A

Weight
Glycaemia
Blood pressure
Dyslipidaemia

41
Q

What is an invasive treatment for diabetes if necessary?

A

Gastric bypass surgery

  • surgical option to address morbid obesity
  • allows improved diabetes control
  • adverse events and nutritional deficiency decreased
  • very expensive and sometimes too late
42
Q

What are the drugs that can be used to treat T2D?

A 
Orlistat
Metformin
Sulphonylureas
Alpha-glucosidase inhibitor
Thiazolidinediones
SGLT2 inhibitors (increase glucose excretion by the kidneys)
43
Q

What is Metformin, who is it used in, what does it do, what are its side effects and who is it NOT used in?

A
  • It is a biguanide, an insulin sensitiser
  • Used in more or less everyone with T2DM, in particular, overweight patients where diet alone has not succeeded
  • It reduces insulin resistance (reduced hepatic glucose output, increased peripheral glucose deposition e.g. into muscle)
  • Very safe but has GI side effects
  • NOT used in the ‘big three’ of failure; severe liver failure, severe cardiac failure, mild renal failure
44
Q

How do beta cells detect glucose and release insulin?

A

Glucose enters beta cell

  • is metabolised to ATP which blocks ATP-sensitive K+ channels
  • this leads to opening of voltage-dependent Ca2+ channels
  • Ca2+ influx, like in so many other places, stimulates insulin-containing vesicles to move to and fuse with the beta cell membrane and secrete the insulin
45
Q

How is the process of insulin secretion pharmacologically exploited in treatment?

A

Sulphonylureas act on a specific receptor (unclear but likely the amino acid receptors as amino acids can cause insulin secretion too)

  • sulphonylureas block the ATP sensitive K+ channels by binding to the amino acid receptors and from there the process continues as normal resulting in insulin release
  • thus sulphonylureas are useful for T2D treatment
46
Q

What is an example of a sulphonylurea, who is it used in, and what are the side effects?

A
  • Gliclazide or Glibenclamide (both insulin secretagogue)
  • Used in lean patients with T2D where diet alone hasn’t succeeded
  • Side effects include hypoglycaemia (from inappropriate insulin secretion) and weight gain
47
Q

What is an example of an alpha-glucosidase inhibitor, how does it work, how effective is it, and what is the side effect?

A

Acarbose

  • prolongs the absorption of oligosaccharides
  • allows insulin secretion to cope following the loss of the first phase insulin response
  • this is AS EFFECTIVE as metformin
  • side effect of flatus (gas in the gut) due to sugars reaching the large intestine where they are fermented
48
Q

What is an example of a thiasolidinedione?

A

Pioglitazone

49
Q

How does pioglitazone (thiazolidinedione drug) work and what are its main therapeutic effects?

A

Peroxisome proliferator-activated receptor (PPAR-gamma) agonists

  • insulin sensitiser, mainly peripheral
  • adipocyte differentiation modified - weight gain but it’s peripheral not central
  • improvement in glycaemia and lipids
  • reduces macrovascular disease
50
Q

What is the incretin effect?

A

An oral glucose load triggers a bigger release in insulin than IV glucose
- related to GLP-1 which is secreted in response to presence of food in the gut

51
Q

What is GLP-1, where is it secreted and by what, and what does it do?

A

Glucagon-like Peptide-1

  • gut hormone, transcription product of the pro-glucagon gene
  • produced by the L-cell in the gut lining
  • stimulates insulin and suppresses glucagon
  • increases beta cell glucose sensitivity
  • also increases satiety so can cause weight loss if administered therapeutically
52
Q

What are gliptins and what is the benefit of these compared with GLP-1 injections?

A

Gliptins are DPP-4 inhibitors

  • inhibit DPP-4 from breaking down GLP-1
  • GLP-1 injections have a short half-life due to the rapid breakdown by DPP-4 so these can be co-administered or gliptins alone can be administered to have a longer effect
53
Q

What are the main effects of GLP-1 injections vs the main effects of Gliptins?

A

GLP-1 agonists - Decrease glucagon
Decrease glucose
Weight loss

Gliptins -
Increase half-life of endogenous GLP-1
Increase concentration of GLP-1
Decrease glucagon
Decrease glucose
Neutral on weight
54
Q

How do SGLT2 inhibitors help treat T2D?

A

Block SGLT2

  • these are channels that allow for reabsorption of glucose in the kidneys
  • therefore reduces glucose reabsorption and increases excretion of glucose in the urine
55
Q

What is an example of an SGLT2 inhibitor, what are its effects and what effects do they have on mortality and heart failure risk?

A

Empaglifozin

  • inhibits Na/Glu transporter (SGLT2), increases glycosuria
  • LOWERS HbA1c
  • 32% reduction in all mortalities
  • 35% reduction in risk of heart failure
56
Q

What are two other aspects of diabetes that should be controlled and are there benefits to treating them?

A

Blood pressure

  • treating is almost inevitable, occurs in almost 90% T2DM cases
  • clear benefits to treatment

Diabetic dyslipidaemia

  • cholesterol is increased
  • triglycerides are increased
  • healthy HDL cholesterol is decreased
  • clear benefits to treatment
57
Q

What are the problems with screening for diabetes and what has been found about preventing T2D?

A

There isn’t really a clear way of screening people effectively for diabetes
- it was found that an intensive lifestyle with a good diet and exercise is better than metformin in reducing the incidence of T2DM (preventative dose given before T2D had even developed)

58
Q

Type 1 and type 2 diabetes are fairly different. How do they differ in terms of prevalence, typical age, onset, habitus (body type), family history, geography?

A

Type 1

  • Prevalence - 0.25%
  • Typical age - child, adolescent
  • Onset - typically acute
  • Habitus - lean
  • Family history - uncommon
  • Geography - europids

Type 2

  • Prevalence - 4-7%
  • Typical age - middle-age+
  • Onset - gradual
  • Habitus - often obese
  • Family history - common
  • Geography - less europids
59
Q

Type 1 and type 2 diabetes are fairly different. How do they differ in terms of; presence of weight loss, whether they’re ketosis prone, serum insulin state, HLA (genetic) association, Islet beta cells state, islet cells antibodies presence?

A

Type 1

  • Weight loss - usual
  • Ketosis prone - yes
  • Serum insulin - low or absent
  • HLA association - DR3, DR4
  • Islet beta cells state - destroyed
  • Islet cell antibodies presence - present (autoimmune destruction)

Type 2

  • Weight loss - uncommon
  • Ketosis prone - no
  • Serum insulin - variable
  • HLA association - none
  • Islet beta cells state - still functioning
  • Islet cell antibodies presence - absent (no autoimmune destruction)
60
Q

What are the key points around type 2 diabetes mellitus?

A
  • Common and increasing
  • Major life threatening complications (not in any way ‘mild’)
  • Aetiology and pathophysiology still not clarified
  • Glucose, but also weight, hypertension and dyslipidaemia all contribute
  • Treatments have good evidence bases

LCRS Year 2 - Endocrinology (21 decks)

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