Endo - T2DM

Question 1

What is T2DM?

Answer 1

→ combination of insulin resistance + beta-cell failure result in hyperglycaemia
→ Associated with obesity but not always
→ resultant chronic hyperglycaemia may initially be managed by changes to diet / weight loss and may even be reversible
→ over time glucose lowering therapy including insulin, is needed

Question 2

What contributes to the insulin resistance in T2DM?

Answer 2

→ genetic risk

→ obesity

Question 3

Can DKA be a feature of T2DM?

Answer 3

yes

Question 4

When can T2DM present in a person’s life?

Answer 4

→ commonly thought to be only a condition of late adulthood

→ literally in every decade tho

Question 5

What is the trend in prevalence of T2DM? Why?

Answer 5

→ varies enormously
→ increasing prevalence
→ occurring + being diagnosed in younger groups
→ greatest ethnic groups moving from rural to urban lifestyle

Question 6

What are the stages of development for T2DM?

Answer 6

→ normal state = normal glucose + insulin production + insulin resistance
→ intermediate state = impaired fasting glucose + impaired glucose tolerance + pre-diabetic or non-diabetic hyperglycaemia + increasing insulin production + insulin resistance
→ T2DM = low insulin production + insulin resistance

Question 7

What are the fasting glucose levels for someone with impaired fasting glucose?

Answer 7

6 < x < 7 mmol/L

Question 8

What are the glucose levels after an OGTT for impaired glucose tolerance?

Answer 8

7.7 < impaired glucose tolerance < 11 mmol/L

Question 9

What are the HbA1c levels for pre-diabetic or non-diabetic hyperglycaemia

Answer 9

42 < pre-diabetic or non-diabetic hyperglycaemia < 48 mmol/L

Question 10

What is relative insulin deficiency?

Answer 10

Insulin is produced by pancreatic beta-cells but not enough to overcome insulin resistance → can’t have DKA under usual hyperglycaemic episodes

Question 11

What is long-duration T2DM?

Answer 11

→ beta-cell failure may progress to complete insulin deficiency
→ usually on insulin but can’t come off at risk of DKA

Question 12

What happens to the first phase insulin release in T2DM?

Answer 12

doesn’t exist

Question 13

What happens to uptake of glucose in muscles in T2DM?

Answer 13

reduced insulin action = less uptake of glucose in skeletal muscles

Question 14

What happens to hepatic glucose production in T2DM? Why?

Answer 14

reduced insulin action = increased hepatic glucose production + increased glucagon action

Question 15

What is the relationship between insulin resistance and insulin secretion in T2DM?

Answer 15

→ as insulin resistance increases, insulin secretion also increases
→ directly proportional

Question 16

What is MODY?

Answer 16

→ maturity onset diabetes of the young

→ monogenic inheritance of Diabetes, can’t avoid it

Question 17

What is the polygenic risk of T2DM?

Answer 17

→ polymorphisms increasing the risk of diabetes

→ not born with it but could develop it later depending on other factors

Question 18

What if the effect of individual SNPs on risk of T2DM?

Answer 18

very little effect

Question 19

What if the effect of cumulative SNPs on risk of T2DM?

Answer 19

much bigger

Question 20

What is the role of obesity in T2DM?

Answer 20

→ Major risk factor for T2DM
→ Fatty acids + adipocytokines important
→ Central vs visceral obesity
→ 80% T2DM are obese
→ Weight reduction useful treatment

Question 21

What else is associated with risk of T2DM?

Answer 21

→ Perturbations in gut microbiota

→ Intra-uterine growth retardation

Question 22

What are the symptoms of of T2DM?

Answer 22

→ Hyperglycaemia
→ Overweight
→ Dyslipidaemia
→ Fewer osmotic symptoms
→ With complications
→ Insulin resistance
→ Later insulin deficiency

Question 23

What are the risk factors of T2DM to look for clinically in a patient?

Answer 23

→ Age
→ large BMI
→ ethnicity
→ PCOS
→ family history
→ inactivity

Question 24

How is T2DM diagnosed?

Answer 24

→ First line test for diagnosis is HbA1c :
→ 1x HbA1c >=48mmol/L with symptoms
→ 2x HbA1c >=48 mmol/mol if asymptomatic

Question 25

What is a hyperosmolar hyperglycaemic state?

Answer 25

→ Presents commonly with renal failure.
→ Insufficient insulin (NOT ABSENT) for prevention of hyperglycemia but sufficient insulin for suppression of lipolysis and ketogenesis.
→ Absence of significant acidosis.
→ Often identifiable precipitating event (infection, MI).
→ osmotic diuresis = dehydration

Question 26

How is T2DM managed?

Answer 26

→ Diet
→ Oral medication
→ Structured education
→ May need insulin later
→ Remission / reversal

Question 27

What are the main principles of a T2DM consultation?

Answer 27

→ Glycaemia: HbA1c, glucose monitoring if on insulin, medication review
→ Weight assessment
→ Blood pressure
→ Dyslipidaemia: cholesterol profile
→ Screening for complications: foot check, retinal screening

Question 28

What is the dietary advice over T2DM?

Answer 28

→ Total calories control
→ Reduce calories as fat
→ Reduce calories as refined carbohydrate
→ Increase calories as complex carbohydrate
→ Increase soluble fibre
→ Decrease sodium

Question 29

What are the 4 facets of pathophysiology of T2DM?

Answer 29

Question 30

How are the 4 facets of pathophysiology managed ideally?

Answer 30

Question 31

How are the 4 facets of pathophysiology managed pharmacologically?

Answer 31

Question 32

How does metaformin work?

Answer 32

→ Biguanide, insulin sensitiser
→ First line if dietary / lifestyle adjustment has made no difference
→ Reduces insulin resistance
→ Reduced hepatic glucose output
→ Increases peripheral glucose disposal
→ GI side effects
→ Contraindicated in severe liver, severe cardiac or moderate renal failure

Question 33

How do sulphonylureas work?

Answer 33

→ Normal insulin release requires closing of the
ATP-sensitive potassium channel
→ Sulphonylureas e.g. gliclazide, bind to the ATP-sensitive potassium channel and close it, independent of glucose / ATP

Question 34

How does pioglitazone work?

Answer 34

→ Peroxisome proliferator-actived receptor agonists PPAR-γ
→ Insulin sensitizer, mainly peripheral
→ Adipocyte differentiation modified, weight gain but peripheral not central
→ Improvement in glycaemia and lipids
→ Evidence base on vascular outcomes
→ Side effects of older types hepatitis, heart failure

Question 35

What is a common side effect of glucose lowering therapies and drugs?

Answer 35

weight gain (except in metformin)

Question 36

How can GLP-1 agonists be used to treat T2DM?

Answer 36

→ Liraglutide, Semaglutide
→ Injectable –daily, weekly
→ Decrease [glucagon]
→ Decrease [glucose]
→ Weight loss

Question 37

How can DPP4-inhibitors be used to treat T2DM?

Answer 37

→ Increase half life of exogenous GLP-1
→ Increase [GLP-1]
→ Decrease [glucagon]
→ Decrease [glucose]
→ Neutral on weight

Question 38

How can SGLT-2 inhibitors be used to treat T2DM?

Answer 38

→ Inhibits Na-Glu transporter, increases glycosuria
→ Empagliflozin, dapagliflozin, canagliflozin
→ HbA1c lower
→ 32% lower all cause mortality
→ 35% lower risk heart failure
→ Improve CKD

Question 39

How does beta-cell function change on drug therapies?

Answer 39

function of beta-cells still declines

Question 40

What surgery can induce remission of T2DM?

Answer 40

gastric bypass surgery

Question 41

How else can remission of T2DM be induced?

Answer 41

low calorie diet

Question 42

What are the other aspects need to be considered in T2DM management?

Answer 42

blood pressure
  → hypertension is v common
  → clear benefits in reduction
lipid management
  → clear benefit in lipid-lowering therapy

Question 43

What is GLP-1? Why is it useful in T2DM?

Answer 43

→ Gut hormone
→ Secreted in response to nutrients in gut
→ Transcription product of pro-glucagon gene, mostly from L-cell
→ Stimulates insulin, suppresses glucagon
→ increases satiety (feeling of ‘fullness’)
→ Short half life due to rapid degradation from enzyme dipeptidyl peptidase-4 (DPP4 inhibitor)