Lecture 17: Type 2 Diabetes Flashcards
1
Q
What is Type 2 diabetes?
A
- Relative insulin insufficiency
- Insulin is secreted but cant overcome the insulin resistance
2
Q
How do we diagnose type 2 diabetes?
A
- Hyperosmolar Hyperglycaemia state (HHS)
- HbA1C over 48
- Fasting glucose: over 7, 2 hours after meal above 11
3
Q
What are the 3 treatment targets of Type 2 diabetes?
A
- Lipids
- Blood pressure
- Blood glucose
4
Q
When HbA1c is less than 9% what type of therapy is used?
A
- Consider monotherapy
- Lifestyle and metformin
5
Q
When HbA1c is greater than or equal to 9%, what therapy is used?
A
- Consider dual therapy
- Lifestyle management, metformin and an additional agent
6
Q
When HbA1C is greater than or equal to 10% and blood glucose is greater than or equal to 300mg/dl what therapy is used?
A
- Combined injectable therapy
7
Q
Give an example of a Thiazolidinediones?
A
- Pioglitazone
8
Q
Give an example of an alpha-glucosidae inhibitor?
A
- Acarbose
9
Q
What do DPP4 inhibitors end in and SGLT2 inhibitors and GLP 1 agonists?
A
- Liptin
- liflozin (dapagliflozin)
- tide, lixisenatide
10
Q
What do sulphonylureas end in?
A
- ide, gliclazide
11
Q
What are side effects of metformin? What is the expected HbA1c drop for metformin, thiazolidinediones, sulfonylureas, DPP4 inhibitors, SGLT2, GLP1?
A
- GI symptoms: diarrhoea, N& V
- 1-2%
- 0.5-1.4%
- 1-2%
- 0.8%
- 1-1.5%
- 0.5-1%
12
Q
What are the side effects of Thiazolidinediones?
A
- Weight gain
- Oedema
- Aneamia
- Gi disturbances
- Headache
- Dizziness
- Visual disturbances
13
Q
What are the side effects of sulfonylureas?
A
- Hypoglycaemia
- GI disturbance
- Weight gain
- Rashes
- Liver function derangment
- Hyponatraemia - for gliclazide and glipizide
14
Q
What are the side effects of DPP4 inhibitors?
A
- GI disturbances
- Headache
- Nasopharyngitis
- Rash
- Musculoskeletal: sitagliptin and saxagliptin
15
Q
What vare the side effects of SGLT2?
A
- Dyslipidaemia
- UTI
- Thrush
- Nausea
- Constipation
- Fourniers Gangrene
- low BP
16
Q
What are the side effects of GLP-1
A
- Gi disturbances (N+V, indigestion)
- Hypoglycaemia
- Headache
- Dizziness
- Skin reactions: rash, pruitis
17
Q
What is the pathogenesis of type 2 diabetes?
A
- Genetic and environmental predisposition: obesity, sdentary lifestyle
- Insulin resistance occurs as insulin binds to receptors all the time and becomes desensitised
- B cells try to compensate by releasing more insulin
- B cells become exhausted and cant keep up wih peripheral demand of insulin and insulin secretion decreases
18
Q
How do free fatty acids lead to insulin resistance
A
- When in excess they are transformed into second messenger DAG
- DAG activates Sr/Thr kinases which phosphorylate insulin receptor (desensiises)
- This attenuates (reduce force)
insulin receptor signal
19
Q
How do Adipokines link to obesiy and insulin resistance?
A
- Released by adipocytes
- Pro-hypergliceamic or anti-hyperglicaemic
- Adiponectin is anti-hyperglycaemic becuase it improves insulin sensitivity by activating AMPK, reduces liver lipogenesis, leading to improved insulin sensitivity
- Adiponectin expression is reduced in obesity
20
Q
How does inflammation reduce insulin sensitivity?
A
- Adipocytes produce Il-6 and Il-1 which attract macrophages to fat deposits and damage insulin receptor
- Reduction of cytokines improve insulin sensitivity
21
Q
How does PPARy improve insulin sensitivity?
A
- Nuclear receptor involved in adipocyte differentiation
- Promotes secretion of anti-hyperglycaemic adipokines
- Agonists used in therapy
- When activated -> promotes adiponectin
22
Q
What is the first therapy given in type 2 diabetes?
A
- Die and excercise
- Excercise helps w/ insulin function -> increases sensitivity to insulin causes translocation of GLUT4 to the surface
23
Q
What is the mechanism of action of Thiazolidinediones (Pioglitazone)?
A
- Agonist of nuclear receptor PPARy
- Promotes expression and secretion of anti-hyperglycaemic adipokines
- Increases insulin sensitivity and reduce resistance
24
Q
What are monitored when Thiazolidinediones are used and wha counselling should be done?
A
- LFTs: before and periodically after
- Risks of livr toxicity: N&V, abdominal pain, dark urine
- Sick day rules
25
What is the mechanism of action of Metformin?
- Acivates AMPK (adiponectin)
- Reduces liver lipogenesis, increases insulin sensitivity
- Increases GLP-1 secretion, stimulates insulin secretion and reduces glucagon secretion
- Reduces gluconeogenesis and glycogenolysis
- Reduces hepatic glucose production
26
What are the side effects of metformin?
- Low B12 levels
- Lactic acidosis
- GI disturbances
- Reduced appetite
- Taste disturbances
27
What are some contraindications of metformin?
- eGFR under 30: dont prescribe (risk of lactic acidosis)
- Between 30-44, reduce dose (dont initiate)
- Alcohol increases risk of lactic acidosis, beta blockers can mask signs of hypo
- Dont initiate in DKA
28
Wha should be monitored when taking metformin?
- Check renal function before starting then annually, 2 x a year if additional risk factors
- Test B12 defieciency is suspected
29
What is the mechanism of action of sulfonylureas?
- Binds to sulfonylurea receptors expressed on membranes on B cells
- Block ATP sensitive K+ channels in B cells
- K+ accumulates inside cells
- B cells depolarise
- Ca2+ channels open and allow insulin secretion
30
Name examples of sulfonylureas?
- Gliclazide
- Glimepiride
- Glipizide
- Tolbutamide
- Glibenclamide
31
What does alpha glucosidae inhibitors (acarbose) do?
- Delay carbohydrates absorption, reducing the postprandial increase in blood glucose
32
What is the mechanism of action of SGLT2 inhibitors?
- Blocks SGLT2 in proximal renal tubules, prevents glucose reabsorption
- Increases glucose excretion in urine
- Causes natiuresis (Na excretion): for each molecule of glucose excreted a molecule of sodium is excreted
33
Name examples of SGLT2 inhibitors?
- Canagliflozon
- Dapagliflozin
- Empagliflozin
- Ertugliflozin
34
What is the mechanism of action of GLP 1 agonists?
- Binds and activates the GLP1 (glucagon like peptide 1 receptor) to increase insulin secretion and suppress glucagon secretion
- Slows gastric emptying
- GLP1 is released from intestinal L cells in response to eating. This secretion is impaired in T2DM
35
Name some examples of GLP-1 agonists?
- Exenatide
- Liraglutide
- Lixisenatide
- Dulaglutide
- Semaglutide
- Tirzepatide
36
What is the mechanism of action of DPP-4 inhibitors?
- Inhibits dipetidylpeptidase - 4 to increase insulin secretion and decrease glucagon secretion
- Increases incretins GLP-1 and GIP
37
Name some examples of DPP-4 inhibitors?
- Alogliptin
- Linagliptin
- Sitagliptin
- Saxagliptin
- Vildagliptin
38
What are the risk factors for type 2 diabetes?
- Obesity
- Age
- Family history
- Gestational diabetes
- PCOS
- Ethnicity
- Hypertension
- Sedentary lifestyle
39
What are the defects of type 2 diabetes?
- Brain: neurotransmitter dysfunction
- Gut: decreased incretin effect
- Liver: Increased hepatic glucose production
- Muscle: Decreased glucose uptake
- Kidney: Increased glucose reabsorption
- Adipose: Accelerated lipolysis
- Pancreas: Decreased insulin secretion and increased glucagon secretion
40
What are the counselling poinst for metformin?
- Take with or just after food
- Dont chew tablet, swallow whole
- Sick day rules: if unwell (shouldnt take)
41
What are some oral dose counselling for Semaglutide and other oral drugs?
- Tablets shouldnt be crushed, chewed ior split
- Store in original blister package
42
What is the initiation criteria for GLP-1?
- If triple therapy with metformin and 2 other oral drugs is not effective, consider triple therapy by switching 1 drug to GLP-1 with T2DM w/ BMI over 35 or when weight loss would benefit, w/ indicators of high risk ASCVD
43
What is the criteria to continue a GLP1?
- If person has had a beneficial metabolic response at least 11mmol/mol HBA1C and a weight loss of at least 3% of initial body weight in 6 months
44
What is hyperosmolar hyperglycaemic state?
- Occurs in type 2 diabetes due to relative deficiency of insulin
- Mostly older patients
- Must be diagnosed promptly and managed intensively
45
What are the signs, symptoms and precipitating factors?
- Precipitating factors: Pneumonia, Urinary tract infections, cerebrovascular disease, MI, trauma
- Symptoms: Hyperviscosity and increased risk of thrombosis (blood sticky), Neurologic signs, N&V, disordered mental function
46
How do you diagnose HHS?
- Hypovalemia
- Hyperglycaemia: above 30mmol/L without significant hyperketonaemia under 3mmol/L
- Osmolarity over 320mosmol/kg
- No acidosis - normal pH
47
How do you manage HHS?
- Fluid replacement: Restore peripheral perfusion, lower BG, shift water intracellularly
- Insulin: only given if BG not fallen from initial fluids
- Electrolytes: Monitor K levels
- Anticoagulation: low molecular weight heparin
- Treat underlying cause: antibiotics if infection
48
What is the pathophysiology of HHS?
- Blood glucose rises to extreme levels >30mmol/L
- This leads to osmotic diuresis - high glucose leads to excessive urination
- Leads to fluid loss and electrolyte imbalance
- Unlike DKA no significant ketone production; some insulin still present
- Blood becomes concentrated due to dehydration
