Type 2 Diabetes mellitus Flashcards
What is type 2 diabetes?
A condition in which the combination of insulin resistance and beta-cell failure result in hyperglycaemia
Associated with obesity but not always
What is another term for type 2 diabetes?
Relative insulin deficiency
How does development of type 2 diabetes associate with age?
Can present in any decade of life
Increasing in all ages but rapidly in early-adulthood
Outline the epidemiology of type 2 diabetes
Prevalence varies across countries enormously
Increasing prevalence
Occurring and being diagnosed younger
Greatest in ethnic groups that move from rural to urban lifestyle
What are the stages of development of type 2 diabetes?
How is type 2 diabetes diagnosed?
Random glucose >11.1 mmol/L + osmotic symptoms
Describe beta-cell function at diagnosis of T2DM
Usually dropped quite low before diagnosis ~ 50%
Why doesn’t hyperglycaemia normally cause ketosis in T2DM?
Insulin is still being produced by beta cells and this is enough to prevent ketosis
What may be observed in long-duration T2DM?
Beta-cell failure may progress to complete insulin deficiency
Usually on insulin at this point but important not to stop as at risk of ketoacidosis
What factors are involved in the pathophysiology of T2DM?
Genes, intrauterine environment and adult environment
Fatty acids are important in pathogenesis and complications
Insulin resistance and insulin secretion defects
Heterogenous - variable BMI, age and progression across individuals
What happens when an individual with T2DM is given an IV glucose challenge?
First phase insulin release is lost
How does T2DM affect skeletal muscle and hepatic glucose production?
Less uptake of glucose into skeletal muscle
Hepatic glucose production is increased due to both a reduction in insulin action and increase in glucagon action
Aside from diet, what also contributes to high plasma glucose in T2DM?
Impaired glucose disposal (clearance) and increased hepatic glucose production (HGP) contribute to increased fasting plasma glucose
How does insulin secretion differ in an individual with T2DM vs an individual without?
For a given degree of insulin sensitivity, people with T2DM secrete less insulin
Describe the genetics of T2DM
Monogenic -> Single gene mutation ==> Diabetes (MODY)
Polygenic -> Polymorphisms increasing risk of diabetes
Approximately how many hits were there in the GWAS for T2DM and how much did they affect risk?
Approximately 450 hits
Each individual SNP has only a mild effect on risk
However cumulative effect of all SNPs have a bigger effect
What is the role of obesity in T2DM?
Major risk factor for T2DM
Fatty acids and adipocytokines important
Central vs visceral obesity
80% T2DM are obese
Weight reduction useful treatment
What other factors, aside from obesity, are associated with T2DM?
Perturbations in gut microbiota:
- Bacterial lipopolysaccharides fermentation to short chain FA
- Bacterial modulation of bile acids
- Inflammation
Intra-uterine growth retardation
How does T2DM present?
Hyperglycaemia
Overweight
Dyslipidaemia
Fewer osmotic symptoms
With complications
Insulin resistance
Later insulin deficiency
What are the risk factors of T2DM?
Age
PCOS
Higher BMI
Family Hx
Ethnicity
Inactivity
How is type 2 diabetes diagnosed?
First line test: HbA1c
1x HbA1c >/= 48 mmol/L with symptoms
Or
2x HbA1c >/= 48 mmol/L if asymptomatic
What can lead to a type 2 diabetes diagnosis?
Osmotic symptoms
Infections
Screening test: incidental finding
At presentation of complication:
- Acute; hyperosmolar hyperglycaemic state
- Chronic; ischaemic heart disease, retinopathy
What is hyperosmolar hyperglycaemic state?
Insufficient insulin for prevention of hyperglycemia but sufficient insulin for suppression of lipolysis and ketogenesis
Absence of significant acidosis
Often identifiable precipitating event (infection, MI)
What does hyperosmolar hyperglycaemic state commonly present with?
Presents commonly with renal failure
What are the differences between DKA and hyperosmolar hypoglycaemic state?
Compare management of type 1 vs type 2 diabetes
Type 1:
Exogenous insulin (basal-bolus regime)
Self-monitoring of glucose
Structured education
Technology
Type 2:
Diet
Oral medication
Structured education
May need insulin later
Remission / reversal
Both require prevention of diabetes-related complications and their risk factors
What are the principles of a T2DM consultation?
Glycaemia: HbA1c, glucose monitoring if on insulin, medication review
Weight assessment
Blood pressure
Dyslipidaemia: cholesterol profile
Screening for complications: foot check, retinal screening
What are some dietary recommendations for people with T2DM?
Healthy eating or diet:
Total calories control
Reduce calories as fat
Reduce calories as refined carbohydrate
Increase calories as complex carbohydrate
Increase soluble fibre
Decrease sodium
What drug deals with excess hepatic glucose production?
Metformin
What drug(s) deals with resistance to action of circulating insulin?
Metformin
Thiozolidinediones
What drug(s) deal with inadequate insulin production required to combat insulin resistance?
Sulphonylureas
DPP4-inhibitors
GLP-1 Agonists
Boost insulin secretion
What drug(s) deal with excess glucose in circulation?
Alpha glucosidase inhibitor
SGLT-2 inhibitor
What is the first line medication if dietary/lifestyle adjustment has made no difference?
Metformin
What is the mechanism of action of Metformin?
Biguanide
Insulin sensitiser
Reduces insulin resistance by reducing hepatic glucose output and increasing peripheral glucose disposal
What are the side effects and contraindications of Metformin?
GI side effects
Contraindicated in severe liver, severe cardiac or moderate renal failure
What is the mechanism of action of sulphonylureas?
Sulphonylureas eg gliclazide, bind to the ATP-sensitive potassium channel and close it, independent of glucose / ATP
What is Pioglitazone?
Peroxisome proliferator-activated receptor agonists PPAR-γ
Insulin sensitizer, mainly peripheral
What is the mechanism of action of Pioglitazone?
Modifies adipocyte differentiation
What are the effects of Pioglitazone?
Improvement in glycaemia and lipids
Evidence base on vascular outcomes
May cause peripheral weight gain
Side effects of older types hepatitis, heart failure
What is GLP-1?
Gut hormone
Secreted in response to nutrients in gut
Transcription product of pro-glucagon gene, mostly from L-cell
Why is GLP-1 used in the treatment of T2DM?
Stimulates insulin, suppresses glucagon
↑ satiety (feeling of ‘fullness’) - weight loss
However, short half life due to rapid degradation from enzyme dipeptidyl peptidase-4 (DPP4 inhibitor)
What do DPPG-4 inhibitors (gliptins) do?
Increase half life of exogenous GLP-1
Increase [GLP-1]
Decrease [glucagon]
Decrease [glucose]
Neutral on weight
What do SGLT-2 inhibitors do?
Inhibit Na-Glu transporter, increase glycosuria
E.g. dapagliflozin, canagliflozin
What are the benefits of SGLT-2 inhibitors?
HbA1c lower
32% lower all cause mortality
35% lower risk heart failure
Improve CKD
What treatments have the potential of T2DM remission?
Gastric bypass
DIRECT/DROPLET study - very low calorie diet for 3-6 months has potential to induce remission
Does treatment stop beta-cell function decline?
No
What are the other aspects of T2DM management?
Blood Pressure management
Lipid management
