Type 2 diabetes Flashcards
What significant morbidity is linked to T2DM?
Cancer Cirrhosis Retinopathy Stroke Heart disease Nephropathy Foot problems
What is T2DM?
Combination of insulin resistance allied to a failure of adequate insulin secretion
Imbalance results in T2DM
Insulin output is unable to match resistance levels
Describe the key features of T2DM disease progression
Hyperinsulinaemia
Insulin resistance
Hyperglycaemia
Macrovascular complications occur earlier on
Microvascular complications are observed later
Why does insulin resistance occur?
> Genetic susceptibility > Environmental triggers > Two major predictors: - Poverty - Ethnicity > Visceral fat producing adipokines > Genetic conditions - small no. with insulin receptor mutations: severe hyperinsulinaemia, associated with acanthosis nigricans and features of hyperandrogenism -> Very strong genetic predisposition - normally all family members are affected
What are adipokines?
Cytokines secreted by the adipose tissue
List the adipokines
Leptin
Adiponectin
TNFalpha
Resistin
Where are adipokines found?
In the visceral fat around organs
What is leptin?
An adipokine
- Tells hypothalamus about amount of stores fat
What is adiponectin?
An adipokine
- Reduced levels of free fatty acids
What is TNFalpha
An adipokine
- Associated with low-grade inflammation
What is resistin?
An adipokine
- Enhances hypothalmic stimulation of glucose production
What factors can affect insulin secretion?
> Glucotoxicity can lead to impaired beta cell function
Glucokinase defects impair insulin secretion
Pancreatic beta cell transcription factor mutations lead to reduced insulin production in response to glucose - still senses glucose levels but inadequate insulin production
What is microvascular disease?
Complications related to smaller blood vessels (e.g. in kidney, eyes and nerves)
How can microvascular disease be prevented?
Reduction of glucose levels
Reducing HbA1c by 10mmol/mol results in a 20% overall risk reduction
Which drug acts on the gut?
Acarbose
- inhibits alpha glucosidase, (a small intestine brush border enzyme) and pancreatic alpha-amylase
- reduces digestion of complex carbohydrates, minimising glucose absorption
Which drugs acts at the muscle bed?
Metformin & Pioglitazone modify glucose uptake at the muscle bed
Insulin also has an impact on glucose uptake at the muscle bed
Which drug acts on the kidney?
SGLT2 inhibitors
Which drugs increase insulin secretion?
> Insulin
sulfonylurea -> constant insulin release
DDP-4 inhibitors -> augment insulin secretion in a glucose-dependent manner
GLP-1 receptor agonists -> augment insulin secretion in a glucose-dependent manner
Which drugs act on the liver?
Reduce glucose production
> Metformin
GLP-1 receptor agonists
DPP-4 inhibitors
Insulin
What are GLP-1 effects in humans?
Secreted upon the ingestion of food
> beta cell - enhances glucose-dependent insulin secretion in the pancreas
alpha cell - suppresses post-prandial glucagon secretion
liver - reduces hepatic glucose output
stomach - slows the rate of gastro emptying
brain - promotes satiety and reduces appetite
How can GLP-1 levels be influenced?
Preventing breakdown by DPP-4 to increase physiological levels
Exogenous GLP-1 agonist
What are the effects of using exogenous GLP-1 agonists?
Significant glucose-lowering benefit
Weight loss
Name DPP-4 inhibitors
Sitagliptin Vildagliptin Saxagliptin Linagliptin Alogliptin
Name GLP-1 receptor agonists
Exanatide Liraglutide Exenatide Lixisenatide Dulaglutide
What is the mechanism of action of SGLT2 inhibitors
Inhibits SGLT2, which reabsorbs 90% glucose in the proximal tubule of the kidney
- More glucose is excreted
- Plasma glucose levels drop
- Weight decreases due to calorie loss
NB: causes osmotic diuresis -> lowers blood pressure
Can predispose to significant acidosis in patients with insufficient insulin
Should NOT be used in T1DM
Name SGLT2 inhibitors
Dapaglifloxin
Canagliflozin
Empagliflozin
What is the first line treatment for T2DM
Lifestyle measures
Metformin or sulphonylurea (if intolerent to metformin or osmotic symptoms present)
What is the second line treatment for T2DM?
If not reaching target after 3-6 months: Check adherence Add one of: - sulphonylurea - pioglitazone - DPP-4 inhibitor - SGLT2 inhibitor
What is the third line treatment for T2DM?
If not reaching target after 3-6 months: Check adherence Add either an oral agent of a different class: - sulphonylurea - pioglitazone - DPP-4 inhibitor - SGLT2 inhibitor OR an injectable agent: - if BMI >30 = GLP-1 agonist - if BMI <30 = basal insulin
