Type 2 Diabetes Flashcards
What is Type 2 Diabetes?
What is T2DM associated with and how can it be managed?
Condition in which the combination of insulin resistance and beta-cell failure result in hyperglycaemia
Associated with obesity
Resultant chronic obesity may be initially managed by changes to diet, lifestyle, weightloss - may even be reversible
With time, glucose lowering therapy with insulin is required
What factors contributes to T2DM? (interactionist approach)
Polygenic disease Genetic vulnerability Trigger = obesity Resulting in insulin resistance Leading to relative insulin deficiency Eventually - hyperglycaemia
Why might it be difficult to diagnose a patient with either T1DM or T2DM?
Patients may present with phenotypes of both
T2DM may present in youth / young adults
Diabetic ketoacidosis can also be a feature of T2DM
At what age can T2DM develop?
At what ages are there increasing numbers of T2DM?
Traditionally thought to be a condition of late adulthood - takes time for obesity / trigger to affect (genetic) vulnerability
Now good evidence that is can present throughout life
Increasing in all age groups, but rapidly in early-adulthood
What groups of people does T2DM affect most?
Greatest in ethnic groups that move from rural to urban lifestyle - Asian, Pacific-islanders, African-Caribbean
What are the stages of development of T2DM?
What can these stages be defined by?
Use fasting glucose levels; 2hr glucose (OGTT); HbA1c
Normal - =<6 mmol/L; =<7.7 mmol/L; =<42mmol/mol
Intermediate state - impaired fasting glycaemia; impaired glucose tolerance; pre-diabetes or non-diabetic hyperglycaemia
T2DM - >=7mmol/L; >=11mmol/L; >=48 mmol/mol
How does insulin resistance change over the 3 stages of T2DM?
Not a linear relationship all the way through, there is a curve
Slight increase when patient presents at normal stage
At intermediate stage, reach max insulin resistance
Plateau at T2DM stage
So why do patients reach T2DM if insulin resistance reaches it’s max at the intermediate stage?
Due to insulin production
At normal stage there is normal insulin production, which increases in production with the increasing insulin resistance
Insulin production peaks at intermediate stage
Then insulin production falls at T2DM
What are the different ways to diagnose DM?
Fasting glucose
2-hr glucose (OGTT)
HbA1c
Random glucose
What happens with beta-cell function during the intermediate stage?
Beta-cell function is already compromised
Beta-cells slowly die from apoptosis - this is due to the toxic environment created from the excess insulin production
How is Beta-cell function mesaured?
HOMA model - this is an index using fasting glucose and 2hr glucose (OGTT)
So is T2DM caused by insulin resistance, compromised beta cells, or both?
Both
What is the relative insulin deficiency in T2DM?
Insulin is produced by pancreatic beta-cells but not enough to overcome the insulin resistance = therefore relative deficiency
Explains why there is hyperglycaemia but not diabetic ketoacidosis
Enough insulin in circulation to suppress the reaction of fatty Acyl-CoA to ketones
What happens to beta cell function over a long duration?
Eventually, over many years, beta cell function will be non-existent - leads to diabetic ketoacidosis
What is the pathophysiology of T2DM?
Genes
Intrauterine environment and adult environment
Insulin resistance and insulin secretion defects
Fatty acids important in pathogenesis and complications
Why is T2DM heterogenous?
People develop T2DM at variable BMIs and progress differently
What occurs at the IV glucose challenge between normal individuals and T2DM patients?
When glucose is given to participants:
In normal individuals, there is an initial first phase insulin release = sharp spike in plasma insulin |\_
This is lost in T2DM patients _____
Does the hyperglycaemia in T2DM patients only come from the diet?
What else occurs in T2DM with the reduced insulin production and hepatic glucose production?
Reduced insulin action = less uptake of glucose into skeletal muscle
Hepatic glucose production is also increased due to both, a reduction in insulin action and increase in glucagon action (converting glycogen to glucose in the liver)
How does the relationship between insulin resistance and insulin secretion change in normal individuals?
How does this change with T2DM patients?
High insulin sensitivity = decreased insulin production
Low insulin sensitivity = increased insulin production
In T2DM patients, they fall off the regular curve, so despite having low insulin sensitivity, they do not increase their insulin production to compensate for it
What are the consequences of insulin resistance on the liver, skeletal muscle and adipocytes?
Liver = cannot uptake glucose as it is insulin dependent, excess glucose release from glycogenolysis
Skeletal muscle - cannot uptake glucose as GLUT4 receptor is insulin dependent
Adipocytes - cannot uptake glucose as GLUT4 is insulin dependent
Lack of insulin also increases the triglycerides in the blood as they cannot be broken down to NEFA and be taken up by adipocytes
What do the excess of inflammatory adipokines cause?
They cause the inflammation that is involved in the pathophysiology of T2DM
What is meant by the terms monogenic VS polygenic?
Monogenic - single gene mutation
Polygenic - multiple factors / genes, a risk that may be triggered later depending on other factors
How can the individual genes contributing / affecting development of T2DM be investigated?
Compare DNA of T2DM patients against normal individuals
Look at SNPs - single nucleotide polymorphism
How do individual SNPs Vs summation of SNPs affect development of T2DM
Individual SNPs = low risk, but summation of SNPs increases risk of T2DM
The more SNPs, the higher the prevalence of T2DM
What is the role of obesity in the T2DM?
Major risk factor for T2DM
80% T2DM are obese
Fatty acids and adipocytokines important
Weight reduction useful treatment
Visceral adipocity > subcutaneous = risk for T2DM
How does T2DM present clinically?
What are the risk factors for T2DM?
Hyperglycaemia Overweight Dyslipidaemia Fewer osmotic symptoms With complications Insulin resistance Later insulin deficiency
Risk factors: Age PCOS High BMI Family Hx Ethnicity Inactivity
What is the first line test for the diagnosis of T2DM?
HbA1c
1x HbA1c >=48mmol/L with symptoms
or 2x HbA1c >=48 mmol/mol if asymptomatic
What is the hyperosmolar hyperglycaemic state?
Acute complication:
Absence of significant acidosis due to insufficient (not absent) insulin - sufficient insulin for suppression of lipolysis and ketogenesis
T2DM patients are v. dehydrated due to slow onset of osmotic symptoms - leads to high hyperglycaemia
What is the management of T2DM?
Diet Oral medication Structured education May need insulin later Monitor HbA1c every few months
What typically occurs in a T2DM consultation?
Gylcaemia monitoring: HbA1c. glucose monitoring if on insulin
Medication review
Weight assessment
Blood pressure
Dyslipidaemia (abnormal amounts of lipid in the blood): cholesterol profile
Screen for complications e.g. foot check (neuropathy), retinal screening (retinopathy)
What are the dietary reccommendations and education?
Total calories control Reduce calories as fat Increase soluble fibre Decrease sodium Refine simple carbs to complex carbs
What are the 4 key pathophysiology facets in T2DM?
What are the different strategies and solutions to target each of these pathophysiologies to treat T2DM?
Excess hepatic glucose production: reduce hepatic glucose production - Metformin
Resistance to action of circulating insulin: improve insulin sensitivity - metformin, thiozolidinediones
Inadequate insulin production for extent of insulin resistance: boost insulin secretion - sulphonylureas, DPP4-inhibitors, GLP-1 Agonists
Excess glucose in circulation: inhibit carbohydrate gut absorption, inhibit renal glucose resorption - alpha-glucosidase inhibitor, SGLT-2 inhibitor
Weightloss helps all issues
What is Metformin?
How does it work?
What are some possible side effects?
Biguanide (oral T2DM medication), 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
What are Sulphonylureas?
How do they work to help treat T2DM?
Normal insulin release requires closer of the
ATP-sensitive potassium channel
Sulphonylureas eg gliclazide, bind to the ATP-sensitive potassium channel and close it, independent of glucose / ATP = boosts insulin production
What is Pioglitazone?
How does it work?
What are some possible side effects?
Agonist in PPARs (Peroxisome proliferator-actived receptor)
Modifies insulin sensitivity
Adipocyte differentiation modified
Improvement in glycaemia and lipids
Side effects of older types hepatitis, heart failure, may cause weight gain (peripheral not central)
What is GLP-1?
What are GLP-1 agonists?
What are DPP4- inhibitors and why do they work?
Gut hormone - stimulated insulin and suppresses glucagon, increases satiety
Short half-life due to degradation by enzyme DPP-4
Discovered when it was found that IV glucose does not increase plasma glucose as much as ingested glucose
GLP1 agonists: e.g. Liraglutide, Semaglutide - injectable – daily, weekly
Decrease [glucagon]
Decrease [glucose]
Weight loss - due to nausea and appetite suppression
DPP-4 inhibitor = increases half life of GLP-1 if the DDP is inhibited as it cannot breakdown the GLP-1
e.g. Gliptins
What are SGLT-2 inhibitors?
How do they work?
e.g. Empagliflozin, dapagliflozin, canagliflozin work to lower HbA1c
Inhibits Na-Glu transporter, increases glycosuria
Improve CKD
How can T2DM be remissed?
- Gastric bypass surgery - potential for remission of T2DM
2. Low-cal diet for 3-6 months has potential to induce remission - sustains for over 2 years
What else can be managed alongside T2DM?
The risks that come with T2DM e.g. hypertension, dyslipidaemia (often raised cholesterol, triglycerides, and reduced HDL)
