Type 2 Diabetes Flashcards
What is Type 2 Diabetes?
condition in which the combination of insulin resistance and beta-cell failure result in hyperglycaemia
What is type 2 diabetes associated with?
obesity but not always
How can you manage the resultant croci hyperglycaemia?
changes to diet / weight loss and may even be reversible
and With time glucose lowering therapy including insulin, is needed
What are the different classifications of diabetes?
•Type 1 Diabetes •Type 2 Diabetes •Hybrid forms •Other •Unclassified -During pregnancy
What is latent autoimmune diabetes in adults (LADA)
Autoimmune diabetes leading to insulin deficiency can present later in life
Can T2D? develop in youth?
Yes, increasing prevalence
In which ethnic groups is the prevalence of T2D?
ethnic groups that move from rural to urban lifestyle
Where is insulin produced?
pancreatic beta-cells
What is relative insulin deficiency?
- not enough insulin produced to overcome insulin resistance
- explains why the hyperglycaemia encountered does not cause ketosis under ‘usual’ circumstances: prevent lipolysis and form ketones
What happens in long duration type 2 diabetes?
beta-cell failure may progress to complete insulin deficiency
Why is it important to be aware of long duration T2D as usually they are already on insulin?
Important not to stop as at risk of ketoacidosis
What causes T2D (pathophysiology)?
- Genes
- intrauterine environment
- adult environment
What is the other pathophysiology of T2 like?
- Insulin resistance and insulin secretion defects
2. Fatty acids important in pathogenesis and complications
When do people develop T2D?
- HETEROGENOUS
* People develop T2D at variable BMI, ages and progress differently
How is the factor that in response to a meal stored insulin is released and more is produced hindered in T2D?
People with T2DM or those who are about to develop diabetes do not have this stored insulin
What does the reduced insulin action cause in T2D?
less uptake of glucose into skeletal muscle
How is hepatic glucose production changed in T2D?
increased due to both a reduction in insulin action and increase in glucagon action
What is the relationship between insulin resistance and insulin secretion in T2D?
- People developing type 2 diabetes have ‘fallen off the curve’
- for a given degree of insulin sensitivity secrete less insulin
What does the excess of TNF-α IL-6
mean?
- Stimulates lipolysis and VLDL secretion
- increases IR Whole body and muscle
- decreases adiponectin expression
What does the excess of Endocannabinoids
mean?
- Insulin inhibits expression in fat
2. Fat IR > increased circulating EC
What does the excess of leptin mean?
- Elevated in obesity
- Increased IR Whole body muscle and liver
- Decreased appetite
- Increased metabolic rate
What does the excess of resistin mean?
- Elevated in obesity and T2DM
- Increased IR Whole body and liver
- Increased Liver TG secretion
What does the excess of glucocorticoids mean?
- Increased 11β HSD-1 in fat
- Increased fat cell size and IR
- Increased glucose BP Lipids
What does excess adoponectin mean?
- Increased insulin resistance
2. Predictive of diabetes
What does excess fatty acids mean?
- Elevated in obesity and T2DM
- Increased IR Whole body muscle and liver
- Decreased B cell function
- Increased Liver TG secretion
- Increased Organ fat, oxidative stress
What does excess apelin mean?
- Insulin stimulates expression in fat
- Elevated in hyperInsulin
- CV effects
What does excess visfatin mean?
- Visceral fat
2. Decreased IR Whole body
What is the monogenic?
- Single gene mutation ==> Diabetes (MODY)
- Born with always gonna develop
What is the polygenic?
- Polymorphisms increasing risk of diabetes
- ‘Not born with it but high risk and may develop later depending on other factors’
What are GWAS in T2 Diabetes?
Look at nucleotide changes present in Type 2 diabetes group but not in controls and asses effect size- 400 different SNP that affect risk - cumulative SNP have bigger effect
What is the role of obesity in T2D?
- Major risk factor for T2DM
- Fatty acids and adipocytokines important
- Central vs visceral obesity
- 80% T2DM are obese
- Weight reduction useful treatment
How are perturbations in gut microbiota in T2D?
- Obesity, insulin resistance T2DM
- Bacterial lipopolysaccharides fermentation to short chain FA, bacterial modulation bile acids
- Inflammation, signaling metabolic pathways
How is Intra-uterine growth retardation associated with T2D?
- Weight at age 1 year <8.16kg, 22% had type 2 diabetes of IGT
- Weight age 1 year >12.25 kg, 6% had type 2 diabetes or IGT
What is the presentation of T2D?
- Hyperglycaemia
- Overweight
- Dyslipidaemia
- Fewer osmotic symptoms
- With complications
- Insulin resistance
- Later insulin deficiency
What are the risk factors for T2DM?
- Age
- PCOS
- Increased BMI
- Family Hx
- Ethnicity
- Inactivity
What is needed for the diagnosis of type 2 diabetes? What are some presentations?
- Osmotic symptoms
- Infections
- Screening test: incidental finding
- at presentation of complication
- Acute; hyperosmolar hyperglycaemic state,
- Chronic; ischaemic heart disease, retinopathy
What HbA1c levels are needed for diagnosis?
1x HbA1c >=48mmol/L with symptoms
2x HbA1c >=48 mmol/mol if aysymptomatic
When does hyperosmolar hyperglycaemic state present?
usually with renal failure
What is a hyperosmolar hyperglycaemic state? When is it often identifiable?
- 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).
- Very dehydrated and presents slowly
What is the management of Type 1 diabetes?
- Exogenous insulin (basal-bolus regime)
- Self-monitoring of glucose
- Structured education
- Technology
What is the management of Type 2 diabetes?
1, Diet
- Oral medication
- Structured education
- May need insulin later
- Remission / reversal
What do you need to prevent in diabetes?
- Retinopathy
- Neuropathy
- Nephropathy
- Cardiovascular
What are the principles in 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 dietary recommendations are suggested for 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
How do you reduce excess hepatic glucose production?
Metformin
How do you combat the resistance to action of the circulating insulin?
- Improve insulin sensitivity
- Metformin, thiozolidinediones
How do you combat inadequate insulin production for extent of insulin resistance?
- Boost insulin secretion
- Sulphonylureas, DPP4-inhibitors, GLP-1 agonists
How do you combat excess glucose in circulation?
- Inhibit carbohydrate gut absorption and inhibit renal glucose respiration
- Alpha glucosidase inhibitor and SGLT-2 inihbtors
What helps everything in Type 2 diabetes?
- Weight loss
- Drugs shelf life as eventually insulin
What is metformin?
- Biguanide, insulin sensitiser
* First line if dietary / lifestyle adjustment has made no difference
What does metformin do?
- Reduces insulin resistance
- Reduced hepatic glucose output
- Increases peripheral glucose disposal
What are the side effects of metformin?
- GI side effects
* Contraindicated in severe liver, severe cardiac or moderate renal failure
How do sulphonylureas act?
- Normal insulin relase requires closure of the ATP sensitive potassium channel
- So boost insulin production by blocking this channel
How do sulphonylureas do this?
e.g gliclazide, bind to the ATP-sensitive potassium channel and close it, independent of glucose / ATP
What is pioglitazone?
- Peroxisome proliferator-actived receptor agonists PPAR-γ - has effect on downstream impact of insulin
- Insulin sensitizer, mainly peripheral
- Adipocyte differentiation modified, causes weight gain but peripheral not central
- Improvement in glycaemia and lipids
- Evidence base on vascular outcomes
What are the side effects of pioglitazone?
Side effects of older types hepatitis, heart failure
What is GLP-1?
Gut hormone
When is GLP-1 secreted?
in response to nutrients in gut
What does GLP-1 do?
- Transcription product of pro-glucagon gene, mostly from L-cell
- Stimulates insulin, suppresses glucagon
- ↑ satiety (feeling of ‘fullness’)
- Short half life due to rapid degradation from enzyme dipeptidyl peptidase-4 (DPP4 inhibitor)
- Used in treatment of diabetes mellitus
What are GLP-1 agonists?
Liraglutide, Semaglutide
How do you give GLP-1 agonists?
Injectable –daily, weekly
What do GLP-1 agonists do?
- Decrease [glucagon]
- Decrease [glucose]
- Weight loss
What does Gliptins (DPPG-4 inhibitor) do?
- Increase half life of exogenous GLP-1
- Increase [GLP-1]
- Decrease [glucagon]
- Decrease [glucose]
- Neutral on weight
What do SGLT-2 inhibitors do?
- Inhibits Na-Glu transporter, increases glycosuria
- Empagliflozin, dapagliflozin, canagliflozin
- HbA1c lower
- 32% lower all cause mortality
- 35% lower risk heart failure
Improve CKD
What type of surgery has the potential to insure remission pf T2DM?
Gastric bypass surgery
What is the direct study/droplet study for remission of T2DM?
very low-calorie diet (800 kcal/day) for 3-6 months has the potential to induce remission, which appears to be sustained at 2 years
How do you manage BP of T2D patients?
- Hypertension very common in T2DM
* Clear benefits for reduction esp with use of ACE-inhibitors
How do you manage the lipids in T2D?
- Total cholesterol raised
- Triglycerides raised
- HDL cholesterol reduced
- Clear benefit to lipid-lowering therapy
What type of insulin deficiency is in type 1 and type 2?
Type 1: Absolute insulin deficiency
Type 2: Relative insulin deficiency
What is a normal fasting glucose?
< or equal to 6mmol/L
What is a type 2 diabetes fasting glucose?
> or equal to 7mmol/L
What is it called if your fasting glucose is between 6 and 6.9?
Impaired fasting glycaemia
What is normal 2hr glucose (OGTT)?
< or equal to 7.7mmol/L
What is type 2 2hr glucose (OGTT)?
> or equal to 11mmol/L
What is 2hr glucose (OGTT) in impaired glucose tolerance?
Between 7.7 and 11
What is normal HbA1c?
< or equal to 42mmol/L
What is pre diabetes or non-diabetic hyperglycaemia HbA1c?
Between 42 and 48
What is type 2 diabetes HbA1c?
> or equal to 48mmol/L
If they have prediabetes do you know why they?
Could have impaired fasting glycaemia or impaired glucose tolerance or both
How does insulin resistance change from normal, to intermediate to type 2?
Graph curve and then plateaus, by time diagnosed have already got maximum insulin resistance
Why does glucose still go up even when insulin resistance doesn’t change between intermediate and type 2?
Insulin production decreases a lot from intermediate tot type 2 - not enough insulin production to deal with insulin resistance
How can you diagnose Type 2 diabetes?
- Fasting glucose
- 2h glucose
- Random (if symptoms as well above 11)
- HbA1c
By the time of diagnosis what has happens to beta cell function?
Already decreased
What happens the higher your fasting glucose?
The slower/lower your skeletal uptake is
What are the consequences for insulin resistance?
- Liver produce excess glucose
- Muscle, less uptake of glucose
- Less glucose uptake in adipocytes and triglycerides rising
What is insulin sensitivity?
How effective insulin will be at clearing glucose from the circulation - if very fast and effective every sensitive
-If system impaired then insulin resistant
Why do you still have hyperglucagonemia in T2?
- Although insulin action is impaired early on in T2D, still high levels in circulation
- Physiology of glucagon is. hyper
What can you have an excess of in T2D?
Inflammatory adipokines
What is first line diagnosis test of T2D?
HbA1c
What can a side effect be of some glucose lowering therapies?
Weight gain (not what you want)
Despite treatment what happen to beta cell function?
Decreases
