Diabetes Mellitus Flashcards
what is diabetes mellitus
- This is a chronic non-communicable disease characterised by hyperglycaemia
- Usually irreversible and its late complications result in reduced life expectancy and major health costs
what causes diabetes mellitus
- Caused by relative insulin deficiency or resistance or both
what is the 7th biggest cause of death
diabetes
what is type 1 diabetes
this is a chronic autoimmune disease where you have an insulin deficiency therefore you have a need for insulin injections
what causes type 1 diabetes
- Characterised by immune T cell mediated disruption of the pancreatic B cells within the islets of Langerhans
is type 1 diabetes genetic
- Type 1 Diabetes is not genetically predetermined but increased susceptibility to the disease may be inherited
- Genetic basis of the disease not fully understood Major genetic determinants only account for ~40-50% of the familial clustering of the disorder)
- Incidence increasing in most populations suggesting that environmental factors are involved in its pathogenesis
what are the types of insulin that are available
short acting and long acting
when does type 1 diabetes usually present itself
usually in young patients before the age of 30 but it can present at any age
what is the most common type of diabetes
- Most common (85-90% of all diabetes)
what age group is type 2 diabetes in
- It used to be more present in older patients (>30 years of age) but increasing in younger population
is type 2 diabetes genetic
- Concordance rates are significantly higher in identical twins compared to non identical twins
- Genetic component to the disease but genes responsible for most of the cases are still not known
- GKRP and PPARG genes are thought to have a role
what are the risk factors for type 2 diabetes
- Obesity
- Family history – first generation, lean otherwise healthy relatives often develop skeletal muscle insulin resistance
- Age – increased mitochondrial dysfunction, inflammation
- Ethnicity
- Increased in incidence follows the trend of urbanisation and lifestyle changes suggesting environmental influences
what is the major risk factor for type 2 diabetes
Obesity
what are the intrinsic and extrinsic factors of obesity that can lead to insulin resistance
Intrinsic factors as obesity can increase these
- (mitochondrial dysfunction, oxidative stress, ER stress) – this eventually impairs the reaction of the insulin
Extrinsic
- Accumulation of lipids and their metabolites or increased concentrations of circulating free fatty acids
- Chronic inflammation
- Altered adipokine levels
what does hyperinulinaemia do
- It increases lipid synthesis and exacerbates insulin resistance
name the most common alterations that can lead to insulin resistances
- Decrease in the number of insulin receptor
- Decrease in the catalytic activity of the receptor
- Increased activity of Tyr phosphatases
- Increased Ser/Thr phosphorylation of the receptor or of IRS
- Decreased PI3K/Akt activity
- Decreased levels and function of GLUT4
how can pro-inflammatory cytokines, saturated free fatty acids and amino acids cause insulin resistant
Pro-inflammatory cytokines, saturated FFAs, amino acids can activate Serine/Threonine kinases that can phosphorylate IRS, reducing its Tyr phosphorylation and also increasing its degradation
Why do not all insulin resistance people have diabetes
- this is because insulin resistance can be overcome by increasing insulin secretion therefore glucose control can be maintained
this happens by
- new Beta cells being generated in response to insulin resistance associated with obesity or pregnancy
- islet of langerhans increase in size and number due to beta cell increase in size and number
- there is an increased beta cell function
what happens in type 2 diabetes which means that they become insulin resistant
- the number of islet cells decrease and there is a reduction in the number of beta cells per islet
- this is due to reduced pancreatic B cell mass, increased death and reduced pancreatic B cell function
- this is all widely due to the fact that many of the genes associated with type 2 diabetes are regulatory of cell turnover and regeneration therefore if they are impaired then the beta cells are not regenerated and insulin secretion is reduced
most of the risk factor for type 2 diabetes act by …
- Most risk variants for Type 2 diabetes in healthy populations act by impairing insulin secretion rather than insulin action
what are the 2 critical precursors in type 2 diabetes
- inherited abnormalities of B cell function
- inherited abnormalities of B cell mass
lack of insulin can lead to….
increased levels of glucagon
why is high levels of glucagon called
hyperglucagonaemia
why does hyperglucagonaemia arise in type 1 diabetes
- In untreated or poorly controlled Type 1 diabetes this is likely due to the insulin deficiency
why can you have hyperglycaemia at the same time as hyperglucagonaemia in type 2 diabetes
- defect of insulin secretion
- resistance of alpha cells to insulin
- resistance of alpha cells to hyperglycaemia
name some other forms of diabetes
- maturity onset diabetes of the young
- gestational diabetes
- latent autoimmune diabetes of adults
- type 3c diabetes
what is maturity onset diabetes of the young
- autosomal dominant inheritance
- causes pancreatic B cell dysfunction
what is gestational diabetes and what is the risk
- Occurs in 2-6% of pregnancies in Europe
- Increased complications during the second half of pregnancy
describe latent autoimmune diabetes of adults
- 5-10 % of phenotypic “Type 2DM” patients have markers of autoimmunity
- Progression to insulin dependency faster than Type 2 DM
what is a risk of having gestational diabetes
- Increased risk of subsequent development of Type 2 DM
what is type 3c diabetes due to
- Diabetes due to diseases of the exocrine pancreas
- (used to be called “pancreatogenic” or “pancreatogenous” diabetes mellitus)
how do you diagnose diabetes using blood tests
One abnormal plasma glucose
(random ≥11.1 mmol/L or fasting ≥7 mmol/L) in the presence of symptoms (thirst, increased urination, recurrent infections, weight loss, drowsiness and coma)
Two fasting venous plasma glucose samples in the abnormal range
(≥7 mmol/L) recommended in asymptomatic people
what is the oral glucose tolerance test
- Patient is asked to fast for 8 hours and then they are given a sugary drink, then measure the glucose levels fasting
what is the advantages of HbA1c
- reliable measure;
- HbA1c levels are relatively stable vs glucose;
- ease of sample collection;
- patient convenience (no need for 8 h fast)
what are the disadvatanges of HbA1c
- cost in some parts of the world;
- influence of Hb traits (e.g. HbS, HbF);
- conditions affecting rbc turnover
how do you use HbA1c to diagnose diabetes
• An HbA1c of 48 mmol/mol (6.5%) is recommended as the cut point for diagnosing diabetes
what is the main aim of treatment of diabetes
- the main aim is to lower blood glucose levels
List some medication that can be used to treat diabetes
- Biguanides (metformin)
- Sulfonylureas
- Meglitinides
- Thiazolidinediones (TZD)
- DPP-4 inhibitors
These try to act at the level of other organs to lower the blood glucose
- SGLT2 Inhibitors
- Alpha-glucosidase inhibitors
- Bile Acid Sequestrants
How do thiazolidinediones TZD work
- work at the transcription level
- try to push the PPARgamma transcription factor
- this causes an increase in glucose uptake in the sketal muscle and adipose muscle
- also produces genes that are responsible for pushing gluconeogensis - this reduces the amount of gluconeogensis in the liver
what are the signs and symptoms of diabetes
Signs and Symptoms: Weight loss. Polyuria (increased urination). Polydipsia (increased thirst). Polyphagia (increased hunger). Blurred vision. Headaches. Fatigue. Nausea and vomiting.
what does HbA1c measure
Hb1Ac measures the levels of glycosylated Hb.
what are the signs and symptoms of type 1 diabetes
Glycosuria.
Polyuria and dehydrations (due to osmotic diuresis).
- Osmotic diuresis occurs when glucose is present in the kidney tubules and is not
reabsorbed.
- This pulls water back into the tubules and it is excreted.
Weight loss.
- Weight loss occurs due to loss of glucose in the urine.
Fatigue.
Diabetic ketoacidosis.
what does metformin do
- Increases insulin sensitivity
- Improved insulin receptor function
- Improved glucose transport
- Reduced fatty acid synthesis
- It inhibits gluconeogenesis
name the drugs that act as agonists of GLP-1 receptor
- GLP1 is normally inactivated by DDP-4
- Sitagliptin inhibits DDP-4
what does GLP-1 do
- Increase the glucose induced insulin secretion
- Inhibits glucagon secretion and hepatic glucose production
- Slows gastric emptying
- Promotes satiety
- In the context of obesity, it slows gastric emptying and gives a longer sense of satiety
- There are some drugs that act as agonist of the GLP-1 receptor
what drugs can cause more insulin secretion
sulfaonylureas and meglitindes
name an example of sulfaonylureas
Glicazide is an example.
How do sulfaonylureas and meglitindes work
Cause increased secretion of insulin.
Sulfonylureas inhibit K+ channels in Beta cells to prevent their efflux.
A build-up of K+ leads to depolarisation in the cell membrane.
Voltage-sensitive Ca2+ channels open, influx of Ca2+.
Ca2+ influx triggers exocytosis release of insulin.
name the side effect son sulfaonylureas
hypoglycaemia and weight gain.
what does DPP-4 usually do
DPP4 is an enzyme which breaks down and inhibits incretins.
If DPP4 is inhibited the levels of incretins can rise.
Sitagliptin is an DPP4 inhibitor.
name a DPP4 inhibitor
Sitagliptin
what do alpha glucosidase inhibitors do
Block disaccharide breakdown.
Reduces intestinal glucose absorption.
Decreases postprandial hyperglycaemia.
what ar ether side effects of alpha glucosidase
- Diarrhoea.
- Flatulence.
- Abdominal pain.
what lifestyle advice can you give someone with type 2 diabetes
Reduce dietary: - Fat. - Sugar. - Salt. Increase dietary fruit and veg content, raises fibre levels. Weight loss. Increased physical activity.
list 2 acute diabetes complications
(acute because they are rapid)
- ketoacidosis
- Hypoglycaemia
how does ketoacidosis occur
– Continual use of fatty acids for energy leads to production of ketone bodies (acetoacetate and -hydroxybutarate)
– Blood and urine acid levels rise, dehydration, coma, death
what is the treatment of ketoacidosis
- fluids(isotonic) and potassium first
- then insulin
name 2 ketone bodies that are produced in keotacidosis
acetoacetate and -hydroxybutarate
describe how hypoglycaemia can occur
- In Type 1 Diabetes this can occur because of high insulin doses (e.g. insulin injection but missed meal).
- Recurrent severe hypoglycaemia affects 1-3% of Type 1 diabetes patients, mostly adults having diabetes for > 10 years
Name the chronic complications of diabetes
Hyperglycaemia
macrovascualr
- atherosclerosis - cardiovascular events
- dyslipidaemia
microvascuarl
- kidney disease (Nephropathy)
- nerve disease (Neuropathy)
- blindness (retinopathy)
- amputations
What harm can hyperglycaemia do
Hyperglycaemia is responsible for tissue damage.
The mechanism of which cause tissue damage are brought about by the formation of reactive oxygen species in the mitochondria; superoxide.
what tissues does hyperglycaemia effect
Tissues which are independent of insulin are affected, these include:
- Neurons.
- Glomeruli.
- Retina.
describe how hyperglycaemia can activate the protein kinase C pathway
Increased glycolysis generates diacylglycerol (DAG).
DAG activates PKC.
PKC alters expression of peptides and growth factors to modify blood vessels:
How does protein kinase C pathway alter blood vessels
- Increased permeability
- Increased occlusion
- Increased reactive oxygen species levels
- Increased inflammation
- Mitochondrial dysfunction
what are the two ways in which diabetic retinopathy are caused
- non proliferative
- proliferative
describe the two ways in which diabetic retinopathy are caused
Non proliferative
- dilation of the retina veins
- microanuerysms
- these can cause internal haemorrhages and oedema in the retina
- oedema in the central retina is the main cause of blindness in this cause
proliferative
- Damaged capillaries occlude and more VEGF is released.
- fragile new blood vessels form near the optic disk
- these grow on the vitreous chamber and elsewhere in the retina
- they can bleed, reduce vision and lead to separation and detachment of areas in the retina
when is diabetic retinopathy caused
- occurs in most people after 20 years of poorly controlled diabetes
- leading new cause of new blindness or partial vision loss in people aged 20-74
what is more common proliferative retinopathy or non-proliferative reitnopathy
non proliferative is very common and has mild severity whereas proliferative is very rare and has more severe severity
what is diabetes nephropathy and what are its characteristics
- Disease of the kidney involving damage to the blood vessels in the glomerulus, which is critical for blood filtration, kidney glomeruli become thickened
It is characterised by:
- proteinuria,
- glomerular hypertrophy,
- decreased glomerular filtration
- renal fibrosis
what is a leading cause of end stage kidney disease
diabetic nephorpahty
what is the clinical presentation of diabetic nephorpathy
Clinical presentation:
- Hypertension.
- Proteinuria.
- Decreased renal function.
what is diabetic neuropathy
- this is when there is damage to the nerve fibres and blood vessels supplying the nerves
what are the 4 types of diabetic neuropathy
- peripheral
- autonomic
- focal
- proximal
describe the 4 types of diabetic neuropathy
Peripheral neuropathy:
- More common, affects the peripheries such as hands and feet.
- Symptoms are: numbness, tingling and loss of balance.
- Blisters/sores occur on feet as injuries are not detected due to loss of sensation.
Autonomic neuropathy:
- Leads to multi-system problems.
- Genito-urinary dysfunction may cause erectile problems or urinary incontinence.
- GI issues may cause vomiting and diarrhoea.
- Cardiovascular problems may cause postural hypotension.
Focal
- It can affect any nerve in the body and it causes pain or weakness
Proximal
- It causes pain in thighs and hips and weakness in legs
what are macrovascular complications of diabetes
- Metabolic injury to large blood vessels (arteries and veins)
describe how microvascular complications of diabetes arise
- AGE modification of oxidised low-density lipoprotein receptor (LDLR) leads to increased LDL uptake into atherosclerotic plaques
- AGE-LDL produces more pro-inflammatory cytokine to be released
- increased Glycation of apolipoprotein impairs cholesterol efflux from atherosclerotic plaques
- Glycation of LDLR and LDL leads to impaired cholesterol clearance
what is the most common cause of death for patients with diabetes
macrovascualr complications
name the macrovascualr complications
The impact of macrovascular complications is reduced nutrient and oxygen supply to
the heart and brain:
- Brain = Stroke.
- Heart = MI, heart failure.
- Extremities = Ulceration or gangrene, peripheral vascular disease.
