3.17 - Type 2 diabetes Flashcards
What is T2DM?
- a condition in which the combination of insulin resistance AND beta cell failure results in hyperglycaemia
- associated with obesity but not always
- resultant chronic hyperglycaemia may initially be managed by changes to diet/weight loss and may even be reversible
- with time, glucose lowering therapy including insulin is needed
What makes T2DM harder to diagnose due to overlap with T1DM?
- T2DM may present in youth/young adults
- diabetic ketoacidosis can be a feature of T2DM
At what ages can T2DM develop and how has our view of this changed?
- traditionally thought to be a condition of adulthood
- now good evidence that it can present throughout every decade of life
- increasing in all age groups but rapidly in early adulthood
What is T2DM in youth associated with?
An earlier death (whereas developing T2DM at an older age, the life expectancy is similar to a normal person)
What is the prevalence of T2DM like now and how is it predicted to be in the future?
- prevalence of T2DM varies massively between countries
- increasing prevalence
- occurring and being diagnosed younger
- greatest increase predicted in ethnic groups that move from rural to urban lifestyles e.g. India
What are fasting glucose levels like in normal, intermediate state and T2DM?
- normal </=6 mmol/L
- impaired fasting glycaemia (IFG)
- T2DM >/=7 mmol/L
What are OGTT (oral glucose tolerance test - 2hr glucose) levels like in normal, intermediate state and T2DM?
- normal <7.7 mmol/L
- impaired glucose tolerance (IGT)
- T2DM >/=11 mmol/L
What are HbA1c levels like in normal, intermediate state and T2DM?
- normal <42 mmol/mol
- intermediate state - pre-diabetes or non-diabetic hyperglycaemia (caused by IFG + IGT)
- T2DM >/=48 mmol/mol
What is insulin production like in normal, intermediate state and T2DM?
Increases during intermediate state, showing the body trying to compensate for the increase in insulin resistance, then starts to fall = by the time you present with T2DM you already have beta cell dysfunction
What is insulin resistance like in normal, intermediate state and T2DM?
Increases during intermediate state and is already maxed out by the time you present with T2DM
What are random glucose levels like in normal and T2DM?
Normal <11.1mmol/L, T2DM >/=11.1 mmol/L
How can a random glucose test be used to diagnose T2DM?
If it is above 11.1 mmol/L and there are symptoms of T2DM e.g. polyuria = diagnosis
What are the beta cell function levels at when you are diagnosed with T2DM?
Their function has already decreased to around 50% at time of diagnosis (not enough to overcome insulin resistance)
What is relative insulin deficiency in type 2 diabetes?
Insulin is still produced by pancreatic beta cells but not enough to overcome insulin resistance = relative deficiency of insulin
How does the relative insulin deficiency explain why T2DM do not usually get diabetic ketoacidosis?
- ketones typically form when there is no insulin, but here there is still some
- insulin needed to suppress lipolysis
- can still present with DKA not spontaneously but because person is unwell (infected/catabolic/septic)
What happens in long duration T2DM?
- beta cell failure may progress to complete insulin deficiency
- patients usually on insulin at this point, but important not to stop as at risk of 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
- heterogenous
What does it mean that T2DM is heterogeneous?
People develop T2DM at variable BMI, ages and progress differently
What is a hyperglycaemic clamp?
When you keep a patient in a steady state with infusions of glucose and insulin
What is insulin response in normal vs impaired glucose tolerance vs T2DM when glucose is added?
- insulin response in normal people - spike as soon as glucose enters blood (IV glucose challenge)
- IGT - blunted response
- T2DM - no response = loss of first phase insulin release
What hormone is increased in T2DM and what does this cause?
Glucagon increased (as body not responding to insulin) = increased gluconeogenesis + glycogenolysis = increased HGO = increased glucose to peripheral tissues
What does a reduction in insulin action cause in T2DM?
- reduced insulin action causes less uptake of glucose into skeletal muscle
- HGO also increased due to both reduction in insulin action and increase in glucagon action (liver producing too much glucose despite already hyperglycaemic = dysregulated metabolism)
What is HGO production and glucose clearance like in T2DM?
- impaired insulin-mediated glucose clearance/disposal
- excessive glucagon-mediated glucose output/production
What is the relationship between insulin sensitivity (resistance) and insulin secretion in normal vs T2DM?
- normal - least sensitive (most resistant) need a lot of insulin secretion for desired effect and vice versa
- people developing T2DM have ‘fallen off the curve’ - for any given degree of insulin sensitivity they secrete less insulin
What are the consequences of insulin resistance in the liver?
Increased HGO (due to hyperglucagonaemia)
What are the consequences of insulin resistance in adipocytes?
- increased fatty acid uptake from gut
- triglycerides form unhealthy types of lipid (usually inhibited by insulin)
- increased fatty acid production
What are the consequences of insulin resistance in muscle?
Usually takes up glucose in presence of insulin, but in T2DM there is less uptake by muscle
What is monogenic diabetes?
- single gene mutation means you are born with it and always going to develop it no matter how much you try
- MODY - maturity onset diabetes of the young
How is T2DM polygenic?
- polymorphisms increase the risk of diabetes
- not born with it but high risk and may develop later depending on other factors
How does genetic and environmental risk interact in the chance of developing T2DM?
- low genetic risk + strong environmental factors –> T2DM
- high genetic risk + weak environmental –> T2DM (why some ethnic groups need lower BMI to get T2DM)
- high genetic risk + high environmental risk = very likely to get diabetes
- low genetic risk + weak environmental = relatively protected against T2DM
What do genome wide association studies of T2DM show?
- GWAS of T2DM done by taking people with and without T2DM and sequencing their whole genome to look for nucleotide changes present in T2DM but not control
- they show that each individual SNP has only a mild effect on risk
- cumulative effect of all SNPs has bigger effect - those with more SNPs more likely to get T2DM
What is the role of obesity in T2DM?
- major risk factor for T2DM - 80% obese
- fatty acids and adipocytokines important in development
- central vs visceral obesity - people with lower BMIs can get T2DM due to more visceral fat
- weight reduction is useful treatment
What roles do perturbations in gut microbiota have on T2DM cases?
- obesity, insulin resistance T2DM
- bacterial lipopolysaccharides fermentation to short chain fatty acids, bacterial modulation bile acids
- inflammation, signalling metabolic pathways
- most studies correlative
What is the role of intra-uterine growth retardation on T2DM?
- if you have underdeveloped in womb or if mother had diabetes, this affects intrauterine growth environment
- people with intrauterine growth retardation are more likely to develop T2DM
- babies with lower body weight had higher % of T2DM/IGT
How does T2DM present? (7)
- hyperglycaemia
- overweight
- dyslipidaemia
- fewer osmotic symptoms
- with complications
- insulin resistance
- later insulin deficiency
What are the risk factors of T2DM? (6)
- age
- increased BMI
- ethnicity
- PCOS
- family history
- inactivity
How/when can we diagnose T2DM?
- osmotic symptoms
- infections
- screening test - incidental finding (e.g. screen for tiredness and find this)
- at presentation of a complication - acute / chronic
What is an acute complication people with T2DM can present with at diagnosis?
Hyperosmolar hyperglycaemic state (life threatening state due to high BGC)
What are some chronic complications people with T2DM can present with at diagnosis?
- ischaemic heart disease
- retinopathy
What is the first line test for diagnosis of T2DM?
- HbA1c
- 1 x HbA1c >=48 mmol/mol with symptoms
- or 2 x HbA1c >= 48 mmol/mol if asymptomatic
What is a hyperosmolar hyperglycaemic state?
- diabetic emergency
- presents commonly with renal failure
- unchecked gluconeogenesis –> hyperglycaemia –> osmotic diuresis –> dehydration
- insufficient insulin (not absent) for prevention of hyperglycaemia but sufficient for suppression of lipolysis and ketogenesis
- absence of significant acidosis
- often identifiable precipitating event (infection, MI)
Table of differences: DKA vs hyperosmolar hyperglycaemic syndrome
- volume status - dehydrated vs hypovolaemic
- glucose (mmol/L) - >11/known diabetes vs >30
- urine ketones - +++(+) vs ++(or less)
- capillary blood ketones (mmol/L) - >3 vs <3
- pH - <7.3 vs >7.3
- bicarbonate (mmol/L) - <15 vs >15
- osmolarity - variable vs >320mosmol/kg
- IV fluids - immediately vs immediately
- insulin - immediately at fixed rate infusion of 0.1 units/kg/h vs immediately only if capillary ketones >1 or urine ketones >2 (at 0.05 units/kg/h); otherwise withhold insulin until fluid resuscitated
What is the management of T2DM? (6)
- diet
- oral medication
- structured education
- may need insulin later
- remission/reversal?
- prevention of diabetes-related complications and their risk factors
What are some diabetes-related complications?
- retinopathy
- neuropathy
- nephropathy
- cardiovascular
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, urine check, retinal screening
What is an example of dietary recommendations and education for T2DM?
- total calories control
- reduce calories as fat and refined carbs
- increase calories as complex carbs and soluble fibre
- decrease sodium
DESMOND
How do we deal with excess hepatic glucose production in T2DM and what drugs can we use?
- reduce hepatic glucose production
- metformin
How do we deal with resistance to action of circulating insulin in T2DM and what drugs can we use?
- improve insulin sensitivity
- metformin and thiazolidinediones
How do we deal with inadequate insulin production for extent of insulin resistance in T2DM and what drugs can we use?
- boost insulin secretion
- sulphonylureas, DDP4-inhibitors, GLP-1 agonists
How do we deal with excess glucose in circulation in T2DM and what drugs can we use?
- inhibit carbohydrate gut absorption - alpha glucosidase inhibitor
- inhibit renal glucose reabsorption - SGLT-2 inhibitor
What one action helps with managing T2DM?
Weight loss
What does metformin do?
- biguanide type of drug, insulin sensitiser
- reduces insulin resistance - reduced HGO, increases peripheral glucose disposal
- GI side effects
When is metformin first line?
When dietary/lifestyle adjustment has made no difference
When is metformin contraindicated? (3)
- severe liver failure
- severe cardiac failure
- severe renal failure
What do sulphonylureas e.g. gliclazide do?
- bind to ATP-sensitive potassium channel and close it, independent of glucose/ATP = insulin production
- boost insulin production of beta cells
What does pioglitazone do?
- insulin sensitiser, mainly in peripheral tissues
- makes action of insulin a bit more efficacious at tissue level
- causes improvement in glycaemia and lipids
- adipocyte differentiation modified
- weight gain (peripheral not central)
What are some side effects of older types of pioglitazone? (2)
- hepatitis
- heart failure
What is a side effect of some older glucose-lowering therapies?
Mild weight gain
How does glucagon-like peptide 1 (GLP-1) work?
- gut hormone secreted in response to nutrients in gut
- transcription product of pro-glucagon gene, mostly from L-cell
- stimulates insulin, suppresses glucagon
- increases satiety
- short half life due to rapid degeneration by DPP4 enzyme
What is the gastrointestinal incretin effect?
Oral glucose causes an increased plasma insulin level than IV glucose
What do GLP-1 agonists do and give examples?
- Liraglutide, Semaglutide
- injectable - daily/weekly
- decrease glucagon and glucose
- weight loss
What do gliptins (DDPG-4 inhibitors) do?
- increase half-life of exogenous GLP-1
- increase GLP-1
- decrease glucagon and glucose
- neutral on weight
What do SGLT-2 inhibitors do?
- inhibits Na-Glu transporter, increases glycosuria
- HbA1c lower
- improve CKD, microalbuminuria
- improve risk of heart failure, strokes, death
What are some examples of SGLT-2 inhibitors? (3)
- empagliflozin
- dapagliflozin
- canagliflozin
Despite treatment, what happens to beta cell function in T2DM?
Continues to decline as there is progressive loss of beta cell function prior to diagnosis
How do we push T2DM patients into remission?
- gastric bypass surgery has potential to induce remission
- very low calorie diet (800kcal a day) for 3-6 months has potential to induce remission, which appears to be sustained at 2 years
- NHS England remission programme being piloted
How is blood pressure managed in T2DM?
- hypertension very common in T2DM
- clear benefits for reductions, especially with use of ACE inhibitors
What are the levels of different types of lipids like in T2DM, and how can this link to management?
- total cholesterol raised
- triglycerides raised
- HDL cholesterol reduced
- clear benefit to lipid-lowering therapy
