(endo) type II diabetes mellitus Flashcards
what is type II diabetes mellitus?
a condition that occurs arises as a result of insulin resistance and beta cell failure causing chronic hyperglycaemia
what is type II diabetes mellitus associated with?
associated w obesity (and genetic risk)
how is the resultant hyperglycaemia of T2DM managed most commonly?
most commonly initially managed by changes to diet + weight loss
with time, may need insulin therapy
how does the age at which T2DM develops affect life expectancy?
if diagnosed later in life = not much change in life expectancy
if diagnosed earlier in life = reduces life expectancy a fair amount
what are the stages of T2DM development?
1) normal
2) intermediate state
3) T2DM
what results are expected in normal healthy patients for the following tests?
1) fasting glucose levels
2) 2-hour glucose OGTT
3) HbA1c
1) fasting glucose = <6 mmol/L
2) OGTT = <7.7 mmol/L
3) HbA1c = <42 mmol/mol
what results are expected in T2DM patients for the following tests?
1) fasting glucose levels
2) 2-hour glucose OGTT
3) HbA1c
1) fasting glucose = >7 mmol/L
2) OGTT = >11 mmol/L
3) HbA1c = >48 mmol/mol
what is it the term to describe a fasting glucose level between 6-7 mmol/L?
impaired fasting glycaemia
what is it the term to describe a OGTT between 7.7-11 mmol/L?
impaired glucose tolerance
what is it the term to describe a HbA1c between 42-48 mmol/mol?
pre-diabetes
non-diabetic hyperglycaemia
explain how insulin resistance and insulin production change as T2DM develops
insulin production is high and resistance is low in healthy patients
progressively, insulin resistance increases and to compensate, initially, insulin production increases
by the time T2DM develops, insulin resistance peaks and insulin production falls very low
(as beta cell failure occurs due to persistent insulin resistance even after increased production)
what is the biggest contributory factor to the development of T2DM?
insulin resistance
but a degree of beta cell failure is required
what random glucose level allows for a diagnosis of diabetes?
a random glucose levels of = 11.1 mmol/L
+ SYMPTOMS
= diagnosis of diabetes
explain how beta cell failure occurs in T2DM
there is compensatory insulin production by beta cells as a response to the increasing insulin resistance in developing T2DM
insulin production begins to wane + cannot keep up w/reverse the insulin resistance
= beta cell failure (due to being overworked)
patients w T1DM have absolute insulin deficiency
patients w T2DM have relative insulin deficiency
differentiate between the two
absolute insulin deficiency = no insulin production at all due to autoimmune damage to the beta cells of the pancreas
relative insulin deficiency = some insulin production occurs BUT is not sufficient enough to overcome the insulin resistance
why does T2DM no usually lead to ketogenesis?
normally w T2DM = there is RELATIVE, not absolute insulin deficiency
so there is sufficient insulin to inhibit ketogenesis in the liver
= reducing the risk of diabetic ketoacidosis
in which scenarios do patients w T2DM present with DKA?
possible due to infection, sepsis etc
what is the biggest risk with long-duration T2DM?
long duration can lead to absolute insulin deficiency as the overworked beta cells lose their function completely eventually
= no insulin production at all
= DKA risk (if not on insulin therapy, which is unlikely at this stage)
what underpins the pathophysiology of T2DM?
adipocytokines internal adiposity insulin resistance beta cell failure genetics
what is the response of the following individuals to an IV glucose challenge?
a) normal glucose tolerance
b) impaired glucose tolerance
c) T2DM
(describe the glucose levels initially and the level of insulin production)
a) normal glucose levels initially; followed by a sharp peak of insulin release (first + second phase)
b) slightly higher than normal glucose levels; followed by a medium peak in insulin levels
c) very high glucose levels; followed by no/negligible peak in insulin
first phase insulin release is lost in patients w T2DM
what does this meal?
in response to a meal, stored insulin is released as part of the first phase insulin response in the first 10 mins and then over the next 2-3 hours, in the second phase insulin response, more insulin is produced
in T2DM, no stored insulin is released (i.e. first phase insulin release) is lost
what are the main implications of a lack of insulin in T2DM?
reduced/no insulin (also increases glucagon secretion)
= less glucose uptake into myocytes and hepatocytes
= increased glycogenolysis + gluconeogenesis
= increased HGO
the metabolic clearance rate of glucose in T2DM is significantly diminished
why is this the case?
in T2DM, no insulin
= no glucose uptake into hepatocytes + no subsequent conversion into glycogen for storage
= resultant excess glucose is converted into lactate
= lactate then taken to liver and converted into glucose
= increases plasma glucose even more
why does gluconeogenesis increase in T2DM?
in T2DM, no insulin
= increased lipolysis and proteolysis
= increased released of substrates (i.e. glycerol, NEFAs, gluconeogenic AAs)
= influx of substrates in the liver that can be used for gluconeogenesis
(further stimulated by increased glucagon secretion)
describe the relationship between insulin sensitivity and insulin secretion
the more insulin sensitive an individual is, the less insulin needs to be secreted to produce the desired effect
(more insulin sensitive individuals are less insulin resistant)
in T2DM, there is an excess of inflammatory adipokines
explain the pathology behind this briefly
T2DM
= excess inflammatory adipokines released by adipocytes
= creates a pro-inflammatory toxic state
= drives insulin resistance in tissues
differentiate between monogenic and polygenic in terms of T2DM
monogenic = single gene mutation
(born w mutation, always going to develop diabetes)
polygenic = loads of small changes ‘polymorphisms’ in the genome
(not born w it but polymorphisms increase risk of developing diabetes)
– lifestyle changes will only make a difference in the polygenic version –
what is the role of obesity in T2DM?
- obesity is a risk factor for T2DM
- obesity is associated w fatty acids & adipocytokines that are involved in T2DM
- central/visceral obesity
besides obesity, which other associations with T2DM exist?
- perturbations in gut microbiota
- intrauterine growth retardation
how does T2DM present?
- overweight
- hyperglycaemia
- dyslipidaemia
- complications (retinopathy, neuropathy, nephropathy, PCD)
- insulin resistance that can deteriorate to insulin deficiency
what are the risk factors of T2DM?
- age
- ethnicity
- family history
- increased BMI/obesity
- PCOS
- inactivity
what is the first line test for diagnosing T2DM?
HbA1c
how is T2DM formally diagnosed?
1) symptoms
+ x1 HbA1c >48 mmol/L
2) asymptomatic
+ x2 HbA1c >48 mmol/L
what are the acute and chronic complications of T2DM?
acute =
hyperosmolar hyperglycaemic state
chronic =
1) microvascular: retinopathy, neuropathy, nephropathy
2) macrovascular: ischaemic heart disease, peripheral vascular disease
compare the acute complication of T1DM to that of T2DM
T1DM = diabetic ketoacidosis
T2DM = hyperosmolar hyperglycaemic state
what is a hyperosmolar hyperglycaemic state?
the acute complication of T2DM
= when the insulin level is at a point that is sufficient enough to suppress lipolysis and ketogenesis but is insufficient to prevent hyperglycaemia
(= absence of significant acidosis)
what does a hyperosmolar hyperglycaemic state commonly present with?
renal failure
what causes a hyperosmolar hyperglycaemic state?
ofter an identificable precipitating event
e.g. infection, MI
what does unchecked gluconeogenesis lead to?
hyperglycaemia
what is the main implications of hyperglycaemia?
causes osmotic diuresis
which leads to dehydration
how does hyperglycaemia cause osmotic diuresis?
hyperglycaemia
= increases osmolarity of the blood in the intravascular space
= water follows in order to maintain the osmotic gradient
= osmotic diuresis
= dehydration
how can DKA and the hyperosmolar hyperglycaemic state be differentiated?
mainly
1) glucose levels
DKA = >11 mmol/L
HHS = >30 mmol/L
2) osmolarity
DKA = variable
HHS = >320 mOsm/L
how are both DKA and HHS managed?
- intravenous fluids
- insulin
compare how T1DM is managed compared to T2DM
T1DM = exogenous insulin, self-monitoring of glucose, technology, structured education
T2DM = diet, lifestyle changes, oral meds, structured education
what are the aspects of a T2DM progress consultation?
1) glycaemia (HbA1c, glucose)
2) dyslipidaemia
3) blood pressure
4) weight assessment
5) complication screening (retinal screening; foot check)
what dietary recommendations are usually made for patients w T2DM?
- total calorie reduction
- decrease sodium
- increase calories as complex carbs + increase soluble fibre
- reduce calories as fats and refined carbs
how is the excess hepatic glucose output managed in patients w T2DM?
reduce HGO
= METFORMIN
how is the insulin resistance managed in patients w T2DM?
improve insulin sensitivity
= METFORMIN, thiozolidinediones
how is the inadequate insulin secretion (disproportionate to resistance) managed in T2DM?
boost insulin secretion
= DPP-4 inhibitors
= sulphonlyureas
= GLP-1 agonists
how is the hyperglycaemia managed in T2DM?
inhibit gut absorption + renal reabsoprtion
= alpha glucosidase inhibitor
= SLGT-2 inhibitor
when is metform used to manage T2DM and how does it work?
first line if lifestyle changes do no make a difference
- insulin sensitiser
- reduce HGO + increase peripheral glucose disposal
when can metformin not be used to manage T2DM?
- contraindicated in sever cardiac/liver failure or moderate renal failure
- GI side effects
why are sulphonylureas used to manage T2DM and how do they work?
increase insulin secretion
= bind to the ATP-sensitive K+ channel, reducing K+ efflux so more remains within th ebeta cells and activates, in turn, the Ca2+
= subsequent Ca2+ influx results in vesicle exocytosis of insulin into the bloodstream
what is pioglitazone?
- insulin sensitiser
= side effects of hepatitis and heart failure
(makes the action o f insulin more efficacious at tissue level)
what is GLP-1?
gut hormone
= glucagon like peptide-1
what is the function of GLP-1?
a gut hormone, secreted from L cells mainly
= that stimulates insulin and suppresses glucagon + promotes feelings of satiety (‘fullness’)
why does GLP-1 have a short half-life and why is this important?
due to the action of the dipeptidyl-peptidase enzyme
= cause rapid degeneration of GLP-1
soooo
= important as DPP-4 inhibitors can prevent degradation of GLP1-
= so more remains to increase insulin and promote satiety
what is the GI ‘incretin’ effect?
when glucose is taken orally as opposed to intravenously, there is a more significant increase in plasma insulin levels
= mediated by the gut GLP-1 hormone
what effect do both GLP-1 agonists and DPP-4 inhibitors have?
both increase the half-life of exogenous GLP-1
= increase GLP-1, decrease glucagon and increase insulin
why are GLP-1 agonists sometimes preferred to DPP-4 inhibitors?
GLP-1 agonists = weight loss
DPP-4 inhibitors = weight neutral
what are SGLT-2 inhibitors and how are they used to manage T2DM?
used to tackle the hyperglycaemia associated w T2DM
= bind to and inhibit the sodium-glucose transporter
= results in glycosuria BUT improves CKD and HbA1c levels
what has the potential to induce remission of T2DM?
- gastric bypass surgery
- low-calorie diet
- weight loss
besides management of the hyperglyceamia, what else has to be monitored in T2DM patients?
1) lipid management
- total cholesterole/triglycerides raised?
- HDL cholesterol reduced?
2) BP management
- hypertension common
what does cardiovascular risk management involve in patients w T2DM?
lowering HbA1c but addressing blood pressure and lipids too
