type 2 diabetes mellitus

Question 1

what is type 2 diabetes mellitus?

Answer 1

condition in which the combination of insulin resistance and beta cell failure result in hyperglycaemia
associated with obesity
the resultant hyperglycaemia may be initially managed with diet and weight loss

with time, glucose lowering therapy and insulin will be needed

Question 2

when dies T2DM develop?

Answer 2

traditionally thought to be a disease of late adulthood
but there is evidence to show it can present through every decade of life
and prevalence is increasing in all age groups, especially early adulthood

Question 3

what is the epidemiology of T2DM?

Answer 3

prevalence varies enormously

overall increasing prevalence

occurring and being diagnosed younger

prevalence is greatest in ethnic groups that move from rural to urban areas (eg. india)

Question 4

what are the stages of development of T2DM?

Answer 4

normal:
insulin resistance low
insulin production normal

intermediate state:
insulin resistance rising (almost at peak)
insulin production is really high

T2DM:
insulin resistance at max
insulin production really low

Question 5

what are the measures of glucose like at different stages during the progression of T2DM?

Answer 5

FASTING GLUCOSE
normal: <6 mmol/L
middle: impaired fasting glycaemia
T2DM: >7 mmol/L

2 HR GLUCOSE (OGTT)
normal: <7.7 mmol/L
middle: impaired glucose tolerance
T2DM: >11 mmol/L

HbA1c
normal: <42 mmol/mol
middle: pre-diabetes
T2DM: >48 mmol/mol

(high random glucose with symptoms of diabetes - diagnosis)

Question 6

what happens to beta cell function in T2DM?

Answer 6

beta cell function decreases over course of disease

at time of diagnosis it is around 50%

it continues to decrease after diagnosis and treatment (depending on efficacy)

Question 7

what does relative insulin deficiency mean in terms of T2DM?

Answer 7

insulin is still being produced by the beta cells of the pancreas, but not enough to overcome insulin resistance
this is relative insulin deficiency

this is important as it explains why T2DM isnt associated with ketoacidosis
ketones usually form when there is no insulin present

(if type 2 people have ketones, it is usually for some other reason, such as infection)

Question 8

what is long duration T2DM?

Answer 8

when beta cell failure may progress all the way to complete insulin deficiency

they are usually on insulin at this point anyways
but it is important not to stop as this could cause ketoacidosis

Question 9

what is the pathophysiology of T2DM?

Answer 9

down to:
genes
intrauterine environment
adult environment

results in insulin resistance and insulin secretion defects

fatty acids are important in pathogenesis and complications

HETEROGENOUS
people develop it at variable BMIs, ages and progress differently

Question 10

what happens to first phase insulin release in T2DM?

Answer 10

it is lost

normally there is a sharp raise in insulin as stored insulin is released

in T2DM, this doesnt happen, there is just a very slow and slight increase.
people with T2DM do not have this stored insulin

Question 11

what is the result of reduced insulin production in T2DM?

Answer 11

there is reduced uptake of glucose into skeletal muscle

also hepatic glucose production is also increased due to both a reduction in insulin and an increase in glucagon action

so glucose is not just coming from the diet

Question 12

what is the normal relationship between insulin secretion and sensitivity compared to that in T2DM?

Answer 12

normally at high insulin secretion, sensitivity is low
and at low secretion, sensitivity is high

in T2DM:
people fall off the curve
for any degree of insulin sensitivity they secrete less insulin

Question 13

what drives insulin resistance?

Answer 13

very complicated

effectively:
a toxic, pro-inflammatory state is created

Question 14

what is the genetics of T2DM?

Answer 14

monogenic:
single gene mutation –> diabetes (MODY)
“born with is, is always gonna develop it”

polygenic:
single nucleotide polymorphisms increase risk of diabetes
“not born with it but high risk and may develop later depending on other factors”

the SNP’s responsible can be investigated using GWAS
each individual SNP only has a mild effect on risk, there are just many

Question 15

what is the role of obesity in T2DM?

Answer 15

major risk factor

fatty acids and adipocytokines are important

also central vs visceral obesity (visceral is worse)

80% of people with T2DM are obese
weight reduction is a useful treatment

Question 16

apart from genes and obesity, what other factors are associated with T2DM?

Answer 16

perturbation is microbiota:
may cause: obesity, insulin resistance
bacterial lipopolysaccharides fermentation to short chain FA, bacterial modulation bile acids
inflammation signalling metabolic pathways
most studies are correlative

intrauterine growth retardation:
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
so lower birth weight means higher chance of T2DM

Question 17

how does T2DM present?

Answer 17

hyperglycaemia
obesity
dyslipidaemia
fewer osmotic symptoms than type 1
complications (micro and macrovascular) (as it comes along more gradually than type 1)
insulin resistance
later insulin deficiency

Question 18

what are risk factors for T2DM?

Answer 18

age
increased BMI
ethnicity
PCOS
family history
inactivity

Question 19

how is T2DM diagnosed?

Answer 19

first line test is HbA1c:
(not used for type 1 as it is sudden onset)
1x HbA1c >48mmol/L with symptoms
OR
2x HbA1c >48 if asymptomatic

Question 20

what is hyperosmolar hyperglycaemic state?

Answer 20

presents commonly with renal failure

insufficient insulin for prevention of hyperglycaemia but sufficient insulin for suppression of lipolysis and ketogenesis

absence of significant ketoacidosis

often has an identifiable precipitating event (infection, MI)

hyperosmolar must mean you are peeing loads

it is a life threatening state

Question 21

how is T2DM managed?

Answer 21

diet
oral medication (metformin)
structured education
may need insulin later
remission/reversal 

(in type 1 you give insulin to treat)

you also have to prevent complications such as retinopathy, neuropathy, nephropathy, CVD

Question 22

what are the principles of what will happen during a T2DM consultation?

Answer 22

glycaemia:
HbA1C
glucose monitoring if on insulin, medication review

weight measurement
blood pressure
dyslipidaemia: cholesterol profile

screening for complications:
foot check
retinal screening
eGFR

Question 23

what are the dietary recommendations for people with T2DM?

Answer 23

total calories control
reduced calories as fat
reduced calories as refined carbohydrate
increase calories as complex carbohydrate
increase soluble fibre
decrease sodium 

(completely different from Type 1 as you dont get them to lose weight)

Question 24

what are the main facets of pathophysiology in T2DM and how do we treat them?

Answer 24

excess hepatic glucose production:
reduce it ->
metformin

resistance to action of circulating insulin:
increase sensitivity ->
metformin
thiozolidinediones

inadequate insulin production for extent of resistance:
boost secretion ->
sulphonureas
DPP4-inhibitors
GLP-1 agonists

excess glucose in circulation:
inhibit carbohydrate gut absorption, inhibit renal glucose reabsorption ->
alpha glucosidase inhibitor
SGLT-2 inhibitor

(all of these are addressed by weight loss)
(gastric bypass has the potential to induce remission)

Question 25

what is metformin?

Answer 25

biguanide, insulin sensitiser

first line if dietary/ lifestyle adjustment has made no difference

reduces insulin resistance:
reduces hepatic glucose output
increases peripheral glucose disposal

GI side effects

contraindicated in severe liver, severe cardiac or moderate renal failure

Question 26

what are sulphonureas?

Answer 26

they bind to the ATP-sensitive potassium channel on beta cells and close it independent of glucose/ATP

this stops the release of insulin

look at the diagram

Question 27

what is pioglitazone?

Answer 27

peroxisome proliferator-activated receptor agonists PPAR-delta

insulin sensitiser, mainly peripheral

adipocyte differentiation modified, weight gain but peripheral not central

improvement in glycaemia and lipids

evidence base on vascular outcomes

side effects of older types hepatitis and heart failure

Question 28

what is GLP-1?

Answer 28

gut hormone

secreted in response to nutrients in gut

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 can therefore be used)

involved in the incretin effect

Question 29

what is the incretin effect?

Answer 29

oral glucose vs IV glucose

oral leads to a much higher rise in insulin levels due to the incretin effect

Question 30

what are GLP-1 agonists?

Answer 30

eg. liraglutide, semaglutide

injectable (daily, weekly)

decrease glucagon concentration

decrease plasma glucose

cause weight loss

Question 31

what are DPPG-4 inhibitors?

Answer 31

gliptins

increase half life of exogenous GLP-1

increase GLP-1 concentration

decrease glucagon conc

decrease plasma glucose

neutral on weight

Question 32

what are SGLT-2 inhibitors?

Answer 32

inhibit Na-Glu transporter, increases glycosuria (reduces glucose reabsorption on kidneys)

eg. empagliflozin

lowers HbA1c

32% lower all cause mortality

35% lower risk of heart failure

improves CKD

Question 33

what is remission of T2DM?

Answer 33

a very low calorie diet (<800/day) has been shown to induce remission, which appears to be sustained at 2 years

also gastric bypass may help

Question 34

what other aspects of management are used in T2DM?

Answer 34

blood pressure management:
hypertension is very common
ACEi or ARB

lipid management:
total cholesterol is raised, triglycerides are raised, HDL is lowered
statins