case 6 - introduction to type 2 diabetes Flashcards
what is diabetes mellitus
metabolic diseases characterised by hyperglycaemia resulting from defects in insulin secretion, insulin action or both
what is type 2 diabetes
metabolic disorder caused by insulin resistance and insulin deficiency resulting in hyperglycaemia
what is pre diabetes and how is it diagnosed
at high risk of developing type 2 diabetes:
Impaired glucose tolerance - IGT
Above normal glucose blood concentration after fasting (impaired glucose fasting - IFG)
Above normal HbA1c - 42-48 = pre diabetes and 48+ is diabetes
what is the epidemiology of type 2 diabetes
in 2015 there were over 415 million people with diabetes worldwide
Type 2 diabetes accounts for around 90% of cases
in the UK, around 3.9 million are diagnosed with diabetes in 2019
Steady increases in diabetes incidence and prevalence
who is type 2 diabetes the most common in
more common in men than in women
65+ age group most affected
Increasing numbers diagnosed under 40 years of age
Childhood type 2 diabetes incidence also increasing
what ethnicity is diabetes the most common in
3-5 times increased prevalence in ethnic minority groups vs white communities.
south asians
in spite of lower BMI, what do south asians have:
more abdominal fat
More insulin resistance + hyperinsulinaemia
Increased inflammatory reponse
Lower adiponectin
More dyslipidaemia
what is the morbidity and mortality causes in type 2 diabetes
cardiovascular disease is the cause of death in around 70%
Commonest cause of chronic kidney disease
Commonest cause of lower limb amputation
Commonest cause of blindness in working population
Non-alcoholic fatty liver disease and most common liver disease in the world
10% of the NHS budget
what is the pathophysiology of type 2 diabetes
- there are genetic predisposition and environmental risk factors
- these risk factors lead to obesity, which leads to insulin resistance
- this leads to decreased glucose uptake which then leads to hyperglycaemia
- then hyperglycaemia leads to type 2 diabetes
- also increased hepatic glucose output, caused by deranged insulin release can also lead to hyperglycaemia
what are the non modifiable risk factors of type 2 diabetes
age
Ethnicity
Family history
Low birth weight
History of GDM
what are the modifiable risk factors for type 2 diabetes
obesity -approximately 80% of the risk for developing T2DM
Hypertension - 20mmhg increase was associated with 58% increase risk of diabetes
Dyslipidemia - low HDL, high triglycerides
PCOS - elevated androgens and insulin resistance
Poor dietary habit
what is the linear relationship between obesity and type 2 diabetes
Visceral and abdominal fat have a much greater associated with type 2 diabetes than cutaneous fat
Variation in distribution of fat with age, ethnicity, and sex
Increased fat mass —> insulin resistance and type 2 diabetes
what are the genetics linked to diabetes
polygenic
The risk of developing the condition is as high as 70% if both parents have suffered from the condition
First degree relatives of individuals with type 2 diabetes are about 3 times more likely to develop the disease
Monozygotic twins, there is a 50-90% concordance for developing the condition
Environments —> genetics
what are the steps in the key pathophysiological processes
- insulin resistance
- insulin secretory defect
- increased production of glucose by the liver
- loss of incretin effect
- other mechanisms such as insulin feedback and CNS changes
what processes does insulin lead to
Insulin leads to a number of anabolic processes, such as building larger molecules from smaller molecules, which are crucial to cellular survival, the growth of cells and tissues and maintaining normal homeostasis
what is the insulin receptor
a modified tyrosine kinase receptor
describe the binding of this receptor and what happens
he insulin receptor is a modified tyrosine kinase receptor
when insulin, as the ligand, binds to the insulin receptor, you get the insulin signalling cascade
An important part of the insulin signalling cascade is the exocytosis of GLUT4 channels to the cell membrane and then the facilitated diffusion of glucose, which is in the blood of course, into the cell
Glucose is then used in glycolysis in cellular respiration so that we get energy
in insulin resistance, what else does this increased glucose lead to
hyperglycaemia
Increased lipolysis
Increased proteolysis
Increased hepatic gluconeogenesis
what else is this glucose used for in anabolic processes and cellular growth
cellular respiration
Proteins and lipid synthesis
Inhibit hepatic gluconeogenesis
Promote hepatic glycogen synthesis
what are the damaging molecules in obese people
free fatty acids
what are free fatty acids used as
used as a substrate, as an energy by the liver and gluconeogenesis is increased
what is there less of because of this free fatty acid accumulation around the liver
there is less insulin feedback
what is there more of because of these free fatty acids
there is more gluconeogenesis and more blood glucose
what happens in the muscles
the muscles will used more fatty acids instead of glucose, so there is less glucose taken up from the blood and therefore less glycogenesis
what is the relationship between free fatty acids and the beta cell
FFAs are toxic to the beta cell and therefore less insulin is released again leading to problems with hypoglycaemia
what mediators are increased with increased lipolysis
inflammatory mediators;
released by adipocytes:
- TNF alpha and IL-6
what kind of activity is increased with lipolysis
greater sympathetic activity
what happens to the beta cells as hyperglycaemia develops
beta cells secrete more insulin to deal with increase in glucose
what happens when the beta cell mass is depleted
insulin levels fall and there is secretory failure
what is shown during autopsy of patients with T2DM
increased deposition of amyloid within islet cells
what is toxic to beta cells
hyperglycaemia (glucotoxicity)
high lipids (lipotoxicity)
what are beta cells damaged by
amyloid deposits
Inflammation
Glucotoxicity
Lipotoxicity
describe the mechanism of action of increased hepatic gluconeogenesis
- Increased availability of gluconeogenic substrates e.g fatty acids leads to increased gluconeogenesis
- Resistance of the liver to the action of insulin leads to improper suppression of hepatic gluconeogenesis
- Elevated glucagon due to resistance to feed back suppression from insulin and glucose
what are incretins
gut peptide hormones that are secreted after nutrient intake and whose primary role is to stimulate insulin release
what is GLP1 secreted by
GLP-1L cells located in the ileum and large intestine
what is GIP secreted by
GIP K cells located in the proximal duodenum
what are the symptoms and signs of type 2 diabetes
asymptomatic
Polyuria and nocturia
Lethargy
Weight change (weight loss once severe insulin deficiency occurs)
Thrush/genetial itching
Prolonged healing time
Visual disturbance
how is type two diabetes diagnosed
diabetes symptoms (e/g polyuria, polydipsia) plus:
HbA1c of >48mmol/mol or
A random venous plasma glucose concentration of more than 11.1mmol/L or
A fasting plasma glucose concentration of more than 7 mmol/L or
Two hour plasma glucose concentrations more than 11.1 mmol/L two hours after 75g anhydrous glucose in an oral glucose tolerance test (OGTT)
how is diabetes type 2 diagnosed without symptoms
two separate positive results from separate days
when do you not use Hb1Ac as diagnoses technique
rapid onset of diabetes - an increase in HbA1c may not be detected until a few weeks later
Pregnancy - HbA1c typically lower
Conditions with decreased red cell survival, haemolytic anaemia, severe blood loss, splenomegaly, antiretroviral drugs
Increased red cell survival may increase Hb1Ac e.g splenectomy
Renal dialysis reduced Hb1Ac especially if treated with erythropoietin
Iron and B12 deficiency and their treatment
for the above (excluding pregnancy) how do we diagnose diabetes then
For the above (except pregnancy) diagnose by fasting glucose more than 7mmol/L twice, or once with symptoms
what are the aims of treatment
- remission
- improve glycemic control
- treat co-existing cardiovascular risk factors
what are the management factors of type 2 diabetes
lifestyle modification - NHS diabetes prevention programme (DPP)
ASSESS cardiovascular risk - e.g QRISK3
Diet and exercise
Weight loss - aim 10% reduction
Can be enough to put diabetes 2 into remission
smoking cessation
what are the treatment targets for type 2 diabetes
-HbA1c <48mmol/mol if not on medication which cause hypoglycaemia ( otherwise <53mmol/mol)
-BP <140/80 (<130/80 if complications present)
-Total cholesterol <4.0 mmol/l, LDL<2.0 mmol/l, HDL >1 (men) >1.2 (women)
when is there treatment escalation
if Hb1Ac is greater than 58mmol/L
what is screened for annually in people with type 2 diabetes
retinopathy - retinal photography
Nephropthaty - urine dipstick, albumin creatine ratio, urea and electrolytes
Neuropathy - foot inspection , 10g monofilament or 128Hz turning fork tests and pulses
what are the different pharmacological treatments in type 2 diabetes
metformin
SGLT2 inhibitors
Sulphonylurea
DPP4 inhibitors
Thiazoidendiones
GLP-1 analogues
Insulin
Meglitindes
Alpha glucosidase inhibitors
what is metformin and what does it do
it reduces insulin resistance and hepatic glucose output
it reduces weight and suppresses appetite
what are the side effects of metformin
Side effects; diarrhoea, nausea, anorexia, lactic acidosis
what are the SGLT2 inhibitors MoA
reduce glucose reabsorption from proximal tubule of nephron
what are the additional effects of SGLT2 inhibitors
Additional effects; weight loss, blood pressure lowering, CVD protection, renal protection
what are the dosage values of metformin
Dosage:: Dapagliflozin 10mg OD, Canagliflozin 100mg – 300mg, Empagliflozin 10-25mg
what are the side effects of SGLT2 inhibitors
increased risk of urinary tract infection, DKA
what does sulphonylurea do
increases insulin secretion
bind to sulphonyurea receptor 9SUR-1) leading to closure of ATP K+ channel
what is the dosage of sulphonylurea
Dosage: *gliclazide 40mg OD, increased to 320mg in divided doses if needed
what are the side effects of sulphonylurea
hypoglycaemia, weight gain
what are DPP4 inhibitors
dipeptidyl peptidase 4 inhibitors
prevent breakdown of incretins, preserving incretin effect
what is the combination therapy DPP4 inhibitors are used in
Usually combination therapy with metformin/metformin + sulphonylurea
what is the dosage of DPP4 inhibitors
Dosage: alogliptin 25mg OD, saxagliptin 5mg OD
what are the side effects of DPP4 inhibitors
GI disturbance, rash, headache, sore throat
what are thiazolidinediones
peroxisome proliferator activted receptor gamma agonist
PPAR gamma - features
is a nuclear receptor
activation decreases insulin resistance
what is the dosage of PPAR gamma
*Dosage: pioglitazone 15mg OD, increased to 45mg OD if required
what are the side effects
Side effects; increased fracture risk, fluid retention, heart failure, small increased risk of bladder cancer
what are the effects of GLP-1 in the pancreas
increased insulin synthesis and secretion
Decreased glucagon secretion
Increased beta cell survival
what are the effects of GLP-1 in the CNS
decreased food intake
increased saiety
what are the effects of GLP-1 in the stomach and intestine
decreased gastric emptying
decreased bowel motility
decreased acid secreiton
what are the effects of GLP-1 in the liver/fat/muscle
increased glucose uptake
Increased glycogen synthesis
Increased lipogenesis in fat
when does one give GLP-1 analogues
BMI of 35kg/m2 or higher and medical problems associated with obesity
OR
BMI less than 35kg/m2 and insulin therapy would have significant implications, or weight loss would benefit other significant obesity-related comorbidities
what are examples of GLP-1 analogues
*Examples: Liraglutide 0.6mg-1.8mg OD, Semaglutide 1mg once weekly subcutaneous injections
what are side effects of GLP-1 analogues
Side effects - vomiting, nausea, diarrhoea, pancreatitis (rare)
when should insulin therapy be considered
inadequate control deste dual therapy (metformin plus another oral anti diabetic drug)
Oral anti diabetic drugs are contraindicated or not tolerated
what would the reasons be for not initiating therapy
obesity
physical and mental health - hypoglycaemia
anxiety about needles
personal preference
concerns relating to license to drive group 2 vehicles
what is the most common insulin therapy
*Neutral Protamine Hagedorn (NPH)insulin (injectedonce or twice daily according to need)
*NPH plus a short acting insulin should be consideredif HbA1c is 75 mmol/mol higher
OR
*Longer acting insulin analogues e.g. insulin detemir or insulin glargine
what is hypoglycaemia
any blood glucose less than 4.0mmol/L
what are the symptoms of hypoglycaemia
hunger, paliptations, sweating, tremors
what can people with hypoglycaemia not do
drive a group 2 vehicle - bus or lorry
