A. DIABETES Flashcards
what is diabetes mellitus
chronic metabolic disorder characertised by hyperglycaemia
what is type 1 DM characterised by
insulin deficiency so patients inject insulin as they can’t make insulin (5-15%)
what is type 2 DM characterised by
impaired β-cell function or loss of insulin sensitivity (insulin resistance)
(85-95%)
normally older people
complex:
- impaired insulin signalling pathways which decrease target-cell inflammation
- nutrient oversupply, cellular stress and inflammation causing molecular changes in cells
what are the 3 main consequences of hyperglycaemia
- glucosuria (glycosuria)
- polyuria (due to osmotic diuresis)
- polydipsia
what are other consequences of hyperglycaemia
- increased urinogenital infections eg: thrush, UTIs due to glucose in urine which is a nice culture of pathogens
- blurred vision/vision disturbance due to altered refractive index of lens
what normally happens with normal glucose plasma concentration
glucose gets filtered into ultra filtrate in kidney and gets reabsorbed back into blood so hardly any glucose in urine
what happens when glucose plasma concentration is greater than 8.9-10.6mmol/L
- glucose levels in the filtrate is very high
- exceeds renal reabsorptive capacity as there is limited reabsorptive capacity
- excess stays in filtrate and appears in urine
what does glucosuria cause
- an increase in urinary osmotic pressure so water stays in filtrate and urine
- leads to a decrease in renal water reabsorption
= OSMOTIC DIURESIS
osmotic pressure increased in urine leading to excessive production of urine
what does polyuria cause
dehydration and hence thirst
how is thirst activated
there is a fall in blood volume and an increase in plasma osmolarity which activates osmoreceptors in hypothalamus
what are metabolic consequences of impaired glucose utilisation
- lethargy, weakness
- weight loss (T1DM)
- ketoacidosis (T1DM)
what are microvascular (affecting capillaries) long-term complications of DM
- nephropathy
- neuropathy
- retinopathy
likely with increased duration of chronic hyperglycaemia/DM
what are macrovascular (affecting medium-large arteries) long-term complications of DM
- ischaemic heart disease
- stroke
- peripheral vascular disease
what are normal plasma glucose levels
- fasting <7.0 mmol/L (for 8 hours)
- random <11.1mmol/L
what are normal HbA1c levels
20–42 mmol/mol (4.0 - 6.0%)
what is HbA1c test
measures glycated or glycosylated haemoglobin - indicator of glycaemic control during previous 2-3 months (lifespan of RBC)
diagnosis of DM with signs/symptoms
1 of:
- fasting ≥ 7.0 mmol/L
- random ≥ 11.1 mmol/L
- HbA1c ≥ 48mmol/mol (or 6.5%)
diagnosis of diabetes in asymptomatic patient
2 abnormal test results on different days
what is type 1 diabetes
- autoimmune
- progressive destruction of islet β-cells by autoantibodies
- onset <40 years
- rapid onset as pathophysiological changes occur much earlier
- need to lose 90% of β-cells to show signs and symptoms
- no secondary complications at diagnosis
- under or normal weight
- tendency to ketosis
what causes type 1 DM
susceptibility genes and environmental triggers like viruses and toxins which which switch the genetically pre-disposed individual to having autoimmune disease
what is ketogenesis
synthesis of ketone bodies by liver from fatty acid breakdown products (C fragments)
example of the breakdown products (ketone bodies) of the fatty acids
2x acetyl CoA which forms acetoacetate by oxidative phosphorylation or tricarboxylic acid cycle (generate ATP in glucose metabolism)
-β-hydroxybutyrate & acetone formed
we normally have a small amount in the blood
how does insulin and glucagon affect ketogenesis
inhibited by insulin
stimulated by glucagon
what happens in starvation and T1DM regarding ketogenesis
Catabolism
- we start to break down fats (energy reserve) as we don’t have insulin action - ketosis/ketoacidosis
- hence we make more ketone bodies which causes metabolic acidosis (decrease in blood pH)
- as we have more acidic ketone bodies (acetoacetate and β-hydroxybutyrate)
treatment of T1DM
- insulin
- regular exercise
- healthy diet
T2DM
- onset >40 years
- gradual onset
- secondary complications present in 25% patients at time of diagnosis due to being hyperglycaemic for a while
- usually overweight
- > 25 years (black, S.Asian) risk is 2-4x greater due to greater risk of developing central adiposity/obesity
- risk is 2-6x greater if have family history of DM
- no ketones in urine
what causes type 2 DM
susceptibility genes and environmental triggers like reduced physical activity and increased calorie consumption
treatment of T2DM
- diet 10-20% then
- drugs (80-90%, 20% insulin) as diabetes advances and β-cells have insufficient activity
secondary causes of DM (ie not caused by gland/hormone directly) - endocrine
- Cushing’s: excess of cortisol
- Acromegaly: excess of growth hormone
- Phaeochromocytoma: excess of adrenaline
These hormones increase blood glucose
secondary causes of DM (ie not caused by gland/hormone directly) - pancreatic disease
- chronic pancreatitis
- surgery
- cystic fibrosis
- tumour
impairs function of pancreas so insufficient islets of Langerhans and hence a decrease in insulin secretion
secondary causes of DM (ie not caused by gland/hormone directly) - genetic disorders
- down’s syndrome
- prader-Willi syndrome
impairs function of pancreas so insufficient islets of Langerhans and hence a decrease in insulin secretion
secondary causes of DM (ie not caused by gland/hormone directly) - drug induced
- steroids
- beta-blockers
- diuretics
disturb lipid and glucose metabolism leading to precipitation/worsening of diabetes
what are the aims of management of DM
- alleviate symptoms
- minimise risk of long-term, secondary complication
non-pharmacological treatment for DM
- healthy diet (weight loss?)
- exercise (improve insulin sensitivity and weight loss to reduce CV risk)
- smoking cessation to decrease CV risk
when is insulin used
type 1 and type 2
inadequate control with drugs or pregnancy
insulin injection sites (sc)
- upper outer arms
- lower abdomen
- upper outer thighs
- buttocks
why do you need to rotate injection site
to avoid lipodystrophy to limit erratic drug absorption
(lipoatrophy - fat shrinkage and lipohypertrophy - fat enlargement)
when are insulin pumps used
T1DM
- continuous subcutaneous insulin infusion
- continuous basal dose with patient-activated bolus doses at meal times
when are insulin injections used
- for fine control in serious illness
- in diabetic ketoacidosis
- in surgery (peri-operative)
short-acting soluble insulin for urgent treatment
cell replacement therapy for type 1 diabetics
- islet transplantation (β-cells) so don’t need insulin
- some require 2 transplants
- require immunosuppression to prevent rejection as autoantibodies may start to destroy transplant β-cells
artificial pancreas for type 1 diabetics
- continuous glucose monitoring system with a insulin pump (hybrid closed system)
what is the first stage of management of type 2 diabetes
diet/lifestyle interventions trialled for 3 months
- healthy cardio protective diet
- weight loss if overweight
- moderation of alcohol
- smoking cessation
what is first line treatment for T2DM
metformin (caution in renal impairment as affects excretion) or
DPP-4 inhibitor (gliptins ie - sitagliptin)
Pioglitazone (eg - thiazolidinedione)
Sulphonylurea (eg - glicazide, tolbutamide)
SGLT2 inhibitor (dapagliflozin)
GLP-1 analogue/incretin mimetic (exenatide, liraglutide)
what is first line treatment for T2DM if have CHF/CVD/QRISK3 ≥10%
metformin + SGLT2 inhibitor (CV and renal benefits)
how does metformin (biguanide) work
MOA not clear, activate AMP kinase which is involved in metabolic activity?
- reduces gluconeogenesis
- increases liver sensitivity by decreasing storage of lipid in liver
- increases glucose uptake/utilisation in skeletal muscle
how do sulphonylureas work
- stimulate insulin release by blocking islet β-cell ATP-sensitive K channel so there is increased exocytosis
how does pioglitazone work
PPARᵧ (peroxisome proliferator activated receptor-gamma) agonist ‘insulin sensitiser’
- improves glucose uptake/utilisation (skeletal muscle, liver, adipose) and lipid metabolism (liver, adipose)
what do incretins do (GLP-1, GIP)
islet β-cells
- stimulate glucose-induced insulin release
islet α-cells
- inhibit glucagon release
therefore lower blood glucose
also:
- reduce gastric emptying as increase transit time of food in gut and hence a rapid rise of blood glucose with carbs is slowed
- promote satiety
- reduce hepatic glucose production (gluconogenesis)
what happens to incretin effects on insulin release in T2DM
decreased
what does DDP-4 (dipeptidyl peptidase-4) do
breaks down incretins
what can GLP-1 analogues be used for
weight loss medications
what is SGLT2 responsible for
reabsorption of glucose from ultrafilitrate
how do SGLT2 inhibitors work (sodium-glucose co-transporter 2)
- inhibit SGLT2 in renal PCT to inhibit renal glucose reabsorption and increase urinary glucose excretion to get a a decrease in blood glucose
- CV and renal benefits in CHF and CKD (unlikely to be released to improvement in glycaemic control)
side effects of SGLT2
polyuria
polydipsia
xerostomia (dry mouth)
what if first line/other drugs don’t work
dual therapy or triple therapy if have CHF/CVD/QRISK3 ≥10%
start insulin with/without other drugs then may need to intensify regime or add drugs due to loss of insulin secretory capacity
bariatric surgery for DM
- BMI ≥ 35, expedited assessment for metabolic surgery
- BMI ≥ 30 (failed to lose weight and failed drug intervention), consider metabolic surgery
(ethnicity prone to central adiposity, BMI ≥ 27.5)
very low calorie diets for DM (on NHS)
- 800 calories per day
- rapid weight loss and reduced CV risk
- can reverse diabetes for at least 2 years
- careful management required
