T2DM Flashcards
What is meant by insulin resistance?
Insulin binds to its receptor on peripheral tissues (adipose tissue, liver, muscle) but there is no mobilisation of GLUT-4 vesicles with the plasma membrane to allow glucose uptake so the issue is post-receptor.
Initially, the beta cells compensate by HYPERSECRETING insulin but eventually (after 10-15 years) become overworked & start to fail, so insulin secretion falls.
Definition
Chronic hyperglycaemia due to combination of insulin resistance and relative (less severe) insulin deficiency. Characterised by hypersecretion of insulin by a depleted beta cell mass.
Pathophysiology
Insulin resistance causes progressive beta cell exhaustion leading to relative insulin deficiency.
- Insulin resistance develops post receptor (like in healthy people, insulin binds to insulin receptor on peripheral tissues (liver, adipose tissue, skeletal muscle) but there is no mobilisation of GLUT-4 vesicles with the plasma membrane to uptake glucose so the issue is post-receptor) ⇒ peripheral tissues don’t uptake glucose
- Beta cells initially hypersecrete insulin in response to hyperglycaemia (due to beta cell hyperplasia & hypertrophy) but eventually become overworked ⇒ progressive beta cell failure (beta cell atrophy) and relative insulin deficiency
- At time of diagnosis, 50% of original beta cell mass remains.
Thus established T2DM is associated with hypersecretion of insulin by a depleted beta cell mass with progression towards absolute insulin deficiency- requiring insulin therapy
Why doesn’t DKA usually develop in T2DM?
Beta cells still secrete SOME insulin (whereas in T1DM there is absolute insulin deficiency). Low insulin levels are sufficient to suppress lipolysis and hepatic ketogenesis.
Epidemiology
- age at onset > 30 years (but increasing incidence in teenagers due to Western diet and sedentary lifestyle)
- M > F
- highest prevalence in South Asian men
Risk factors
Non-modifiable:
- Family history of diabetes
- Ethnicity- South Asian, African Carribbean, Middle Eastern
- Male
- older age - onset typically after 30 yrs
Modifiable:
- central obesity
- sedentary lifestyle
- hypertension
- high refined carbohydrate diet
Signs & symptoms
Patient tends to have central obesity in DMT2 rather than being lean like in DMT1.
Symptoms
- polyphagia (hunger)- because blood glucose is high but there is reduced glucose uptake by peripheral tissues, lack of usable energy source
- polyuria - due to osmotic diuresis
- polydipsia
- fatigue
- blurred vision- visual acuity reduced as lens absorbs water & changes shape
- recurrent infections e.g. vaginal candidiasis
Signs
- glycosuria - glucose filtered into urine, above 10mmol/L glucose kidneys reach maximal resorptive capacity so excess glucose spills into urine
- With severe T2DM, patients have acanthosis nigiricans (blackish pigmentation of nape of neck & axillae)
What features are suggestive of type 2 rather than type 1?
- presents in over 30s
- patient typically has central obesity
- gradual symptom onset (whereas type 1 has sudden unexplained weight loss)
- 100% concordance in identical twins- therefore stronger genetic predisposition than type 1
Investigations
- HbA1c ≥ 48mmol/L or >6.5% = gold standardGlycated Hb (glucose attached to Hb)- reflects average blood glucose over past 3 months
- Fasting plasma glucose ≥ 7mmol/LFPG > 7 mmol/L = diabetes diagnosis for symptomatic individualFor asymptomatic individuals 2 repeated abnormal values are needed to confirm diabetes.NB: fasting = no food intake for 8hrs
- Random plasma glucose ≥ 11.1mmol/LRPG > 11.1 mmol/L = diabetes diagnosis in symptomatic individualFor asymptomatic individuals, 2 abnormal values needed.
- Oral glucose tolerance test fasting ≥ 7mmol/L or 2hr value ≥ 11.1mmol/LGive 75g glucose bolus after 8 hour fast then measure blood glucose
1 abnormal value needed to diagnose symptomatic patient; 2 abnormal values needed for asymptomatic patients.
Also need to consider impaired glucose tolerance (IGT) & impaired fasting glucose (IFG) which indicate prediabetes diagnosis (unique window for lifestyle intervention, can reverse diabetes).
Prediabetes diagnosis
- Prediabetes can be reversed with lifestyle modifications (diet & exercise). There are 2 abnormalities of glucose regulation; there may be lower risk of progression to T2DM with IFG compared to IGT.
- HbA1c is 42-47 mmol/L OR fasting plasma glucose = 6.1-6.9 mmol/L OR OGTT 2h value = 7.8-11 mmol/L
Impaired glucose tolerance
OGTT 2h value = 7.8-11 mmol/L
& fasting plasma glucose is normal < 6mmol/L
Impaired fasting glucose
Fasting plasma glucose = 6.1-6.9 mmol/L AND OGTT 2hr value is normal < 7.8 mmol/L
Treatment
- 1st line: lifestyle changes
Target HbA1c with lifestyle modifications is48 mmol/mol(6.5%). Weight loss, dietary modifications (low GI carbohydrate sources, limit trans & saturated fatty acids, exercise, blood pressure control using ACE-i, statins for hyperlipidaemia) - 2nd line: Immediate-release Metformin
- 3rd line: Dual therapy of Metformin with DPP-4 inhibitor/Pioglitazone/Sulfonylurea/SGLT-2 inhibitor
- 4th line: 4th line: triple therapy of Metformin + 2 other drugs: SGLT-2 inhibitor/sulfonylurea/DPP-4 inhibitor/ pioglitazone/ GLP-1 analogue
- Last resort = insulin
Treatment targets for HbA1c
- Lifestyle changes inc diet management- 48mmol/L
- Lifestyle changes inc diet & drug NOT associated with hyperglycaemia e.g. Metformin - 48mmol/L
- Drug treatment with drug associated with hypoglycaemia e.g. sulfonylurea -53mmol/L
Metformin mechanism & info & contraindication
Metformin is a biguanide. It increases sensitivity of peripheral tissues to insulin & decreases hepatic gluconeogenesis.
CI in renal impairment (eGFR <30) because metformin is excreted by the kidneys by active tubular secretion.
Metformin Side effects
- lactic acidosis
- GI discomfort, nausea & vomiting
How is metformin excreted?
It is excreted by the kidneys by active tubular secretion (actively transported from blood to filtrate against concentration gradient) & excreted unchanged in urine.
