Week 9 Flashcards
Define diabete mellitus:
A metabolic disorder of multiple aetiology characterized by chronic hyperglycaemia with disturbances of carbohydrate, protein and fat metabolism resulting from defects in insulin secretion, insulin action, or both
What are the WHO diagnostic criteria for DM?
WHO Criteria
- Fasting plasma glucose of >7.0 mmol/L
- Random plasma glucose of >11.1 mmol/L
- One abnormal values diagnostic if symptomatic
- Two abnormal values if diagnostic if asymptomatic
- HbA1c 6.5% or 48 mmol/mol
- Diabetes should not be diagnosed on the basis of glycosuria or a BM stick
- OGTT only required for diagnosis if IFG or GDM
Describe the pathogenesis and epidemiology of T1DM:
5% of DM.
Chronic, progressive metabolic disorder characterised by hyperglycaemia and the absence of insulin secretion.
Type 1 diabetes results from autoimmune destruction of the insulin-producing beta cells in the islets of Langerhans.
Occurs in genetically susceptible subjects and is probably triggered by one or more environmental agents.
Lifetime risk of developing T1DM:
No family history – 0.4 percent
Offspring of an affected mother – 1 to 4 percent
Offspring of an affected father – 3 to 8 percent
Offspring with both parents affected – reported as high as 30 percent
Non-twin sibling of affected patient – 3 to 6 percent
Dizygotic twin – 8 percent
Monozygotic twin – 30 percent within 10 years of diagnosis of the first twin, and 65 percent concordance by age 60 years 5% of DM.
Describe the pathogenesis and epidemiology of T2DM:
90% of DM.
Chronic, progressive metabolic disorder characterised by hyperglycaemia, insulin resistance and relative impairment of insulin deficiency
Common with a prevalence that rises markedly with increasing levels of obesity
Most likely arises through a complex interaction among many genes and environmental factors
39% have at least one parent with T2DM
Lifetime risk for a first-degree relative of a is 5 -10 times higher than that of age- and weight-matched without family history of diabetes.
Describe the pathogenesis and epidemiology of GDM:
1-2% of DM (often unrecognised)
Caused by change in a single gene (monogenic). Autosomal dominant (50% chance of inheriting)
6 genes have been identified accounting for 87% of UK MODY (HNF1-A around 70%)
3 main features:
Often <25yrs onset
Runs in families from one generation to next
Managed by diet, OHAs, insulin (not always)
Describe the pathogenesis and epidemiology of MODY:
Carbohydrate intolerance with onset, or diagnosis, during pregnancy
Studies show that appropriate interventions reduce adverse outcomes in pregnancy
Risk factors include high body mass index, previous macrosomic baby or gestational diabetes, or family history of, or ethnic prevalence of, diabetes
Compare and contrast T1 and T2DM
Learn grid in summary sheets
What are the causes of 2ndry diabetes?
Secondary Diabetes
Genetic Defects of beta-cell function Genetic defects in insulin action Disease of exocrine pancreas Pancreatitis/Carcinoma/CF/Haemochromatosis Endocrinopathies Acromegaly/Cushings/Phaeochromocytoma Immunosuppressive agents Glucocorticoids/Tacrolimus/Ciclosporin Anti Psychotics – Cloazpine/Olanzipine Genetic syndromes associated with DM Down’s Syndrome Friedreich’s Ataxia, Turner’s Myotonic Dystrophy, Kleinfelter’s Syndrome.
What are the diagnostic criteria for GDM?
All women with risk factors should have an OGTT at
24 to 28 weeks. Internationally agreed criteria for gestational diabetes using 75 g OGTT:
Fasting venous plasma glucose ≥ 5.1 mmol/l, or
One hour value ≥ 10 mmol/l, or
Two hours after OGTT ≥ 8.5 mmol/l
How is micro and microvascular disease managed in diabetes?
Retinopathy: annual photographic retinal screening with triggers for ophthalmology referral
Nephropathy: annual monitoring of renal function and urinary albumin excretion, referral to renal team if nephropathy progresses e.g. CKD4, macroalbuminuria
Neuropathy/foot disease: annual foot-screening (minimum) with risk stratification and referral to podiatry/vascular as appropriate e.g. progressive neuropathy, structural change, ischaemia
CVS disease: keep BP <130/80, lower nephropathy. Statin therapy if T2DM and age >40 regardless of DM duration and baseline cholesterol. Consider in T1DM especially if complications
Describe hypoglycaemia, and driving and diabetes:
5 to drive
Describe insulin secretion:
- Raised glucose blood concentration
- Increased uptake of glucose into beta cells by GLUT2
- Increased ATP:ADP ratio closing ATP-gated K+ channels
- K+ ions no longer shunted across cell membrane, leading to rise of positive charge inside cell and depolarisation of cell
- Net effect is activation of voltage gated calcium channels, increasing intracellular calcium concentration
- Increased calcium triggers export of insulin by exocytosis and diffusion into nearby blood vessels
Describe hypoglycaemia, and driving and diabetes:
4.6 mmol/l - inhibition of insulin release - general malaise: headache, nausea
3.8 mmol/l - release of counterrgulatory hormones glucagon and adrenaline – onset of autonomic symptoms (most occur ~3 mmol/l) - sweating, palpitations, shaking, nausea, anxiety, hunger
BUT 70-80% of readings at this level no symptoms
2.5 -2.8 mmol/l - impairment of cognitive function and concentration, inability to perform complex tasks - confusion, drowsiness, odd behaviour, speech difficulty, incoordination, weakness, visual change, dizziness, tiredness
<2mmol/l – EEG changes, seizures
<1.5 mmol/l - coma, convulsions
5 TO DRIVE
Compare and contrast DKA and HHS:
DKA: absolute or relative insulin deficiency + increase in stress hormones leading to lipolysis (FFA: ketogenesis), gluconeogenesis (severe hyperglycaemia) and osmotic diuresis + acidosis leading to dehydration
Treat with fluid rehydration, electrolyte replacement (potassium) and insulin
HHS: hypovolaemia from hyperglycaemia, bicarbonate > 15mmol/l, absence of significant ketones
Treat with fluid, insulin and electrolyte replacement (sodium)
Describe the pharmacology of T2DM treatments:
Suplhonylureas: found to inhibit ATP-sensitive K+ channels in beta cells
Biguanides (metformin): mimics insulin by inhibiting hepatic gluconeogenesis, MoA uncertain but all involve inhibition of liver mitochondrial function
Pioglitazone: stops inappropriate deposition of lipid in non-adipose tissues (which leads to insulin resistance), therefore improves insulin sensitivity
DPP4 inhibitors: inhibit DPP4 which inactivates gastrointestinal hormones that potentiate insulin secretion, increasing endogenous incretin-mediated increase in insulin secretion
GLP1 receptor agonists: mimic incretins and are not cleaved by DPP-4, improving insulin secretion
SGLT2 inhibitors: inhibit renal re-uptake of glucose from filtrate by SGLT2, reducing hyperglycaemia. Also reduce blood pressure
