8. Diabetes Mellitus Flashcards
Define diabetes mellitus
Metabolic disease of multiple causes
Characterised by;
- chronically elevated blood glucose level
- disturbances in carb/fat/protein metabolism
Caused by;
- defects in insulin secretion, insulin action, both
Briefly describe glucose homeostasis + regulation
Blood glucose levels maintained in narrow range: 3.5-6.5mmol/L
Tightly regulated by insulin + counter regulatory hormones;
- insulin = decreases blood glucose (smaller level IGF1 too)
- glucagon, GH, T3+4, catecholamines, steroids = increase blood glucose
Describe insulin + its actions
Insulin = hormone of plenty
- secreted by beta cells of pancreas
- peptide hormone (secreted as prohormone)
Actions; OVERALL = DECREASE BLOOD GLUCOSE
RAPID;
- increased transport of glucose, a acids + K+ into insulin sensitive cells
- includes striated muscle, adipose tissue + liver cells
INTERMEDIATE;
- stimulation of protein synthesis
- activation of glycolysis + glycogen synthesis
- inhibition of GNG
DELAYED;
- increase in lipogenesis
Describe the effects of insulin on adipose tissue, striated muscle tissue + liver tissue
Adipose tissue;
- increased glucose uptake
- increased lipogenesis
- decreased lipolysis
Striated muscle;
- increased glucose uptake
- increased glyogen synthesis
- increased protein synthesis
Liver;
- decreased GNG
- increased glycogen synthesis
- increased lipogenesis
Describe the processes that happen during insulin deficiency
Decreased glucose uptake
Increased protein catabolism = increased plasma a acids
- both cause hyperglycemia + glycosuria
Increased lipolysis = increased plasma FFAs
All result in dehydration + acidosis = coma + death
Describe the pathogenesis of diabetes
Insulin resistance > relative insulin deficiency > absolute insulin deficiency
How is diabetes mellitus classified?
Type I
Type 2
Gestational Genetic-MODY Iatrogenic Secondary causes Associated diseases
What causes type 1 diabetes, how does it present + what are the risk factors?
Cause;
- absolute insulin deficiency
- B cells destroyed by autoimmunity
Presentation;
- acute
- commonly presents as complications like DKA
Risk factors;
- positive family history
- younger patient group
What causes type 2 diabetes, how does it present + what are the risk factors?
Cause;
- relative insulin deficiency
- insulin resistance
Presentation;
- hyperglycemia: polyuria, polydipsia, nocturia, blurred vision, weight loss
Risk factors;
- overweight
- middle/older age group
- strong family history
What is the old diagnostic criteria for DM?
Old criteria based on glucose
Any 2 of the following;
- symptoms, e.g. polyuria, polydipsia, unexplained weight loss
- random plasma glucose >= 11.1mmol/L
- fasting plasma glucose >= 7.0mmol/L
- 2hr level in OGTT >11.1mmol/L (2hr after 75g anhydrous glucose)
What is the new diagnostic criteria for DM?
New criteria based on HbA1c
WHO 2011 decision to accept use of HbA1c testing in diagnosing DM
Recommended cut off point for DM = 48mmol/mol (6.5%)
- lower value does not exclude DM diag using glucose
Treat as high risk = 42-47mmol/mol (6.0-6.4%)
What is HbA1c?
HbA1c = glycated Hb, Hb covalently bound to glucose
Formed in non-enzymatic glycation pathway by Hb exposure to plasma glucose
- after prolonged exposure to high conc
Why is HbA1c used to diagnose diabetes + what does it indicate?
Test measures the beta-N-1 deoxyfructosyl component of Hb
Measured to identify the 3 month average glucose concentration; (HbA1c ~~ Glucose levels)
- diag test for DM + assessment test for glycemic control in diabetics
- limited to 3 month average as RBC lifespan = 4 months (~120 days) but don’t all lyse at same time
Where does the term HbA1c come from?
HbA separates into fractions on cation exchange chromatography > based on order of elution
Why were the units for HbA1c changed?
Was reported as % but newer units were employed for global harmonisation
IFCC standardised units of mmol/mol
Dual reporting until June 2011
What two ways is HbA1c testing carried out?
Fingerprick HbA1c;
- convenient POCT
- should only be used if national quality assurance guidelines are met in lab
- must be confirmed by lab venous HbA1c test in all pts
Venous HbA1c testing
What risk categories can HbA1c testing identify + what are the recommendations for these pts?
HbA1c <48mmol/mol (6.5%);
- may still fulfill WHO glucose criteria for diag of DM
- use glucose test only if symptoms present/v high risk pt
- not recommended routinely in this situation
HbA1c <42mmol/mol (6.0%);
- may still have high diabetes risk
- review personal risk + treat as high diabetes risk if clinically indicated
When is HbA1c testing not appropriate?
All children + young people
Any age suspected of having T1 DM
Symptoms of DM <2 months
High risk DM who are acutely ill (e.g. req hosp admission)
Taking medication that may cause rapid glucose rise, e.g. steroids, antipsychotics
Acute pancreatic damage inc pancreatic surgery
Pregnancy
Presence of genetic, hematological + illness related factors that influence HbA1c + its measurement, e.g. hemoglobinopathies
What are the long standing complications of DM?
- Macrovascular;
- ischemic heart disease
- peripheral vascular disease - Microvascular;
- nephropathy
- retinopathy
- neuropathy
What are the acute complications of DM?
Hypoglycemia (secondary to treatment)
Diabetic ketoacidosis (DKA)
Hyperosmolar non-ketotic coma (HONK)
What is DKA?
Diabetic Keto Acidosis = extreme metabolic state caused by insulin deficiency
Breakdown of FAs (lipolysis) produces ketone bodies (ketogenesis) = acidic
Acidosis occurs when ketone levels exceed body’s buffering capacity
What are the causes of DKA?
Common in T1 DM
Most common cause = omission of regular insulin
Ppted by infection + stress
How does DKA present?
Acute presentation
Polyuria + polydipsia
Weight loss, nausea, vomiting
Weakness + lethargy
Altered mental state
Characterist;
- acetone on breath
- Kussmaul respiration (deep hyperventilation)
How serious is DKA?
If left untreated can be life threatening
Describe the pathophysiology of DKA
Normally, glucose in blood take up by muscle + adipose tissue under influence of insulin
If insulin deficient; Decreased glucose uptake in tissues, e.g. muscle Inc glucagon (excess) = inc GNG = inc glucose/ketones Increased lipolysis = increased FFAs + ketones
One of the ketone bodies = beta-hydroxybutyrate
- predominant ketone in DKA
- used as energy source in brain when low glucose
- able to cross BBB: acts as iHDAC on HDAC 2 + 3
Accumulation of acidic ketones = acidosis;
- causes vomiting + osmotic diuresis = hypovolemia
- further concentrates ketones + glucose = increasing acidity
How can DKA be identified in the lab?
Unchecked GNG + glycogenolysis = hyperglycemia
Osmotic diuresis, vomiting, poor intake = dehydration
Unchecked ketogenesis = ketosis
Dissociation of ketone bodies into H+ and anions = anion-gap metabolic acidosis
Often a ppting event is identified e.g. infection, lack of insulin admin
What are ketone bodies? When and how are they produced?
3 water-soluble molecules containing the ketone group;
- acetoacetate > acetone (spontaneous breakdown)
- beta-hydroxybutyrate = predominant in DKA
Characteristics;
- all 3 interchangeable
- ketone group = fruity smell
- acidic
Produced by liver from fatty acids;
- during fasting/starvation
- carb restrictive diets
- prolonged intense exercise
- alcoholism
- untreated (or inadequately treated) type 1 DM
- pregnancy
Define osmotic diuresis
Increased urination due to presence of certain substances in the filtrate causing water retention in the tubule
E.g. glucose in tubules can’t be reabsorbed = increased osmotic pressure = water retention in tubule = increased urine output
Define GNG
A metabolic pathway that generates glucose from non-carbohydrate carbon substrates, e.g. lactate, glycerol, glucogenic amino acids, lipids
What biochemical abns are found in DKA?
BLOOD; ABG analysis = acidosis Serum electrolytes analysis; - hyperkalemia - increased urea - increased creatinine - increased beta-hydroxybutyrate
URINE;
Dipstick analysis;
- ketones
- glucose
What is the treatment for DKA?
IV insulin (for hyperglycemia) IV fluids (for dehydration) Antibiotics if underlying infection
Regular bedside monitoring of bloodsugar
2x daily urine dipstick for ketones
Regular lab monitoring of electrolytes, phosphate, acid-base balance + beta-hydroxybutyrate
Describe HONK, its biochemical characteristics + treatment
Hyperosmolar non-ketotic coma
Complication of DM when high blood sugar = high osmolarity without significant ketoacidosis
Common in T2 DM
Biochem;
- high blood glucose >30mmol/L = high plasma osmolality
- no ketones in urine
- plasma ketones normal
Treatment = IV fluids + insulin
What is the role of the lab in DM?
Diagnosis
Monitoring/follow-up
Acute complications
Chronic complications
Give an example of the labs role in DM diagnosis
Random/fasting samples of glucose for diagnosis;
- serum or plasma
- GP/hospital samples
Require grey topped fluoride tubes;
- inhibits glycolysis
- prevents glucose levels falling during long sample transit times
Measured by enzymatic colorimetric assay
Give an example of the labs role in DM monitoring
Monitoring of glucose levels
Short time monitoring;
- in hospital emergency/inpatient
- GP surgery
- self monitoring by pts
Glucose meters used for short term monitoring;
- cap blood used as sample
- metres not sensitive at lower range of blood glucose
- lab has pivotal role in QC of meters
Lab blood glucose always reliable at low glucose conc
How is HbA1c estimated in the lab for DM diagnosis/monitoring?
Many methods of estimation;
- HPLC = gld std
- immunoturbidimetric method: HbA1cAb
- affinity chromatography
- electrophoretic methods
- methods based on chemical reactions
How is the lab involved in acute complications of DM?
Hourly electrolyte profile 12 hourly serum beta-hydroxybutyrate ABG CRP, Mg, PO4 Hourly blood glucose
How is the lab involved in chronic complications of DM?
DM long term complications = increased risk ischemic HD + CKD
Assess IHD risk = fasting lipids
Assess CKD risk = serum creatinine, eGFR, ACR
ACR = albumin:creatinine ratio in urine;
- no albumin in urine if kidney function normal
- early sign of KD = leak of albumin into urine
- levels of albumin so low not detected by dipstick
What diagnostic tests detect impaired glucose homeostasis + regulation? What doe these tests indicate?
Impaired fasting plasma glucose;
- FPG 6.1-7 mmol/L
- can indicate pre-diabetes
Impaired glucose tolerance;
- 2hr PPG (postprandial glucose) 7.1-11.1 mmol/L
- if person doesn’t produce/respond properly to insulin then elevated blood sugar from meal remains unregulated
- indicates pre-diabetes/DM + if DM under control
Oral glucose tolerance test;
- evaluates ability to regulate glucose metabolism by anhydrous glucose challenge
When is the OGGT indicated for use?
- equivocal (unclear/indeterminate) fasting/random blood glucose result
- unexplained glycosuria
- gestational diabetes
- diagnosis of acromegaly
Describe the prep + protocol for an OGGT
Prep;
- normal diet 3 days, fast overnight for min 8 hrs
- rest throughout test
- smoking not allowed
- water allowed
Protocol;
- baseline blood sample for glucose
- 75g anhydrous glucose in 300ml of water orally over 5-10min
- sample taken after 120min
How is an OGGT interpreted?
DM;
- fasting glucose >7.1 mmol/L
- 2H post glucose >11.1 mmol/L
Impaired fasting glucose;
- fasting glucose 6.1-7.1
- 2H post glucose <7.4
Impaired glucose tolerance;
- fasting glucose <7
- 2H post glucose 7.4-11.1
