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UG Biochemistry > 8. Diabetes Mellitus > Flashcards

8. Diabetes Mellitus Flashcards

1
Q

Define diabetes mellitus

A

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

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2
Q

Briefly describe glucose homeostasis + regulation

A

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
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3
Q

Describe insulin + its actions

A

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

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4
Q

Describe the effects of insulin on adipose tissue, striated muscle tissue + liver tissue

A

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
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5
Q

Describe the processes that happen during insulin deficiency

A

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

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6
Q

Describe the pathogenesis of diabetes

A

Insulin resistance > relative insulin deficiency > absolute insulin deficiency

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7
Q

How is diabetes mellitus classified?

A

Type I
Type 2

Gestational
Genetic-MODY
Iatrogenic
Secondary causes
Associated diseases
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8
Q

What causes type 1 diabetes, how does it present + what are the risk factors?

A

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
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9
Q

What causes type 2 diabetes, how does it present + what are the risk factors?

A

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
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10
Q

What is the old diagnostic criteria for DM?

A

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)
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11
Q

What is the new diagnostic criteria for DM?

A

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%)

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12
Q

What is HbA1c?

A

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

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13
Q

Why is HbA1c used to diagnose diabetes + what does it indicate?

A

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
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14
Q

Where does the term HbA1c come from?

A

HbA separates into fractions on cation exchange chromatography > based on order of elution

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15
Q

Why were the units for HbA1c changed?

A

Was reported as % but newer units were employed for global harmonisation

IFCC standardised units of mmol/mol

Dual reporting until June 2011

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16
Q

What two ways is HbA1c testing carried out?

A

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

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17
Q

What risk categories can HbA1c testing identify + what are the recommendations for these pts?

A

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
18
Q

When is HbA1c testing not appropriate?

A

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

19
Q

What are the long standing complications of DM?

A
  1. Macrovascular;
    - ischemic heart disease
    - peripheral vascular disease
  2. Microvascular;
    - nephropathy
    - retinopathy
    - neuropathy
20
Q

What are the acute complications of DM?

A

Hypoglycemia (secondary to treatment)
Diabetic ketoacidosis (DKA)
Hyperosmolar non-ketotic coma (HONK)

21
Q

What is DKA?

A

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

22
Q

What are the causes of DKA?

A

Common in T1 DM
Most common cause = omission of regular insulin
Ppted by infection + stress

23
Q

How does DKA present?

A

Acute presentation

Polyuria + polydipsia
Weight loss, nausea, vomiting
Weakness + lethargy
Altered mental state

Characterist;

  • acetone on breath
  • Kussmaul respiration (deep hyperventilation)
24
Q

How serious is DKA?

A

If left untreated can be life threatening

25
Q

Describe the pathophysiology of DKA

A

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
26
Q

How can DKA be identified in the lab?

A

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

27
Q

What are ketone bodies? When and how are they produced?

A

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
28
Q

Define osmotic diuresis

A

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

29
Q

Define GNG

A

A metabolic pathway that generates glucose from non-carbohydrate carbon substrates, e.g. lactate, glycerol, glucogenic amino acids, lipids

30
Q

What biochemical abns are found in DKA?

A 
BLOOD;
ABG analysis = acidosis
Serum electrolytes analysis;
 - hyperkalemia
 - increased urea
 - increased creatinine
 - increased beta-hydroxybutyrate

URINE;
Dipstick analysis;
- ketones
- glucose

31
Q

What is the treatment for DKA?

A 
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

32
Q

Describe HONK, its biochemical characteristics + treatment

A

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

33
Q

What is the role of the lab in DM?

A

Diagnosis
Monitoring/follow-up
Acute complications
Chronic complications

34
Q

Give an example of the labs role in DM diagnosis

A

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

35
Q

Give an example of the labs role in DM monitoring

A

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

36
Q

How is HbA1c estimated in the lab for DM diagnosis/monitoring?

A

Many methods of estimation;

  • HPLC = gld std
  • immunoturbidimetric method: HbA1cAb
  • affinity chromatography
  • electrophoretic methods
  • methods based on chemical reactions
37
Q

How is the lab involved in acute complications of DM?

A 
Hourly electrolyte profile
12 hourly serum beta-hydroxybutyrate
ABG
CRP, Mg, PO4
Hourly blood glucose
38
Q

How is the lab involved in chronic complications of DM?

A

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
39
Q

What diagnostic tests detect impaired glucose homeostasis + regulation? What doe these tests indicate?

A

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

40
Q

When is the OGGT indicated for use?

A
  • equivocal (unclear/indeterminate) fasting/random blood glucose result
  • unexplained glycosuria
  • gestational diabetes
  • diagnosis of acromegaly
41
Q

Describe the prep + protocol for an OGGT

A

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
42
Q

How is an OGGT interpreted?

A

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

UG Biochemistry (14 decks)

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