8. Diabetes Mellitus Flashcards
Define diabetes mellitus.
“Diabetes” = passing through (excessive urination) “Mellitus” = sweet
Several distinct chronic diseases characterized by:
- Inadequate effect of hormone insulin
- Absolute inadequacy
- Relative inadequacy of increased resistance to insulin action
- Defects in insulin secretion, insulin action, or both
- Hyperglycaemia is common end point
What is the significance of diabetes mellitus?
8
- Insulin key regulatory hormone
- Inadequate insulin effects carbs, fat, and protein metabolism
- Chronic disease, but can be modified
- Long term complications increase mortality
- Burden of morbidity
- Mostly increased risk of CVD due to atheroma
- Risk factors for CVD due to atheroma:
- DM
- Hypertension
- Smoking
- Abnormal lipids (high LDL, low HDL cholesterol, high triglycerides)
- Lifestyle (weight, diet, exercise) - Commonest cause of end stage renal disease, adult blindness, non-traumatic lower limb amputation
How do you diagnose DM? (ADA)
4
- 2hr OGTT PG: standard 75g glucose load, and measured after 2h
- Fasting PG: 8h fasting
- HbA1C: measured through venous blood w/ special tube and fluoride added
- Random PG: capillary blood glucose through finger prick test
- Confirmation of diagnosis must be repeated on different days except high random w/ symptoms of hyperglycaemia - Random plasma glucose >11.1mmol/l + symptoms of hyperglycaemia (polyuria, polydipsia, weight loss)
OR - 2 hour post-75g glucose load (oral GTT) plasma glucose (2hr-PG) >11.1mmol/l (N <7.8mmol/l)
OR
- Fasting plasma glucose (FPG) >7mmol/l (N <5.6mmol/l ADA, <6.1mmol/l WHO)
OR
- Glycated haemoglobin (HbA1C) >48 mmol/mol (new units), >6.5% (old units) —> NEWER
a. HbA1C most acceptable test, but more expensive
b. HbA1C unsuitable: if acutely unwell, for diagnosis of type 1 DM, haemoglobinopathy or haemolysis
What are ways of point of care testing?
5
- Capillary blood glucose —> glucose tear: good for bedside and at home self-management
- Urine dipsticks
- Blood gas analyzes in ICU
- Self-testing for INR for management of anticoagulation
- Troponin and BNP in A+E
- Need validation against lab standards
What is HbA1C?
HbA1C( glycated hemaglobin): average blood glucose concentration over preceding few months
- RBC life span: 120d
- Glycolysation of heme is a non-enzymatic reaction, with the rate only related to concentration of blood glucose
- Expressed as mmol of glycated heme per mol of heme
Why is testing for glucose in urine not accurate?
5
- Not diagnostic
- False negative
- False positive
- Not reliable
- 1% of pop have inherited low renal threshold for tubular re-absorption of glucose (so can easily spill glucose into urine = false positive)
- Test for KETONES is urine (dipstick) or blood
What are the features of pre-diabetes?
3
- Impaired fasting glucose: FPG 5.6-6.9 mmol/l (ADA), FPG 6.1-6.9 mmol/l (WHO)
- Impaired glucose tolerance: FPG normal, 2hr-PG level in GTT 7.8-11.0 mmol/l
- Pre-diabetes measured by HbA1C: 37-48 mmol/mol (5.7-6.4%)(ADA), 42-48 mmol/mol (6-6.4%)
- Risk may be modulated: diet, weight loss, exercise
- Pre-diabetes associated with increased cardiovascular risk due to atheroma (but not as much as in overt DM) compared to normal
Describe insulin.
What does it inhibit?
(4)
What does it promote?
(3)
- Key anabolic (build up) hormone that regulates utilization and storage of energy
- Synthesised in beta cells of pancreas (islets of Langerhans) as pro-insulin (pro insulin —> C-peptide (longer 1/2 life, better measure of insulin) + insulin
—> Alpha cells secrete glucagon, beta cells secrete insulin - Blood glucose tightly controlled - rarely goes outside range 3.5-8mmol/l by insulin and counter- regulatory hormones —> glucagon, adrenaline, steroids, GH
- Constant basal level of insulin secretion, and bursts of insulin following eating, which is stimulated by rising blood glucose >3.9mmol/l
- Secretion primed by incretin hormones released from gut (glucagon-like peptide 1, GLP1)
- Most tissues require insulin for uptake of glucose —> skeletal muscle, liver, and adipose tissue (exceptions include brain, renal tubules, RBCs)
INHIBITS
- Gluconeogenesis and glycogenolysis in liver
- Ketone body formation
- Protein breakdown
- Lipolysis
PROMOTES
- Glycogen synthesis in liver
- Fatty acid uptake by adipose tissue to form triglycerides
- AA uptake + protein synthesis
What does acute hypoglycaemia stimulate?
(2)
What does chronic hypoglycaemia stimulate?
(1)
What do the counter-regulatory hormones do?
EFFECTS
- Catabolic hormones are stimulated by hypoglycaemia —> fasting, “stress” such as illness or infection, exercise
Hypoglycaemia acutely stimulates:
1. Glucagon and adrenaline release
2. Causes autonomic activation (mainly sympathetic —> tachycardia, but also sweating) and behavioural change (agitation, restlessness)
Chronic hypoglycaemia stimulates:
1. Adrenal steroid and growth hormone release
- Each of these counter-regulatory hormones tends to maintain/increase blood glucose, combination of:
1. Increased intake
2. Glycogen breakdown in liver and muscle
3. Stimulation of hepatic gluconeogenesis (new glucose from glycerol, amino acids, lactate)
4. Decreased peripheral utilization of glucose - Mobilization of alternative energy sources:
1. Fat breakdown (lipolysis) with inhibition of fat formation
2. Chronic hypoglycaemia, formation of ketone bodies from fatty acid breakdown, can be used by brain, muscle, heart as energy
Describe the pathophysiology of inadequate insulin.
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- Despite adequate amounts of blood glucose, peripheral uptake into fat and muscle is not stimulated due to lack of insulin
- Hepatic glucoeneogensis or glyconolysis not inhibited, which leads to hyperglycaemia
—> Hyperglycaemia causes blurred vision
—> Lens glucose level passively related to that of blood glucose - Renal tubular threshold for glucose reabsorption exceeded:
—> Glycosuria, osmotic diuresis, polyuria - Triglyceride breakdown in fat unopposed, stored in liver cells (fatty change)
- Weight loss and appetite stimulated (polyphagia)
- Loss of fluid and electrolytes
- Dehydration, thirst stimulated (polydipsia)
- Ketone bodies formed in liver from fatty acid breakdown (substitutes for glucose)
- Ketonaemia leads to metabolic acidosis and ketonuria
How is diabetes classified?
Differentiate between T1DM and T2DM. See chart.
(3)
What factors pre-dispose diabetes?
(3)
How does diabetes progress?
- Classified based on pathogenesis NOT diagnosis or treatment
T1DM
1. Beta cell destruction in islets (5-10% of total DM)
—> severe / complete insulin deficiency (that’s why almost ALWAYS needs insulin)
—> auto-immune aetiology (type 1A)
2. Usually children <25 (10-14, 4-6), but can happen in adulthood
—> Not all young people with DM have type 1 disease —> consider type 2 DM or MODY if appropriate
T2DM
1. Deficiency of insulin relative to need, due to b-cell exhaustion, a/w insulin resistance of target organs (90% of total DM)
—> Insulin levels may be high initially, but decline later (however, often requires insulin as well)
2. Seen in adults, but can be seen in children who are obese or high risk ethnic groups
FACTORS
1. Genetic: single gene AD conditions involving insulin secretion (few, insulin action), rare
—> “Maturity onset diabetes of the young” (MODY)
2. Diseases of exocrine pancreas or surgery to pancreas: haemochromatosis, chronic pancreatitis, CF, pancreatectomy, pancreatic trauma
3. Endocrinopathies:
—> Over-secretion of counter-regulatory hormones
—> Acromegaly, Cushing’s, phaeochromocytoma, glucagonoma, hyperthyroidism
4. Drugs: steroids, thiazides, atypical anti-psychotics, cyclosporin, HAART, GnRH agonists, OCP
** Latter three often emerge on background of tendency to type 2 DM **
PROGRESSION
- Established DM of both type 1 and type 2 preceded by a phase of abnormal glucose homoeostasis as the disease progresses
o Short, rarely recognised prgoression phase in type 1 DM
o Longer duration of progression in type 2 DM, increasingly may be recognised as pre-diabetes
- Progression from normal to pre-diabetes to established type 2 DM may be modified or even reversed —> diet, exercise, weight loss
Describe T1DM (pathogenesis, genetics, environmental triggers, auto immune destruction , screening, clinal presentation)
- Autoimmune destruction of islet cells rendered antigenic in genetically susceptible individuals as a consequence of exposure to environmental triggers
- Silent progression over months, sometimes longer
- Clinically manifest with acute symptoms when critical mass of beta cells lost
—> Hyperglycaemia with polyuria, polydipsia, polyphagia, weight loss, blurred vision, DKA - Insulin dependent always – absolute insulin deficienc
—> Absent C-peptide, often islet auto-antibodies - Hints:
1 .Ketosis-prone, not obese, early need for insulin
2. Positive islet cell auto-antibodies (anti-GAD, anti-IA2, anti-insulin) and low/absent C-peptide levels - Due to acute development of symptomatic disease, vascular complications of type 1 DM exceptional at dx —> arise 15-20 years after diagnosis
GENETICS
- A/w HLA-DR3 and HLA-DR4 genotypes
- Monozygotic twins: only 40-50% concordance —> environmental trigger significant
ENVIRO TRIGGERS
- Viral infection —> molecular mimicry of islet cell antigens in susceptible individuals or possible direct damage
- Geographical and seasonal variations in incidence
- Timing and nature of triggers may be important
AUTOIMMUNE DESTRUCTION
- Circulating auto-antibodies to islet cell components in >90% of type 1 diabetics (anti-GAD, anti-IA2, anti-insulin)
- Lymphocytic inflammation of islets (insulitis)
- Immunosuppression after diagnosis may delay absolute beta cell destruction, but no effective prevention yet possible
- Association with other AI diseases: all type 1 screened for thyroid (antibodies in 25%), coeliac disease (5%)
SCREENING
1. not effective to screen even in higher-risk siblings
2. Screen for complications:
o Retinopathy (by ophthalmology)
o Nephropathy (urine for microalbuminuria)
o Appropriate foot care (podiatry/chiropody)
o Look for treatable associated risks - clinical exam (blood pressure) and blood tests (lipids)
Describe T2DM (pathogenesis, genetics, environmental triggers, auto immune destruction , screening, clinal presentation)
What is metabolic syndrome?
What specific gene defects cause diabetes?
- Deficiency of insulin relative to need, a/w obesity, limited physical activity, age
- Initiated by insulin resistance due to impairment of signalling pathway associated with insulin receptors in target organs - fat, skeletal muscle, liver
- Initially insulin resistance compensated for by high insulin levels to maintain normal glucose levels (high C-peptide)
- Insulin levels remain normal or high
- Hyperglycaemia itself impairs beta cell function, leading to eventual beta cell loss
- End-organ insulin resistance and impaired insulin secretion may both contribute to hyperglycaemia in type 2 diabetes
- Even at end stage, there is still some insulin secretion, tends to inhibit ketogenesis
GENETICS
- Monozygotic twins: 90% concordance
- Polygenic inheritance: multiple genes controlling insulin response and insulin secretion
- 40% those w/ type 2 DM have first degree relative with DM
- More frequent in some ethnic groups
ENVIRONMENT
1. Obesity, lack of exercise, increased frequency with increasing age
2. Intra-uterine factors: a/w LBW (“thrifty phenotype” of poor beta cell development a/w intra-uterine scarcity)
PRESENTATION
1. Hyperglycaemia for years becoming clinically evident
—> Polyuria, polydipsia, weight loss, fatigue, blurred vision, infections
2. Complications (neuropathy or MI)
3. Rarely with acute biochemical complications (DKA, HHS), but if happens it happens with intercurrent illness (MI) or infection
SCREENING
- Screen at risk patients, and identify early during undiagnosed latent period
- Everyone +45y, FPG/HbA1C evert 3 years
- Earlier if risk factors: raised BMI, family history, high risk ethnicity, habitual physical inactivity, abnormal lipids, hypertension, known vascular disease, obstetric history (big babies, GDM), PCOS, previous pre-diabetes
DIABETES DUE TO SPECIFIC GENE DEFECTS
- Rare cause of diabetes in young, strong family history, AD
- Single gene defects involving insulin secretion hepatic nuclear factors 1α and 4α, glucokinase
- Not insulin dependent, treated with sulphonylureas, no phenotypic signs of insulin resistance
o “Maturity onset diabetes of the young” (MODY)
What are the complications of diabetes?
2
- Acute biochemical complications:
- Marked hyperglycaemia may lead to DKA or HHS - Chronic complications:
- Risk related to duration of hyperglycaemia
- Microvascular complications specific to DM: nephropathy, retinopathy, neuropathy
- Macrovascular complications related to diabetes being a major risk factor for cardiovascular disease due to atheroma
- Non-vascular complications
How does DKA develop?
What is HHS?
- Classically associated with type 1 diabetes
o Presenting feature, intercurrent illness, insulin interrupted - Marked hyperglycaemia (not as much as in HHS)
- Polyuria/osmotic diuresis with marked dehydration
- Unopposed counter-regulatory hormones lead to ketone body formation with metabolic acidosis and electrolyte depletion (especially potassium)
- CP: nausea & vomiting, gastroparesis, abdominal pain, acute renal failure, coma, death
- Occasional type 2 diabetics “ketosis-prone”
HHS
- Rare & more typical of type 2 DM
- Older patients + a/w drugs, illness, surgery
- High mortality, often due to underlying illness
- Gross hyperglycaemia (>50mmol/l) a/w dehydration, coma
- Small amount of residual insulin secretion in type 2 diabetes inhibits lipolysis and prevents ketogenesis
