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Back to medical school: beginners guide to type 1 DM
SG Gilbey 24/5/07
1) What is type 1 diabetes mellitus?
2) How does it present?
What are its consequences?
1. general health: staying alive
2. diabetic complications
3. special situations eg adolescence, pregnancy
4. Living: work, driving, travel
3) How is it treated?
Kinds and choice of insulin
Different methods of administration
Aims of treatment
Complications of treatment: eg hypoglycaemia
4) Practical skills of diabetes management
Hypers and hypos
Dose adjustment
Recognizing disaster: when to admit/refer
Patient advice eg travel, driving, pregnancy
The Pancreatic beta cells
Make insulin in response to food intake and rising
glucose levels.
The purpose of insulin is to instantaneously store
energy in the liver, muscle, fat
As a consequence 1) glucose levels are remarkably
stable 2) we do not starve between meals
Glucose & insulin fluctuations
compared 800
700
Glucose (mg/dl) 600
500
400 NORMAL
OBESE
300
200
100
0
4 0800
8 1200
12 1600
16 2000
20 2400
24 0400
28
160 Clock time (hours)
140
800
120
700
NORMAL
Insulin ( U/ml)
600
100 OBESE
Glucose (mg/dl)
500
80
400 NORMAL
60 OBESE
300
40
200
20
100
0
4 0800
8
8 1200
1200
12
12 1600
1600
16
16 2000
2000
20
20 2400
2400
24
24 0400
0400
28
28
Clock time (hours)
Type 1 Diabetes
The beta cell is destroyed by lymphocytes as part of
an autoimmune phenomenon
Glucose levels rise but the body thinks it is starving –
glucose is released from its stores, high blood
glucose levels cause overflow into the urine
Thinking it is starving: the body switches on ketone
metabolism giving rise to high levels of ketone
bodies acidosis, and metabolic instability
Islet cell: lymphocytic infiltration
What do patients present with?
Thirst
Polyuria
Weight loss
Susceptibility to infection
Visual disturbance
Typically below 25 years: may be any age
May present over a period of weeks or months
Making the diagnosis:
Clinical history
Family history
Hyperglycaemia
Ketonuria
Recheck if not certain
Other tests autoantibodies: GAD, Islet Cell
Can we get the diagnosis wrong?
1. Missing the diagnosis
2. Misdiagnosing type 1 diabetes as type 2 diabetes
(LADA)
3. Misdiagnosing type 2 DM as type 1 DM – not such a
worry
4. Take a family history: rare cases of MODY –
strong FH and may present very young (eg under 6
months)
5. Underlying pancreatic disease (eg CF, cancer,
pancreatitis: usually obvious)
Diseases associated with type 1 DM
Thyroid disease
Addison‘s disease
Coeliac disease
Implications: 1) may complicate clinical picture and
management
2) is it worth screening diabetic
patients regularly?
Progressive shortfall of insulin
Normal insulin Balanced metabolism
Insulin supply
Moderately Raised glucose
reduced
Severely Protein (muscle) breakdown
reduced
Absent Breakdown of fats
Ketosis
Insulin
fatty acids
Fat stores
Liver Energy
Adrenaline/
Ketosis
noradrenaline
fatty acids
Fat stores
Liver Energy
Ketone bodies
= acids
Excreted via kidneys Buffer by overbreathing
Why do patients get Type 1 diabetes?
Inherited predisposition to immune damage (HLA
DR3)
―Two hit hypothesis‖ (viz risk in identical twins)
Increasing prevalence ?why (but numerically swamped
by type 2 diabetes)
North-South divide: now closing
Which age groups are affected?
Two peaks:
a) infancy (1-4y)
b) early adolescence (8-12y)
May present at any time in life (if ~ type 2:
LADA)
Problems with differential
diagnosis
Age 0 20 40 60 80 years
Type 1
Type 1 Type 2
Type 2
BMI 15 20 25 30 35 kg.m-2
Differentiation
Profound insulin deficiency (keto-acidosis)
Type 1 autoimmunity: islet cell antibodies
anti-GAD antibodies
(Family history)
(‘Metabolic syndrome’)
Incidence of diabetes rapidly
increasing
3000
Diabetes prevalence (thousands)
Type 1
Type 2
2500
2000
1500
1000
500
0 1995 2000 2010
Amos AF et al. Diabet Med 1997;14(Suppl 5);S1–S85
Life for a type 1 diabetic
Condition for life
Condition affecting
– every day
– every meal
– every physical activity
– every social relationship
– Parent-child relationship
Life for a type 1 diabetic
Burden of ‗control‘: loss of autonomy
Threat of hypoglycaemia
Threat of early death, blindness, gangrene & amputation,
kidney failure
Jobs, driving, life insurance, marriage
Risk of type 1 diabetes in offspring (what is it?)
Aims of treatment
1) Stay alive and well
2) Maintain quality of life
3) Avoid complications
Microvascular
Macrovascular
4) Avoid premature death: diabetics diagnosed between 25
and 35 years lose 15 years of life expectancy
Capillary damage
Microaneurysms
Hard exudates
Haemorrhages
feet
DiabeticIschaemic ulcer and gangrene
Neuropathic heel ulcer
Toe deformity and ulcer Charcot foot + ‘rocker’ ulcer
Maintaining good blood glucose
control
DCCT (Type 1 diabetes)
– intensive therapy delayed the onset and
slowed the progression of microvascular
disease by 35–70% compared with
conventional therapy
Threshold for retinopathy
FPG 7.0 mmol/l
2hPG 11.1 mmol/l
Prevalence of retinopathy in a population survey
by deciles of glycaemia
Glucose
molecules
HbA1c value
Not diagnostic
Any Diabetes Related Endpoint
5
p<0.0001
Hazard ratio
1
12% decrease per 10 mm Hg decrement in BP
0.5
110 120 130 140 150 160 170
Updated mean systolic blood pressure
UKPDS 36. BMJ 2000; 321: 412-19
Any diabetes
endpoint
Risk factors and complications
Microvascular disease Macrovascular disease
Eyes Ischaemic heart disease
Feet Strokes
Kidneys
Nerves Peripheral vascular
disease
Hyperglycaemia Hypertension
Coagulopathy
Dyslipidaemia
Smoking
Treatment
Insulin: the perfect treatment for blood glucose in
diabetes
Are there any alternatives?
immunosuppression
pancreas or islet cell transplantation
Patients will do anything to avoid insulin
The aim of treatment
Stay alive
Avoid hypos
Maintain day to day living
Achieve optimal control – a glucose as near to normal
as possible for most of the time
BLOOD GLUCOSE MONITORING IS ESSENTIAL
(how often?)
Choices of insulin
Fast acting: cover a meal
Intermediate: 6-12 hours
Long acting: up to 24 hours
Beef—Pork—Human—Analogue
24-hour plasma glucose and 1.10
insulin profiles in healthy
individuals
©Elsevier Science. Reproduced with permission from Elsevier Science (The Lancet,
2001, Vol 358, pages 739–746).
Owens DR et al. Lancet 2001;358:739–746
Analogue Insulins:
Short acting: Novorapid, Humalog, Glulisine
Pre-mixed (30/70): Mix 25, Novomix 30
Very long acting: Glargine, Levemir
Very few differences between insulins, some
differences between insulin delivery systems
(pens)
Short-acting Insulin
• Soluble Action
• Clear
• Onset 30 minutes
• Peak 1 - 3 hours
• Duration of action up to Time
8 hours
Note: The graphical representation above is for educational and illustrative purposes only
Slide no 9 • MEDINFO/AIRE/182 Date of Preparation November 2004 •
Rapid-acting Analogues
• Soluble
Action
• Clear
• Onset 10 - 20 minutes
• Peak 1 - 3 hours
• Duration of action up Time
to 5 hours
Note: The graphical representation above is for educational and illustrative purposes only
Slide no 15 • MEDINFO/AIRE/182 Date of Preparation November 2004 •
Lispro insulin (Humalog)
Intermediate-acting Insulin
• Crystals in suspension (need to re-suspend prior to injection)
• Cloudy
• NPH or Isophane (NPH = Neutral Protamine Hagedorn)
• Onset 1 1/2 hours
• Peak 4 - 12 hours
• Duration of action up to 24 hours
Action
Time
Note: The graphical representation above is for educational and illustrative purposes only
Slide no 10 • MEDINFO/AIRE/182 Date of Preparation November 2004 •
Long-acting Analogues
• Clear - no need for re-suspension
• Delayed and prolonged absorption from injection site
• Flatter profile than NPH (peak reduced)
• Longer duration of action than NPH
• Duration of action up to 24hrs depending on dose
Action
Time
Note: The graphical representation above is for educational and illustrative purposes only
Slide no 17 • MEDINFO/AIRE/182 Date of Preparation November 2004 •
Primary structure of insulin glargine
A-chain A21[Gly] COOH
NH2 COOH
B-chain S S B31[Arg]
S
NH2 B32[Arg]
S S
S
Premixed Analogue Combinations
• Premixed combinations of short and intermediate acting
analogues
• Cloudy (needs re-suspending)
• 3 different combinations (25, 30, 50)
• Onset 10-20 minutes
• Peak 1-4 hours
• Durations of action up to 24 hours
Action
Time
Note: The graphical representation above is for educational and illustrative purposes only
Slide no 16 • MEDINFO/AIRE/182 Date of Preparation November 2004 •
Ideal Basal/Bolus Insulin
Absorption Pattern
Breakfast Lunch Dinner
Plasma insulin
4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00
Time
Novopen (rechargeable)
Flexpen (disposable)
Storage of Insulin
• Before use
• store in fridge (2-8oC)
• In-use vials
• store out of fridge to max 25oC
(analogues 30°C – check SPC)
• use within 4-6 weeks (depending on insulin)
• In-use pens and cartridges
• store out of fridge at max 30oC
• use within 4-6 weeks (depending on insulin)
• always check SPC for specific insulin
Slide no 29 • MEDINFO/AIRE/182 Date of Preparation November 2004 •
Insulin regime choices
Once a day (eg Glargine): rarely the choice for
type 1 DM
Twice daily premixed: surprisingly popular
(why?)
Basal-bolus: the best for flexibility, intensive
control – but more injections, more monitoring
A simple regime for blood glucose
monitoring and dose adjustment
Once a day (eg Glargine): measure fasting BG
and adjust glargine to keep below 7 mmol/L
A simple regime for blood glucose
monitoring and dose adjustment
Twice a day pre-mix: adjust evening dose to
achieve pre-breakfast below 7 mmol/L, and
moring dose to achieve pre-evening meal below
7 mmol/L
A simple regime for blood glucose
monitoring and dose adjustment
Basal-bolus: adjust glargine to achieve
pre-breakfast below 7 mmol/L, pre-meal
analogue to achieve less than 10 mmol/L
one hour after meal
A simple regime for blood glucose
monitoring and dose adjustment
If the patient is having hypos: work out when
they are. Is it the insulin dose or regime, food
intake, or exercise? Do they need a regular
snack? Do they need a different regime? Are
they being reliable?
HBA1c: Quality control
Carbohydrate counting
Freedom to eat what you like
Training in calculating carbohydrate
content of meals
Adjust bolus insulin dose according to
anticipated (eg 2 units per 10grams
CHO)
Significant learning curve for patient
Technological advances
Insulin pumps:
24 hr adjustable basal
infusion
Mealtime bolus doses
Continuous glucose monitors
400
300
250
200
Type 1
150
100
Normal 50
Meal Meal Meal Meal Meal Meal
0
Midnight Noon Midnight Noon Midnight
2-day tracing
CSII - HbA1c
10.0
9.5 Pre-pump Post-pump
.09
8.5
HbA1c
8.0
7.5
7.0
6.5
6.0
5.5
5.0
Bell Rudolph Chanteleau Bode Boland Chase
n = 58 n = 107 n = 116 n = 50 n = 25 n = 56
Mean dur. = 36Mean dur. = 36 Mean dur. = 54 Mean dur. = 42 Mean dur. = 12 Mean dur. = 12
Adults Adolescents
Chantelau E, et al. Diabetologia. 1989;32:421–426; Bode BW, et al. Diabetes Care. 1996;19:324–327;
Boland EA, et al. Diabetes Care. 1999;22:1779–1784; Bell DSH, et al. Endocrine Practice. 2000;6:357–
360;
Chase HP, et al. Pediatrics. 2001;107:351–356.
Better nocturnal control
6
5
4
3 MIT
CSII
2
1
0
MIT CSII
CSII Reduces Hypoglycemia
160
140 Pre-pump Post-pump
120
100
80
60
40
20
0
Bode Rudolph Chanteleau Boland Chase
n = 55 n = 107 n = 116 n = 25 n = 56
Mean age 42 Mean age 36 Mean age 29 Mean age 14 Mean age 17
Chantelau E, et al. Diabetologia. 1989;32:421–426; Bode BW, et al. Diabetes Care. 1996;19:324–327;
Boland EA, et al. Diabetes Care. 1999;22:1779–1784; Chase HP, et al. Pediatrics. 2001;107:351–356.
For a patient to be given a pump
They must fulfill NICE criteria
Committed
Able to engage with diabetes team and learn to
carbohydrate count
At significant risk of hypoglycaemia on conventional
regimes
Expensive: PCT authorises
CGMS
1.13
―Closed loop‖ systems
Will enable the simultaneous
measurement of glucose and
administration of insulin: no need for
any calculations
Side effects of insulin
HYPOGLYCAEMIA – glucose less than 2.8 mmol/L
Insulin allergy
Injection site problems lipohypertrophy, lipoatrophy
Allergic reactions
Needle phobia
Causes of hypoglycaemia
Inappropriate dosage/poor technique
Inappropriate eating
Exercise
Alcohol
Changes in insulin requirement:
Weight changes, occupation, life style, pregnancy,
breast feeding etc…
3.4
Symptoms of hypoglycaemia
Autonomic Neuroglycopaenic
•Increased heart rate •Impaired intellectual activity
•Sweating •Impaired cognitive function
•Increased systolic blood pressure •Diminished psychomotor skills
•Tremor •Loss of coordination
•Palpitations •Sensation of drowsiness
•Coma/fits
Pickup J, Williams G. Textbook of Diabetes. 2nd edition. London: Blackwell Science, 1997;Vol 1:40.1–40.23
Outcomes of hypoglycaemia by 3.5
blood glucose concentration in
healthy individuals
©Blackwell Science. Adapted with permission from Blackwell Science (Textbook of Diabetes [2nd edition], 1997,
Vol 1, pages 40.1–40.23).
Pickup J, Williams G. Textbook of Diabetes. 2nd edition. London: Blackwell Science, 1997;Vol 1:40.1–40.23
3.6
Hypoglycaemia unawareness
Associated with:
– tighter glycaemic control
– long duration of diabetes
Carries 5–6-fold increase in frequency of severe
hypoglycaemia
More frequent in pregnancy
If permanent: disqualifies from holding a driving licence
Pickup J, Williams G. Textbook of Diabetes. 2nd edition. London: Blackwell Science, 1997;Vol 1:40.1–40.23
3.7
Nocturnal hypoglycaemia
Occurs after bedtime administration of
insulin and prior to waking
Prevalence difficult to ascertain
Type 1 diabetes (DCCT): ~50% of severe
episodes were nocturnal
May persist for several hours without waking
the patient, increasing the likelihood of
coma
Pickup J, Williams G. Textbook of Diabetes. 2nd edition. London: Blackwell Science, 1997;Vol 1:40.1–40.23
DCCT. Am J Med 1991;90:450–459
Alternative delivery
Rectal
Nasal
Inhaled: Exubera
– On the market now
– NICE say: for needle phobics only
Dose Adjustment for Normal Eating
DAFNE
Modified 5 day training course
Patients learn to count carbohydrates
Adjust insulin accordingly
Results: no change in weight, lipids,
hypoglycaemia
Improvement in HBA1c, QOL
Dafne
Process of carbohydrate
counting
Starchy Foods
– Bread
– Potatoes
– Pasta
– Rice
– Cereals
– Noodles
– Pulses
Process of
Carbohydrate Counting
Sugar Foods
- Sugary Foods
e.g chocolate sweets, biscuits,
honey
- Fruit Sugar
(Fructose)
- Milk Sugar
(Lactose)
Process of
Carbohydrate Counting
DoNot Count
–Protein
Meat,
Eggs,Fish
- Fat
Oils, Spreads
*Remember
processed foods
Process of
Carbohydrate Counting
Add up total carbohydrate from a
meal
Divide total by 10
Multiply answer by ratio required
* Ratio is decided based on diet
history taken, carbohydrates
consumed, insulin given and post
prandial blood sugars
Process of
Carbohydrate Counting
Lunch
– 2 slices wholemeal bread =
30g
– Packet of crisps = 15g
– Total 45g
– 1 unit per 10g = 4.5 units of
insulin
Main meal
4 Roast Potatoes = 40g
Small Yorkshire pudding
= 10
Total = 50
1 unit per 10g = 5 units
of insulin
Process of
Carbohydrate Counting
Factors to be considered
– Activity
– GI of foods
– Weight
– Nutritional adequacy of diet
– Management of hypoglycaemia
– Correction doses of insulin
– Illness Management
Gestational Diabetes
ADA (1995) advocate 40 % energy
intake from carbohydrate
British advice suggests 45 - 60% in
the form of low GI foods (Dornhorst
& Frost, 2002)
May impose slight calorie restriction
to limit weight gain
As focus is reducing post prandial
glycaemia will also look at portion
sizes of carbohydrate glycaemic
Special situations
Pregnancy including pre-conception
Adolescents/Students
Very young and very old
Diabetes and pregnancy in
England and Wales 2005
Babies
Increased of women with diabetes in
risks for babies of women with diabetes
England, Wales and N Ireland
Stillbirths 4.7x
continue to have an increased risk of
Death of baby in first four weeks 2.6x
perinatal mortality and congenital
anomaly
Major congenital anomaly 2x
http://news.bbc.co.uk
The End
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