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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




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