TYPE 1 DIABETES, INSULIN PUMP and ISLET CELL
TRANSPLANTATION
Dr Sunil Zachariah
Consultant Endocrinologist
Spire Gatwick Park Hospital Presentation (December 12th, 2012)
CURRENT CLASSIFICATION
• Type 1 Diabetes (5-25% cases, pancreatic islet
beta cell deficiency)
• Type 2 Diabetes (75-95% cases): defective
insulin action (resistance) or secretion
• Others
OTHERS
• 1] Genetic defects of beta cell function (MODY)
• 2] Genetic defects of insulin action: Type A insulin
resistance, leprechaunism (T2DM, IUGR, dysmorphic
features), lipoatrophic diabetes
• 3] Disease of exocrine pancreas: pancreatitis,
surgery, neoplasia, pancreatic destruction (cystic
fibrosis, haemochromatosis), endocrinopathies
(cushings, acromegaly), drug induced, infections
(congenital rubella), antiinsulin receptor antibodies,
genetic syndromes
• 4] Gestational diabetes
Type 1 Diabetes
• Autoimmune: associated with anti-glutamic
acid decarboxylase (GAD), islet cell and insulin
antibodies
• WHO definition: ‘a condition of deficiency of insulin secretion
from the pancreas, usually due to auto-immune damage of
the insulin producing cells. However the clinical condition is
generally recognized on the basis of diabetes (high blood
glucose levels) occurring in mainly younger and thinner
people in the absence of other precipitating causes’
Spectrum in Europe
Idiopathic type 2
Predominant beta cell
defect (type 1 like)
Type 1
50%
18%
Latent autoimmune
diabetes in adults
MODY
10%
15%
5%
Mitochondrial diabetes 1%
with deafness (MIDD)
Insulin receptor defects <1%
Type 1 diabetes Type 2 diabetes
Peak age of
onset
UK prevalence
12 years
60 years
0.25%
Aetiology
Autoimmune
5-7% (10% >65
years)
Insulin
resistance, beta
cell dysfunction
Genetics (Type 1 diabetes)
• The overall lifetime risk in a white population
of developing type 1 diabetes is 0.4%, but this
rises to
• 1-2% if your mother has it
• 3-6% if your father has it
• Siblings should have about 6% risk
• Monozygotic twins have a 36% concordance
rate
Antibodies
• Chance of finding one of the 3 antibodies is 88%
(anti-GAD, islet cell and insulin antibodies)
• Should NOT be regularly used
• Islet cell antibodies are seen in 3% of oxford school
children, but in 40% of monozygotic twins and 6% of
siblings of type 1 diabetes
• 90% of type 1 diabetes in UK have either HLA-DR3 or
DR4 (human leucocyte antigen)
• 10 distinct genetic areas identified
MODY (Maturity onset diabetes of the young)
• Genetic defect of beta cell function
• The following characteristics suggest the possibility of a
diagnosis of MODY:
• Mild to moderate hyperglycemia (typically 7-14)discovered
before 30 years of age.
• A first degree relative with a similar degree of diabetes.
• Absence of positive antibodies
• Persistence of a low insulin requirement (e.g., less than 0.5
u/kg/day) past the usual latent phase
• Absence of obesity (although overweight or obese people can
get MODY)
• Cystic kidney disease in patient or close relatives.
• Non-transient neonatal diabetes or apparent type 1 diabetes
with onset before 6 months of age.
MODY
• 1] HNF1 alfa: 70% of MODY patients. Peak age
group 21 years. 1/3rd require insulin.
• 2] Glucokinase: 10%. Presents in early
childhood. 90% controlled on diet alone
• 3] HNF4 alfa: 5%. High frequency of
microvascular complications
Management
• Patient-centered care
• Multidisciplinary team approach
• Patient education: Culturally appropriate education should be offered
after diagnosis to all adults with Type 1 diabetes. It should be repeated as
requested and according to annual review of need
• Blood glucose control (insulin choice, education,
hypoglycemia)
• Arterial risk factor control
• Complications screening, including erectile
dysfunction
• Other Autoimmune condition screening
Self-monitoring
• Adults with Type 1 diabetes should be advised
that the optimal targets for short-term
glycaemic control are:
• pre-prandial blood glucose level of 4.0–7.0
mmol/l and
• post-prandial blood glucose level of less than
9.0 mmol/l.
HbA1c
• HbA1c should be performed every two to six
months depending on:
• achieved level of blood glucose control
• stability of blood glucose control
• change in insulin dose or regimen
• Fructosamine
CGMS
• Continuous glucose monitoring systems have a role
in the assessment of glucose profiles in adults with
consistent glucose control problems on insulin
therapy, notably:
• repeated hyper- or hypoglycaemia at the same time
of day
• hypoglycaemia unawareness, unresponsive to
conventional insulin dose adjustment.
Insulin regime
• Basal bolus regime is preferred insulin regime
• Hypoglycemia management, particularly
nocturnal hypoglycemia
• Rotating sites, lipohypertrophy
Insulin Pump
• Continuous subcutaneous insulin infusion (insulin
pump therapy) is recommended as an option for
people with Type 1 diabetes provided that:
• multiple-dose insulin therapy has failed and (7.5%
without disabling hypoglycaemia)
• those receiving the treatment have the commitment
and competence to use the therapy effectively.
What are the acute complications?
• Diabetic ketoacidosis (DKA)
• Hyperosmolar non-ketotic state (HONK)
• Hypoglycaemia (Hypo)
Diabetic Ketoacidosis
• Mortality of 2-5%
• Many deaths occur due to delays in
presentation and initiation of treatment, with
a mortality of 30-40% in the elderly
Diagnosis
• Usually based on a collection of biochemical
abnormalities
• Hyperglycemia>11.1 mmol/l
• Acidosis pH<7.35, serum bicarbonate<15,
base excess<-10
• Ketonuria
• Some dip testing methods only check for acetoacetate and acetone, but
not betahydroxybutyrate
• Ketones may also interfere with some creatinine assays and give falsely
high readings
• Affects predominately people with Type 1
diabetes
• Incidence is 5-8/1000 diabetic patients per
year
• 25% cases are patients with newly
diagnosed/presenting diabetes
• Very rarely, it can be seen in people with Type
2 diabetes (mostly lean people)
Pathogenesis
• Occur as a result of insulin deficiency and counter regulatory
hormone excess
• Insulin deficiency results in excess mobilization of free fatty
acids from adipose tissue. This provides the substrate for
ketone production from the liver.
• Hyperglycemia and ketonuria cause an osmotic diuresis and
hypovolaemia, leading to dehydration. Glomerular filtration is
reduced and counter regulatory hormones like glucagon rise
• Metabolic acidosis due to ketone accumulation leads to
widespread cell death and is fatal if untreated
Precipitants
•
•
•
•
•
Infection (30-40%)
Non-compliance with treatment (25%)
Inappropriate alterations in insulin (13%)
Newly diagnosed diabetes (10-20%)
Myocardial infarction (1%)
Clinical features
• Polyuria, polydypsia and weight loss
• Muscle cramps, abdominal pain and shortness of breath (air
hunger or kussmaul’s breathing, with regular rapid breaths,
suggesting acidosis)
• Subsequent nausea and vomiting can worsen dehydration
• Postural hypotension, hypothermia, hypovolaemia
Management
•
•
•
•
•
•
•
•
Refer immediately to hospital
Aggressive fluid rehydration
Potassium replacement
Insulin
ECG
Exclude underlying infection
Heparin
Cerebral oedema typically presents 8-24 hours after starting
IV fluids with a declining conscious level
• Patient education to avoid further occurrence or earlier
presentation if it does occur
Insulin Pump Therapy
Pump Therapy Indications
•
•
•
•
•
•
•
Improvement in glycaemic control
Recurrent hypoglycaemia
Hypoglycaemia unawareness
Dawn phenomenon
Pregnancy
Gastroparesis
Hectic lifestyle
Pharmacokinetic Advantages:
CSII vs MDI
• Use quick acting insulin (Humalog and NovoRapid)
– More predictable absorption than with modified
insulins (variation 3% vs 10- 52%*)
• Uses one injection site for 2 to 3 days
– Reduces variations in absorption due to site rotation
• Eliminates most of the subcutaneous insulin depot
• Programmable insulin delivery allows closest match with
physiological needs
* Lauritzen: Diabetologia 1983; 24:326-9
Insulin Pump Therapy-Patient Selection
 Highly Motivated – Responsible for self care
 Able to cope with principles of FIT
 Prepared to do 4-6 BG tests every day
 Dawn phenomenon
 Want a better quality of life – want to be in control
 Just want to feel well again
 Suffering from/wanting to do something about
– Erratic day to day BG levels
– Frequent &/or severe hypos (especially at night)
– High insulin doses yet repeat DKA’s
– Restrictions in lifestyle-mealtimes & exercise
Insulin Pump Therapy-Patient Selection
 Exclusion criteria
 Psychological conditions
 Manipulative behaviour
 Drug dependencies – alcohol etc
 Eating disorders
 Unwilling to do sufficient SMBG
 Want a quick fix – pump = cure
 Disruptive family environment
 Stabilise/treat pre & proliferative retinopathy
 Gastroparesis difficult
Carbohydrate counting
•
•
•
•
Identifying carbohydrates
Calculate total CHO in food
Work out insulin to CHO ratio
Practice
Rules for Meal Boluses
 On average 10g carbohydrate raises blood sugar by
2.5 mmol
 On average 1 i.u. is taken per 10g carbohydrate
 Practice accurate carbohydrate counting
 Every main meal and snack >5g carbohydrates
requires a bolus!
 With > 50 g carbohydrates use split bolus /
extended bolus
ISLET CELL TRANSPLANTATION
Introduction
• Whole organ pancreas transplantation has
been performed successfully since late 1960s,
but transplantation of the insulin-secreting
islets has only recently become a successful
procedure
• Historically, extracting islet cells from pancreas
was difficult, and islet function tended to
deteriorate rapidly after transplantation
making the whole process unviable
• All this changed in 2000 following publication
from James Shapiro’s group in Edmonton,
Canada, describing 7 patients who successfully
remained insulin free for 1 year following islet cell
transplantation.
• Key factors were use of multiple transplants of
fresh islets and a new steroid-free
immunosuppression regimen based on sirolimus
and tacrolimus (‘Edmonton Protocol’)
• Although these patients were unable to maintain
freedom from insulin, majority enjoyed long term
graft function and avoidance of severe
hypoglycaemia.
• This eventually led to islet transplantation centres
• Diabetes UK funded 12 islet transplant centres as
part of research project. All patients achieved
complete resolution of severe hypoglycaemia.
• The National Specialist Commissioning Group
provided central funding for the service. Islet
cell transplantation is now NICE-approved and
UK benefits from having one of the only
government-funded islet cell transplantation
services in the world
• In UK, emphasis is on protection against
severe hypoglycaemia rather than on insulin
independence
Patients with T1DM suitable for islet cell transplantation
• 2 or more episodes of severe hypoglycaemia
(requiring other people to help) within last 2
years
• Impaired awareness of hypoglycaemia
• Severe hypoglycaemia, impaired awareness or
poor glycaemic control despite best medical
therapy in those who have a functioning
kidney transplant
People who are probably not suitable for islet cell
transplantation
• Patients requiring>0.7 units/kg/day of insulin
(50 units/day for a 70 kg patient)
• Weight>85 kg
• Poor kidney function (GFR<60 ml/min, and
<30 ml/min in renal transplant patients)
How common is severe hypoglycaemia
• One-third of type 1 diabetes patients each year will
experience an episode of ‘severe hypoglycaemia’
(requiring assistance)
• In T1DM>15 years, annual proportion experiencing
severe hypoglycaemia is 45%. In 10% of these instances
they may require assistance from paramedics or
require hospitalisation
• Every year there are 6-10 deaths in young people with
T1DM, attributed to ‘dead in bed’ phenomenon, which
is thought to be caused by nocturnal hypoglycaemia.
• Impaired awareness of hypoglycaemia increases
risk of severe hypoglycaemia 3-6 fold.
• Due to decreased protective responses of
sympathetic nervous system and counterregulatory hormones
• In UK hypoglycaemic study, the incidence of
impaired awareness of hypoglycaemia was 7% in
those with short duration of T1DM, but 35% in
those with diabetes duration>15 years
Pathway to islet cell transplantation
• Indicated for patients with disabling recurrent
hypoglycaemia despite best medical therapy
• 1. Structured education in flexible insulin therapy
(DAFNE, BERTIE): matching insulin and
carbohydrate counting, adjusting for exercise and
sickness. They have been shown to halve the
number of severe hypoglycaemia, and restore
awareness after 1 year in 50-60% who report
hypoglycaemia unawareness before the course
• 2. Insulin pump therapy: Indicated by NICE in
those TIDM who cannot achieve HbA1c<8.5%
without disabling hypoglycaemia. Recent meta
analysis showed pump therapy was associated
with 0.4% HbA1c improvement and 4 fold
reduction of severe hypoglycaemia (Not essential
criteria)
• 3. Continuous Glucose monitoring (CGMS):
reduce hypoglycaemia, and helpful in patients
with hypoglycaemic unawareness.
UK experience and outcomes
• 54 islet transplants in 34 patients in UK
• Primary graft function in all but 1 patient, and
1 year graft survival of 87%, comparable to
CITR data
• Frequency of severe hypoglycaemia was
reduced from 23/patient per year to
0.56/patient per year (p<0.01) at 1 year posttransplant, with mean HbA1c reduction from
8.2 to 6.8%
Risks of islet cell transplantation
• Bleeding from liver capsule during procedure
• Cancer related to immunosuppressant: excess
risk of cancer of 4% over 6 year period
(including skin cancers)
• Infection related to immunosuppressant: 1 in
6 islet cell recepients
7 UK Islet Cell Transplant Centres (Centrally funded)
•
•
•
•
•
•
•
Bristol
Edinburgh
London (Kings College): Dr Pratik Choudhary
London (Royal Free): Dr Miranda Rosenthal
Manchester
Newcastle
Oxford
Work up for Islet Cell transplantation
• Initial screening (exclude other causes of hypo
like coeliac, adrenal insufficency)
• Insulin pump, Type 1 educational programme,
CGMS
• Isotope assessment of renal function, liver
ultrasound, tissue typing
• Average time on waiting list is 6-9 months
• Suitable donor pancreata are sent to one of 3 UK islet
isolation labs (Oxford, Kings College, edinburgh), where
islets are extracted from organ
• Isolated islets are cultured for 12-24 hours before being
transported to local islet transplant centre
• During this time patient is admitted to hospital for
assessment and induction treatment. This can be with
a combination of IL-2R antagonist like basiliximab
(original edmonton protocol) or more aggressive T-cell
depleting agents such as alemtuzumab. Sometimes
TNF-alfa antagonists like etanercept
• Islets are then infused transcutaneously into
the portal vein under radiological guidance
(under heparin cover to prevent portal vein
thrombosis).
• Most patients will then receive a second
transplant within 3 months. Maintenance
immunosuppression is usually with tacrolimus
and mycophenolate
What is the main alternative to islet cell
transplantation?
• Whole organ pancreas transplantation
• As of 2011, 35000 pancreas transplantation reported to
International Pancreas transplant registry. 93% with or
following a kidney transplant, only 7% were ‘pancreas
transplant alone’.
• In UK criteria is similar: Recurrent disabling
hypoglycaemia
• More complex procedure, contraindications include
poor cardiac reserve, PVD, 3% mortality, 50% five year
graft failure
• Advantages: Can be used in patients with high insulin
requirement