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Dr Sunil Zachariah Consultant Endocrinologist

Spire Gatwick Park Hospital Presentation (December 12 th , 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 15% 10% 5% Mitochondrial diabetes with deafness (MIDD) 1% Insulin receptor defects <1%

Peak age of onset UK prevalence Type 1 diabetes Type 2 diabetes 12 years 0.25% 60 years 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


• • • • • 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.


• • • 1] HNF1 alfa: 70% of MODY patients. Peak age group 21 years. 1/3 rd require insulin.

2] Glucokinase: 10%. Presents in early childhood. 90% controlled on diet alone 3] HNF4 alfa: 5%. High frequency of microvascular complications


• • • • • • • 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


• • • 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 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


• • • 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


• • • • • • 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)


• • • • 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


• • • • • 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


• • • • • • • • • 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



• • 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 counter regulatory 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 post transplant, 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