Type 1 Diabetes (6) Flashcards
Eliminating T1D - Is prevention or cure possible?
Clinical goal for individuals with recent onset and long-standing T1D
To improve metabolic outcomes and quality of life for people living with the daily challenges and long-term risk of complications associated with T1D
> life expectancy reduced by about 10 years on avergae
Recall lecture 4: Exogenous insulin is a treatment, not a cure for T1D
Optimal glycaemic control requires:
> multiple BGL measurements 4x a day
multiple-dose insulin regimen (>4x injections/day) to mimic physiological insulin release
> detecting hypoglycaemia events (lollies)
Beta cell substitution
Manual to hybrid-loop systems of insulin delivery
> insulin pumps etc
> unless inventions are shown to create value by improving outcomes like improving life expectancy, the govt is unlikely to fully fund the new tech that comes along to manage diabetes unless it can be proven to be much better than conventional therapy
Glucose levels of a child with T1D using a conventional insulin pump
Detection by continuous blood glucose monitoring (day and night)
>difficult to maintain normo-glycaemic levels even with automatic infusion of exogenous insulin (i.e. insulin pump)
Intensive insulin treatment: less complications, but more hypoglycaemia
As HbA1c levels increase,
>rate of severe hypo decreases
>rate of progression of retinopathy increases
Disadvantages with current treatment?
Even with continuous glucose monitoring and insulin pumps:
>frequent dosing adjustments (meal type, physical activity, illness, stress)
>not possible to mimic physiological glucose control
<30% of people with T1D achieve recommended glucose control
>maintain glucose levels within target range
>maintain HbA1c under target threshold (<7.5% for children, <7% in adults)
>Increased risk for hypoglycaemia events and long-term complications
Uniquely burdensome
>inject multiple times per day or maintain insulin pump
>ongoing collaboration of machines and algorithms (still have daily finger pricks)
*Exogenous insulin treatment falls well short of a cure
Artificial Pancreas: Closed-loop system for T1D
Artificial pancreas controller + continuous glucose sensor + insulin/glucagon dual pump
> hard to determine potential of these new systems for 2 reasons
1) companies constantly pushing out new systems, old ones being studied, hard to understand true potentials
2) most people that are being tested on have well controlled diabetes, and not tested on real world cohorts of patients with poor control of diabetes
*big step forward in BGL management but still dont represent a cure
Artificial Pancreas: Limitations that need to be addressed
One of the barriers for working out the potentials of these devices is the risk aversion of the companies that make these devices
>reluctant to push the algorithms for very tight glucose control levels in case they cause problems
>Biohacker movement where people are re-jigging the algorithms of the devices off label to try and make these devices work better and have tighter glucose control
Adoption of an artificial pancreas: Potential and Limitations
Potential
>63% use insulin pumps
>30% use continuous glucose monitors
>82% of parents/caregivers reported devices made it easier for their family members to achieve health targets
Limited adoption due to:
>cost of device
>insurance obstacles
>hassle of wearing devices
Other
>skin related issues (e.g. contact dermatitis)
>Types and duration of physical activity
>discontinuity/disruption of insulin delivery
>kinking or blockage of the deliver tubes
>leakage from the site
>bruising and bleeding
How to improve adoption of artificial pancreas?
> miniturising the devices and improving wearability through innovations
incorporating implantable components
incorporating inputs beyond glucose concentration
taking advantage of big data analysis and machine learning algorithms
The ultimate goal: glucose control without external devices
Develop a beta cell replacement therapy that will safely restore normal glycaemic control fully independent of exogenous insulin, thereby eliminating the burden of insulin use for people with T1D
> 2 things have to be addressed:
beta cell mass
autoimmune response
Cell therapy: The ‘natural’ way to glucose normalisaiton
Cadeveric Donor Islets > islet isolation > transplant direcetly into patient > immunosuppression, tolerance
*once stage 3 T1D, not enough beta cells to produce enough insulin, at Stage 1 and 2 still can try and preserve the remaining beta cells
Requirements:
1) Cell source of highly functioning insulin-producing cells
2) Strategy to protect the implanted cells from alloimmune and autoimmune-mediated destruction
3) an optimal implantation site
Indications for Islet Allotransplantation
Who is eligible to receive a transplant?
(islet transplant makes more sense than whole pancreas transplant, only 2% of your cells non-functional)
>Adults with T1D having problematic hypuglycaemia unawareness
>Adults, T1D, having kidney transplant if unsuitable for whole pancreas (usually whole pancreas along with kidney transplant)
>Adults, T1D, hypoglycaemia unawareness but responsive to conventional treatment
>Individuals with other types of beta cell failure: MODY, T2D
How many islets are needed?
>typically >1 transplant (infusion) is required per recipient to become insulin independent
>10000-12000 islet equivalents per kg of body weight
Pancreatic islet isolation and transplantation procedure
- Donor pancreas
- Ricordi Chamber: key islet isolation device
- Separated islets
- Islets are introduced into the recipient liver
- Transplanted islets secreting insulin in the liver
(put into portal vein that drains gut into liver, via radiology procedure, cannot put in pancreas)
Steps for Islet Isolation
1) Pancreas harest
>retrieval
>organ preservation
2) Organ preparation
>cleaning
>duct annulation
>enzyme injection
3) Isolation
>enzymatic digestion
>mechanical digestion
4) Purification
>filtration
>density separation
5) Culture >plating quality control -viability -count -sterility
Issues of transplantation
One big issue is the need for immunosuppression in any form of allo-transplantation (from anyone who is not an identical twin)
- need to transplant into liver - use heparin as anticoagulant
- induction during immunosuppression
Islet transplant patient results
Evolution vs Technology - in an islet transplant pt
With transplantations, HbA1c and BGL is highly improved, this particular PT could eventually stop taking exogenous insulin
Not putting in something that is new, putting in something from someone who is dead, so there is issues around the efficacy of the implanted tissue
Classification of beta-cell graft function
Functional status:
>failure if C-peptide level is baseline
Optimal, good, and marginal status all have c-peptide levels above baseline
Evaluation of Patients Receiving Islet Transplant
Showed that hypoglycaemia is very successfully controlled in this way, even when insulin is required
Artificial Pancreas vs Islet Transplant
Glucose control better in islet transplant
Pancreatic islet allotransplantation: Pros and Cons
Pros
>islets can be isolated at multiple sites using a common manufacturing process
>50% of recipients achieve independence from exogenous insulin at one year from transplant
>Glycaemic control is improved even when insulin independence is not achieved
>Effectively treats hypoglycaemia unawareness - freedom from severe ‘hypo’ events
Cons
>limited availability of organ donors: quantity and subsequent quality of isolated islets
>immunosuppression required to prevent allo- and auto-immune rejection of transplanted islets
>longevity of islet graft function (eventual loss of function)
>expensive (>$140,000 per isolation/transplant) - procedure not covered by health insurance
Future sources of islets and beta cells for transplantation
Caderveric Donor Islets
Porcine Islets (genetic modification)
Pluripotent Stem Cells
(differentiation, manufacturing)
What we really need is an unlimited supply of insulin producing cells, potential sources are stem cells or animal islets
Other element that is potentially possible in the future is regeneration of the insulin producing cells that remain- hard especially in adults
Animal organs: Why the pig?
Organ size, physiology and function similar to humans
High reproductive capacity (gestation <4 months, large litters)
High donor consistency (inbred lines available)
Low risk of transfer of infections (defined pathogen-free)
Pig organs and tissues trigger a powerful rejection response in humans (xenograph immune response is extremely strong but there has been progress)
Preventing Rejection of Pig Organs
Immunosuppress the patient
>drug side effects
>risk of infection
>risk of cancer
>cost benefit has to be there for the pt for immunosuppressants
>also calcineurin inhibitors suppress kidney function
Genetically modify the donor pig
>make them immunologically inert so no immunosuppression is required
>CRISPR/Cas9 genome editing
>delete pig genes encoding ‘xenoantigens’
>Add human genes to regulate the human immune response
>remove porcine endogenous retroviruses
