LT7 New Treatments

Question 1

What are the current and new treatments for T1D?

Answer 1

Current = T1D and pancreas/islet cell transplantation

New = immunotherapy, artificial pancreas, encapsulated islet cells

Question 2

When is pancreas transplantation applied?

Answer 2

Reserved for renal failure = so pancreas and kidney are transplanted together

Uncontrollable severe hypoglycaemia with insulin treatment

Question 3

What is needed when transplantation is undertaken?

Answer 3

Life long immunosuppresive drugs for rejection

Question 4

What are the benefits of islet cell transplantation?

Answer 4

Less critical operation than pancreas/kidney transplantation

Reduces the risk of severe hypoglycaemia

Question 5

How is islet transplantation done?

Answer 5

Deceased donor pancreas islets harvested

Ricordi chamber = key islet isolation device

Separate islets

Islets are introduced into liver over receipient

Transplanted islets secreting insulin in the LIVER

Question 6

What are the limitations of transplantation?

Answer 6

Donor availability

Risk of rejection

Question 7

One year after islet transplantation, what effect did this have on hypoglycaemia?

Answer 7

NO severe hypoglycemic events were seen in 21/22 patients

With 1/22 experiencing ONE event

Question 8

How did islet transplantation affect insulin dose for kg of recipient weight?

Answer 8

Before transplant 0.42 insulin needed per kg

One year after 0.26 insulin needed per kg

Nearly half the dose of insulin needed

15/29 were reported to have achieved INSULIN INDEPENDECE at some points during their 1st post-transplant

Question 9

What are the current treatments for T2D?

Answer 9

Lifestyle changes

Tablets

Insulin = last resort

Bariatric surgery

Question 10

When is bariatric surgery usually applied in T2D?

Answer 10

For very obese patients

Question 11

Rank the efficacy of the 3 bariatric surgeries?

Answer 11

Best = gastric bypass

Vertical-banded gastroplasty

Worst = banding (long-term weight loss % is less)

Question 12

What are intensive medical therapies for diabetes?

Answer 12

Lifestyle counselling
Weight management
Frequent glucose monitoring
Use of drug therapies

Question 13

What are some future therapies for T1D?

Answer 13

Glucose responsive “smart” insulins

Increase beta-cell mass via islet transplant, regenration (stem cells), GLP-1EA

Cytokin blockade

Cell-based therapies with T regs

Abatacept (CTLA4-ig)

Improved biomarkers

Question 14

What mediates T1D?

Answer 14

Auto immune disease

T-cell mediated

Question 15

What is the mechanism of action of Teplizumab?

Answer 15

Monoclonal antibody that binds CD3, which is a cell surface antigen found on T cells

Mode of action
1. Deactivate autoreactive T cells
2. Increase T regs
3. Reduce immune infiltration

Question 16

How is autoimmunity initiated?

Answer 16

Virus
Apoptotic B cells, which release inflamamtory cytokines
DC can activate T cells

Effector mechanism in beta cell destruction

Question 17

What is the role of T regs and NK cells?

Answer 17

T regs normally stop the immune system from attacking own cells

NK cells normally kill cells that don’t display the correct human-leukocyte antigen

Question 18

What is MultiPepT1De?

Answer 18

Mix of peptides from islet autoantigen

Designed to induce/restore immunological tolerance to the veta-cell

Thus control or limit autoimmunity to protect beta-cells

Question 19

What is the need for immunotherapy trials for T1D?

Answer 19

Safety profile

Assess residual beta cell function and markers or metabolic control

Assess T cell immune response to islet cell antigens

Question 20

What was the inclusion criteria for multiple islet peptide administration?

Answer 20

Age 18-45

Specific genotype because insulin given has the epitope for that specific cell

Only 1/3 autoantibodies = so still ahve SOME islets that can secrete insulin

Stimulated C-peptide on MMTT

Question 21

What were the effects of proinsulin C19-A3 on C-peptide levels?

Answer 21

Changes for low, high and placebo were all negative

Low freq = every 4 weeks of proinsulin increased C-peptide the most

Question 22

How did

Question 23

Summarize the benefits of Teplizumab

Answer 23

Proloning insulin production in people recently diagnosed with T1D

T1D can be delayed for a median of 2 years in children and adults at high risk

Question 24

Side effects of Teplizumeb

Answer 24

Short-time side effects of rash and low white blood cell counts were observed

Low WBC count recovers over 1 month

Question 25

How does an artificial pancreas work?

Answer 25

1. Continuous glucose mointoring 2. Computer-controlled algorithm 3. Insulin pump 4. Patient effect

Question 26

What are the 3 types of artificial pancreas?

Answer 26

Closed-loop artificial pancreas = continuous glucose monitor and insulin pump Bionic pancreas = two pumps infusing insulin and glucagon repectively Implanted artificial pancreas = a gel that responds to changes in blood glucose levels

Question 27

How do encapsulated islet cells work?

Answer 27

Allows nutrients and glucose pass through the capsule Prevents autoantibodies from destroying islet Allows insulin to leave capsule

Question 28

What is capsule for islet made from and where is it placed?

Answer 28

Designed from hydrogels (alginate = seaweed-derived polymer) Implanted either subcuteneously, abdominally, or nearl liver/pancreas Micro and macrocapsule = hold one or many islets

Question 29

What factors impact insulin resistance?

Answer 29

Excess weight Excess caloric intake Sedentary lifestyle Genetics

Question 30

How does glucose enter muscle cells?

Answer 30

Leaves bloot and enters extracellular space GLUT4 transports it into muscle cells It is then phosphorylated and goes through glycolysis etc...

Question 31

How does the ECM communicate?

Answer 31

Integrins = transmembrane cell surface receptors Integrins bind the ECM and transduce signals through the plasma membrane to activate intracellular signaling.

Question 32

How do integrins transduce signals through the plasma memrbane to activate intracellular signalling?

Answer 32

Integrins themselves lack kinase activity. Thus, they are reliant on scaffolding proteins and downstream kinases for signal transduction. Integrins signal through various proteins including focal adhesion kinase (FAK) and integrin-linked kinase (ILK)

Question 33

What happended to ECM components in muscle of insulin resistant, obese mice?

Answer 33

Increased ECM components when mice were fed a high fat diet Collagen III, IV, and hyaluronan

Question 34

What is the role of hyaluronan?

Answer 34

Hydration: HA binds water molecules, keeping tissues hydrated, elastic, and pliable, especially in skin, joints, and eyes. Cell Movement: HA serves as a scaffold that allows cells to migrate during wound healing, immune responses, and tissue regeneration. Tissue Repair: HA regulates the extracellular matrix and influences cell migration, proliferation, and differentiation, helping in tissue repair and wound healing. Regulation of Signaling: HA interacts with receptors to modulate cellular signaling pathways, controlling inflammation, cell survival, and tissue regeneration.

Question 35

Why does increased ECM collagen and hyaluronan increase muscle insulin resistance?

Answer 35

Accumulated ECM can cause 1. Physical barrier 2. Cell signalling Physical barrier = decrased vascular insulin delivery Cell signalling = decreased insulin signalling, endothelial dysfunction Overall causing muscle insulin resistance

Question 36

Why may anti-fibrotic drugs reduce insulin resistance in muscles?

Answer 36

Fibrosis is an increased ECM (collagen and hyaluronan) Prevents this ECm remodelling to fibrotic state Thus reducing insulin resistance caused by increased ECM components

Question 37

What is PEGPH20?

Answer 37

PEGylated Hyaluronidase Reduces muscle hyaluronan Helps reduce insulin resistance

Question 38

What affect does PEGPH20 have in high fat fed obese mice?

Answer 38

Amerliorates muscle insulin resistance in a DOSE-dependent manner

Question 39

What does CLT-28643 do?

Answer 39

A small moleculr inhibitor of INTEGRIN a5b1 Anti-fibrotic

Question 40

What new targets are being looked at for T2D?

Answer 40

Insulin sensitizing drugs Targeting hepatic glucose metabolism Targeting CNS Statified, personalized medicine Comorbidities

Question 41

What biomarkers could there be for insulin resistance?

Answer 41

miRNA can be used as biomarkers for insulin resistance

Question 42

How can you biomarker insulin resistance?

Answer 42

Measure fasting INSULIN levels HOMA-IR Check glucose levels Inflammatory markers FA and lipotoxicity If these are all elevated can indicate insulin resisitance