Type I Diabetes

Type I diabetes is an _______ disease that results in the destruction of ________,

autoimmune, insulin-producing beta cells

T1D results in _______ and causes _____ if not treated

little to no insulin production, hyperglycemia

The trigger for T1D is _______

not filly understood

Primary treatment of T1D is ____-

insulin replacement

Proper management of glucose levels is important to prevent complications like ___, _______, ______, ______, and _____

Ketoacidosis, CVD, nerve damage, kidney disease, vision problems

T1D is often diagnosed in ____ or ____ but can develop in ___ too

Childhood, adolescence, adults

_____ can increase risk of T1D

Viral infection

Onset in T1D vs T2D

Before vs after age 40

Ketoacidosis in T1D vs T2D

Risk vs rare

Obesity in T1D vs T2D

Not typically associated vs associated

Autoimmunity in T1D vs T2D

Yes vs no

Cause of T1D vs T2D

Autoimmune destruction of beta cells vs insulin secretion + insulin resistant

Treatment of T1D vs T2D

Insulin vs diet, exercise, GLP-1 analogues, oral agents, insulin

Symptoms of untreated T1D (7)

• Polyuria

• Polydipsia

• Polyphagia

• Weight loss

• Dehydration

• Weakness/dizziness/blurred vision

• Slow wound healing

• Red and inflamed gums

If a T1D individual progresses to ketoacidosis

• Abdominal pain

• Nausea and vomiting

• Loss of appetite

• Kussmahl breathing (rapid, deep)

• Mental confusion

• Acetone scented breath

Insulin in the liver

• Decreased glucose production

• Increased glucose oxidation

• Increased glycogenesis

• Decreased ketogenesis

Insulin in the blood

Decreases glucose, ketone bodies, FFAs, AAs

Insulin in the muscle

• Increased glycogenesis

• Increased glucose uptake + oxidation

• Decreased proteolysis

• Increased protein synthesis

Insulin in fat cells

• Increased triglyceride synthesis

• Increased FFA uptake

• Decreased lipolysis

• Glucose uptake and oxidation

When insulin is absent, glucose entry into cells is significantly _____ and accumulates in the _____

decreased, bloodstream

When insulin is absent, glucose is __________

secreted in urine

When insulin is absent, fats are used as an _______

Energy source

• Break down FAs

• Ketones accumulate and blood acidifies

• DKA can occur and cause coma/death

How does T1D begin?

• Genetic predisposition

• Immune activation

• Development of single autoantibody

Stage 1 T!D

• Normal blood sugar

• No symptoms

• >2 antibodies

Stage 2 T1D

• Abnormal blood sugar

• No symptoms

• >2 antibodies

Stage 3 T1D

• Clinical diagnosis

• Symptoms

• >2 autoantibodies

Treatment with insulin often boost insulin production, leading to a________ where _______

honeymoon period, less insulin is needed

Stage I B cell autoimmunity, B cell loss, Dysglycaemia, Symptoms

Present, present, absent, absent

Stage 2 B cell autoimmunity, B cell loss, Dysglycaemia, Symptoms

Present, Present, hyperglycemia, absent

Stage 3 B cell autoimmunity, B cell loss, Dysglycaemia, Symptoms

Present, present, hyperglycaemia, present

_____ region is responsible for genetic predisposition to T1D

HLA (human leucocyte antigens)

Class 1 region

Involved in T cell receptor antigen binding on cells

Class 2 region

Antigen presentation

_______ are associated with increased risk of T1D with the _______ accounting for 50% of genetic susceptibility

Haplotypes, IDDM1 susceptibility gene

Viral risks for T1D

Enteroviruses (coxsackievirus B) linked to formation of autoantibodies

Early dietary factors

Unclear relationship

Gut microbiome on T1D

No causal relationship identified but different in T1D

Environmental toxins and chemicals in T1D

Toxins may damage beta cells and disrupt immune regulation

Physical/Psychological stress on T1D

Stress induced inflammation or immune

B cell secretes ________ to ________ for processing

autoantigen, APC

APC releases _____ and binds CD4 T helper cells using ____ and ____

IL-12, MHC-II, TCD

CD4 T helper cells release _____ to activate ______ 

IFNy, cytotoxic macrophage

CD4 T helper cells secrete ___, ____, ____, ____ to ______

IL-2, IL-4, IL-10, TGFB

Cytotoxic macrophage releases ____, ____, ____, and ____ to trigger ____ and _______

IL-1, TNF-a, IFNy, free readicals, apoptosis, perforin granzyme secretion

Primed CD8+ cells trigger _____ through _____ and _____ binding

apoptosis, TCR, MHC-1

____ bind MHC molecules and selection for _____ takes place in the _____ for them to escape to the periphery

Peptides, autoreactive T cells, thymus

Activation of ______ following the presentation of ______ by ______ occurs in the pancreas lymph nodes

Autoreactive T cells, antigenic peptides peripheral APCs

In the ____, apopotitic release of ______ in development

pancreas, islet autoantigen

____________ T cells have limited _____ at initiation

Activated, antigen specificity

Further ________ after initial T cell damage

Autoantigen release

Expansion of _________ of _______

Autoreactive T cells, multiple antigenic specificities

Secondary prevetion

Preserve remaining B cell mass

Tertiary prevention

Prolong honeymoon phase

Primary prevention

Prevention of autoimminity in susceptible populations or people with genetic risk

Examples of primary prevention

• Vitamin D

• N-3 fatty acids

• Avoiding cows milk (no evidence)

• Antigen based therapies

Examples of secondary prevention

• Antigen based therapies (induce regulatory T cells)

• Immunotherapy (biologic)

Examples of tertiary prevention

biologic and antigen based treatment

Immunotherapies for T1D

• Atmost have delayed onset

• No success in achieving remission or prevention

• Important knowledge about autoimmunity and mechanistic lessons

Tolerizing vaccines

• Harnessing tolerogenic power of the gut (oral insulin)

• Formulations for peripheral immunization provides the basis for antigen specific therapies

_____ or ______ of autoreactive T cells to crhonically exhaust ________ and induce tolerance

Depletion, inhibition, effector T cells

Examples of therapies to deplete autoreactive T cells

• Methyldopa

• Teplizumab (Anti-CD3)

• ATG

• Alefacept

Step 1 of immunopathogenesis

Antigen taken up by APC and presented to T cells

Step 2 of immunopathogenesis

• T cell activated by antigen specific T cell receptor binding MHC presented antigen

• Costimulation through CD80/CD86 binding with CD28 on T cell

Step 3 of immunopathogenesis

• Effector T cells induce apoptosis of beta cells

• Macrophage production of cytokines

Step 4 of immunopathogenesis

Cytokine environment determines if T cells differentiate into effector or regulatory T cells

_____ improve tolerance by inhibiting ____-

Tregs, Teffs

Examples of proposed immunotherapies

• Oral insulin GAD-vaccine

• Anti-CD3 thymoglobulin

• Abatacept

• IL-2

• Alefacept

• Anti-IL-1B, TNFa, IL-6r

Abatacept modulates T cell activity by blocking ________ in the ______ pathway

costimulation signals, CD80/86:CD28 pathway

______ has shown promise in preserving beta cell function in clinical trials but no significant delay of ___, ___

Abatacept, AGT, T1D

Delivert of tolerogenic agents (Stage 1)

Administer immunosuppresant/immunomodulatory agent

Delivery of autoantigen (stage 1)

Autoantigen binds target ligands causes APC presentation without costimulation, causing T cell death

Antigen and immunomodulation (Stage 1)

Immunosuppressants promote induction of Tregs and tolerogenic APCs (cellular/humoral tolerogenic phenotype)

Tolerogenic artificial APCs (stage 1)

Artificial APCs, lead to T cell death

Teplizumab (Anti CD3) is a _______ that targets _____ on T cells, reducing _____ on beta cells

monoclonal antibody, CD3 receptors, immune attack

Binding of _____ to the CD3 subunit on the T cell receptor reduces _________

Anti-CD3, T cell responsiveness

Anti-CD3 induces _____, increasing ______ and _______ with the help of ____

Treg cells, IL-10, Treg activation, TGFB

_____ can delay the onset of T1D in at-risk individuals, and has been approved by the FDA

Teplizumab

_______ can stop beta cell destruction however side effects are unacceptable

Chronic immune suppression

Therapies with demonstrated but transient effects and/or unacceptable side effects

Cure: CTLA4-Ig, aCD3. aCD2, aIL-21 + liraglutide

Side effects: ATP, cyclosporine, HDIS-AHST, aCD20, aTNF

Therapies with ongoing study

JAK inhibitors, aCD2+CTLA4-Ig

Rapid acting insulins

Mealtime insulin analogues that have a more rapid onset and shorter duration of action

Long acting insulins

Meant for basal insulin replacement. Meant for use in combination with rapid-acting insulins and provide baseline insulin throughout the day.

Modifications of _____ and ____ are used to modulate insulin kinetics

insulin structure, formulation

INsulin infusion pumps

Reduces the number of injections required and provides both mealtime boluses and basal infusion

Continuous glucose monitor

Subcutaneous sensors that enable continuous glucose measurements and monitoring of trends

Hybrid closed-loop automated insulin delivert

Data from continuous glucose monitor feeds into an algorithm to inform insulin infusion rates

Advantages of closed-loop insulin delivery

• Improved treatment targets (Better HbA1c or time in target glucose range)

• Fewer patinet inputs

Disadvantages of closed-loop insulin delivery

• Not fully autonomous (carbohydrate entries at mealtimes are needed)

• Lag time

_____ with insulin from beta cells and is absent in T1D

Amylin is co-secreted 

Role of amylin

Slows gastric emptying, suppresses glucagon, increases satiety

_____ is a commercially available amylin analogue

Pramlintide

Co-administration of pramlintide with insulin reduces ________ at mealtimes

Glycemic excursions

Only 1% of patients use pramlintide because it requires a _____ and is not compatible with ___-

Second injection, pumps

______ is used as a rescue medication to counter ______ (stimulates ________ from the liver)

Glucagon, hypoglycemia, glycogen

Previus challenges and improvements for glucagon in hypoglycemic rescue

• Formulation used to have to be resuspended immediately before use (difficult for care providers)

• New nasal spray fixes issue

Current insulin formulation research

• Alternative insulin dosage forms (oral, transdermal, inhaled ie. Afreeza)

• Insulin-pramlintide co-formulations

• Ultra-fast insulin formulation

• GLP-1 analogues

• Glucose-responsive materials (not yet approved)

Advantages of pancreas transplants

• Successful transplant patients can be insulin-independent for several years

• 1-year graft survival rates are 85-90%

• Improved quality of life

Challenges of pancreas transplants

• Lifelong immunosuppression to prevent rejection

• High surgical risk

• Limited donor supply

• Declining function after 5-10 years

Islet cell transplantation is a _____ alternative to a full pancreas transplant where _____ are trnasplanted into the ____

less invasive, islets, liver

Challenges of islet cell transplantation

• Lifelong immunosuppresion

• Limited donor supply

• Longevity - islets have shorter lifespan

• Many still require some insulin