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Pharmacology of the Treatment of Metabolic Disease > LT2 Treatments for T1D & T2D > Flashcards

LT2 Treatments for T1D & T2D Flashcards

1
Q

How does T1D occur?

A

Autoimmune disease causing b-cell destruction
Usually leading to absolute insulin deficiency

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2
Q

How does T2D occur?

A

Insulin resistance means that cells don’t respond to insulin properly

b-cells produce even more insulin causing b-cell exhaustion

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3
Q

How does gestational diabetes mellitus occur?

A

Transient diabetes occurs in 2nd or 3rd trimester of prenancy

12x increased risk of developing T2D if you get GDM

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4
Q

What other causes of diabetes are there?

A

Monogenic diabetes syndromes (e.g MODY)

Disease of the exocrine pancreas (cystic fibrosis)

Drug- or chemical-induced diabetes (in treatment of HIV/AIDS or after organ transplant)

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5
Q

What happens in the autoimmune disease T1D?

A

Selective T lymphocytes mediate destruction of beta cells of the pancreatic islet

Meaning no insulin can be made = glucose levels can not be controlled and extreme hyperglycaemia occurs

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6
Q

What can having one autoimmune disease increase risk of?

A

Attaining other autoimmune diseases

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7
Q

What happens when a person produces autoantibodies?

A

Can cause diseaes directly or can be generated as a results of tissue damage

Antibodies raised against own tissue = resulting in inflammation and damage

Can be used as a marker of early stages of disease

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8
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A
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8
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A
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9
Q

Explain how autoantibodies can be generated as a result of tissue damage

A

Healthy cells keep certain proteins inside, where the immune system can’t see them. When cells are damaged (like during injury or disease), some of these “hidden” proteins are released into the bloodstream. The immune system might then see these proteins and think they are invaders, even though they’re from the body itself.

Sometimes, the immune system gets confused and starts attacking these released proteins as if they were foreign invaders (like viruses or bacteria). This leads to the production of autoantibodies, which are antibodies that target the body’s own tissues.

Loss of immune tolerance

Molecular Mimicry (Look-Alike Proteins): Sometimes, the immune system mistakes the body’s proteins for those from an infection (like a virus). This happens because the body’s proteins and the infection’s proteins look similar. The immune system may attack the body’s tissues thinking it’s fighting off an infection, which also leads to autoantibodies being made.

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10
Q

What is immune tolerance?

A

The immune system normally recognizes and protects the body’s own cells, avoiding attacks on them.

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11
Q

What are the 4 antigens that autoantibodies usually target in T1D?

A

Beta cell proteins

IA-2
IA-2b
GAD (most common)
Zn-T8

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12
Q

Why does NHS not screen everyone for autoanitbodies?

A

Only 10% of people have T1D

So would be easier to do TARGETED screening = screen people with higher risk of developing T1D
(if relateive has T1D = genetic link)

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13
Q

How frequently do T1D patients have these autoantibodies?

A

93% of T1D will have at LEAST ONE of these autoantibodies detectable around time of diagnosis

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14
Q

Is T1D a monogenetic or polygenic condition?

A

Polygenic condition

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15
Q

What genes have been found to cause T1D?

A

Around 40 genes = mostly related to the immune system

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16
Q

Which gene contributes to ~50% of genetic susceptibility of T1D?

A

Human leukocyte antigen (HLA) on chromosome 6

HLA are expressed on antigen presenting cells
Present antigen to CD4 T-myphocytes

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17
Q

What genotype are present in about 90% of T1D children?

A

Class II HLA genes encoding cell surface receptors

DR4-DQ8
DR3-DQ2

Genotypes with both haplotypes = carries highest RISK of diabetes

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18
Q

Does having both HLA haplotypes mean you get T1D?

A

No
It only increases the risk

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19
Q

What would be the best way to screen for those most likely to develop T1D?

A

Genetic and autoantibody screens

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20
Q

What environmental triggers autoimmune diseases?

A

Viral infeciton

Potential geographic variation

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21
Q

When do beta cell autoabtibodies typically develop?

A

9 months - 2 years of age

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22
Q

How do viral infections trigger autoimmune disease?

A

Many viruses have been proposed

Strong evidence supports development of autoimmunity following enterovirus infection

Mechanism uncertain

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23
Q

How may geographic variation trigger autoimmune disease?

A

North/South hypothesis = suggests that the higher incidence of T1D in northern latitudes

Different sun exposure (Vit A and Vit D exposure)

Vitamin D is known to play a crucial role in regulating the immune system. Some studies suggest that low levels of vitamin D might increase the risk of autoimmune diseases, including Type 1 Diabetes (T1D), because it can affect immune function and tolerance.

Vitamin A also plays a role in immune system regulation, particularly in the development and function of T cells. It is essential for maintaining the immune system’s ability to distinguish between self and non-self, helping to prevent autoimmune responses.

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24
What is a possible intervention point for T1D?
As beta cell mass starts to decrease due to autoantibodies But have not been completely destroyed so the body is still capable of secreting insulin
25
What are the classic symptoms of all diabetes?
Polyuria = excessive peeing Polydipsia = excessive thirst
26
What are the symptoms of T1D?
Polyuria and polydipsia Weight loss = because insulin helps with fat accumulation and T1D cannot produce insulin General malaise = fatigue Diabetic ketoacidosis (DKA) more common in T1D
27
Why does diabetic ketoacidosis occur in T1D?
Without insulin, the body's cells can't use glucose for energy. The cells begin to "starve" for energy, even though there's plenty of glucose in the blood. As a result, the body starts looking for alternative sources of energy, which leads to the breakdown of fat stores. When fat is broken down for energy, the liver produces substances called ketones as a byproduct. Ketones are normally used as an alternative energy source, but in excess, they can become toxic and accumulate in the blood. As ketones build up in the blood, they cause the blood to become more acidic. This is known as ketoacidosis. The increased acidity of the blood can lead to serious complications if not treated promptly, such as damage to organs and tissues. High blood sugar causes the kidneys to work overtime to filter out excess glucose, leading to increased urination and dehydration.
28
What would greatly reduce the risk of DKA at presentation?
Autoantibody screening
29
How is type of diabetes diagnosis distinguished?
T1D has a sudden onset, occurs in the young and DKA commonly occurs if not caught Weight loss more linked to T1D (T2D is higher weight) GAD autoantibodies and C-peptide can confirm T1D
30
What are the aims of T1D therapy?
Treat acute symptoms (hyperglycaemia) Avoid hypoglycaemia Prevent chronic health complications (long term care)
31
What chronic health complications occurs with T1D?
Microvascular and macrovascular disease Acute metabolic complications = DKA Psychosocial morbidity
32
How does the body control glucose levels so well?
Highly physiological process to ensure Accurate sensing of blood glucose changes Correct amount of insulin released to maintain euglycaemia Counterregulatory mechanisms ot protect against hypoglycaemia rebound
33
What are the cells of pancreatic islet?
alpha and beta cells Delta cells = secrete somatostatin PP cells = secrete pancreatic polypeptide
34
What cuts the C-peptide chain of proinsulin?
Ca2+ dependent endopeptidases
35
What is the glucose sensor in beta cells?
Glucokinase
36
How is insulin secreted?
Glucose enters beta cells through GLUT2 GK phosphorylates glucose to G6P Increased metabolism of glucose = increased intracellular ATP conc ATP inhibits K_ATP channel = depolarization of the cells (because no hyperpolarization) Depolarization of cell membrane results in opening of v.g Ca2+ channels Leads to fusion of secretory vesicles with cell membrane (SNAPs, SNAREs, and synaptotagmin) Release of insulin
37
How many ATP produced per glucose?
36 ATP
38
When do beta cells secrete insulin?
Should only be in response to blood glucose rising above 5mM
39
How does insulin resistance occur?
Beta cells lost ability to sense changes in glucose due to hyperglycaemia taking glucose conc outside the range of glucokinase Km
40
Why is release of insulin biphasic?
1st phase = prevents severe hyperglycaemia 2nd phase = fine tuning, reacts to the conc of glucose intake
41
What do the two phases of insulin release represent?
5% of insulin = immediately available for release (readily releasable pool) Reserve pool = must undergo preparatory reactions to become mobilized and available for release
42
How are ultra short-acting insulin analogues made?
Swap pro28 and lys29 on B chain To make lys28 and pro29 (short-acting insulin)
43
What is the name of short-acting insulin and its characteristics?
Lispro Monomeric not antigenic Most rapidly acting insulin = injected within 15mins of beginning a meal Short duration of action = must be used in combination with long-acting insulin for T1D (unless used for continuous infusion)
44
How are long-acting insulins made?
Change asparagine21 to glycine21on A chain Add two Arg to the end of B chain
45
What is the name of long-acting insulin and its characteristics?
Glargine Precipitates in the neurtral env oc subcutaneous tissue Peakless prolonged action Administered as single bedtime dose
46
What are the limitations of currently available insulin?
Insulin injection or pumped into subcutaneous tissue Peaks too slowly to prevent post-meal hyperglycaemic spike Slow clearance Compared to pancreatic insulin secretion = directly into blood stream entering liver, rapidly prevents post-meal hyperglycaemic spike, two phases, rapidly cleared
47
How do glucose monitors work?
Sensor filament is inserted 5mm under skin surface Measure glucose in the interstitial fluid (subcutaneous tissue) Interstitial fluid contains glucose transported form blod capillaries Glucose levels in interstitial closely follow blood glucose = slight time delay
48
What maintainance needs to be done with glucose monitors?
Machine needs to be calibrated Needle needs to be changed
49
What novel ways can insulin be delivered?
Inhaled insulin Glucose-responsive insulin = is engineered to bind and release insulin in response to changes in blood glucose. This is achieved by modifying the insulin molecule or using a delivery system that can sense glucose levels. The key idea is that insulin is only activated or released when glucose levels are high, thus reducing the risk of hypoglycaemia (low blood sugar) which is a common side effect of regular insulin therapy Liver-targted insulin = aims to enhance the insulin action in the liver, reduce excessive glucose production, and improve overall glucose control without affecting other tissues as much.
50
Why is there limited availability for kidney-pancreas transplants?
Because donor needs to be dead
51
Who are transplantations typically reserved for?
Those with epidsodes of severe hypoglycaemia Server and progressive long-term copmlicaitons despite maximal therapy Uncontrolled diabetes despite maximal treatment
52
Why is lowering glucose the primary focus of T2D treatment?
Because hyperglycaemia is the cause of the issue not a symptom Reduction of HbA1c by 0.9% was associated iwth 25% reduction in rates of retinopathy, nephropathy, and neuropathy Reduced blood glucose = reduced risk of microvascular disease and coronary heart disease
53
What class of drug is Metformin?
Biguanide
54
What is the active ingredient of Metformin?
Guanidine (toxic)
55
What is the mechanism of action of metformin?
OCT1 predominantly expressed in the liver = allows metformin uptake into cells Metformin inhibits Complex 1 of ETC = reduced ATP AMP/ATP ratio increases = activates AMPK by phosphorylation at Thr172 site by LKB1 AMPK inhibits gluconeognesis and increases glucose utilization
56
What does metformin do?
Induces insulin-like REPRESSION OF HGP in liver by inhibition of gluconeogenesis Increases glucose uptake into muscle MAY regulate glucose transport across the gut wall
57
Why was action of metformin initially dismissed?
Because diebetes wasn't separated into T1D and T2D It was when they realised insulin wasn't the answer to everything
58
What are phenformin and buformin?
Analogues of metformin
59
Why were phenformin and buformin withdrawn from use?***
They inhibit mitochondrial respiration, particularly complex I of the electron transport chain, leading to reduced ATP production and increased lactate levels in the blood Causing ketoacidosis
60
What are the multiple therapeutic effects of metformin?
Does not cause hypoglycaemia or weight gain Counters insulin resistance Anti-hyperglycaemic May improve lipid parameters Anti-atherothrombotic effects Benefits PCOS Possible anti-cancer effects Slows down progression of impaired glucose tolerance
61
What are the issues with metformin?
Only works in 50% of diabetics Causes acidosis in a small number of people = can be fatal Lactic acidosis mainly seen in patietns with kidney damage Not pleasant to take = gas problems Resistance to metformin often occurs after a few years
62
What is a common therapy for diabetes now?
Combination therapy with SURs and now incretins
63
What is metformin better than?
Better long term health outcomes compared with: SUR Insulin Diet and exercise alone Metformin's advantage is NOT based on glycaemic control alone

Pharmacology of the Treatment of Metabolic Disease (11 decks)

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