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L16 Flashcards

1
Q

what is the glucose concentration in diabetic people

A

> 7 mM

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2
Q

what is the safe range of glucose concentration

A

2.5 mM to 7 mM

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3
Q

what are the features of type 1 diabetes

A

Caused by a failure of insulin
secretion

Characterised by very low/absent [insulin] and high [glucose]

Has sudden onset

Usually develops early in life

Sometimes referred to as juvenile

Relatively rare (~5% of diabetes)

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4
Q

what are the features of type 2 diabetes

A

Caused by insulin resistance in tissues

Insulin present in circulation but [glucose] remains elevated

Has gradual onset

Usually develops later in life

It is the most common form of diabetes – and is becoming much more common

Associated very strongly with obesity

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5
Q

describe Type 1 diabetes pathogenesis

A

Type 1 diabetes is caused by

destruction of β cells

Involves an autoimmune mechanism (CD8 cytotoxic T cells mediated)

Total failure of insulin secretion

Evidence of hereditary tendency although environmental factors crucial (viral infections, autoimmune disorders)

However can develop spontaneously in absence of family history or environmental trig

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6
Q

what does CD8 T react to

A

against peptides of insulin and of other specific proteins which are complexed with MHC II

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7
Q

what allotypes are associated with type 1 diabetes

A

HLA-DR3 and DR4

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8
Q

what haplotype is associated with type 1 diabetes for caucasians

A

DR4-DQ8

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9
Q

what mutation is common in Caucasians

A

substitution of Asp57 to Val/Ala/Ser in the HLA-DQ β1 chain

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10
Q

what are the symptoms of type 1 diabetes

A

Tissues cannot accumulate and store glucose

Tissues cannot use glucose as metabolic fuel

Body cannot store excess energy as fat

Reduced synthesis of protein

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11
Q

how does hyperglycemia lead to dehydration

A

High [Glucose] enters glomerular filtrate and overwhelms glucose absorbing capacity of proximal convoluted tubule

Increased fluid osmolarity in tubules

More water is secreted from cells into the proximal convoluted tubule

causes increased urine flow – diuresis
Water reabsorption is reduced

Dehydratation, excessive urine production and thirst

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12
Q

what are the effects of insulin on ketoacidosis

A

fatty acids and proteins are metabolised in the absence of insulin leading to rapid weight loss

degradation of fatty acids produces Ketone bodies

ketone bodies are acidic so blood pH is lowered leading to metabolic acidosis

this leads to acidotic coma

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13
Q

how can you predict glucose values of the past 6-8 weeks and to monitor the long term control

A

Glycosylated haemoglobin

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14
Q

how does lipohypertrophy happen

A

A major effects of insulin is to promote
the deposition of fat

Cells close to site of insulin injection exposed to high [insulin]

If same site used again and again will promote deposition of fat around injection site (lipohypertrophy)

Also clinically important as leads to unpredictable rate of insulin absorption

This could lead to poor glycaemic control and patients could experience hyper/hypoglycaemic events

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15
Q

what are the forms of insulin used for therapy

A

Animal insulin (porcine/bovine)

Human insulin

Human insulin analogue

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16
Q

what are the types of human insulin

A

soluble insulin

isophane insulin

insulin zinc suspension

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17
Q

what are the features of soluble insulin

A

Rapid and short lived

Used intravenously in emergency treatment of hyperglycemic emergencies only (e.g. chetoacidosis)

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18
Q

give features of Isophane insulin

A

Tends to form precipitates.

Intermediate acting

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19
Q

give features for Insulin zinc suspension

A

Tends to form precipitates

Long acting

20
Q

what are the types of insulin analogues

A

Insulin Lispro

Insulin glargine & detemir

21
Q

what are the features of Insulin Lispro

A

A modified insulin (analogue) obtained by switching a Lys28 and Pro29

Very rapid and very short lived. Normally taken from patients before a meal

22
Q

what is Glargine

A

A modified insulin (analogue) obtained by mutating Asn21 in Gly and by adding 2 Arg at the end of the B chain.

Long-acting.

23
Q

what is Detemir

A

A modified insulin (analogue) obtained by mutating Thr 30 (deletion)

Long-acting

24
Q

what are the features of Insulin glargine & detemir

A

Normally taken from patients before a meal in combination with a short-acting form

Forms a micro-precipitate at the physiological pH of subcutaneous tissue

Slowly absorbed

25
what is Teplizumab
a monoclonal antibody that targets CD3 changing the interaction between APC and T cell this leads to less of CD8 T cells and promoting more production of T reg cells T reg cells inhibit the immune response
26
what are the steps of getting type 2 diabetes
1. Genetic and environmental predisposition - Life style - Bad dietary habits - Obesity 2. Insulin resistance - Glucose uptake - Insulin pathway defects 3. Hyperinsulinemia - β cells try to compensate for peripheral - - - - - resistance - Normal glucose levels can be maintained for years 4. β cells failure and hypoinsulinemia - β cells become “exhausted” and cannot keep up with the peripheral demand of insulin - Insulin secretion decrease 5. Diabetes - Hyperglicemia develops - Total failure of insulin secretion - Exhausted Beta cells may convert to Alpha cells
27
what are the factors that lead to type 2 diabetes in FAT people
Free fatty acids (FFAs) Adipokines PPARγ Inflammation
28
how do FFAs contribute to type 2 diabetes
Lead to insulin resistance in muscle and liver. When in excess they are transformed in second messenger DAG DAG activate PKC which phosphorylate IRS-1 This attenuates Insulin Receptor signal
29
how do Adipokines contribute to type 2 diabetes
Released by adipocytes Adiponectin is anti-hyperglicemic, because improves insulin sensitivity by activating AMPK, enzyme promoting lipolysis in liver and muscle Adiponectin expression is reduced in obesity Also activates IRS1/2 improving insulin signalling and GLUT4 improving glucose uptake. (all of this is reduced in obese people) AMPK activators can be used in therapy (metformin)
30
what are the types of adipokines
Pro-hyperglicemic anti-hyperglicemic
31
how does PPARγ lead to type 2 diabetes
Nuclear receptor involved in adipocyte differentiation Promotes secretion of anti-hyperglicemic adipokines Mutations/Post-translational modifications (Ser273 phosphorylation) can cause diabetes Agonists used in therapy
32
how inflammation contribute to type 2 diabetes
Adipocytes overexpress certain cytokines (IL-1/IL-6) Cytokines activate JAK-STAT signalling Promoting SOCS expression SOCS3 compete for binding to phosphotyrosine residues attenuating insulin signalling
33
what does type 2 diabetes therapy include
Diet/Excercise Thiazolidinediones Metformin Sulphonylureas Insulin (Once disease fully developed)
34
what are the features of Thiazolidinediones – e.g. (Pioglitazone)
Agonist of nuclear receptor PPAR-γ Promotes expression and secretion of anti-hyperglycaemic adipokines (so increase lipolysis) Increase hypoglycaemic action of insulin by sensitizing cells to its action Collectively reduce insulin-resistance in liver and other peripheral tissues
35
what are the features of Metformin
Suppress glucose release from liver Activate AMPK increase lipolysis in liver and muscles and therefore improving insulin receptor signalling Suppress glucose release from liver Useful in obese type 2 patients
36
how does Sulphonylureas (e.g. Gliclazide) work
Bind to sulphonylurea receptors expressed on membranes of β cells Block ATP-sensitive K + channels in β cells K + accumulates inside cells β cells depolarize Ca++ channels open and allow insulin secretion by exocitosis
37
what Type 2 diabetes drugs are under research
Selective β3 agonists α2 adrenoreceptor antagonists GLP-1 (Glucagon like peptides) receptor agonists SGLT-2 inhibitors (Sodium-glucose co-transporter
38
how would Selective β3 agonists work
β3 adrenoreceptors control lipolysis in fat cells Under development Potentially important for treating obese patients with type 2 diabetes
39
how would α2 adrenoreceptor antagonists work
Increase insulin secretion
40
how would GLP-1 (Glucagon like peptides) receptor agonists work
Increase insulin secretion from Beta cells Pro-survival effect on Beta cells Promote weight loss (loss of appetite) Renoprotective
41
how would SGLT-2 inhibitors (Sodium-glucose co-transporter work
Increase excretion of glucose in urine Lower blood glucose and blood pressure Induce ketogenesis
42
name a strategy under research for treating type 2 diabetes
Alpha-cells reprogramming
43
what is Alpha-cells reprogramming and how is it achieved
Reprogramming alpha-cells in insulin producing cells In mice MafA and Pdx1 overexpression experimentally showed to convert Alpha to Beta cells
44
how are the long term consequences of diabetes caused
extra glucose is oxidised into reactive oxygen species ROS ROS damage blood vessels leading to Microvascular complications which lead to retinopathy, leading to macrovascular complications nephropathy (increased levels of LDL cholesterol, blood pressure, and insulin resistance) also lead to macrovascular complications
45
how are AGEs linked to the long term consequences of diabetes
glucose binds to protein producing AGEs AGEs bind to receptors on endothelial cells of blood vessels promoting ROS production which increases inflammation and metabolic an structural defects
46
describe AGEs and collagen effects on blood vessels
AGE’s crosslink with collagen The basal membrane of the endothelium thickens The thickened endothelium traps LDL and IgGs leads to Oxidation, complement activation and inflammation resulting in Blood vessel damage
47
give 2 examples of molecules that can lead to insulin resistance
DAG IL-1

BMS2002 (21 decks)

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