Diabetes lecture 2 Flashcards Preview

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Flashcards in Diabetes lecture 2 Deck (19):
1

Treatment

All patients benefit from advice on nutrition, physical activity, weight loss and smoking cessation
Dietary control considered to be the mainstay of treatment for type 2 but plays an integral role in type 1
Generally, healthy eating advice is the same for diabetics as the general population

2

Insulin therapy

All patients with type 1 diabetes require treatment with insulin
Exogenous insulin is used to mimic the normal physiological secretion of insulin
Insulin preparations differ in: species of origin, onset of action, time to peak effect and duration of action

3

Fast acting insulin

Soluble insulins, appear in the circulation after 10 mins, peak concentration occurs around 2 hours and declines over a further 4-8 hours
Relatively closely mimics normal endogenous insulin secretion
Fast acting recombinant analogues are more rapidly absorbed than others and have a shorter duration of action

4

Intermediate acting insulin

Insoluble cloudy suspensions of insulin complexed with either protamine or zinc
The insulin must dissociate from the protamine
Onset of action is ~1-2 hours and the peak effect is 4-8 hours
There is significant inter-patient variability but generally twice daily administration is required

5

Long acting insulin

Insulin glargine and insulin deltemir more recently developed using recombinant technology
Duration of action is around 24 hours and have a very flat PK profile
Limited peak/trough effect
Limited inter- or intra- patient variability

6

Insulin glargine

The two added glargines result in a change in the isoelectric point from 5.4 to 6.7
Combined with the aspargine replacement, glargine remains soluble at pH of 4
The product is buffered to pH 4 and when it is injected it forms a microprecipitate
This allows slow absorption from the injection site

7

Insulin deltemir

Deltemir omits the terminal threonine residue but has myristic acid attached
This allows the deltemir to bind to albumin following absorption
Long duration of action is due to the slow dissociation of the insulin molecule from albumin

8

Insulin regimens

May vary from between two to five injections daily
Must be tailored to the individual patient and will depend on lifestyle, willingness to achieve the best control and the ability to cope with injecting and monitoring blood glucose
Mealtime plus basal regimens: comprises mealtime injections of fast acting plus one or two injections of a basal
Twice daily regimens: premixed insulin twice daily

9

Sulphonylureas

Major action is to increase release of insulin from the pancreas
Bind to a 140kDa high affinity sulphonylurea receptor that is associated with a beta cell ATP sensitive potassium channel
Inhibits the efflux of potassium ions through the channel and results in depolarisation
Extrapancreatic effects also evident

10

Meglitinides

Meglitinides have two binding sites in common with the sulphonylureas and one unique binding site
Repaglinide is licensed as a single agent when diet, weight reduction and exercise have failed or in combination with metformin
Nateglinide is only licensed for combination therapy with metformin when metformin alone is inadequate

11

Biguanides (metformin)

Primary effect is to activate AMP-activated protein kinase resulting in the potentiation of insulin action at an unknown intracellular location
This results in decreased hepatic glucose production by both gluconeogenesis and glycogenolysis
Also stimulates glucose tissue uptake esp muscle and is thought to reduce GI absorption of carbohydrates
Diabetes related deaths reduced by 40% in overweight subjects who took metformin for 10 years cf. sulphonylureas or insulin, MI also reduced by 39%

12

Glitazones

Acts as antagonists of the peroxisome proliferator activated receptor G
PPARis mostly expressed in adipose but also in pancreatic cells, vascular endothelium and macrophages
Receptors modulate the expression of the genes involved in lipid and glucose metabolism, insulin signal trans-duction, and adipocyte and other tissue differentiation
Key effects include increased glucose transporter expression, decreased free fatty acid levels and decreased hepatic glucose output

13

A-glucosidase inhibitors

Acarbose reduces carbohydrate digestion by interfering with GI glucosidase activity- potent inhibitor of glucoamylase, a-amylase and sucrase
Acarbose has the molecular mass and structural features of a tetrasaccharide and very little is absorbed
Whilst overall carbohydrate absorption is not significantly altered, post-prandial hyperglycaemic peaks are markedly reduced

14

Incretins

An oral glucose load results in a higher insulin response compared to an equivalent IV dose
This is because gut hormones are released, particularly glucagon-like peptide 1 and glucose dependent insulinotropic peptide which amplify the glucose induced insulin secretion
When GLP 1 is infused into patients, it stimulates insulin release and lowers glucose levels
The GLP1 effect is glucose dependent and therefore GLP1 has a lower risk of causing hyoglycaemia than sulfonylureas

15

Dipeptidyl peptidase-4 inhibitors (gliptins)

Licensed for dual therapy with metformin, a sulfonylurea or a thiazolidinedione
Sitagliptin is also licensed for both mono- and triple- therapy with metformin, a suulfonylurea or a thiazolidinedione

16

Glucagon-like peptide-1 receptor agonists

Exanatide added to metformin and a sulfonylurea as a third line therpay
This is an alternative to insulin, a thiazolidinedione or DPP-4 inhibitors

17

Hypoglycaemia

Serum glucose level <3.0mmol/L
Most common causes are a decrease in carbohydrate intake, excess carbohydrate utilisation e.g. from exercise or increase in circulating insulin
If the patient is able to swallow safely then glucose should be given, if this is not possible then IV glucose or IM glucagon

18

Diabetic ketoacidosis

Occurs because the absence of insulin causes extreme hyperglycaemia
Ketone bodies, acetoacetate and hydroxybutyrate are formed and released into the circulation, osmotic diuresis occurs causing dizziness and weakness due to postural hypotension
Weakness is increased by potassium loss, caused by urinary excretion and vomiting due to ketones stimulating the brain's vomit centre
Eventually coma ensues

19

Hyperosmolar hyperglycaemic state

Associated with type 2 diabetes
15% mortality rate- higher than diabetic ketoacidosis
Usually occurs in middle aged or elderly people
No significant ketone production and therefore no severe acidosis
Dehydration due to osmotic diuresis which if severe leads to hyperosmolarity
This can increase blood viscosity and the risk of thromboembolism