What is blood glucose rises in diabetes due to?
- An inability to produce insulin due to beta cell failure
- Insulin resistance preventing insulin from working effectively, despite adequate insulin production
Why is diabetes considered to be a progressive disoder?
Beta cell function declines and there is a deteroration of glycaemic control
What effect does diabetes have on the risk of cardiovascular disease?
It increases it
What has caused the diabetes epidemic?
Environment, not genetics
What is the net change in glucose per day under normal glucose homeostasis?
0g/day
What is the average daily glucose input?
250g/day
What contributes to the net glucose input?
- Dietary intake
- Glucose production
How much glucose is taken in in the diet per day?
About 180g/day
How much glucose is produced by the body per day?
70g
By what processes does the body produce glucose?
- Gluconeogenesis
- Glycogenolysis
How much glucose does the body take up for its use per day?
250g
How much glucose does the brain take up for its use per day?
125g
How much glucose does the kidney filter per day?
About 180g
What happens to the glucose filtered by the kidney?
It reabsorbs and refilters it
How is glucose reabsorbed by the kidney?
- 90% by SGLT2
- Remaining glucose by SGLT1
How is type 1 diabetes treated?
- Lifestyle
- Insulin
How is type 2 diabetes treated?
- Lifestyle
- Non-insulin therapies
- Insulin
What are the non-insulin therapies used in the treatment of type 2 diabetes?
- Biguanides
- Sulphonylureas
- Thiazolidinediones
- DPP4 inhibitors
- alpha-Glucosidase inhibitors
- SGLT2s
- GLP1
- Analogues
What do both type 1 and 2 diabetes require in their management?
- Patient education
- Ability to monitor results of therapy
Why is patient education required in diabetes?
Need to know how to self manage with regard to diet, exercise, and healthy living
Why is it important to consider the key challenges for patients with type 2 diabetes?
Because they are important in patient adherence and quality of life
What are the key challenges for patients with type 2 diabetes?
- Weight gain, or fear of
- Hypoglycaemia, or fear of
Why is weight gain a key challenge for patients with type 2 diabetes?
Insulin is an anabolic hormone, and so builds up protein and lays down fat
How are newer drugs reducing the problem of weight gain in patients with diabetes?
Newer drugs are weight neutral, or promote weight loss
What is the result of patients fearing hypoglycaemia?
Patients often run a little higher to prevent hypoglycaemic episodes
Why is hypoglycaemia a potential problem for patients with type 2 diabetes?
Excessive stimulation of beta-cells can cause increased insulin, and so reduced blood glucose
When is insulin-induced hypoglycaemia especially common?
- Between meals and overnight
- In elderly
What is the NICE HbA1c target in type 2 diabetes?
6.5-7.5%
What % of type 2 diabetics achieve the NICE HbA1c target?
<50%
How should diabetes be treated if the HbA1c is 6.5%?
Using diet and first 2 treatment steps
What should be done if the HbA1c is above 7.5% in patients with diabetes?
Go beyond the first 2 treatment steps, unless at risk of severe hypoglycaemia
What is the action of metformin?
- Decreases insulin resistance, leading to increased glucose utilisation by tissues
- Decreases hepatic glucose production
What are the advantages of metformin?
- Limits weight gain
- Decreases incidence of CVS events
- Can be combined with all other diabetes medications
- Cheap
Who is offered metformin?
All patients presenting with type II diabetes without contraindications
What should be done if control of diabetes is not sufficient on metformin?
The patient should be left on metformin, and other medications should be added
What effect does metformin have when it is given with insulin?
It allows better control with lower doses of insulin when used in conjunction with metformin
What are the problems with metformin?
- Side effects
- Rarely, lactic acidosis
- Uncommonly, vitamin B12 deficiency
What are the side effects of metformin?
- Nausea
- Vomiting
What should be done when a patient on metformin develops side effects?
Should stop the medication, and try modified release preperation
How can metformin cause vitamin B12 deficiency?
It can interfere with B12 absorption at the terminal ileum
What are the contraindications for metformin?
- Renal failure
- Cardiac failure
- Respiratory failure
- Liver failure
At what GFR should metformin not be given?
<30ml/min
Why should metformin not be given in renal failure?
Risk of accumulation and lactoacidosis
What is the action of sulphonylureas?
Stimulate beta cells to release insulin by attaching to a receptor on the beta cell
What are the advantages of sulphonylureas?
- Decreased microvascular risk
- Low cost
What are the problems with sulphonylureas?
- Weight gain
- Hypoglycaemia
What are the two most commonly used sulphonylureas?
- Gliclazide
- Glimepiride
What are the possible formations of gliclazide?
Standard or slow release
In what special situation can gliclazide be used?
In renal impairment
Why can gliclazide be used in renal impairment?
As it is metabolised hepatically
How is acarbose unique?
It is the only alpha-glucosidase inhibitor available
What is the action of acarbose?
It inhibits the breakdown of carbohydrates to glucose in the bowel by blocking the action of the enzyme alpha-Glucosidase
What are the side effects of acarbose?
- Flatulence
- Loose stools
- Diarrhoea
Why is acarbose rarely, if ever, used nowadays?
It is not very effective
By how much can acarbose reduce HbA1c?
0.5%
What is the mechanism of action of glitazones?
Binds to and activates one or more peroxisome proliferator activated receptors, which increases insulin sensitivity in muscle and adipose tissue, and decreases hepatic glucose output
What are the advantages of glitazones?
Can be used in combination with other oral agents
Give two examples of glitazones
- Rosiglitazone
- Pioglitazone
Why is rosiglitazone no longer used?
Due to cardiovascular concerns
Is pioglitazone still used?
Yes, but there are concerns
What are the concerns regarding pioglitazone?
- Weight gain
- Fluid retention
- Heart failure
- Bone metabolism
- Bladder cancer
What are the concerns regarding pioglitazone and bone metabolism?
Increased risk of fractures due to exacerbation of oesteoporosis, especially in elderly women
What is high glucose in type 2 diabtes due to?
Insufficient insulin release, and over production of glucagon
What does GLP-1 therapy do?
It increases insulin secretion from beta cells, and decreases production of glucagon from alpha cells
What is GLP-1 released from?
Intestinal L cells
What does GLP-1 act on physiologically?
- Brain
- Stomach
- Pancreas
- Liver
- Muscle
What effect does GLP-1 have on the brain?
It increases satiety, and therefore decreases food intake
What is the end effect of GLP-1 action on the brain?
Causes patients to loose weight
What effect does GLP-1 have on the stomach?
Decreases gastric emptying
What effect does GLP-1 have on the pancreas?
- Increases inuslin secretion
- Decreases glucagon secretin
- Increases insulin biosynthesis
What effect does GLP-1 have on liver?
Indirectly decreases glucose production
What effect does GLP-1 have on muscles?
It indirectly increases glucose uptake
What are the types of GLP-1 therapies?
- Oral preparations
- Injectables
What are the oral preparations of GLP-1 therapies known as?
DDP-4 inhibitors, or gliptins
What is the mechanism of action of gliptins?
Protect the native GLP-1 from inactivation by DPP-4, and therefore increases postprandial active GLP-1 concentrations
Give 4 examples of gliptins
- Sitagliptin
- Vildagliptin
- Saxagliptin
- Linagliptin
What are the advantages of gliptins?
- Low risk of hypoglycaemia
- Weight neutral, or promote weight loss
What are the problems with gliptin therapy?
- GI symptoms
- Possible increased risk of pancreatitis
- Only a modest HbA1c reduction
- High cost
How much does gliptin therapy cost?
£30 a month
What are the injectable GLP-1 therapies known as?
GLP-1 receptor agonists
What is the mechanism of action of GLP-1 receptor agonists?
They mimic the nature of native GLP-1
What are the advantages of GLP-1 receptor agonists?
- Low risk of hypoglycaemia
- Generally perceived to be safe and well tolerated agents
Do GLP-1 receptor agonists cause pancreatitis?
Despite concerns, NICE and the FDA found no evidence of pancreatitis in reported studies
What are the problems with GLP-1 receptor agonists?
- Side effects
Ocassionally painful to inject
What are the side effects of GLP-1 receptor agonists?
- Nausea
- Loose stools/diarrhoea
- Gastro-oesophageal reflux
Why are GLP-1 receptor agonists ocasionally painful to inject?
Because it is an acidic solution
What are the contraindiciations for treatment with GLP-1 receptor agonists?
- eGFR <30ml/min
- Organ failure
What should be used instead of GLP-1 receptor agonists in organ failure?
An agent with a more predictable metabolism, e.g. insulin
Give two examples of GLP-1 receptor agonists
- Exanatide
- Liraglutide
How often is exanatide taken?
Twice daily, or once weekly
Give an example of a sodium-glucose co-transporter 2 inhibitor
Glifozin
What approach does glifozin take to remove excess glucose?
A novel insulin-independant approach
Who can glifozin be used in?
Patients with type 2 diabetes, as an add on therapy
Not currently prescribed for type 1, but trials ongoing
What are the side effects of glifozin?
- Increased risk of lower urinary tract symptoms
- Polyuria
In what % of men and women on glifozin do genital or urinary tract infections occur?
- 5% of women
- 1% of men
What action should be taken if a patient on glifozin presents with a genital or urinary tract infection?
If it happens once, treat the condition. If it happens again, stop the drug
How much extra urine is produced due to glifozin treatment?
Up to 350ml/day
Give three examples of glifozins?
- Dapagliflozin
- Canaglifozin
- Empaglifozin