diabeties 2

Question 1

what are the causes of type 2 diabeties

Answer 1

Type II diabetes is characterised by reduced insulin secretion and insulin resistance.

Insulin resistance means that ‘normal’ biological effects of insulin (i.e. inhibition of hepatic glucose output, skeletal muscle uptake of glucose, suppression of lipolysis) are not observed at physiologically-relevant insulin concentrations.

Relative insulin deficiency results from pancreatic beta-cell dysfunction:
At Type II diabetes diagnosis, a 50% reduction in beta-cell mass is common.
Further beta cell loss (4%) can occur post-diagnosis.

It is still not fully understood the events that lead to insulin insensitivity and beta-cell dysfunction in Type II diabetes.

Question 2

relationship between insulin sensitivity and insulin secretion

Answer 2

One model proposes that, as insulin sensitivity falls, insulin secretion increases to compensate. When max. insulin secretion is reached, secretion declines and blood glucose levels rise as the individual develops impaired glucose tolerance and, eventually diabetes

Both insulin resistance and beta-cell dysfunction (e.g. reduction in beta cell mass) occur early but can often be reversed through lifestyle inventions

Question 3

people with type ii diabetes - secrete more or less insulin

Answer 3

People with Type II diabetes secrete less insulin daily

They lose the early phase insulin release in response to glucose but compensate for this by an exaggerated second phase response

This exaggerated second phase response can cause hypoglycaemia 3-4 hours after a meal

Question 4

what are the symptoms of type ii diabetes

Answer 4

Gradual and insidious onset of illness (months-years), or asymptomatic:
Almost one third of people are diagnosed by chance (!) as a result of routine screening or a diabetes-related complication.
Increased thirst and hunger.
Increased frequency of urination (especially at night).
Fatigue.
Blurred vision.
Infection.
Hyperosmolar Hyperglycaemic State (HHS):

Question 5

what is Hyperosmolar Hyperglycaemic State (HHS):

Answer 5

Hyperosmolar Hyperglycaemic State (HHS): a medical emergency involving hyperglycaemia, dehydration and uraemia.
Used to be called HONK is a presenting feature for up to 25% cases (especially in middle-aged, elderly and Afro-Caribbean individuals).

Question 6

how can type ii diabetes be prevented

Answer 6

Type II diabetes can be prevented (or at least delayed) by lifestyle intervention

Lifestyle interventions can significantly reduce incidence of diabetes:
reduce weight,
reduce fat intake,
increase dietary fibre, and,
exercise

Lifestyle interventions not easy as type II diabetes can be asymptomatic for up to a decade before complications become apparent

Question 7

how is type ii diabetes screened? / testing

Answer 7

As Type II diabetes can be prevented (or delayed) and many people with Type II diabetes are undiagnosed, or have already developed complications by diagnosis, screening programmes are essential.

Universal screening is not practical: screening programmes should focus on those at risk.

Screening tests could include random blood glucose levels (OGTT), or fasting blood glucose levels and HbA1c levels.

Question 8

higher the bmi higher the risk of diabetes .. true or false?

Answer 8

true

Question 9

why is screening programmes imperative?

Answer 9

Diabetic complications (macrovascular and microvascular) can develop in asymptomatic diabetics
diabetes is commonly diagnosed by cardiac units treating a patient following a heart attack
20% people with newly diagnosed diabetes have retinopathy

Good management of type II diabetes is needed to prevent these complications

Question 10

what are the treatment goals for type ii diabetes

Answer 10

Preserve life.

Alleviate symptoms.

Achieve good glycaemic control to avoid long-term complications.

Avoid iatrogenic side effects (i.e. hypoglycaemia).

Question 11

how can type ii diabetes be managed?

Answer 11

Lifestyle interventions (first line)
Diet and weight loss
Exercise,

Education

Then add drug treatments:
Oral hypoglycaemic agents
Insulins

Question 12

what are the advice given to people with type ii diabetes

Answer 12

Successful lifestyle modification and maintaining good glycaemic control is key to avoiding diabetic complications:
People with diabetes have increased mortality and morbidity risk.
Diabetic retinopathy is the most common cause of blindness in people of working age.
Diabetics have 2-3 fold higher risk of CVD.
16% of patients requiring kidney replacement are diabetic.
Erectile dysfunction affects 50% of diabetic men.
15% of diabetics will develop foot ulcers, and due to impaired wound healing and infection: 5-15% of these people will require amputations.

Remember: education about complications can improve compliance.

Question 13

when is oral hypolycaemic agent added?

Answer 13

If diet and exercise alone fails, oral hypoglycaemic agents are added

Question 14

what does oral hypoglycaemic agents require

Answer 14

Oral hypoglycaemic agents require some residual capacity to be effective

Question 15

what are the categories for oral hypoglycaemics?

Answer 15

Categories of oral hypoglycaemics are used:
Insulin sensitisers
Insulin secretagogues
Inhibitors of glucose absorption from GI tract
Inhibitors of renal glucose uptake

Question 16

what is the mechanism of action of blood glucose lowering medicines?
- drug classes and location

Answer 16

• LIVER - biguanides and thiazolidineodiones reduces glucose production
  -SMALL intestine - alpha- glucosidase inhibitors slow down absorption of sucrose and starch
  -PANCREAS - GLP-1 (incretins) improve response to glucose levels
  insulin secretogogues: sulphonylureas and megiltitnides increase insulin production
  -SKELETAL MUSCLE and ADIPOSE TISSUE - thiazolidinediones and biguanides reduce insulin resistance

Question 17

what is insulin sensitisers and examples?

Answer 17

Enhance the effect of endogenous circulating insulin, increasing the sensitivity of peripheral tissues to insulin and decreasing glucose production in liver

Biguanide, metformin, and thiazolidinediones (“glitazones”) are insulin sensitisers

Question 18

what is the drug class of metformin, aims, common side effects and cautions.
moa

Answer 18

Metformin is the only biguanide currently available and is the “first line” treatment for type II diabetes

Typically will reduce HbA1c by 1.5-2%

Suppresses appetite, helps achieve weight loss and has a cardio-protective effect (reduced mortality and morbidity)

Common side effects (e.g. abdominal pain, nausea, diarrhoea) minimised by gradual increases to reach therapeutic dose or by modified release formulations

Metformin cannot be used in patients with renal impairment, cardiac failure or liver failure as it is associated with lactic acidosis (potentially fatal)

moa : It activates energy sensor AMP kinase which promotes cellular energy uptake

Question 19

what is the mode of action of thiazoldinediones?

Answer 19

Bind to peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and, through regulation of gene transcription, enhance glucose and fatty acid uptake and utilisation in adipocytes, reduce secretion of cytokines that inhibit insulin action
Reduced availability of fatty acids in muscle improves insulin sensitivity

Reduce hepatic glucose output

Question 20

how long can thiaxolidinediones take to show maximal effects?

Answer 20

Can take up to 3 months to see maximal effect as have indirect effect on blood glucose but, once achieved, effect is comparable to metformin and sulphonylureas

Question 21

what can glitazones increase the risk of? - pioglitazone

Answer 21

Link between the “glitazones” and increase risk of cardiovascular disease

Pioglitazone associated with increased risk of heart failure (especially when combined with insulin) and bladder cancer. (Should not be used in patients with history of these conditions)
Associated with fluid retention (precipitating heart failure)

Induces weight gain but weight gain is limited to hips and thighs (a “lower risk” pattern of distribution) and intraabdominal fat is reduced

Question 22

what is insulin secretagogues

Answer 22

Stimulate insulin release from the pancreas
Aim to restore early phase insulin release and return plasma insulin levels to pre-prandial levels rapidly to avoid post-meal hypoglycaemia

Sulphonylureas and meglitinides are insulin secretogogues

Question 23

what is the moa of Both sulphonylureas and meglitinides

Answer 23

close K+ ATP channel but do so by binding to different (but related receptors)

Question 24

name a short acting Sulphonylureas

Answer 24

gliclazide or tolbutamide

Question 25

what is long acting sulphonyureas

Answer 25

glibenclamide

Question 26

what is the moa of sulphonylurea
common side effects

Answer 26

Increase insulin release from the pancreas by binding to sulphonylurea receptor, closing the K+ ATP channel, which causes a rise in intracellular calcium and insulin release

Typically will reduce HbA1c by 1.5-2%.

Common side effects include weight gain (not first choice for overweight patients).
Can cause sustained hypoglycaemia (worse in elderly or with hepatic impairment; often requiring hospital treatment)

Can be used in combination with insulin sensitisers

Question 27

what are examples of meglitnides

Answer 27

nateglinide (derivative of phenylalanine; only licenced for use with metformin) and repaglinide (derivative of long-acting sulphonylurea glibencamide)

Question 28

what is the moa of meglitinides?
side effects

Answer 28

Increase insulin release from the pancreas by binding to a different but closely related receptor to that recognised by sulphonylueas, closing the K+ ATP channel, which causes a rise in intracellular calcium and insulin release

Less marked effects on glycaemic control so reduced place in therapy.

Side effects reduced compared to other insulin secretogogues
(i.e. short-acting so reduced risk of hypoglycaemia and reduced need to snack, less weight gain)

Question 29

what is an example of inhibitors of gastrointestinal glucose absorption

moa

side effects

Answer 29

i.e. acarbose; an alpha-glucosidase inhibitor that reduces glucose uptake in the small intestine

Acts by binding to alpha-glucosidase with higher affinity than dietary carbohydrates. Therefore, dietary carbohydrate break-down is inhibited

Slows digestion and absorption of glucose after a meal, reducing the post-pranial peak in blood glucose, stabilising blood glucose levels throughout the day

Less effective than metformin etc at reducing HbA1c %

Associated with GI disturbance (flatulence, bloating, diarrhoea)

Question 30

what are therapies based on glucagon-like-peptide- 1 (GLP-1)

Answer 30

Glucagon-like peptide-1 plays a key role in glucose control
In the pancreas, it stimulates insulin release from beta-cells and suppresses glucagon release from alpha-cells

It slows gastric emptying, slowing digestion and absorption of nutrients, moderating blood glucose levels and blunting blood glucose fluctuations.

Reduces appetite

Question 31

what are examples of dpp4 inhibitors

Answer 31

Saxagliptin, sitagliptin, vildagliptin (oral route)

Question 32

what is the mode of action of dpp-4 inhibotor - Dipeptidylpeptidase-4

Answer 32

GLP-1 is degraded by DPP-4

By inhibiting DDP4, GLP-1 degradation decreases which leads to increased insulin secretion and decreased glucagon secretion

Used in combination with metformin, a sulfonylurea or pioglitazone or, in case of sitagliptin, as a monotherapy or with insulin

Question 33

what are examples of GLP-1 analogues (incretin mimetics)
moa

Answer 33

i.e. exenatide, dulaglutide, liraglutide (delivered by subcutaneous injection) and semaglutide (oral and SC injection)

DPP-4 resistant analogues of GLP-1 that bind to and activate the GLP-1 receptor, leading to increased insulin secretion and decrease glucagon secretion, slow gastric emptying, promoting weight loss

Used in combination with oral hyperglycaemic medications

Question 34

what is semaglutide and examples

Answer 34

Ideal candidate for oral delivery with permeation enhancer as has low molecular weight, long half-life, and high potency.

Oralsemaglutide(RybelsusⓇ, Novo Nordisk) for Type 2 diabetes, administered once-a-day, was launched in UK in 2020

A non-enteric coated tablet consists of either 3mg, 7mg or 14mg semaglutide with 300mg of salcaprozate sodium (SNAC)

Oral bioavailability in humans is 0.4 – 1.0% but SNAC decreases degradation and increases transcellular uptake.

Question 35

how does sglt2 regulate blood glucose levels

Answer 35

SGLT2, located in the proximal tubules (kidneys) is responsible for 90% of glucose reabsorption.
SGLT2 inhibition leads to decrease in blood glucose by increasing renal glucose excretion.

Question 36

*Selective sodium-glucose co-transporter 2 (SGLT-2) inhibitors - what are examples of sglt2 inhibitors
moa
what is it used for and with

Answer 36

i.e. canaglifozin, dapagliflozin, empagliflozin (oral route)

Independent of insulin-mediated glucose control pathways, SGLT-2 inhibitors block the reabsorption of glucose in the kidney and promote its urinary excretion

Used as a monotherapy if diet and exercise fail and metformin is inappropriate/contra-indicated or as an add-on therapy with other glucose-lowering medicines to help establish good glycaemic control

Question 37

what is gestational diabeties
what are the complications
risk factors

Answer 37

Defines as diabetes occurring for the first time during pregnancy affects 2-5% of all pregnancies

Increases risk of miscarriage, baby having congenital malformations, still birth or baby dying in first year of life

Complications can be reduced through maintenance of tight glycaemic control

Risk factors are the same as for type II diabetes (family history, age, weight etc)

Question 38

insulin resistance in pregnancy- what does it encourage ?

Answer 38

Insulin resistance encourages nutrient transfer to the growing foetus

Maximal insulin resistance is observed in second and third trimesters (requirement for insulin increases by 50-100%)

High risk pregnancies are screened for gestational diabetes
i.e. Routine tests for glucosuria during antenatal appointments and OGTT commonly performed between 24-28 weeks
Gestational diabetes puts woman at increased risk of developing type I or type II diabetes
i.e. 50% women will develop diabetes within 10 years of the diabetes-affected pregnancy

Question 39

what is the treatment of gestational diabetes

Answer 39

Lifestyle modification
Diet that stabilises maternal blood glucose levels but provides calories required (i.e. low in fat and high in complex carbohydrates, low fat dairy foods, fruit and vegetables)
Exercise (30 minutes daily)

Insulin therapy may be required if lifestyle modification is not sufficient

Although insulin is drug of choice for gestational diabetes, some oral hypoglycaemic drugs might be considered (i.e. metformin or glibenclamide after 11 weeks gestation (both unlicensed))