Lecture 10: Diabetes 2

Question 1

What are the acute complications of DM?

Answer 1

Hypoglycaemia
DKA
HHS (hyperosmolar hyperglycaemic state)

Question 2

What are the chronic complications of DM?

Answer 2

Microvascular (eyes, kidneys and nerves)

Macrovascular (stroke, heart disease and peripheral vascular disease which can lead to diabetic foot disease)

Question 3

Under what circumstances can hypoglycaemia occur in DM?

Answer 3

Taking too much insulin

Question 4

True or false: patients with DKA have increased fluid (overhydrated)

Answer 4

False: they become very dehydrated

Question 5

What is the pathogenesis of DKA?

Answer 5

deficiency of insulin but increase in counter regulatory hormones so:
- breakdown of protein for gluconeogenesis
- breakdown glycogen to produce glucose
–> both of which contribute to the hyperglycaemia (result in polyuria and dehydration)
- breakdown of triglycerides (lipolysis) increases free fatty acids that are converted to ketones to produce energy via the Krebs cycle
- accumulation of ketones results in ketoacidosis

Question 6

What causes the chronic macrovascular complications of DM?

Answer 6

hyperlipidaemia

Hypertension

endothelial dysfunction caused by high blood pressure and high cholesterol and diabetes resulting in artery clogging heart disease and strokes

Question 7

What causes the chronic microvascular complications of DM?

Answer 7

glycation of proteins

polyol production in the form of sorbitol

Protein kinase C activation

Question 8

What factors can influence the development of chronic complications in DM?

Answer 8

• genetic susceptibility
• glycaemic control
• duration of DM
• blood pressure
• cholesterol
• medical care received

Question 9

How does hyperglycaemia affect microvascular function?

Answer 9

Hyperglycaemia results in the formation of advanced glycation end (AGE) products formation that cause altered function of proteins and increase in pro-inflammatory cytokines that change blood flow, coagulation, vascular cell growth and endothelial permeability
–> causes inflammation that can destroy nerves and small arteries

Question 10

Why do 50% of newly presenting patients with T2DM already have one or more chronic complications at diagnosis?

Answer 10

on day of diagnosis, patients have lost 50% of beta cell mass so damage has been going on for a long time

Question 11

What are the stages of diabetic nephropathy leading to renal failure?

Answer 11

normal renal function
–> microalbuminuria
–> overt proteinuria
–> glomerular destruction (increased serum creatinine, decreased eGFR)
–> renal failure

Question 12

What occurs in diabetic retinopathy?

Answer 12

intraretinal haemorrhages (dot and blot haemorrhages)
- can result in formation of new blood vessels that encroach on the retina and block the retina (these blood vessels may be more susceptible to haemorrhage contributing to blindness)

Question 13

What occurs in diabetic neuropahy?

Answer 13

• peripheral neuropathy (numbness and tingling in hands and feet - eventually all sensation can be lost)
• loss of sensation results in formation of pressure ulcers and poor arterial supply results in poor healing of ulcers
  –> become easily infected and can lead to amputations

Question 14

How is glycaemic control monitored?

Answer 14

• symptoms
• urinalysis (redundant)
• capillary glucose (finger prick)
• HbA1c
• Interstitial glucose (continuous glucose monitoring (CGM), flash glucose monitoring)

Question 15

What is flash glucose monitoring?

Answer 15

small needle remains in arm attached to sensor and can be worn for up to 14 days
- data transmitted to monitor when swiped over the sensor (flash)
–> now acts more like a CGM following updates and alarms to warn of hypoglycaemia

Question 16

What is the difference between continuous glucose monitors and flash glucose monitors?

Answer 16

Sensor monitors interstitial glucose and the data can be wirelessly transmitted to insulin pumps to adjust the levels of insulin being secreted by the pump (artificial pancreas maintains good glycaemic control)

–> CGMs are more expensive than flash glucose monitors

Question 17

What is the downside of HbA1c testing for monitoring of glycaemic control?

Answer 17

It is an average over 3 months and doesn’t give the extremes (E.g. person may have good glycaemic control and have the same average as a person with hypoglycaemia half the time and hyperglycaemia the other half)

Question 18

What is more helpful in assessing glycaemic control?

Answer 18

Time in range (gives time patient was out of the normoglycaemic range and time in range) - can only happen with the newer glucose monitors

Question 19

How is T1DM treated?

Answer 19

Glycaemic control: insulin and diet

Treat to prevent complications: antihypertensive drugs, ACE inhibitors (to treat nephropathy), statins (for hyperlipidaemia)

Question 20

What future T1DM treatments are being looked into?

Answer 20

prevention of T1DM by immunotherapy (vaccinations) to prevent autoimmune disease

Question 21

What insulin is typically received by DM patients?

Answer 21

Genetically engineered insulin analogues

Question 22

What are the aims of DM treatment?

Answer 22

• avoid/reduce symptoms of hyperglycaemia
• avoid/reduce hypoglycaemia (make sure treatment doesn’t cause hypoglycaemia)
• restore metabolism and glucose homeostasis to as near normal as possible
• delay or prevent development of chronic complications

Question 23

True or false: when fasting/not eating, insulin levels in the serum is zero until a meal is consumed?

Answer 23

False: there is always low level baseline secretion of insulin (has other roles in the body)
- rise in insulin with consumption of food

Question 24

How is insulin given to diabetic patients to mimic physiological insulin concentrations in non-diabetics?

Answer 24

Basal-bolus regime
- one long term basal insulin injection to mimic low level continual insulin concentration
- one injection of prandial rapid insulin with consumption of food (adjusted according to carbohydrate content of meals and blood glucose levels)

Question 25

What is the correlation between HbA1c and development of diabetic retinopathy?

Answer 25

higher HbA1c, more likely to get progression of retinopathy

Question 26

How does losing weight affect insulin sensitivity in T2DM?

Answer 26

losing weight can increase insulin sensitivity and help treat insulin resistance

Question 27

How is metformin used to treat T2DM?

Answer 27

Increases glucose uptake and utilisation by target tissues to decease insulin resistance

Decreases hepatic gluconeogenesis to reduce hyperglycaemia

Question 28

Why can metformin not be used in the treatment of T1DM?

Answer 28

it does not promote insulin secretion, just increases sensitivity to insulin (so requires insulin present for its action)

Question 29

How are sulfonylureas used to treat DM?

Answer 29

• bind to and close the ATP-sensitive K+ channels on cell membrane of pancreatic beta cells, which depolarises the cell
• depolarisation opens voltage-gated Ca2+ channels
• rise in intracellular calcium leads to increased fusion of insulin granules with cell membrane and increased secretion of pre-proinsulin from beta cells (which is then processed to mature insulin)

Question 30

What two major side effects of using sulfonylureas to treat DM?

Answer 30

constant action results in continuous and unregulated secretion of insulin, which can increase change of hypoglycaemia in patients if they do not eat

increase in insulin increases hunger so individuals eat more and gain weight

Question 31

What 2 different molecules can be used incretin-based therapy?

Answer 31

• DPP-IV inhibitors (inhibit breakdown of incretins to inactive substrates to maintain concentration of incretins that act on pancreas to increase insulin secretion and decrease glucagon secretion in order to decrease blood glucose levels) - needs insulin to work
• GLP-1 analogue/agonists that has a longer half life and can cause the same effect (decrease blood glucose)

Question 32

What is the incretin effect?

Answer 32

Administration of the same concentration of glucose via IV or orally results in a much greater release of insulin when oral glucose is administered due to the release of incretin hormones in the gut in response to food that increase insulin secretion and reduce glucagon secretion

Question 33

The incretin effect is ______ in people with T2DM?

Answer 33

diminished/decreased/reduced

Question 34

Explain the role of incretins in glucose homeostasis

Answer 34

Ingestion of food results in release of incretins (GLP-1 and GIP) from the gut that are normally broken down by DPP-IV enzyme to inactive substrates.

Before breakdown of GLP-1 and GIP by DPP-IV, they act on the pancreas and cause glucose-dependent increased insulin secretion from beta cells and decreased secretion of glucagon by the alpha cells
–> decreases blood sugars

Question 35

What are the two gut incretin hormones called?

Answer 35

GLP-1 and GIP

Question 36

What is responsible for glucose reuptake from glomerular filtrate in the kidney nephron?

Answer 36

SGLT1 and SGLT2 (sodium-glucose co-transporters)

Question 37

How can SGLT2 inhibitors be used to treat DM?

Answer 37

inhibits the re-uptake of glucose in the nephron so glucose released into the urine to prevent uptake of excess glucose

Question 38

When an individual has hyperglycaemia, what happens to the number of SGLT Na-Glucose co-transporters in the nephron proximal convoluted tubule?

Answer 38

increase in expression of SLGT/upregulation transports to try and take up more of the glucose (body doesn’t understand that you are already hyperglycaemic)

Question 39

Why can SLGT2 inhibitors be used to treat T1DM as well as T2DM?

Answer 39

doesn’t require insulin to function (just reduces the amount of glucose that is reabsorbed back into the blood) will still reduce blood glucose levels

Question 40

What are some of the side effects of SLGT2 inhibitors to treat DM?

Answer 40

about 75g glucose lost in urine every day (about 300 calories) = weight loss

loss of water weight in urine (as glucose is osmotically active)

Question 41

Can SLGT2 inhibitors cause hypoglycaemia? why/why not?

Answer 41

No because doesn’t lower the glucose in the circulation as has no effect on insulin

Question 42

How other than decreasing blood glucose levels, how else can GLP-1 analogues/agonists be used to treat DM?

Answer 42

can cause massive weight loss - has massive role on brain to reduce appetite
- caused reduction in rate of gastric emptying

• massive weight loss helps patients to go back into remission (diabetes is gone)