Introduction To Diabetes 07.12.23

Question 1

In the fasting state, what happens in regulation of CHO metabolism in non diabetic humans

Answer 1

In the fasting state
all glucose comes from liver (and a bit from kidney)
Breakdown of glycogen
Gluconeogenesis (utilises 3 carbon precursors to synthesise glucose including lactate, alanine and glycerol)
Glucose is delivered to insulin independent tissues, brain and red blood cells
Insulin levels are low
Muscle uses FFA for fuel
Some processes are very sensitive to insulin, even low insulin levels prevent unrestrained breakdown of fat

Question 2

After feeding, what happens in regulation of CHO metabolism in non diabetic humans

Answer 2

After feeding (post prandial) - physiological need to dispose of a nutrient load
Rising glucose (5-10 min after eating) stimulates insulin secretion and suppresses glucagon
40% of ingested glucose goes to liver and 60% to periphery, mostly muscle
Ingested glucose helps to replenish glycogen stores both in liver and muscle
High insulin and glucose levels suppress lipolysis and levels of non-esterified fatty acids (NEFA or FFA) fall

Question 3

Microstructure of islets of langerhans

Answer 3

Slide 7

Question 4

How does insulin secretion occur in the beta cells?

Answer 4

Slide 8

Question 5

How does insulin act in muscle and fat cells

Answer 5

Slide 9

Question 6

What are the key hormonal regulators of carbohydrate metabolism

Answer 6

Insulin
Glucagon
Adrenaline
Cortisol
Growth hormone

Question 7

What does insulin do?

Answer 7

Supresses hepatic glucose output
 Glycogenolysis
 Gluconeogenesis
Increases glucose uptake into insulin sensitive tissues (muscle, fat)
Suppresses
Lipolysis
Breakdown of muscle

Question 8

What does glucagon do?

Answer 8

Increases hepatic glucose output
 Glycogenolysis
 Gluconeogenesis
Reduce peripheral glucose uptake
Stimulate peripheral release of gluconeogenic precursors (glycerol, AAs)
Lipolysis
Muscle glycogenolysis and breakdown

Question 9

Define diabetes mellitus

Answer 9

A disorder of carbohydrate metabolism characterised by hyperglycaemia

Question 10

How does diabetes mellitus cause mortality and morbidity

Answer 10

Acute hyperglycaemia which if untreated leads to acute metabolic emergencies diabetic ketoacidosis (DKA) and hyperosmolar coma (Hyperosmolar Hyperglycaemic State )
Chronic hyperglycaemia leading to tissue complications (macrovascular and microvascular)
Side effects of treatment- hypoglycaemia

Question 11

What complications are diabetes associated with?

Answer 11

Diabetic retinopathy
Diabetic nephropathy
Stroke
Cardiovascular disease
Diabetic neuropathy

Question 12

What are the types of diabetes?

Answer 12

Type 1
Type 2 (inc. gestational and medication induced diabetes)
MODY (Maturity onset diabetes of youth)/monogenic diabetes
Pancreatic diabetes
Endocrine diabetes (acromegaly/cushings)
Malnutrition related diabetes

Question 13

Define diabetes

Answer 13

Symptoms and random plasma glucose > 11 mmol/l
Fasting plasma glucose > 7 mmol/l
No symptoms - GTT (75g glucose) fasting > 7 or 2h value > 11 mmol/l (repeated on 2 occasions)
HbA1c of > 48mmol/mol (6.5%)

Question 14

Define type 1 diabetes

Answer 14

An insulin deficiency disease characterised by loss of beta cells due to autoimmune destruction

Question 15

How does type 1 diabetes occur?

Answer 15

Beta cells express antigens of HLA histocompatability system perhaps in response to an environmental event (?virus)
Activates a chronic cell mediated immune process leading to chronic ‘insulitis’

Question 16

What does failure of insulin secretion leads to??

Answer 16

Continued breakdown of liver glycogen
Unrestrained lipolysis and skeletal muscle breakdown providing gluconeogenic precursors
Inappropriate increase in hepatic glucose output and suppression of peripheral glucose uptake

Question 17

Why does urinary glucose increase in type 1 diabetes?

Answer 17

Rising glucose concentration results in increased urinary glucose losses as renal threshold (10mM) is exceeded

Question 18

What does failure to treat type 1 diabetes with insulin leads to what?

Answer 18

Increase in circulating glucagon (loss of local increases in insulin within the islets leads to removal of inhibition of glucagon release), further increasing glucose
perceived ‘stress’ leads to increased cortisol and adrenaline
progressive catabolic state and increasing levels of ketones

Question 19

Slide 20

Question 20

Impaired insulin action leads to

Answer 20

Reduced muscle and fat uptake after eating
Failure to suppress lipolysis and high circulating FFAs
Abnormally high glucose output after a meal

Question 21

Even low levels of insulin prevent muscle catabolism and ketogenesis so profound muscle breakdown and gluconeogenesis are restrained and ketone production is rarely excessive

Question 22

What are the principle treatment of diabetes

Answer 22

Control of symptoms
Prevention of acute emergencies, ketoacidosis, hyperglycaemic hyperosmolar states
Identification and prevention of long-term microvascular complications
Limited evidence yet that glucose control per se reduces cardiovascular events (confirmed by recent clinical trials, ACCORD, ADVANCE) in the short-term
But long-term follow-up indicates a modest reduction in IHD from tight glucose control if started at diagnosis
HbA1c 50mmol/mol (6.5%) (as low as possible in those not on insulin or sulphonylureas)

Question 23

Treatment on type 2 diabetes in real life

Answer 23

Ideally consists of weight loss and exercise which if substantial will reverse hyperglycaemia
Lifestyle changes are important if they can be achieved
but most with Type 2 diabetes have been making the ‘wrong’ lifestyle choices all their lives and rarely respond to these approaches
At present, management usually consists of medication to control BP, blood glucose and lipids

Question 24

What are thiazolidinediones (pioglitazone - ACTOS)

Answer 24

Bind to the nuclear receptor PPAR (peroxisome proliferator-activated receptor)
Activate genes concerned with glucose uptake and utilisation and lipid metabolism
Improve insulin sensitivity
Need insulin for a therapeutic effect
Glitazones relatively rarely used but may be useful in some sub-groups
Increase weight
Increase the risk of heart failure
Increase the risk of fractures

Question 25

What would the ideal drug in type 2 diabetes consist of?

Answer 25

Reduce appetite and induce weight loss
Preserve -cells and insulin secretion
Increase insulin secretion at meal time
Inhibit counterregulatory hormones which increase blood glucose such as glucagon
Not increase the risk of hypoglycaemia during treatment

Question 26

What is GLP-1 and where and when is it produced?

Answer 26

Upon ingestion of food GLP-1 is secreted from L cells in the intestine

Question 27

What are GLP-1 modes of action

Answer 27

Slide 34

Question 28

Slide 36

Question 29

Slide 37

Question 30

What is the first line treatment for type 2 diabetes

Answer 30

Metformin