Diabetes and hypoglycaemia

Question 1

What is our main source of energy?

Answer 1

Glucose is our main source of energy

Question 2

How are blood glucose levels maintained in the level of 4-6mmol/L?

Answer 2

• Dietary carbohydrate is absorbed; glucose uptake into cells with the help of insulin

Question 3

Define Glycogenolysis

Answer 3

breakdown of glycogen

Question 4

Define Gluconeogenesis

Answer 4

• Gluconeogenesis is the formation of glucose from non-glucose substrates such as lactate or amino acids, occurs when glucose levels are used up in the body and forms glucose from non-glucose sources (lactate, aa and fatty acids).

Question 5

What is the role of the liver?

Answer 5

• After meals – stores glucose as glycogen
• During fasting – makes glucose available through glycogenolysis and gluconeogenesis
• 2 hours after eating, blood glucose levels go to 4-6mmol/L
• Before that blood glucose levels are very high
• Insulin helps with the uptake of glucose into cells so it stays within the normal range
• If you are fasting, then blood glycose levels can lower
• This is sensed by the liver which released glucagon which breaks down glycogen so more glucose is released into the circulation
• If you use up all your glycogen storage (long term fasting), then the liver does gluconeogenesis to increase blood glucose levels to the normal range

Question 6

Why should glucose levels be regulated? (4)

Answer 6

• Normal blood glucose level is 45
• Brain and erythrocytes require continuous supply of glucose and cannot make it themselves: - therefore always need glucose. Must avoid deficiency to avoid defects in brain and red blood cells functionality.
• High glucose and metabolites cause pathological changes to tissue e.g micro/macro vascular diseases e.g neuropathy – therefore you avoid excess
• Important to maintain normal blood glucose level
• Diabetes can cause neuropathy because of high blood glucose levels damaging the small blood vessels which supply the nerves. This prevents essential nutrients reaching the nerves. The nerve fibres are then damaged or disappear.
• Patient must take blood glucose lowering medication if this occurs.
• Must avoid excess and deficiency – the liver ensures this does not occur ( and maintains blood glucose levels in the normal range)

Question 7

Where is insulin produced?

Answer 7

Insulin is secreted by beta cells of the pancreas

Question 8

What does insulin do?

Answer 8

Insulin decreases: 
•	Gluconeogenesis
•	Glucogenolysis
•	Lipolysis
•	Ketogenesis
•	Proteolysis
•	Ketogenesis
•	Proteolysis

When there is high levels of glucose, insulin causes glucose uptake into the liver which stores it as glycogen

Low levels of insulin -> protein breakdown occurs. Patients which T1D are phenotypically slimmer and smaller in size. Insulin resistance mean proteolysis occurs which leads to weight loss.

Question 9

What is glucagon?

Answer 9

• Secreted by alpha cells of the pancreas in response to hypoglycaemia
• This stimulates glycogeneolysis and gluconeogenesis

Question 10

What is Adrenaline?

Answer 10

Increased glycogenolysis and lipolysis (breakdown of lipids)

Question 11

What does Growth hormone do?

Answer 11

Increases glycogenolysis and lipolysis

Question 12

What does Cortisol do?

Answer 12

Increases gluconeogenesis

Question 13

What is Diabetes mellitus?

Answer 13

• Metabolic disorder characterised by chronic hyperglycaemia (always a high level of blood glucose), glycosuria (glucose in urine) and associated abnormalities of lipid and protein metabolism
• Hyperglycaemia result of increased hepatic glucose production and decreased cellular glucose uptake
• Blood glucose > 10mmol/L exceeds renal threshold – glycosuria
• Long term complications – micro/macrovascular disease

Question 14

Describe type 1 and type 2 diabetes

Answer 14

Type 1:
Insulin deficiency
Insulin secretion is deficient due to autoimmune destruction of -cells in pancreas by T-cells

Secondary:
Chronic pancreatitis, pancreatic surgery, secretion of antagonists

Type 2:
Insulin secretion is retained but there is target organ resistance to its actions
Pancreatitis is inflammation of the pancreas/ pancreas could’ve been removed

Secondary:
Chronic pancreatitis, pancreatic surgery, secretion of antagonists

Question 15

Describe type 1 DM

Answer 15

• Predominantly in children and young adults; but other ages as well
• Sudden onset (days/weeks)
• Appearance of symptoms may be preceded by ‘prediabetic’ period of several months – when blood glucose levels are 6.1-6.9 - associated with growth failure in children fall in insulin response to glucose various immunological abnormalities.
• Commonest cause is autoimmune destruction of B-cells
• Interaction between genetic and environment factors
• Strong link with HLA genes within the MHC region on chromosome. 6
• Environment: viruses (CMV, mumps, Rubella, EBV), drugs, stress. Can all cause destruction of beta-cells

Question 16

Describe the Pathogenesis of Type 1 DM

Answer 16

On document

Question 17

What are the Metabolic complications of Type 1 DM?

Answer 17

• Insulin deficiency leads to increased hepatic output and impaired glucose uptake – hyperglycaemia
• Increased glucose osmotic effect and causes diuresis, dehydration and circulatory collapse
• Increased lipolysis blood level of ketone bodies formation (DKA) and metabolic acidosis.

Question 18

What are the effects of insulin defficieny?

Answer 18

On image

Insulin deficiency – cannot uptake glucose from blood into tissues, thus increasing glucose levels in blood  hyperglycaemia
Hyperglycaemia makes you more thirsty (as increased glucose in urine draws water with it so you lose more water too)
Polyphagia – excessive hunger; start to eat too much
When there are high levels of glucose in the kidney it causes osmotic changes – urinate more due to the increased osmotic pressure in the kidney tubule  remove too much water in system  feel thirst and drink more water
So, blood volume depletes  drop in BP  can lead to diabetic coma
In the absence of insulin you get increased lipolysis (lipids broken down)  free fatty acids produced  go into beta oxidation to produce ketone bodies  ketoacidosis which can lead to diabetic coma too

Question 19

What are the metabolic complications of type 2 DM?

Answer 19

• Hyper-osmolar non-ketotic coma (HONK)
[Hyperosmolar Hyperglycaemic State (HHS)]
• Development of severe hyperglycaemia
• Extreme dehydration
• Increased plasma osmolality (+ within the kidney due to high level of glucose in the tubule)
• So, more water goes into the tubule
• Impaired consciousness occurs if you do not drink enough water/ do not take medications
• No ketosis
• Death if untreated
• Ketone bodies are not involved here – lipolysis is not occurring – as the presence of even minimal insulin action deters the formation of ketone bodies

Question 20

How can we diagnose DM type 2?

Answer 20

the presence of symptoms: (polyuria, polydipsia & weight loss for Type I)
• Random plasma glucose ≥ 11.1mmol/l (200 mg/dl ).
OR
• Fasting plasma glucose ≥ 7.0 mmol/l (126 mg/dl) Fasting is defined as no caloric intake for at least 8 h
OR
• Oral glucose tolerance test (OGTT) - plasma glu ≥ 11.1 mmol/l
• In the absence of symptoms: test blood samples on 2 separate days
OR

• Random is defined as any time of day without regard to time since last meal.
• The classic symptoms of hyperglycaemia include polyuria, polydipsia, & unexplained weight loss

Question 21

Describe IGT (Pre-diabetes) and IFG

Answer 21

• Impaired Glucose Tolerance (IGT) – pre diabetic form
o Fasting plasma glucose >7mmol/L**
o OGTT value of 7.8 – 11.1 mmol
• Impaired fasting glycaemia (IFG) – possibility that you have a high risk of developing some cardiovascular disease
o Fasting plasma glucose < 7.0 mmol/L** and
o OGTT value of <7.8
o If you have impaired fasting glycaemia, you are also thought to have an increased risk of developing diabetes. Your risk of developing cardiovascular disease is also increased but this seems to be lower than if you have pre-diabetes (impaired glucose tolerance). The rest of this leaflet is about pre-diabetes.
• ** OGTT used in individuals with fasting plasma glucose of < 7.0 mmol/L to determine glucose tolerance status

Question 22

When should we carry out an oral glucose test?

Answer 22

• In patients with IFG
• In unexplained glycosuria
• In clinical features of diabetes with normal plasma glucose values
• For the diagnosis of acromegaly
• 75g oral glucose and test after 2 hours
• Blood samples collected at 0 and 120 mins after glucose

Question 23

How can diabetes type 2 be treated?

Answer 23

• Thiazolidinediones: activate PPARγ (Peroxisome proliferator-activated receptor gamma) receptor (controller of lipid metabolism), which (somehow) reduces insulin resistance
• SGLT2 (sodium, glucose co-transporter) inhibitors: promote glucose excretion via kidney
• DPP-4 inhibitors (prevent breakdown of natural incretins)
• Synthetic GLP-1 analogues
• First thing to take seriously is the diet and exercise
• Doing exercise and eating foods that have lower glycaemic index
• If that doesn’t help, you are put on medication – metformin helps increase glucose uptake from blood
• If that doesn’t help, you take other medications
• Different medications depending on the problem
• Can take medications that help secrete more insulin (e.g. sulphonylureas)
• Gliptins (DPP4 inhibitors) – DPP4 are enzymes that destroy incretins (which help stimulate insulin secretion) therefore the inhibitors prevent the enzymes from destroying the incretins

Question 24

What is Metformin?

Answer 24

Metformin helps the body to control blood sugar in several ways. Metformin exerts its effect mainly by decreasing gluconeogenesis and by increasing peripheral utilisation of glucose.

Question 25

Define Sulphonylureas

Answer 25

Sulphonylureas - they work mainly by stimulating the cells in the pancreas to make more insulin.

Question 26

Define Dipeptidyl peptidase inhibitor (DPP-4; Gliptins):

Answer 26

Dipeptidyl peptidase inhibitor (DPP-4; Gliptins): inhibitors work by blocking the action of DPP-4, an enzyme which destroys the hormone incretin.

Question 27

What are Incretins?

Answer 27

Incretins help the body produce more insulin only when it is needed and reduce the amount of glucose being produced by the liver when it is not needed.

Question 28

Define hypoglycemia

Answer 28

• Defined as plasma glucose < 2.5 mmol/L • Hypoglycaemia in diabetes • Hypoglycaemia in patients without diabetes • Causes of hypoglycaemia • Drugs are the most common cause; o common in type 1 diabetes o Less common in type 2 diabetes taking insulin & insulin secretagogues o uncommon in patients who do not have drug treated DM: o In these patients hypoglycaemia may be caused by alcohol, critical illnesses such as hepatic, renal or cardiac failure, sepsis, hormone deficiency, inherited metabolic dx.

Question 29

How can we treat patients with hypoglycemia?

Answer 29

• Exogeneous insulin & insulin secretagogues such as glyburide, glipizide and glimepiride are examples of some of the more commonly used sulfonylureas. o Stimulation of endogenous insulin suppresses hepatic and renal glucose production and increase glucose utilisation • Among drugs used to treat type 2 diabetes earlier in the disease, insulin sensitizers (metformin, Glitazones); glucosidase inhibitors; glucagon-like pepdide-1 (GLP-1) receptor antagonist and DDP-4 inhibitors should not cause hypoglycaemia. • Exogeneous insulin & insulin secretagogues such as glyburide, glipizide and glimepiride are examples of some of the more commonly used sulfonylureas. • Stimulation of endogenous insulin suppresses hepatic and renal glucose production and increase glucose utilisation • Among drugs used to treat type 2 diabetes earlier in the disease, insulin sensitizers (metformin, Glitazones); glucosidase inhibitors; glucagon-like pepdide-1 (GLP-1) receptor antagonist and DDP-4 inhibitors should not cause hypoglycaemia. • Dipeptydl peptidase IV inhibitor (DPP-4) • These type 2 diabetes drugs rely on residual endogenous insulin secretion for efficacy, and insulin secretion should decrease appropriately as plasma glucose concentration decline into normal range. • However, all these drugs increase the risk for hypoglycaemia if used together with insulin secretagogues. • Alpha-glucosidase inhibitors (AGIs), sometimes referred to as starch blockers, are anti-diabetic medicines that help to reduce post meal blood glucose levels. There are two medications in this group, or class, of drugs: acarbose (Precose) and miglitol (Glyset).

Question 30

How can you get hypoglycemia without diabetes?

Answer 30

* Drugs such as alcohol may cause hypoglycaemia; * Other drugs most commonly found to cause hypoglycaemia are quinolone, quinine, beta blockers, ACE inhibitors and IGF-1 * Endocrines disease; e.g. cortisol disorder * Inherited metabolic disorders, e.g. hereditary fructose intolerance. * Insulinoma * Others: severe liver disease, non-pancreatic tumours (beta cell hyperplasia), renal disease (metab. acidosis, reduced insulin elimination). * There have been conflicting reports about the effects of ACE inhibitors on insulin sensitivity and glycaemic control. A number of studies, both with captopril and with enalapril, have shown small increases in insulin sensitivity, and there is evidence that this is due to enhanced glucose uptake into skeletal muscle. * Ethanol: inhibit gluconeogenesis, but not glycogenolysis. * The hypoglycaemia will typically follow several days alcohol binge with limited food intake; resulting in hepatic depletion of glycogen. * Sepsis: relatively common cause of hypoglycaemia. * Cytokine accelerated glucose utilization and induced inhibition of gluconeogenesis in the setting of glycogen depletion * CKD: mechanism not clear, but likely to involve impaired gluconeogenesis, reduced renal clearance of insulin and reduce renal glucose production.

Question 31

What is reactive hypoglycemia?

Answer 31

* Also known as postprandial hypoglycaemia, drops in blood sugar are usually recurrent and occur within four hours after eating.. * Can occur in both people with and without diabetes, * Thought to be more common in overweight individuals or those who have had gastric bypass surgery. * Cause is unclear * Possibly a benign (non-cancerous) tumour in the pancreas may cause an overproduction of insulin, * Too much glucose may be used up by the tumour itself. * Deficiencies in counter-regulatory hormones: e.g. glucagon. * Scientists believe reactive hypoglycaemia to be the result of too much insulin being produced and released by the pancreas following a large carbohydrate-based meal. * This excess insulin production and secretion continues after the glucose derived from the meal has been digested, causing the amount of glucose in the bloodstream to fall to a lower-than-normal level. * What causes this increase in pancreatic activity is unclear. * One possible explanation is that in rare cases, a benign (non-cancerous) tumour in the pancreas may cause an overproduction of insulin, or too much glucose may be used up by the tumour itself.

Question 32

What happens when normal glucose levels fall?

Answer 32

* When plasma glucose level decline in fast state pancreatic beta-cells secretion of insulin is decreased (1st defence); * Hepatic glycogenolysis and gluconeogenesis is increased * There is reduced glucose utilisation of peripheral tissue, inducing lipolysis and proteolysis * Counter-regulatory hormones are released: * Pancreatic alpha cells secrete glucagon to stimulate hepatic glycogenolysis (2nd defence) * Epinephrine release from adrenomedullary to stimulate hepatic glycogenolysis and gluconeogenesis; renal gluconeogenesis * If hypo is prolonged beyond 4 hours; cortisol and GH will support glucose production and limit utilisation. * Epinephrine has similar hepatic effect as glucagon; inhibits insulin secretion.. On image

Question 33

What are the signs and symptoms of hypoglycemia?

Answer 33

2 main ones include neurogenic and neuroglycopenic symptoms. NEUROGENIC (autonomic – SNS activated): • Triggered by falling glucose levels • Patients recognise that they are experiencing a hypoglycemic episode. • These symptoms are activated by the ANS and are mediated in part by sympathoadrenal release of catecholamines (norepinephrine and epinephrine) from the adrenal medullae and acetylcholine from postsynaptic sympathetic nerve endings. • The sympathoadrenal system is a physiological connection between the sympathetic nervous system and the adrenal medulla and is crucial in an organism’s physiological response to outside stimuli. • Signs and symptoms include: elevated epinephrine levels include shakiness, anxiety, nervousness. NEUROGLYCOPAENIA • Due to neuronal glucose deprivation – brain deprived of oxygen • Signs and symptoms include: confusion, difficulty speaking, ataxia (cannot walk straight, instead sideways) , paraesthesia (pins and needles), abnormal mentation, irritability, stupor, and eventually (if untreated) seizures, coma, and even death.