Diabetes and Hypoglycaemia

Question 1

What is Glucose and how is the blood glucose level maintained ?

Answer 1

Glucose is a major energy substrate

Blood glucose levels are maintained through :
Dietary Carbohydrate
Glycogenolysis
Gluconeogenesis

Question 2

What is the role of the liver ?

Answer 2

Following Meals - Stores glucose as glycogen

During Fasting -Makes Glucose available through glycogenolysis (break down of glycogen ) and gluconeogenesis (production of glucose from non-glucose sources )

Question 3

Why is it important to regulate blood glucose level ?

Answer 3

Brain and erythrocytes require continuous supply therefore this will avoid deficiency

High glucose can cause pathological changes to tissues :
e.g. micro/macro vascular diseases, neuropathy

Question 4

What is the function of insulin in the adipose tissue , striated muscle and liver ?

Answer 4

Adipose tissue :
Increases glucose uptake
Increases lipogenesis
Decreases lipolysis

Striated Muscle:
Increases glucose uptake
Increases glycogen synthesis
Increases protein syntheiss

Liver :
Decreases gluconeogenesis
Increases glycogen synthesis
Increases lipogenesis

Question 5

What are the counter-regulatory hormones to insulin and what are there functions ?

Answer 5

1. Glucagon -Mobilies fuels ,mainintains blood glucose in fasting
   - Actvates gluconeogenesis /glycogenolysis and activates fatty acid release
2. Epiniphrine -Mobilises fuels in acute stress
   - Stimulate glycogenolysis and stimulate fatty acid release
3. Cortisol -Changing long term
   - Amino acid mobilisation and gluconeogenesis

Question 6

Define Diabetic Mellitus

Answer 6

This is a metabolic disorder characterised by chronic hyperglycaemia , glycosuria and associated abnormalities of lipid and protein metabolism

The hyperglycaemia results from increased hepatic glucose production and decreased cellular glucose uptake

Question 7

What is classified as glycosuria?

Answer 7

This is excess sugar in the urine

More than 10mmol/L exceeds renal threshold

Question 8

What are the different classifications of Diabetes ?

Answer 8

Type 1: Insulin secretion is deficinet due to autoimmune destruction of beta-cells in pancreas by T-cells

Type 2:Insulin secretion is retained but there is target organ resistance to its actions

Secondary :Chronic pancreatitis, pancreatic surgery ,secretion of antagonists

Gestational -Pregnancy

Question 9

Describe Type 1 DM

Answer 9

Predominantly in children and young adults

Sudden onset

Appearance of symptoms may be preceded by prediabetic period of several months.

Cause-Autoimmune destruction of B-cells:

Interaction between genetic /environmental factors

Strong link with HLA genes within the MHC region on chromosome 6

In susceptible individual , environmental factors may trigger immune-mediated destruction

Question 10

What is the pathogenesis of Type 1 DM?

Answer 10

1. Destruction of B-cells starts with autoantigen formation
2. Autoantigens are presented to T-lymphocytes to initiate autoimmune response
3. There would be circulating autoantibodies to various cell antigens against:
   - Glutamic acid decarboxylase
   - Tyrosine-phosphatase like molecule
   - Islet auto-antigen

Most commonly detected antibody is the islet cell antibody

Question 11

How do both genetic predisposition and environmental factors link when it comes to pathogenesis of Type 1 DM ?

Answer 11

In a susceptible individual a environmental factor such as an infection by Epstein-Barr virus / CMV this will cause autoantigens to form on insulin-producing beta cells and circulate in the blood stream and lymphatics.

This will then be processed and presented as autoantigen by antigen presenting cells.

Activation of T helper 1 lymphocytes which will secrete interferon gamma and interleukin 2.
Interferon gamma will activate macrophages by releasing interleukin 1 and tumour necrosis factor alpha.

Interleukin 2 will activate autoantigen specific T cytotoxic cells.

Activation of T helper cell 2 will secrete IL-4 which will lead to activation of B lymphocytes which produces islet cell autoantibodies and antiGAD antibodies.

This will destroy beta cells with decreased insulin secretion

Question 12

What is the most common antibodies found in Type 1 DM ?

Answer 12

Islet cell auto antibody

anti-glutamic acid dicarboxylic antibody.

Question 13

What is amylin?

Answer 13

This is a glucoregulatory peptide hormone which is co-secreted with insulin.
It lowers blood glucose by slowing gastric emptying and supressing glucagon output from pancreatic cells

Question 14

What are the metabolic complications of Type 1 DM?

Answer 14

Check slide

Question 15

What is the presentation of Type 2 DM ?

Answer 15

1.Slow onset
2.Patients middle aged/elderly prevalence will increase with age
3.Strong familiar incidence
4.Pathogenesis uncertain-insulin resistance , Beta-cell dysfunction:
May be due to lifestyle factors, obesity ,lack of exercise

Question 16

What is the pathophysiology of Type 2 DM ?

Answer 16

Insulin resistance
This can lead to compensatory Beta-cell hyperplasia.This is a method used to normolise blood sugar.Eventually , there is beta-cell failure (early) and if they can not create enough insulin there will be impaired glucose tolerance.
Following this , is beta-cell failure (late) which can lead to diabetes.

In cases where there is primary beta-cell failure there will be diabetes straight away

Question 17

What are the metabolic complications of Type 2 -DM

Answer 17

Hyper-osmolar non-ketotic (HONK)
Development of severe hyperglycaemia due to insulin resistance

Extreme dehydration

Increase plasma osmolality (blood becomes viscous)

Impaired consciousness

No ketosis

Death if untreated

Question 18

Describe the pathogenesis of the HONK state

Answer 18

Low insulin will lead to increased gluconeogenesis and glycogenolysis which both lead to hyperglycaemia .
This leads to glycosuria (sugar in urine ), this leads to osmotic diuresis which is the loss of water thus dehydration through loss of water and electrolytes.

The loss of water and electrolytes can also lead to thrombosis.

Hyperglycaemia also increases plasma osmolarity which can cause increased blood viscosity and thrombosis as well as cerebral dehydration

Question 19

How can HONK be diagnosed ?

Answer 19

Increased glucose
Increase osmolarity
Decreased pH (no ketones)

Question 20

How is Diabetes diagnosed? what are the symptoms

Answer 20

Type 1 :
presence of symptoms :
and weight loss

-Random plasma glucose higher that 11.1mmol/l
Fasting plasma glucose more than 7.0mmol/l.
(No calorific intake for more than 8h)

HbA1c (haemoglobin ) test more than 48mmol/l - two tests

Oral glucose tolerance test
(plasma glucose is greater than 11.1 mmol/l

Where there are no symptoms :
Test blood samples on two seperate days

Question 21

What is the IGT and IFG ?

Answer 21

Impaired glucose tolerance (IGT)
-Fasting plasma glucose is above 7mmol/l then must do OGTT and check if between 7.8-11.1mmol = pre diabetic

Impaired Fasting glycaemia (IFG)
Fasting plasma glucose 6.1 to 76.9 mmol/L and a OGTT value of less that 7.8mmol/L

Question 22

When should the oral glucose tolerance test be carried out ?

Answer 22

OGTT should be carried out:
In patients with IGT,IFG
In unexplained glycosuria
In clinical features of diabetes with normal plasma glucose values
For the diagnosis of acromegaly (excess growth hormone )

75g oral glucose and test after 2 hours
Blood samples collected at 0 and 120 mins after glucose
Subjects tested fasting after 3 hours of normal diet containing at least 250 g carbohydrate.

Question 23

Outline the treatment of T2D(type 2 diabetes )

Answer 23

1. Diet and exercise
2. Oral monotherapy (Metformin )
3. Oral combination (Sulphonylureas,Gliptins,GLP-1 analogues)
4. Insulin +oral agents

Question 24

How does Sulphonylurea work ?

Answer 24

It works by stimulating cells in pancreas to make more insulin

Question 25

Outline the mechanism of Gliptins ?

Answer 25

This is a peptidyl-peptidase inhibitor which works by blocking peptidyl-peptidase 4 which is an enzyme which destroys the hormone incretin. Incretin helps the body produce more insulin and reduces the amount of glucose being produced by the liver when not needed. Gliptins will block the enzyme which destroys incretin.

Question 26

What are GLP-1 analogues ?

Answer 26

Anatagonist which mimics the actions of nitra-incretin hormones to help lower the blood glucose levels after a meal.

Question 27

Describe the drug treatment of Type 2 diabetes mellitus

Answer 27

Metformin: Decreases gluconeogenesis Sulfonylureas: bind and close KATP channels, depolarize B cell releasing insulin Glitazones: activate PPARγ receptor (controller of lipid metabolism), which (somehow) reduces insulin resistance SGLT2 inhibitors: promote glucose excretion via kidney Incretin targeting drugs: potentiate insulin release in response to rising plasma glucose -DPP-4 inhibitors (prevent breakdown of natural incretins) -Synthetic GLP-1 analogues

Question 28

How is the glycaemic levels monitored?

Answer 28

They are monitored to prevent complications and to avoid hypoglycaemia Self-monitoring is encouraged : Capillary blood measurement Urine analysis :glucose in urine gives indication of blood glucose concentration above renal threshold 3-4 months: Blood HbA1c(glycated Hb; covalent linkage of glucose to residue in Hb) Urinary albumin -kidney damage (index of risk of progression to neuropathy) ( damage or dysfunction of one or more nerves that typically results in numbness, tingling, muscle weakness and pain in the affected area)

Question 29

What are the long term complications of Type 1/2 diabetes?

Answer 29

Micro-vascular disease: Retinopathy, Nephropathy, Neuropathy Macro-vascular disease: Related to atherosclerosis heart attack /stroke Exact mechanisms of complications are unclear

Question 30

Define Hypoglycaemia and causes

Answer 30

It is defined as plasma glucose <2.5 mmol/L - Hypoglycaemia in diabetes - Hypoglycaemia in non-diabetic patients Causes: Drugs Common in type 1 diabetes Less common in type 2 diabetes taking insulin +insulin secretagogues (substance which promotes secretion) Uncommon in patients who do not have drug treated DM In these patients hypoglycaemia may be caused by : Alcohol Critical illness (hepatic ,renal ,cardiac failure,sepsis,hormone defieincy,inherited metabolic dx)

Question 31

What are some commonly used sulfonylureas?

Answer 31

``` Exogenous insulin Insulin secretagogues : -glyburide glipizide glimepiride ``` Stimulation of endogenous insulin suppresses hepatic and renal glucose production and increases glucose utilisation

Question 32

What drugs are used to treat type 2 diabetes earlier in the disease ?

Answer 32

- Insulin sensitisers (Metamorfin, Glitazones) - Glucosidase inhibitors - glucagon-like peptide-1 (GLP-1)receptor antagonist - DPP-4 inhibitors These should not cause hypoglycaemia

Question 33

What can cause hypoglycaemia in non-diabetic patients ?

Answer 33

``` Alcohol Drugs: Quinolone Quinine Beta blockers Ace inhibitors IGF-1 ``` Inherited metabolic disorders e.g. hereditary fructose intolerance Insulinoma (tumour) severe liver disease, non-pancreatic tumours (beta cell hyperplasia),renal disease (metab. acidosis, reduced insulin elimination).

Question 34

How does ethanol lead to hypoglycaemia ?

Answer 34

It inhibits gluconeogenesis but not glycogenolysis The hypoglycaemia will follow several days alcohol binge with limited food intake This results in hepatic depletion of glycogen

Question 35

How does Sepsis cause hypoglycaemia ?

Answer 35

Common cause Cytokine accelerated glucose utilisation and induced inhibition of gluconeogenesis in the setting of glycogen depletion

Question 36

How can CKD cause hypoglycaemia ?

Answer 36

The mechanism is not entirely clear Involves impaired gluconeogenesis , reduced renal clearance of insulin and reduce renal glucose production

Question 37

Outline reactive hypoglycaemia and the cause

Answer 37

This is also known as postprandial hypoglycaemia -Drops in blood sugar are usually recurrent and occur within four hours after eating Can occur in both diabetic +non diabetic patients More common in overweight individuals/ gastric bypass surgery The actual cause is unclear : -benign tumour in the pancreas causing overproduction of insulin - Too much glucose may be used up by the tumour itself - Deficiencies in counter-regulatory hormones e.g. glucagon

Question 38

What is the normal response to hypoglycaemia ?

Answer 38

1. When plasm,a glucose level declines in fast state , pancreatic beta cells secretion of insulin will decrease +hepatic glycogenolysis and gluconeogenesis are increased +reduced glucose utilisation of peripheral tissue , inducing lipolysis and proteolysis 2.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.

Question 39

Outline the counter-regulatory respone to hypoglycaemia

Answer 39

Look at slide

Question 40

What are the signs and symptoms of hypoglycaemia ?

Answer 40

1. Neurogeneic (Autonomic) - Triggered by falling glucose levels - Activated by ANS and mediated by sympathoadrenal release of catecholamine and Ach 2.Neuroglycopaenia -Due to neuronal glucose deprivation -Sign and symptoms: Confusion Difficulty speaking Ataxia-degenerative disease of the nervous system -Paraesthesia-abnormal sensation of the skin -Seizures -Coma -Death