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Molecular Basis of Disease(Sem 4) > Diabetes and Hypoglycaemia > Flashcards

Diabetes and Hypoglycaemia Flashcards

1
Q

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

A

Glucose is a major energy substrate

Blood glucose levels are maintained through :
Dietary Carbohydrate
Glycogenolysis
Gluconeogenesis

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2
Q

What is the role of the liver ?

A

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 )

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3
Q

Why is it important to regulate blood glucose level ?

A

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

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4
Q

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

A

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

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5
Q

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

A
  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
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6
Q

Define Diabetic Mellitus

A

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

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7
Q

What is classified as glycosuria?

A

This is excess sugar in the urine

More than 10mmol/L exceeds renal threshold

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8
Q

What are the different classifications of Diabetes ?

A

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

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9
Q

Describe Type 1 DM

A

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

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10
Q

What is the pathogenesis of Type 1 DM?

A
  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

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11
Q

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

A

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

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12
Q

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

A

Islet cell auto antibody

anti-glutamic acid dicarboxylic antibody.

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13
Q

What is amylin?

A

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

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14
Q

What are the metabolic complications of Type 1 DM?

A

Check slide

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15
Q

What is the presentation of Type 2 DM ?

A

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

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16
Q

What is the pathophysiology of Type 2 DM ?

A

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

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17
Q

What are the metabolic complications of Type 2 -DM

A

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

18
Q

Describe the pathogenesis of the HONK state

A

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

19
Q

How can HONK be diagnosed ?

A

Increased glucose
Increase osmolarity
Decreased pH (no ketones)

20
Q

How is Diabetes diagnosed? what are the symptoms

A

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

21
Q

What is the IGT and IFG ?

A

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

22
Q

When should the oral glucose tolerance test be carried out ?

A

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.

23
Q

Outline the treatment of T2D(type 2 diabetes )

A
  1. Diet and exercise
  2. Oral monotherapy (Metformin )
  3. Oral combination (Sulphonylureas,Gliptins,GLP-1 analogues)
  4. Insulin +oral agents
24
Q

How does Sulphonylurea work ?

A

It works by stimulating cells in pancreas to make more insulin

25
Q

Outline the mechanism of Gliptins ?

A

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.

26
Q

What are GLP-1 analogues ?

A

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

27
Q

Describe the drug treatment of Type 2 diabetes mellitus

A

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

28
Q

How is the glycaemic levels monitored?

A

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)

29
Q

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

A

Micro-vascular disease:
Retinopathy, Nephropathy, Neuropathy

Macro-vascular disease:
Related to atherosclerosis heart attack /stroke

Exact mechanisms of complications are unclear

30
Q

Define Hypoglycaemia and causes

A

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)

31
Q

What are some commonly used sulfonylureas?

A 
Exogenous insulin 
Insulin secretagogues :
-glyburide
glipizide
glimepiride

Stimulation of endogenous insulin suppresses hepatic and renal glucose production and increases glucose utilisation

32
Q

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

A
  • Insulin sensitisers (Metamorfin, Glitazones)
  • Glucosidase inhibitors
  • glucagon-like peptide-1 (GLP-1)receptor antagonist
  • DPP-4 inhibitors

These should not cause hypoglycaemia

33
Q

What can cause hypoglycaemia in non-diabetic patients ?

A 
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).

34
Q

How does ethanol lead to hypoglycaemia ?

A

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

35
Q

How does Sepsis cause hypoglycaemia ?

A

Common cause

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

36
Q

How can CKD cause hypoglycaemia ?

A

The mechanism is not entirely clear

Involves impaired gluconeogenesis , reduced renal clearance of insulin and reduce renal glucose production

37
Q

Outline reactive hypoglycaemia and the cause

A

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
38
Q

What is the normal response to hypoglycaemia ?

A
  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.
39
Q

Outline the counter-regulatory respone to hypoglycaemia

A

Look at slide

40
Q

What are the signs and symptoms of hypoglycaemia ?

A
  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

Molecular Basis of Disease(Sem 4) (28 decks)

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