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SEM 4: Clinical Biochemistry > Diabetes and Hypoglycaemia > Flashcards

Diabetes and Hypoglycaemia Flashcards

1
Q

Ways blood glucose levels are maintained

A
  • Dietary carbohydrate
  • Glycogenolysis
  • Gluconeogenesis
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2
Q

Liver’s role in Blood glucose homeostasis

A
  • After meals, it stores glucose as glycogen.
  • During meals, it breaks down glycogen and makes glucose more readily available through glycogenolysis and gluconeogenesis.
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3
Q

Why should glucose levels be regulated?

A
  • Brain and erythrocytes require a continuous supply.
  • Therefore, avoid deficiency.
  • High glucose and metabolites cause pathological changes to tissue e.g. micro/macrovascular diseases, neuropathy, therefore, avoid excess.
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4
Q

Actions of insulin

A

INCREASE:

  • Glucose uptake in muscle and adipose tissue
  • Glycolysis
  • Glycogen synthesis
  • Protein synthesis
  • Uptake of ions (especially K+ and PO4(3-))

DECREASE:

  • Gluconeogenesis
  • Glucogenolysis
  • Lipolysis
  • Ketogenesis
  • Proteolysis
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5
Q

Diabetes Mellitus

A

A metabolic disorder characterised by chronic hyperglycaemia, glycosuria and associated abnormalities of lipid and protein metabolism.

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6
Q

How does hyperglcaemia occur in diabetes mellitus?

A
  • Results from increased hepatic glucose production and decreased cellular glucose intake.
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7
Q

Signs and symptoms of diabetes mellitus

A
  • These patients will present as being skinny because glucose is not taken into the cells and is lost in the urine instead.
  • Blood glucose increase more 10mmol which leads to the renal threshold limit being met and therefore glucose starts to appear in the urine.
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8
Q

Type 1 diabetes mellitus

A

Insulin secretion is deficient due to autoimmune destruction of beta-cells in the pancreas by T-cells.
Predominantly in children and young adults, but other ages as well.
Sudden onset of days or weeks.

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9
Q

Type 2 diabetes mellitus

A

Insulin secretion is retained but there is target organ resistance to its action.

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10
Q

Secondary diabetes

A

Chronic pancreatitis, pancreatic surgery, secretion of antagonists

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11
Q

Gestational diabetes

A

Occurs for first time in pregnancy

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12
Q

Symptoms of type 1 diabetes mellitus

A
  • Appearance of symptoms may be preceded by prediabetic period of several months.
  • Meaning symptoms may come before the patient becomes diabetic
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13
Q

Describe the autoimmune destruction of beta cells in the pancreas in type 1 diabetes

A
  1. B cells are responsible for the production of insulin.

2. Therefore, destruction of beta cells means no production of insulin.

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14
Q

Genetic and Environmental type 1 diabetes

A
  • There is an interaction between genetic and environmental factors
  • There is a strong link between the HLA genes within the MHC region on chromosome 6.
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15
Q

How is the autoimmune response initiated in Type 1 DM?

A
  • HLA class II cell surface present as foreign and self-antigens to T lymphocytes to initiate autoimmune response.
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16
Q

Circulating autoantibodies in type 1 DM

A

There are circulating autoantibodies to various cell antigens against:

  • Glutamic acid decarboxylase - this is an enzyme in the pancreas and therefore circulating antibodies can attack it.
  • Tyrosine-phosphatase like molecule
  • Islet auto-antigen
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17
Q

Most common antibody: islet cell antibody in type 1 DM

A
  • Islet cells include alpha and beta cells which secrete glucagon and insulin
  • Destruction of pancreatic B cell causes hyperglycaemia due to absolute deficiency of both insulin and amylin
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18
Q

Amylin

A

A glucoregulatory peptide hormone co-secreted with insulin.

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19
Q

Function of amylin

A

Lowers blood glucose by showing gastric emptying (which lowers the reabsorption of glucose) and suppressing glucagon output from pancreatic cells

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20
Q

Mechanism of action of Type 1 DM

A
  1. Genetic predisposition and environmental factors both play a role in DM.
  2. This leads to the formation of autoantigens on insulin-producing beta cells and circulate in the blood stream and lymphatics.
  3. This leads to processing and presentation of autoantigens by antigen presenting cells.
    • Activation of T helper 1 lymphocytes -> Activation of macrophages with release of IL-1 and TNFalpha and Activation of autoantigen-specific T cytotoxic (CD8) cells -> Destruction of beta cells with decreased insulin secretion
    • Activation of T helper-2 lymphocytes -> Activation of B lymphocytes to produce islet cell autoantibodies and antiGAD65 antibodies -> Destruction of beta cells with decreased insulin secretion
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21
Q

What does insulin deficiency lead to?

A
  • Increased hepatic output and impaired glucose uptake which leads to hyperglycaemia
  • Increased glucose osmotic effect and causes diuresis, dehydration and circulatory collapse
  • Increased lipolysis, blood level of ketone bodies formation (DKA) and metabolic acidosis
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22
Q

How does polyuria occur?

A
  1. Insulin is responsible for glucose uptake into the cell and therefore insulin deficiency leads to hyperglycaemia.
  2. And therefore, when blood glucose levels increase past the threshold limit, it leads to glucose being lost in the urine which is glycosuria.
  3. More glucose in the kidney leads to more water in the kidney and therefore an increase in urine volume which is called polyuria.
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23
Q

How does polydipsia occur?

A
  1. Lost of a lot of urine and leads to volume depletion and therefore dehydration.
  2. Due to dehydration, you drink more water which is called polydipsia.
  3. This can also lead to diabetic coma.
24
Q

How does diabetic coma occur?

A
  1. Increase lipolysis which is breakdown of lipids into free fatty acids.
  2. The fatty acids get oxidised in the liver.
  3. This leads to ketoacidosis and therefore it can lead to diabetic coma.
25
Q

Presentation of type 2 DM

A
  • Slow onset takes months and years
  • Patients are typically middle ages or elderly
  • The prevalence increases with age
  • Strong familiar incidence
  • Pathogenesis uncertain - insulin resistance B cell dysfunction: ay be due to lifestyle factors such as obesity, lack of exercise
26
Q

What is a metabolic complication of type 2 DM?

A

Hyper-osmolar non-ketotic coma (HONK)

27
Q

What is HONK?

A
  • Development of severe hyperglycaemia
  • Extreme dehydration
  • Increased plasma osmolality
  • Impaired consciousness
  • No ketosis
  • Death if untreated
28
Q

Diagnosis of DM: presence of symptoms

A
  • Polyuria, polydipsia and weight loss for type 1
  • Random plasma glucose levels higher than 11, 1 mmol/L
  • Fasting plasma glucose levels higher than 7 mmol/L
  • Oral glucose tolerance test higher than 11, 1 mmol/L
29
Q

Diagnosis of DM: absence of symptoms

A
  • Test blood samples on 2 separate days
30
Q

Impaired glucose tolerance (IGT)

A
  • fasting plasma glucose lower than 7 mmol/L

- oral glucose tolerance test value of 7.8 - 11.1mmol

31
Q

Impaired fasting glycaemia (IFG)

A
  • fasting plasma glucose levels of 6.1 - 6.9 mmol/L

- oral glucose tolerance test value less than 7.8 mmol/L

32
Q

Oral glucose tolerance test

A

Used in individuals with fasting plasma glucose levels less than 7.0 mmol/L to determine glucose tolerance status

33
Q

When is the oral glucose tolerance test (OGTT) used?

A
  • In patients with IFG
  • In unexplained glycosuria
  • In clinical features of diabetes with normal plasma glucose values
34
Q

How is the OGTT carried out?

A

75g oral glucose and test after 2 hours

  1. Blood samples collected at 0 and 120 mins after glucose
  2. Subjects tested fasting after 3 days of normal diet containing at least 250g carbohydrate.
35
Q

Stepwise treatment of Type 2 diabetes

A
  1. First stage of treatment includes change in diet and increasing exercise
  2. If the patient does not improve, they take oral monotherapy such as metformin.
  3. If the patient does not improve, they take oral combination pills such as sulphonylures, gliptins ec
36
Q

Metformin

A

Helps insulin take up the glucose in the blood

37
Q

Sulphonylures

A

Helps improve the B cells make insulin

38
Q

Gliptins

A

Dipeptidyl peptidase inhibitors

39
Q

What do the sulphonylures and gliptins do?

A

The sulphonylures and gliptins are enzymes that breakdown incretin which is needed for glucose absorption, therefore if you block the enzymes then the incretin will not breakdown and there will be uptake of glucose into the cells.

40
Q

Why is it important to monitor glycaemic control?

A

To prevent or avoid hypoglycaemia

41
Q

How is self-monitoring of glycaemia done?

A
  • Capillary blood measurements can be taken via pricking the finger and measuring the blood glucose levels
  • Urine analysis, measurement of glucose in urine gives indication of blood glucose concentration to see if it is above the renal threshold.
42
Q

What else is monitored every 3 to 4 months in diabetic patients?

A
  • Blood HbA1

- Glycated Hb: covalent linkage of glucose to residue in Hb.

43
Q

What other glycaemic control mechanisms are used to monitor?

A
  • Urinary albumin

- Index risk of progression to nephropathy

44
Q

What are the long-term complications in both type 1 and type 2 DM?

A
  • Microvascular disease: retinopathy, nephropathy and neuropathy
  • Macrovascular disease: related to atherosclerosis heart attack/stroke
  • Exact mechanisms of complications are unclear
45
Q

Hypoglycaemia

A

Defined as plasma glucose less than 2.5 mmol/L

46
Q

Causes of hypoglycaemia

A
  • Drugs are the most common cause
  • Common in type 1 diabetes but less common in type 2 diabetes taking insulin and insulin secretagogues (drugs that make insulin)
  • Uncommon in patients who do not have drug treated DM: in these patients hypoglycaemia may not be caused by alcohol, critical illnesses such as hepatic, renal, or cardiac failure, spesis, hormone deficiency and inherited metabolic disease
47
Q

Exogeneous insulin and insulin secretagogues

A
  • Glyburide, glipizide and glimepiride are types of sulfonylureas which cause hypoglycaemia
  • They lead to the stimulation of endogenous insulin that suppresses hepatic and renal glucose production and increase glucose utilisation.
48
Q

Drugs used to treat type 2 diabetes

A

Should not cause hypoglycaemia
Metformin and glitazones which are insulin sensitizers
Glucosidase inhibitors, glucagon like peptide 1 (GLP-1) receptor antagonist and DDP-4 inhibitors

49
Q

What causes hypoglycaemia in patients without diabetes?

A
  • Drugs such as alcohol may cause hypoglycaemia: ethanol inhibits gluconeogenesis but not glycogenesis. The hypoglycaemia will typically follow several days of alcohol binge with limited food intake resulting in hepatic depletion of glycogen storage.
  • Drugs such as Quinolone, quinine, beta blockers, ACE inhibitors and IGF-1 are most common to cause hypoglycaemia
  • Endocrine disease such as cortisol disorder
  • Inherited metabolic disorders such as hereditary fructose intolerance
  • Insulinoma
  • Others such as severe liver disease, non-pancreatic tumours and renal disease
  • Sepsis: cytokine accelerated glucose utilisation and induced inhibition of gluconeogenesis in the setting glycogen depletion
  • Chronic kidney disease: likely to involve impaired gluconeogenesis, reduced renal clearance of insulin and reduce renal glucose production
50
Q

When does reactive hypoglycaemia/postprandial hypoglycaemia occur?

A
  • Occurs after eating
  • Unlike in normal people where after a meal, their insulin levels decrease, this their insulin levels stay high.
  • A drop-in blood sugar is recurrent and occur within four hours after eating
  • Occur in both people with and without diabetese, although it is thought to be more common in overweight individuals or those who have gastric bypass surgery - Cause is unclear but can be:
    • Benign tumour in the pancrease that may cause an overproduction of insulin
    • Too much glucose may be used up by the tumour itself
    • Deficiences in counter-regulatory hormones such as glucagon
51
Q

Response to hypoglycaemia in normal subjects

A
  1. When plasma glucose level in fast state pancreatic beta cells secretion of insulin is decreased. This is the first line of defence.
  2. Hepatic glycogenolysis and gluconeogenesis are increased.
  3. There is reduced glucose utilisation of peripheral tissue, inducing lipolysis and proteolysis.
52
Q

What is released in response to hypoglycaemia?

A

Counter regulatory hormones

  • Pancreatic alpha cells secrete glucagon to stimulate hepatic glycogenolysis. This is the second line of defence.
  • Epinephrine release from adrenomedullary to stimulate hepatic glycogenolysis and gluconeogenesis.
  • If hypoglycaemia is prolonged beyond 4 hours, cortisol and GH will support glucose production and limit utilisation.
53
Q

Categories of symptoms of hypoglycaemia

A
  • Neurogenic (automatic) symptoms

- Neurogenic symptoms

54
Q

Neurogenic (autonomic) symptoms

A
  • Triggered by falling glucose levels
  • Activated by ANS and mediated by sympathoadrenal release of catecholamines (adrenaline and noradrenaline) and Ach from the post sympathetic nerve endings
  • they cause the patients to recognise that they are experiencing a hypoglycaemic episode
55
Q

Neurogenic symptoms

A
  • These are due to neuronal glucose deprivation
  • Signs associated with elevated adrenaline levels include shakiness, anxiety, nervousness, palpitations, sweating, pallor and pupil dilation
  • Dry mouth due to deydration

SEM 4: Clinical Biochemistry (7 decks)

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