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Clinical Biochemistry > Diabetes and Hypoglycaemia > Flashcards

Diabetes and Hypoglycaemia Flashcards

1
Q

What is the significance of glucose in the body?

A

Glucose is a major energy substrate maintained at 4 - 6 mmol/L

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2
Q

How are blood glucose levels maintained?

A

Blood glucose levels are maintained via:

  • dietary carbohydrate
  • glycogenolysis
  • gluconeogenesis
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3
Q

Describe the role of the liver after meals

A

After meals the liver stores glucose as glycogen

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4
Q

What is the role of the liver during fasting?

A

During fasting the liver makes glucose available through glycogenolysis and gluconeogenesis

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5
Q

What is glycogenolysis?

A

Glycogenolysis: - breakdown of glycogen store to glucose

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6
Q

What is gluconeogenesis?

A

Gluconeogenesis:- making glucose from non-glucose sources,

e.g. lactate, alanine, fatty acids

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7
Q

Why is it important to maintain a sufficient blood glucose supply?

A

Brain and erythrocytes require continuous supply - Avoid deficiency

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8
Q

What is the consequence of excess blood glucose?

A

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

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9
Q

What is insulin?

A

Insulin is the regulatory hormone of circulating glucose levels - reuptake of blood glucose into tissues

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10
Q

What is the role of insulin in the liver?

A

Stores glucose in liver in the form of glycogen

  • Increases glycogen synthesis
  • Increases lipid synthesis
  • Decreases gluconeogenesis
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11
Q

What is the effect of insulin on muscles?

A

In muscles, glucose uptake is increased and converted into glycogen and proteins

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12
Q

How does insulin effect adipose tissues?

A

In adipose tissue, glucose uptake is increased and so is lipogenesis; lipolysis is decreased

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13
Q

Which metabolic processes does insulin inhibit?

A
  • Gluconeogenesis
  • Glycogenolysis
  • Lipolysis
  • Ketogenesis
  • Proteolysis
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14
Q

List the metabolic processes activated by insulin

A
  • Glucose uptake in muscle and adipose tissue
  • Glycolysis
  • Glycogen synthesis
  • Protein synthesis
  • Uptake of ions (Esp. K and PO₄⁻³
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15
Q

What is diabetes Mellitus?

A

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

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16
Q

What causes hyperglycaemia in DM patients?

A

Hyperglycaemia results from

  • increased hepatic glucose production
  • decreased cellular glucose uptake
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17
Q

Why does glycosuria occur in DM patients?

A

blood glucose > ~ 10mmol/L exceeds renal threshold – glycosuria

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18
Q

What are the 4 ways diabetes is classified

A
  • Type 1
  • Type 2
  • Secondary
  • Gestational
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19
Q

What is type 1 diabetes?

A

Deficient insulin secretion due to autoimmune destruction of pancreatic B-cells by T-cells

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20
Q

Outline Type 2 Diabetes

A

Insulin secretion retained but target organs are resistant to its actions
Body can’t re-uptake glucose - plasma glucose levels increased

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21
Q

What is secondary diabetes?

A

Chronic pancreatitis, pancreatic surgery, secretion of antagonists cause diabetes

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22
Q

What is gestational diabetes?

A

Gestational diabetes occurs during pregnancy but mostly returns to normal.

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23
Q

Why are some patients unable to recover from gestational diabetes?

A

Patients unable to return glucose levels to normal after giving birth is usually because of lack of exercise or poor diet

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24
Q

Which population is mainly affected by Type 1 DM?

A

Predominantly in children and young adults; but other ages as well

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25
Q

Describe the onset of symptoms in type 1 DM patients

A 
Sudden onset (days/weeks)
Appearance of symptoms may be preceded by ‘prediabetic’ period of several months
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26
Q

What causes Type 1 DM?

A

Commonest cause is autoimmune destruction of B-cells

  • interaction between genetic and environment factors
  • strong link with HLA genes within MHC region on chromosome 6
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27
Q

What initiates the autoimmune response against B-cells 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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28
Q

Describe the autoimmune response in Type 1 DM

A

Circulating autoantibodies to various cell antigens against:

  • glutamic acid decarboxylase (pancreas)
  • tyrosine-phosphatase-like molecule
  • Islet auto-antigen

If autoantibodies to these cell antigens are found, we can assume B-cells are being destroyed in the pancreas

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29
Q

What is the most common autoantibody found in Type 1 DM patients?

A

The most commonly detected antibody associated with type 1 DM is the islet cell antibody

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30
Q

Outline the process of Type 1 DM Autoimmune response

A
  1. Genetics / environmental factors cause B-cell
    autoantigens to form and circulate in blood + lymphatics
  2. APCs present autoantigens to activate Th1 or Th2
  3. Th cells secrete cytokines, especially: INF-ɣ, IL-2
  4. These 2 cytokines activate macrophages to release IL-1
    and TNF-𝛼
  5. TNF-𝛼 and Il-1 induce destruction of pancreatic B-cells
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31
Q

How do activated Th1 cells destroy pancreatic B-cells?

A

Activated Th1 secretes IL-2 which activates a specific autoantigen for T-cytotoxic CD8 cells which induce destruction of B-cells

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32
Q

How do Th2 induce pacreatic B-cell destruction?

A

Activated Th2 secretes IL-4 to stimulate B-lymphocytes production of islet cell autoantibodies (& antiGADes antibodies) - these destroy pancreatic B-cells

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33
Q

What is the consequence of B-cell destruction in Type 1 DM?

A

Destruction of pancreatic ß-cell causes hyperglycemia due to absolute deficiency of both insulin & amylin

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34
Q

What is amylin?

A

Amylin, a glucoregulatory peptide hormone co-secreted with insulin

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35
Q

What are the functions of amylin?

A

Lowers blood glucose by slowing gastric emptying, & suppressing glucagon output from pancreatic cells

36
Q

Why does Type 1 DM cause metabolic complications?

A

Insulin deficiency leads to

increased hepatic output and impaired glucose uptake – hyperglycaemia

37
Q

How does Type 1 DM cause dehydration?

A

Increased glucose osmotic effect causes diuresis, dehydration and circulatory collapse

38
Q

How does Type 1 DM cause metabolic acidosis?

A

Increased lipolysis, blood level of ketone bodies formation (DKA) and metabolic acidosis.

39
Q

Describe the presentation of Type 2 DM

A

Slow onset (months/years)
Patients middle aged/elderly – prevalence increases with age
Strong familial incidence

40
Q

Describe the pathogenesis of type 2 DM

A

Pathogenesis uncertain – insulin resistance; β-cell dysfunction:
may be due to lifestyle factors - obesity, lack of exercise

41
Q

What are the metabolic complications of Type 2 DM?

A
  • Hyper-osmolar nonketotic coma (HONK)

- [Hyperosmolar Hyperglycaemic State (HHS)]

42
Q

Outline the consequences of type 2 DM metabolic complications

A
  • Development of severe hyperglycaemia
  • Extreme dehydration
  • Increased plasma osmolality
  • Impaired consciousness
  • No ketosis
  • Death if untreated
43
Q

What symptoms enable a type 1 DM diagnosis?

A

In the presence of symptoms: (polyuria, polydipsia & weight loss for Type I)

44
Q

Describe the glucose levels required for a DM diagnosis

A

Random plasma glucose
- ≥ 11.1mmol/l (200 mg/dl ).

Fasting plasma glucose
- ≥ 7.0 mmol/l (126 mg/dl)

Oral glucose tolerance test (OGTT)
- plasma glu ≥ 11.1 mmol/l

45
Q

How is diabetes diagnosed in absence of symptoms?

A

test blood samples on 2 separate days

46
Q

What is defined as impaired glucose tolerance?

A

Impaired Glucose Tolerance (IGT)
Fasting plasma glucose >7mmol/L**

OGTT value of 7.8 – 11.1 mmol

47
Q

What is impaired fasting glycaemia?

A

Impaired Fasting Glycaemia (IFG)
Fasting plasma glucose 6.1 to 6.9 mmol/L, and
OGTT value of < 7.8mmol/L

48
Q

When is OGTT used?

A

OGTT used in individuals with fasting plasma glucose of ‹ 7.0 mmol/L to determine glucose tolerance status.

49
Q

What is the significance of IFG?

A

If you have impaired fasting glycaemia, you are also thought to have an increased risk of developing diabetes

50
Q

When should an OGTT be carried out?

A
  • in patients with IFG
  • in unexplained glycosuria
  • in clinical features of diabetes with normal plasma glucose values
51
Q

Outline how an OGTT is carried out?

A

75g oral glucose and test after 2 hour
Blood samples collected at 0 and 120 mins after glucose

Subjects tested fasting after 3 days of normal diet containing at least 250g carbohydrate

52
Q

What drug is used to treat T2DM?

A

Metformin

53
Q

How does metmorfin reduce effects of T2 DM?

A

Metformin decreases gluconeogenesis and increases peripheral utilisation of glucose

54
Q

Why is metmorfin not able to treat all T2 DM patients?

A

Only acts in presence of endogenous insulin

So only effective if residual functioning pancreatic islet cells are present

55
Q

How do sulphonylureas work to reduce DM symptoms?

A

Work by stimulating pancreatic cells to make more insulin and help insulin work more effectively in the body.

56
Q

What are DPP-4 gliptins?

A

Dipeptidyl peptidase inhibitor (DPP-4; Gliptins):

inhibitors work by blocking the action of DPP-4, an enzyme which destroys the hormone incretin.

57
Q

What is the role of incretin?

A

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

58
Q

What is the aim of controlling glycaemic control?

A

Aim: to prevent complications or avoid hypoglycaemia

59
Q

How can patients self monitor glycaemic control?

A 
Self-monitoring to be encouraged:  
- Capillary blood measurement 
- urine analysis: 
  glucose in urine gives indication of blood glucose 
  above renal threshold
60
Q

How are blood HbA1c used to monitor glycaemic control?

A

Every 3-4 months

blood HbA1c tested for glycated Hb; covalent linkage of glucose to residue in Hb

61
Q

How is renal glycaemic control measured?

A

urinary albumin (index of risk of progression to nephropathy)

62
Q

Why are DM patients more susceptible to stroke?

A

Abnormalities in serum lipids common in T1DM & T2DM increase risk of MI and stroke
HbA1c – aim at <7%

63
Q

What are the long term complications of T1 and T2 DM?

A

Microvascular disease:
- retinopathy, nephropathy, neuropathy

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

Exact mechanisms of complications are unclear

64
Q

What is hypoglycaemia?

A

Defined as plasma glucose < 2.5 mmol/L

65
Q

What are the common causes of hypoglycaemia?

A

Drugs are the most common cause;

common in type 1 diabetes

Less common in type 2 diabetes taking insulin & insulin secretagogues

Uncommon in patients who do not have drug treated DM:

66
Q

Why may patients who’re untreated for DM develop hypoglycemia?

A

May be caused by alcohol, critical illnesses such as hepatic, renal or cardiac failure, sepsis, hormone deficiency, inherited metabolic dx

67
Q

Name some commonly used sulfonylureas to treat DM

A

Exogenous insulin & insulin secretagogues
e.g.
glyburide, glipizide and glimepiride

68
Q

How do sulfonylureas use lead to hypoglycemia?

A

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

69
Q

What is a safer alternative to sulfonylureas to treat DM?

A

Insulin sensitizers
- metformin, Glitazones

Glucosidase inhibitors

  • GLP-1 receptor antagonist
  • DDP-4 inhibitors

These should not cause hypoglycaemia

70
Q

What other non-diabetic drugs are commonly known to cause hypoglycemia?

A

Other drugs most commonly found to cause hypoglycaemia are quinolone, quinine, beta blockers, ACE inhibitors and IGF-1

71
Q

What disorders may lead to hypoglycemia?

A

Endocrines disease;
- e.g. cortisol disorder

Inherited metabolic disorders
- e.g. hereditary fructose intolerance.

Insulinoma

Severe liver disease, non-pancreatic tumours (beta cell hyperplasia), renal disease (metab. acidosis, reduced insulin elimination).

72
Q

How does alcohol lead to hypoglycaemia?

A

Ethanol inhibits gluconeogenesis, but not glycogenolysis.

Hypoglycaemia typically follows several days after alcohol binge with limited food intake

> results in hepatic depletion of glycogen

73
Q

How does sepsis cause hypoglycemia?

A

Relatively common cause of hypoglycaemia

Cytokine accelerated glucose utilization
Induced inhibition of gluconeogenesis in setting of glycogen depletion

74
Q

Explain how CKD may lead to hypoglycemia

A

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

75
Q

What is reactive hypoglycemia?

A

Hypos After Eating
AKA postprandial hypoglycaemia

Drops in blood sugar recurrent and occur within four hours after eating

76
Q

Who is affected by postprandial hypoglycemia?

A

Can occur in both people with and without diabetes,

More common in overweight individuals / those with gastric bypass surgery

77
Q

What are the potential causes of reactive hypoglycemia?

A

Benign (non-cancerous) tumour in pancreas may cause Insulin overproduction

Excess glucose may be used up by tumour itself.

Deficiencies in counter-regulatory hormones: e.g. glucagon

78
Q

What is the first natural defence against hypoglycemia?

A

Pancreatic beta-cells secretion of insulin is decreased
- hepatic glycogenolysis and gluconeogenesis is increased

  • Reduced glucose utilisation of peripheral tissue, inducing lipolysis and proteolysis
79
Q

What is the 2nd Defence against hypoglycemia?

A

Counter-regulatory hormones are released:

Pancreatic alpha cells secrete glucagon to stimulate hepatic glycogenolysis

Adrenaline release from adrenomedullary to stimulate hepatic glycogenolysis and gluconeogenesis; renal gluconeogenesis

80
Q

Describe what happens when hypoglycaemia occurs for > 4hrs

A

If hypo is prolonged beyond 4 hours; cortisol and GH will support glucose production and limit utilisation

81
Q

Describe the effects of adrenaline in glucose metabolism

A

Epinephrine has a similar hepatic effect as glucagon; inhibits insulin secretion

82
Q

Define hypoglycaemia clinically

A

Hypoglycaemia defined as plasma glucose level < 70 mg/dL (3.9 mmol/L)

83
Q

Outline the counter-regulatory hormone response to hypoglycemia

A

Inhibition of endogenous insulin secretion

Stimulation of glucagon, catecholamines; (nor)adrenaline, cortisol and growth hormone secretion

84
Q

What is the effect of the counter-regulatory hormone release against hypoglycemia?

A

Stimulate hepatic glucose production and cut down glucose utilization in peripheral tissues, increasing plasma glucose levels.

85
Q

Outline the neurogenic signs & symptoms of hypoglycemia

A

Neurogenic (autonomic):
- Triggered by falling glucose levels
- Activated by ANS & mediated by sympathoadrenal
release of catecholamines and Ach

86
Q

What is neuroglycopenia?

A

Shortage of glucose (glycopenia) in the brain, usually due to hypoglycemia.

87
Q

What are the signs and symptoms of neuroglycopenia?

A
  • confusion
  • difficulty speaking
  • ataxia
  • paresthesia
  • seizures
  • coma
  • death

Clinical Biochemistry (7 decks)

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