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Block 1 > Pathophysiology Of Diabetes > Flashcards

Pathophysiology Of Diabetes Flashcards

1
Q

What is Diabetes Mellitus (DM)?

A

A heterogenous complex metabolic disorder characterized by elevated blood [glucose] secondary to either resistance to the action of insulin, insufficient insulin secretion, or both

One end of a continuum of disordered glucose metabolism

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2
Q

How big a problem is the diabetes epidemic?

A

Worldwide = 415 million people expected to rise to 552 million people by 2030

UK prevalence = 3.7 million (85% type 2) including children but 850,000 estimated to be undiagnosed

Occupy 10% of NHS hospital beds

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3
Q

What is the function of glucose?

A

Main metabolic fuel for the brain normally

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4
Q

Why do we need glucose?

A

The body is unable to store or synthesize it, which is why we need a continuous steady supply

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5
Q

How can the body get glucose?

A

Dietary sources

Glycogenolysis (breakdown of glycogen stores)

Gluconeogenesis (formation of new glucose)

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6
Q

What are some important properties of glucose?

A

Hydrophilic so only diffuses slowly across the lipid cell membrane thus, it requires specific transport proteins (GLUT & SGLT) to move into cells

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7
Q

What type of transport to the GLUT family facilitate?

A

Facilitated diffusion (not energy dependent)

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8
Q

What are the functions of the different types of GLUTs?

A

1, 3 + 4: allow movement at low (basal) glucose levels

But 4 has a insulin dependent response in fat + muscle whilst 1, 2 + 3 are insulin independent

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9
Q

Where are the different GLUT transporters found?

A

1: ubiquitous so provide basal glucose to all cells
2: on β islet cells & tissues exposed to large glucose fluxes e.g. intestine, kidney + liver
3: mainly neurons
4: adipose tissue + muscles

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10
Q

What is the function of Sodium Dependent Glucose Transporters (SGLTs)? What are the different types?

A

Use Na to move glucose against concentration gradient

1: dietary uptake in intestines
2: major role in glucose reabsorption in kidneys

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11
Q

What does glucose homeostasis have to be able to cope with?

A

Changes in glucose delivery e.g. when fasted or after meals

Demand e.g. during exercise

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12
Q

What is involved in glucose homeostasis?

A

Inter-regulating hormones

Storage in excess (in fed state)

Release & production in deficit (in fasted state)

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13
Q

What is gluconeogenesis?

A

Production of glucose in the liver and kidneys from molecules (not carbohydrates) such as:

  • Lactate (from non-oxidative metabolism i.e. Cori cycle)
  • Glycerol (from fats)
  • Glutamine + alanine (from protein)
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14
Q

What is glycogen?

A

A multi-branched polysaccharide that is a energy storage molecules in humans; primarily stored in liver + muscle cells

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15
Q

What happens if there is a defect in glycogen synthesis or breakdown?

A

A spectrum of diseases called glycogen storage diseases

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16
Q

What are the major hormonal players in glucose homeostasis? What do they do?

A

Insulin: decrease glucose production + lipolysis but increase glucose utilisation

Glucagon: increase glucose production + lipolysis but decrease glucose utilisation

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17
Q

What are the minor players in glucose homeostasis? What do they do?

A

Catecholamines (A/NA), GH & cortisol: increase glucose production + lipolysis but decrease glucose utilisation

FFA: increase glucose production but decrease glucose utilisation

Incretins (GLP-1): decrease glucose production + lipolysis but increase glucose utilisation

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18
Q

What isinsulin?

A

A 51 AA peptide (protein) hormone which 2 protein chains linked by disulphide bonds

Pancreatic origin; produced by β cells of Islets of Langerhans which provide endocrine function

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19
Q

What are the 3 major cell types of the pancreas? What do they do?

A

α: produce glucagon

β: produce insulin

δ: produce somatostatin (strong inhibitor of insulin + glucagon although exact role is unclear)

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20
Q

How does insulin secretion occur?

A
  1. EC glucose transported into β cell via GLUT 2
  2. Glucose metabolised increasing ATP:ADP ratio within cell
  3. ATP dependent K+ channels close
  4. Cell membrane depolarisation occurs
  5. Voltage gated dependent Ca channels open causing a Ca influx
  6. Exocytosis of stored insulin vesicles
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21
Q

Explain the concept of biphasic insulin secretion.

A

Insulin secretions occurs in 2 phases:

1) 1st phase - rapid onset + lasts 10 minutes when there is release of pre-docked & primed vesicles
2) 2nd phase - prolonged plateau lasting as long as hyperglycaemia persists because release of insulin from granules is complex (involves transport -> docking -> priming -> fusion)

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22
Q

How much stored insulin is released when stimulated? Why?

A

Only a portion, even under max stimulation implying that insulin levels are regulated by release rather than synthesis

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23
Q

What are the actions of insulin?

A

Predominantly anabolic:

  • Activate insulin receptor on target cell membrane (outcome depends on 2ndary pathway activated e.g. gluconeogenesis inhibition)
  • Glucose transport
  • Glycogen synthesis
  • Other
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24
Q

How insulin facilitate glucose transport into cells?

A

Promotes fusion of IC vesicles containing predominantly GLUT4 + transporter insertion into cell walls

25
Q

How does insulin stimulate glycogen synthesis?

A

Promotes activation of glycogen synthase

26
Q

What are the other actions of insulin?

A

Promotes protein synthesis + inhibits protein breakdown

Promotes lipogenesis + inhibits lipolysis (via hormone sensitive lipase)

Promotes mitogenesis (induces cell division) via insulin-like GH homology

Suppress ketogenesis

27
Q

What is glucagon? When is it secreted?

A

Major counter-regulatory hormone produced by pancreatic islet α cells

Secretion regulated primarily by blood glucose levels (released in hypoglycaemia) & suppressed by insulin

28
Q

What are the actions of glucagon?

A

Stimulates gluconeogenesis & glycogenolysis

Stimulate proteolysis

Increase hepatic FA oxidation & ketone formation

Stimulates lipolysis in adipose cells, increases circulating FFA & reduce adipocyte glucose uptake

29
Q

What is the post-absorptive (fasted) state?

A

14-16 hours fast where glucose levels are relatively stable because balance of glucose entrance & utilisation is equal

30
Q

How is glucose entering the system in a post-absorptive (fasted) state?

A

80% from liver: 50% glycogenolysis + 50% gluconeogenesis -> proportion shift to 90% gluconeogenesis by 48hrs as fast progresses + glycogen stores deplete

Kidneys contribute primarily via gluconeogenesis (contain little glycogen) with output of this process comparing to the liver

31
Q

In the post-absorptive (fasted) state, what does the insulin:glucagon ratio look like?

A

Favours glucagon because its a primarily catabolic state

Loss of insulin action to supress lipolysis + proteolysis so there is production of precursors of gluconeogenesis + production of other fuels e.g. ketones

32
Q

What happens in the post-prandial (fed) state?

A

Insulin responds to rising glucose levels & acute exposure to FFA so insulin:glucagon ratio favours insulin as this is a primarily anabolic state

33
Q

What is the entero-insular axis?

A

L-cells of SI produce GI insulinotropic polypeptides such as Glucagon-Like Peptide (GLP) + Gastric Inhibitory Peptide (GLP) which augment insulin secretion in response to oral glucose load

Enzymes rapidly degraded by Dipeptidyl Peptidase 4 (DPP4)

34
Q

How is the autonomic nervous system involved in glucose homeostasis?

A

ANS directly innervates the pancreatic islets:

Sympathetic response releases A/NA which inhibit insulin + promotes glucagon secretion

Parasympathetic response has opposite action

35
Q

How are cortisol and Growth Hormone (GH) involved in glucose homeostasis?

A

Take several hours to have effect but promote gluconeogenesis + inhibit glucose transport into cells

Cortisol also directly inhibits insulin secretion (important when considering prescribed steroids, syndromes of cortisol or GH excess)

36
Q

What are the 4 stages of diabetes mellitus (DM)?

A
  1. Normal
  2. Impaired fasting glycaemia
  3. Impaired glucose tolerance
  4. Diabetes
37
Q

How is diabetes mellitus (DM) classified?

A

MAINLY into type 1 + type 2 by underlying pathogenesis

Other types + causes: monogenic, gestational, genetic, pancreas, endocrine or drugs

38
Q

What is type 1 diabetes mellitus (T1DM)?

A

Autoimmune disease with selective destruction of β cells resulting in complete insulin deficiency - associated with other autoimmune conditions e.g. thyroid disorders, coeliac disease

Accounts for 5-10% of DM

39
Q

What are the important features of type I diabetes mellitus (T1DM)?

A

Typically rapid but can be a honeymoon period

Only treated with insulin

Typically seen in younger, lean patients

40
Q

What are the symptoms of type 1 diabetes mellitus (T1DM)?

A 
Hyperglycaemia
Polyuria
Polydipsia
Weight loss
Fatigue
Ketoacidosis
41
Q

What is the normal blood glucose concentration?

A

< 7.8 mmol/L

42
Q

Why do patients with type 1 diabetes mellitus (T1DM) experience hyperglycaemia?

A

There is loss of insulin secretion so an inability to uptake glucose into cells or store it as glycogen

Also, unopposed glucagon action (as in a fasted state) causes glycogenolysis + gluconeogenesis

43
Q

Why do patients with type 1 diabetes mellitus (T1DM) experience polyuria?

A

Hyperglycaemia results in glycosuria which exceeds the renal capacity to reabsorb glucose so patients urinate more often to rid the body of glucose

Glucose in urine also inhibits concentrating ability of kidney

44
Q

Why do patients with type 1 diabetes mellitus (T1DM) experience polydipsia?

A

Physiological response to dehydration to maintain fluid balance

High blood [glucose] directly stimulates thirst response too

45
Q

Why do patients with type 1 diabetes mellitus (T1DM) experience weight loss?

A

Unopposed lipolysis + proteolysis for gluconeogenesis precursors

46
Q

When are ketones produced? What are the 3 types?

A

Product of FA metabolism produced as an alternative energy source

  1. Acetone
  2. Acetoacetate
  3. β-hydroxybutyrate)
47
Q

What is diabetic ketoacidosis (DKA)?

A

When ketone production leads to acidaemia -> medical emergency seen almost exclusively in T1DM patients (can be 1st presentation in undiagnosed T1DM often preceded by other acute illness due to stress hormone release or insulin omission)

48
Q

How does diabetic ketoacidosis (DKA) present?

A

Signs of shock from severe dehydration

High RR (to blow off acid)

Abdominal pain (can be severe)

49
Q

What is type 2 diabetes mellitus (T2DM)?

A

Heterogenous condition characterized by insulin resistance + initially hyperinsulinaemia

Loss of 1st phase insulin response + β cell exhaustion occurs over time

50
Q

What are the symptoms of type 2 diabetes mellitus (T2DM)?

A

Indolent; often asymptomatic at presentation

51
Q

What are the modifiable risk factors associated with type 2 diabetes mellitus (T2DM)?

A 
Overweight/obesity (BMI > 25kg/m^2)
Central/visceral obesity
Lack of physical activity 
Smoking
Poor diet (high saturated fat, low fibre, dyslipidaemia)
Low socioeconomic status
52
Q

What are the non-modifiable risk factors associated with type 2 diabetes mellitus (T2DM)?

A 
Age > 40yrs (>25 if South Asian origin)
FH
Ethnicity (Black African, South Asian)
History of gestational diabetes/baby > 4.5kg at birth
Impaired glucose regulation (prediabetes or non-diabetic hyperglycaemia)
Mental health/antipsychotic use history 
HTN, CVD or stroke history
Low birth weight
POS
53
Q

What waist circumference indicates central obesity?

A

Men: >94cm
South Asian men: >90cm
Women: >80cm

54
Q

What is the treatment for type 2 diabetes mellitus (T2DM)?

A

Diet, exercise + lifestyle measures

Oral hypoglycaemic agents

Injectable agents

55
Q

What oral hypoglycaemic agents exist? What do they do?

A

Biguanides (e.g. metformin): decrease hepatic gluconeogenesis

Sulfonyureas: increase insulin secretion

Thiazolidinediones: reduce insulin resistance

α-glucosidase inhibitor: decrease carb absorption

DPP-4 inhibitors: prevent breakdown of GLP

SGLT2 inhibitors: promote glycosuria

56
Q

What injectable agents exist for type 2 diabetes mellitus (T2DM)?

A

GLP-1 analogues

Insulin

57
Q

What are some complications of diabetes mellitus (DM)?

A

Hypoglycaemia of treatment

Microvascular: nephropathy, retinopathy or neuropathy

Macrovascular: IHD, cerebrovascular disease or PVD

58
Q

What are the symptoms of hypoglycaemia?

A 
Sweats
Illness
Agitation
Aggression
Irrationality 
Memory loss

Block 1 (54 decks)

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