Type I Diabetes Flashcards

(38 cards)

1
Q

Pancreas

A

glandular organ in the digestive and endocrine systems of vertebrates

functions as an exocrine and endocrine gland

drains directly into duodenum

highly vascularised

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2
Q

Exocrine gland

A

secretes enzymes that aid digestion and absorption of nutrients

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3
Q

Endocrine gland

A

synthesises important metabolic hormones such as insulin, glucagon and somatostatin

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4
Q

Pancreatic exocrine secretions

A

Enzymes digest proteins, carbohydrates and lipids; high bicarbonate concentration neutralises stomach acid

Secretion controlled by hormones released in stomach (i.e. gastrin)

Exocrine secretions released into pancreatic duct by two main cell types

Proteases such as trypsinogen and chymotrypsinogen, plus pancreatic lipase and amylase

Released as zymogens (proenzymes) to prevent autodigestion before reaching site of action; activated in gut by enteropeptidase (and then trypsin) → broken down so they can function as enzymes

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5
Q

Ductal cells

A

release bicarbonate

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6
Q

Acinar cells

A

synthesise and release enzymes

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7
Q

Islets of Langerhans

A

Clusters of endocrine cells - up to 1 million clusters, closely associated with local capillary network within the pancreas

contain multiple cell types

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8
Q

Main role of endocrine secretions

A

regulation of glucose metabolism and blood glucose concentration

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9
Q

Alpha (α) cells

A

release glucagon (increases blood glucose)

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10
Q

Beta (β) cells

A

release insulin (decreases blood glucose)

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11
Q

Delta (δ)cells

A

release somatostatin (inhibits a and β cells function)

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12
Q

Gamma (γ) cells (PP cells)

A

release pancreatic polypeptide

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13
Q

Importance of glucose regulation

A
  • Glucose is key energy source for mammalian cells; CNS in particular
  • Need adequate supply to cope with variable demands & intermittent food intake - so we don’t have to eat all the time
  • Feeding provides more energy than immediately required; excess stored as glycogen (in liver) or fat (in adipose tissue)
  • Energy stores are mobilised between meals and during fasting
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14
Q

Insulin

A

the main regulatory hormone, encourages cellular uptake of glucose and utilisation or storage of energy derived from glucose

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15
Q

Actions of insulin

A
  • Actions on liver, fat and muscle
  • Encourages conservation of energy
  • Regulates glucose utilisation
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16
Q

Regulation of insulin secretion (β cell)

A

Glucose transport through GLUT1/2 receptor

Glucokinase - phosphorylates glucose to undergo glycolysis

ATP - from krebs cycle

Kir6.2 channel - ATP blocks this potassium-gated ion channel, causing depolarisation of membrane

L-type Ca2+ channel - influx of calcium

Increase in [Ca2+]i - intracellular calcium, stimulates pool of insulin

Release of insulin - immediately releasable pool of insulin

Reserves of insulin - reserve pool primed when immediately releasable pool is depleted

biphasic release of insulin

17
Q

Insulin - structure

A
  • Peptide hormone
  • Two chains of amino acids (21aa & 30aa)
  • Linked by disulphide bridges
  • First protein ever to be sequenced
  • Frederick Sanger (Cambridge, 1952)
18
Q

Cellular effects of insulin

A

-insulin acts on other cells locally, binding to insulin receptor stimulating MAP kinase signalling pathway and PI-3K signalling pathway

-PI-3K stimulates GLUT4 production, facilitating its trafficking in vesicles to cell membrane → able to take in more glucose and store it

-fat, liver and muscle tissue

19
Q

MAPK signalling pathway

A

cell growth, proliferation, gene expression

20
Q

PI-3K signalling pathway

A

synthesis of lipids, proteins and glycogen

cell survival and proliferation

GLUT4 production and trafficking to membrane - facilitates glucose uptake

21
Q

Insulin inhibits (metabolic)

A

gluconeogenesis
glucogenolysis
lipolysis
ketogenesis
proteolysis

22
Q

Insulin promotes (metabolic)

A

glucose uptake in muscle and adipose tissue
glycolysis
glycogen synthesis
protein synthesis
uptake of ions (especially K+ and PO4-3)

23
Q

Diabetes mellitus

A

Excess blood glucose (hyperglycaemia) is characteristic symptom → inability to control blood glucose

Fasting plasma glucose > 7 mmols/L
Post-prandial glucose > 11 mmols/L
Glycated HbA1c > 7 %

24
Q

Acute clinical signs of diabetes

A

Glycosuria - sugar in urine
Polyuria - increased urine production
Polydipsia - excessive thirst

multiple metabolic and physiological consequences

25
Type 1 diabetes
chronic autoimmune disorder Immune system attacks the insulin-secreting β-cells in the pancreas β-cells destroyed = insulin deficiency Cause unknown: genetic, environmental, viral, vaccination Insulin replacement therapy is required for control of blood glucose
26
Acute consequences of type 1 diabetes
Thirst, excessive urine production Blurred vision Weight loss, fatigue If untreated, then ketoacidosis, dehydration, coma & death
27
Chronic consequences of type 1 diabetes
Cardiovascular disease (heart disease, atherosclerosis, stroke) Kidney disease Eye problems (retinopathy) Peripheral neuropathy Poor peripheral circulation leading to lower limb amputation
28
Treatment
Insulin replacement therapy required Difficult to mimic physiological insulin secretion Good glycaemic control is necessary to limit long-term consequences Insulin is a peptide; not effective by oral route, degraded in GI tract before it gets to site of action
29
Traditional insulin therapy
insulin extracted from bovine or porcine pancreas potential to elicit allergic response if not adequately purified
30
Current insulin therapy
Recombinant human insulin now used Insulin gene inserted into E. coli Large scale production of human insulin in vitro Monitor serum glucose Administer required amount of insulin by subcutaneous injection (i.m. or i.v. in emergency) Units of insulin tailored to food intake
31
Physiological release of insulin
Continuous basal release accounts for ~50% of daily insulin release Remaining ~50% is released in high-level bursts in response to food intake Modern treatment of T1D attempts to mimic this pattern
32
Duration of Insulin Replacement Therapy
create different mutations to make insulin that lasts over either a shorter or longer period of time - Rapid-acting (3-4hrs) - Short-acting (6-8hrs) - Intermediate (13-20hrs) - Long-acting (>24hrs)
33
Rapid and long-acting forms used more widely
Better control achieved with single long-acting administration at night plus multiple rapid-acting injections before meals to deal with taking in more glucose
34
Short-acting and intermediate insulins
- Regular insulin -Native human insulin protein in solution -Short-acting - Neutral protamine Hagedorn (NPH) -First synthesised in 1936 using porcine insulin; now human -Suspension of crystalline zinc insulin combined with the positively charged polypeptide, protamine -Intermediate; onset 1-4hrs, peak 6-10hrs, duration 10-16hrs
35
Rapid-acting insulins
Created by minor modifications to amino acid sequence Compared to regular insulin: higher peak insulin level, time to reach peak level reduced, duration of effect reduced -Aspart: Pro at B28 replaced by Asp -Glulisine: Asn at B3 replaced by Lys, Lys at B29 replaced by Glu -Lispro: Pro at B28 replaced by Lys, Lys at B29 replaced by Pro
36
Long-acting insulins
Changes to amino acid sequence and/or addition of lipophilic side chains Compared to regular insulin: lower peak insulin level (or no peak), time to reach peak level extended, duration of effect greatly enhanced Detemir: Thr at B30 removed, fatty acid side chain added to Lys at B29 Glargine: Asn at A21 replaced by Gly, two Arg residues added at B31 & B32 Degludec: Thr at B30 removed, long fatty acid side chain added to Lys at B29 via L-glutamic acid linker
37
Mixed insulins
Improve adherence with treatment & reduce number of injections Traditionally: regular and NPH insulins mixed immediately prior to injection Later: rapid-acting formulations provided as a pre-mix with NPH i.e. 30:70 aspart to NPH and 25:75 lispro to NPH Recently: premix of 30:70 aspart to degludec has been licensed in EU Do not allow adjustment of individual constituents
38
Novel therapeutic approaches
- Insulin pump – external, implantable - Insulin inhaler - Dried microparticles, dissolve on contact with alveoli, peak level in 10-15 mins - Transdermal insulin patch - Absorption enhanced by ultrasonic stimulation of patch; in trials - Oral insulin - encapsulation and enteric coating enables oral insulin to be given allowing it to reach site of action - Structural modifications, encapsulation, enteric coatings, etc. - Buccal insulin spray - Pancreatic transplantation and stem cell therapy