Type I Diabetes Flashcards
Pancreas
glandular organ in the digestive and endocrine systems of vertebrates
functions as an exocrine and endocrine gland
drains directly into duodenum
highly vascularised
Exocrine gland
secretes enzymes that aid digestion and absorption of nutrients
Endocrine gland
synthesises important metabolic hormones such as insulin, glucagon and somatostatin
Pancreatic exocrine secretions
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
Ductal cells
release bicarbonate
Acinar cells
synthesise and release enzymes
Islets of Langerhans
Clusters of endocrine cells - up to 1 million clusters, closely associated with local capillary network within the pancreas
contain multiple cell types
Main role of endocrine secretions
regulation of glucose metabolism and blood glucose concentration
Alpha (α) cells
release glucagon (increases blood glucose)
Beta (β) cells
release insulin (decreases blood glucose)
Delta (δ)cells
release somatostatin (inhibits a and β cells function)
Gamma (γ) cells (PP cells)
release pancreatic polypeptide
Importance of glucose regulation
- 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
Insulin
the main regulatory hormone, encourages cellular uptake of glucose and utilisation or storage of energy derived from glucose
Actions of insulin
- Actions on liver, fat and muscle
- Encourages conservation of energy
- Regulates glucose utilisation
Regulation of insulin secretion (β cell)
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
Insulin - structure
- Peptide hormone
- Two chains of amino acids (21aa & 30aa)
- Linked by disulphide bridges
- First protein ever to be sequenced
- Frederick Sanger (Cambridge, 1952)
Cellular effects of insulin
-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
MAPK signalling pathway
cell growth, proliferation, gene expression
PI-3K signalling pathway
synthesis of lipids, proteins and glycogen
cell survival and proliferation
GLUT4 production and trafficking to membrane - facilitates glucose uptake
Insulin inhibits (metabolic)
gluconeogenesis
glucogenolysis
lipolysis
ketogenesis
proteolysis
Insulin promotes (metabolic)
glucose uptake in muscle and adipose tissue
glycolysis
glycogen synthesis
protein synthesis
uptake of ions (especially K+ and PO4-3)
Diabetes mellitus
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 %
Acute clinical signs of diabetes
Glycosuria - sugar in urine
Polyuria - increased urine production
Polydipsia - excessive thirst
multiple metabolic and physiological consequences
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
Acute consequences of type 1 diabetes
Thirst, excessive urine production
Blurred vision
Weight loss, fatigue
If untreated, then ketoacidosis, dehydration, coma & death
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
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
Traditional insulin therapy
insulin extracted from bovine or porcine pancreas
potential to elicit allergic response if not adequately purified
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
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
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)
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
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
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
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
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
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
