L13: The endocrine pancreas Flashcards
Where is the pancreas located?
Upper left region--> Left hypochondriac Upper middle region--> Epigastric region Posterior to the stomach Head nestled in curvature of duodenum Tail towards the spleen
Which part of the gut does the pancreas develop from? Therefore, what is its blood supply?
Foregut
Coeliac blood supply
What are the functions of the pancreas?
Exocrine–> secrete digestive enzymes into the duodenum (majority of gland)
Endocrine–> secrete hormones into the blood stream , from Islets of Langerhans
What is different in structure between the endocrine and exocrine portion of the pancreas?
Endocrine–> cells cluster–> good blood supply
Exocrine–> cells form acinir–> around a duct
What are the important hormones secreted by the pancreas? Which cells produce them?
Polypeptide hormones Insulin --> β cells Glucagon--> α cells Somatostatin--> δ (delta) cells Pancreatic Polypeptide --> PP cells Ghrelin--> E cells Gastrin--> G cells Vasoactive Intestinal Peptide--> VIP cells
What two hormones are the most important for regulation of plasma glucose?
Insulin –> lowers plasma glucose
Glucagon–> Increases plasma glucose
Regulation of metabolism of carbohydrate, proteins and fats
Compare the actions of insulin and glucagon?
Insulin --> Feeding --> Liver, adipose tissue, skeletal muscle --> carbohydrate, proteins and lipids --> Anabolic Glucagon --> Fasting --> Liver, adipose tissue --> Carbohydrate and lipids --> Catabolic
Why is plasma glucose tightly controlled?
Brain uses glucose at fastest rate
Blood–> sensitive to changes in glucose, increase or decrease in osmolarity, circulation of glucose controlled
What the normal level for blood glucose?
Normal= 3.3-6 mmol/L
After meal 7-8 mmol/L
Renal threshold- 10mmol/L
What is meant by renal threshold? When is it normal to be above or below?
Level at which the kidney can no longer deal with plasma glucose
>10 mmol/L –> glucosuria (glucose in urine)
Pregnancy renal threshold decreases
Elderly renal threshold increases
What are the properties of insulin and glucagon?
Water soluble hormones
Dissolve in plasma–> no transport proteins required
Short T1/2–> 5 mins –> responsive to changes in eating habits, not hanging around
Interact with cell surface receptors
Inactivated by internalisation–> destroyed
What is the function of insulin?
Carbohydrate metabolism --> ↑ Glucose transport into cells --> ↑ glycolysis, by ↑ hexokinase and 6-phosphofructokinase activity --> ↑ glycogen synthesis, ↓ breakdown Lipid metabolism --> ↓ lipolysis --> ↑ FA synthesis and TAG synthesis --> ↑ uptake of TAG from blood --> ↓ FA oxidation in muscle and liver Proteins metabolism --> ↑ transport of AA into tissues --> ↑ proteins synthesis in muscle, adipose tissue, liver and other tissues --> ↓ protein degradation in muscles Anabolic Anti-gluconeogenic Anto-lipolitic and anti-ketotonic
How is insulin synthesised?
- Pre-proinsulin synthesis on rER -> single 109 aa
- Once entered the cisternal space, signalling peptide is removed (23aa) –> Proinsulin
- Proinsulin folds –> disulphide bonds form between cysteine residues
- Proinsulin–> rER to golgi where it is packaged for secretion
- Proteolysis in secretory vesicle removes connecting peptide C-peptide from middle of chain
- Mature insulin–> two chains held together by disulphide bonds
- Marginated to cell surface in pancreatic β cell until stimulated for release–> exocytosis
What is the structure of insulin? How does this compare to proinsulin and pre-proinsulin?
Big peptide–> 51 aa–> alpha helix structure
Two unbranched peptide chains held together by disulphide bonds
Proinsulin–>2 polypeptide chains, A and B chains, with C-peptide connecting them and disulphide bonds between cysteine residues
Pre-proinsulin–> signal sequence attached
What is contained within the secretory vesicle?
Insulin and C peptide
Stored as crystallin zinc-insulin compound
What is the function of C-peptide?
Not fully understood BUT absent in type 1 diabetics Treatment accompanied by increased blood flow in SM and skin Diminished glomerula hyperfiltration Reduced urinary albumin excretion Improved nerve function
What can measurements of C-peptide be useful for?
Monitor endogenous insulin production
How is insulin secretion regulated?
- Dependent on K+ ATP channels
- Resting membrane potential ATP sensitive K+ channels open –> Efflux of K+ –> hyperpolarisation
- Glucose >7mmol/L –> enters the cell through GLUT 2 transported (facillitated diffusion)
- Phoshorylated to glucose-6-phosphated by glucokinase–> enters kreb cycle –> OP produces ATP
- ATP:ADP ratio increased–> closes ATP sensitive K+ channels–> reduces efflux
- Depolarisation -20mV
- L type (voltage gated) Ca2+ channels open (P/Q-type and N-type)–> influx of Ca2+
- Exocytosis of insulin containing granules
- Activity of delayed rectifier voltage dependent K+ channels and Ca2+ sensitive K+ channels repolarise the membrane
What is the structure of a ATP sensitive K+ channel?
Kir6.2 and sulfonylureal receptor (SER1)
Briefly summaries how the ATP sensitive K+ channel works?
Metabolism low–> glucose low–> ATP K+ channel open–> No insulin secreted
Metabolism high–> glucose high–> ATP sensitive K+ channel closed –> Insulin secreted
What does insulin do?
Increase glucose uptake into target cells
GLUT 4 transporter inserted into membrane
Liver, SM and adipose tissue:
–> increase glucose transport
–> increase glycogen synthesis (glycogenesis)
–> increase lipogenesis and esterification of FA
–> increase AA uptake and protein synthesis
–> increase glycolysis
–> increase lipoprotein lipase activity in capillary bed of tissue
–> decrease glycogenolysis
–> decrease gluconeogenisis
–> decrease lipolysis
–> decrease ketogenesis
–> decrease proteolysis
What sort of receptor is the insulin receptor?
Tyrosine kinase receptor
Dimer
Two subunits made of one α (exterior) and one β (integral) chain connect by single disulfide bond
Insulin binds to receptor–> autophosphorylation of each other
Activates a signalling pathway though IRS pathway
How does glucagon work?
Raise blood glucose levels Glycogenolytic Gluconeogenic Lipolytic Ketogenic Mobilises energy release
How is glucagon secretion controlled?
Not fully understood
α cells in Islet of Langerhans release it when blood glucose low
ATP sensitive K+ channel likely involved
How is glucagon synthesised?
Synthesised on rER and transported to golgi body
Packaged into granules
Effect mainly in the liver
Granules move to cell surface
Fuse with cell membrane –> release via exocytosis
What is the structure of glucagon?
29 aa in 1 polypeptide chain
No disulphide bridges
Large precursor molecule pre-proglucagon
Undergoes post translational processing to produce the biologically active molecule
What are the effect of glucagon?
Binds to GPCR–> activate adenylate cyclase –> increased cAMP production–> activate PKA–> activated enzymes
Increase glycogen breakdown–> glycogenolysis
Stimulates pathway for synthesis of glucose from AA–> gluconeogenisis
Stimulates lipolysis to increase plasma FA
What happens to insulin and glucagon level when there is an increase in AA?
Insulin levels increase–> increase protein synthesis, decrease breakdown
Glucagon levels increase–> increase AA catabolism
ONLY when AA given on own
How quickly are carbohydrate, lipids and proteins metabolised?
Depends what needs doing to them Glucose uptake into SM and Adipose--> Rapid Glycolysis--> rapid Lipolysis--> rapid AA uptake--> rapid Ketogenesis--> rapid Gluconeogenesis, glycogenesis, Glycogenolysis--> Intermediate Protein synthesis--> intermediate Lipogenesis --> delayed
What happens when you have abnormal insulin or glucagon levels?
Insulin
High –> hypoglycaemia (glucose low)
Low–> hyperglycaemia (glucose high)
Glucagon
High–> makes diabetes worse (more glucose released)
Low–> may contribute to hypoglycaemia (no glucose released)
What is Diabetes Mellitus?
Elevated glucose in blood plasma
May appear in urine–> Glycosuria
How id diabetes mellitus diagnosed?
Venous plasma glucose concentration (blood test)
- -> Normal 3.3-6mmol/L
- -> Fasting > 7.0 mM
- -> Randon > 11.1mM
HbA1c > 48mmol/L (6.5%) suggest glucose bound to haemoglobin for a while
–> Glycated haemoglobin test
What is type 1 diabetes? What is the difference between relative and absolute?
Insulin deficiency
Autoimmune disease
Destruction of β pancreatic cells–> no insulin produced
Relative–> Secretion from β cell very slow or small–> failure to secrete adequate amount
Absolute–> Pancreatic β cells destroyed
What is seen in neonatal diabetes mellitus?
Mutation in the Kir6.2 subunit and sulfonylurea receptor 1
What is type 2 diabetes mellitus?
Normal insulin secretion
Peripheral insulin resistance
–> defecitve insulin receptor mechanism, change in receptor number and/or affinity
–> defective post receptor events (tissue insensitive to insulin)
–> Excessive or inappropriate glucagon secretion
What causes insulin resistance?
Combinatin of genetics and environmental factors
- -> obesity
- -> sedentary lifestyle
What is classified as type 2 diabetes in the young?
Insulin resistance present before 12+ years
Onset of hyperglycaemia and development of type 2 diabetes
How does the body initially respond to insulin resistance?
Initially–> β cells compensate by increasing insulin production–> maintain normal blood glucose
Eventually–> β cells unable to maintain increased production–> impaired glucose tolerance
Finally–> β cell dysfunction leads to relative insulin deficiency –> Overt type 2 diabetes
