7.1 The endocrine pancreas Flashcards
where is the pancreas located?
In the upper left abdomen, behind the stomach
describe the blood supply to parts of the gut
Foregut (liver and stomach) : coeliac trunk
Midgut (large intestine) : Superior mesenteric artery
Hindgut (small intestine) : Inferior mesenteric artery
how does the pancreas develop?
embryologically as an outgrowth of the foregut
what are the 2 main functions of the pancreas?
- Produces digestive enzymes released through the acinar and duct tissue and secreted directly into duodenum (exocrine action)
Exocrine function forms the bulk of the gland. Alkaline secretions via pancreatic duct to duodenum - Hormone production (endocrine action)
From Islets of Langerhans
the pancreas has both endocrine and exocrine functions, what proportion of the gland contributes to each function?
majority of the pancreas involved in exocrine functions.
~ 1% endocrine tissue, 99% exocrine tissue
how does the tissue of the pancreas appear on a H&E stain?
majority of the tissue has an exocrine function and is basophilic, appearing dark purple (haematoxilyn).
small circular patches of lighter stained areas can be seen within this tissue. These are the islets of Langerhans (endocrine function)
describe the structure of the exocrine tissue of the pancreas?
acinar and duct tissue
describe the structure of the endocrine function of the pancreas
Islets of Langerhans
what important endocrine polypeptide hormones are secreted by the pancreas?
– Insulin – Glucagon – Somatostatin – Pancreatic polypeptide (PP) – Ghrelin - Gastrin - Vasoactive intestinal peptide (VIP)
what subtype in the Islets of Langerhans secretes insulin?
Beta cells
what subtype in the Islets of Langerhans secretes glucagon?
Alpha cells
what subtype of cells in the Islets of Langerhans secrete somatostatin?
Delta cells
what is the function of somatostatin in the pancreas?
released by the delta cells of the islets of Langerhans in the pancreas to inhibit the release of glucagon and insulin
what hormones are used in glucose regulation?
insulin
glucagon
what is the function of insulin?
to promote glycogenesis thereby lowering blood glucose levels
what is the function of glucagon?
to stimulate glycolysis and gluconeogenesis to therefore raise blood glucose levels
how are endocrine cells stimulated to release hormones?
by blood sugar levels.
what is the signal for insulin production?
feeding (high blood sugar)
what is the target tissues of insulin
liver
adipose
skeletal muscle
what dietary components does insulin affect the metabolism of?
anabolic action on the metabolism of:
proteins
carbohydrates
lipids
how to the actions of insulin and glucagon vary?
insulin is anabolic
glucagon is catabolic
what is the signal for the production of glucagon?
fasting (low blood sugar)
what is the target tissue of glucagon?
liver
adipose
what dietary components does glucagon affect the metabolism of?
catabolic action on:
carbohydrates
lipids
why is it important that the plasma glucose levels are tightly regulated?
to keep the glucose levels of blood constant even though supply is inconsistent.
- glucose dependent tissues such as the brain and RBCs require a regular supply of glucose. Sensitive to falls in glucose concentration.
- an increase in glucose levels results in increased osmolarity (cells shrink)
what is the normal reference range for blood sugar
3.3 - 6 mmol/L
what is meant by renal threshold?
The renal threshold is the point at which the tissues in the kidney cannot deal with the amount of blood glucose. Cannot reabsorption all the sugar. Exceeding the renal ability means that glucose appears in the urine. Renal threshold is 10mmol/L
what is glycosuria?
glucose appearing in urine. Occurs when blood glucose level is above the renal threshold
how does the renal threshold vary?
decreases in pregnancy (more likely to have glucose in urine)
increases in elderly
what common properties do insulin and glucagon both have?
Both Water soluble hormones:
– Carried dissolved in plasma (no special transport proteins)
– Short 1⁄2 life 5 mins
– interact with cell surface receptors on target cells
– receptor with hormone bound can be internalised – inactivation
insulin is anti-gluconeogenic. what does this mean?
at high doses, insulin lowers incorporation of pyruvate into blood glucose, but also stimulated its incorporation into liver glycogen. Promotes storage of pyruvate.
why is insulin anabolic?
as it promotes small carbohydrate molecules to build up a larger storage molecule of glucogen. Insulin is also anti-gluconeogenic, anti-ketogenic and anti-lipolytic.
Describe the structure of insulin
- alpha helix structure
- 2 unbranched peptide chains
- chains connected by 2 disulfide bridges
- 51 amino acids
how does insulin affect carbohydrate metabolism?
- increase glucose transport across the cell membrane
- Increase glycolysis and therefore production of pyruvate
- stimulate glycogen synthesis and decreases glycogen breakdown
how does insulin affect lipid metabolism?
- decreases lipolysis in adipose tissue
- stimulates fatty acid and TAG synthesis
- increases uptakes of TAGs from the blood
- decreases fatty acid oxidation in muscles and the liver.
how does insulin affect protein metabolism?
- increases the transport of some amino acids into tissues
- Increases protein synthesis
- decreases protein degradation in muscle
what is c-peptide?
a component of pro insulin that is lost to form insulin.
Why can measuring c-peptide levels be beneficial?
if insulin levels are significantly higher than c-peptide levels then it indicates that excess insulin has been added.
What are K(ATP) channels?
channels on the membrane of pancreatic beta cells that links the electrical excitability to glucose levels. These KATP channels can open and close, thereby controlling the flux of potassium
How are KATP channels affected by glucose blood levels?
when blood glucose levels are low, the ATP to ADP ratio is low. The KATP channel is open, calcium channels are closed and the membrane is hyperpolarised. No insulin is secreted as the cell is not excitable due to the low RMP.
When glucose blood levels are high, more ATP can be produced through metabolism and therefore the ATP to ADP ratio is high. Increased ATP stimulates the KATP channels to shut. The membrane is depolarised and calcium channels open. Influx of calcium into beta cells in the pancreas causes insulin to be released.
how does insulin increase glycogen synthesis?
- increases glucose uptake by target cells by insertion of GLUT4 channels
- increases glycogen synthesis in the liver
- inhibits glycogen breakdown
- increases uptake of amino acids in muscles to promote protein synthesis
- inhibits breakdown of amino acids and fatty acids.
- increases the storage of TAGs in adipose tissue
what are GLUT 2 channels?
glucose transport channels located in the plasma membrane of the liver, pancreatic, intestinal, kidney cells as well as in the portal and the hypothalamus areas.
describe the structure of the insulin receptor
- Dimer
- two identical subunits spanning the cell membrane
- Each subunit is composed of an alpha and beta chain which are connected together by a single disulphide bond
- alpha-chain on exterior of the cell membrane
- beta chain spans the cell membrane in a single segment
what action is initiated by insulin binding to the insulin receptors within cell membranes?
once insulin binds to the insulin receptor, signalling molecules are released that open the GLUT-4 glucose transporter, allowing glucose to flow into cells.
what is glucagon?
- Hormone that opposes insulin (raise blood glucose levels, glycogenolytic, gluconeogenic, lipolytic, ketogenic)
- It mobilizes energy release
how is glucagon produced?
produced in pancreatic alpha cells. Synthesized in Rough ER and transported to Golgi before being packaged in granules
what stimulates glucagon to be secreted from alpha cells?
low glucose levels in alpha cells
what tissues does glucagon mainly affect?
liver
what is margination?
movement of storage vesicles to cell surface
what is exocytosis?
fusion of vesicle membrane with plasma membrane
with the release of the vesicle contents.
describe the structure of glucagon
29 amino acids in 1 polypeptide chain
No disulphide bridges, flexible structure
what effects does glucagon produce?
rise in blood glucose levels by increasing glycogenolysis in the liver and stimulating gluconeogenesis from amino acids
when is glucagon administered?
Glucagon in emergency medicine is used when a person with diabetes is experiencing hypoglycemia and cannot take sugar orally
when proteins are administered, which glucose metabolism hormones are produced?
both glucagon and insulin.
how does insulin affect carbohydrate metabolism?
- increases glucose uptake into muscle and adipose tissues
- increases glycolysis
- increases glycogenesis
how does glucagon affect carbohydrate metabolism?
- increases glycogenolysis
- increases gluconeogenesis
how does insulin affect lipid metabolism?
increases lipogenesis
how does glucagon affect lipid metabolism?
increases ketogenesis and lipolysis
how does insulin affect amino acid metabolism?
insulin increases amino acid uptake and protein synthesis
how does glucagon affect amino acid metabolism?
increases the rate of amino acid catabolism
how is diabetes mellitus diagnosed?
Diagnosis basis of venous plasma glucoseconcentration:
• normal range 3.3-6mmol/L plasma glucose
in a patient with diabetes mellitus the plasma glucose levels would be elevated (fasting > 7.0mM). Random > 11.1.mM
Hba1c over 48mmol/L
what causes diabetes mellitus type 1?
Type 1 is absolute insulin deficiency.
Insulin deficiency can result from autoimmune destruction of pancreatic Beta-cells.
- Absolute deficiency when pancreatic beta-cells are destroyed.
- Relative deficiency when secretory response of beta-cell is abnormally slow or small (Insulin deficiency – failure to secrete adequate amounts of insulin from beta-
cells.
how do mutations in the Kir6.2 subunit result in diabetes mellitus type 1?
Kir6.2 subunit forms the pore in the channel protein KATP alongside SUR1. Mutations in either of these subunits result in diabetes mellitus. The KATP channels become insensitive to increases in ATP and therefore the membrane does not depolarise, calcium channels do not open and calcium channels remain closed and reactions are not initiated to trigger insulin exocytosis.
what is diabetes mellitus type 2?
normal secretion of insulin but relative peripheral insulin resistance.
Peripheral insulin resistance can result due to:
1. Defective insulin receptor mechanism – change in receptor number and/or affinity.
2. Defective post-receptor events (Insulin resistance – tissues become insensitive to insulin)
3. Excessive or inappropriate glucagon secretion
what factors contribute to insulin resistance?
genetic factors environmental factors (obesity, sedentary lifestyle)
what is insulin resistance?
insulin resistance is when the main sites of glucose utilisation (adipose, liver and skeletal muscle) show decreased response to normal circulating concentrations of insulin.
how do beta pancreatic cells adapt in type 2 diabetes mellitus?
Initially:
– Beta-cells compensate by increasing insulin production to maintain normal blood glucose. (hypertrophy)
Eventually:
– beta-cells unable to maintain increased insulin production - impaired
glucose tolerance.
Finally:
– Beta-cell dysfunction leads to relative insulin deficiency - overt type 2 diabetes
Which glucose transporter is the primary transporter of glucose in pancreatic β cells?
GLUT2 is the primary glucose transporter in pancreatic beta cells allowing the glucose entry that ultimately regulates insulin synthesis and release by casuing an increase in ATP concentration. GLUT2 is also the major transporter in liver. It is a bidirectional transporter, allowing glucose to flow in both directions (both out of and into the hepatocyte). GLUT2 therefore allows the hepatocytes to export glucose made by gluconeogenesis into the blood. GLUT2 is not regulated by insulin
With respect to the release of insulin, what effect would an increase in the intracellular concentration of ATP have on a pancreatic β cell?
More ATP produced from the metabolism of glucose results in inhibition of the ATP-sensitive potassium channels (KATP channels). Less positively charged potassium leaving the cell through KATP channels results in depolarisation of the plasma membrane (i.e. makes the resting membrane potential less negative). This depolarisation is sensed by voltage activated calcium channels which open allowing calcium to flow down its electrochemical gradient into the cell. It is this influx of calcium ions into the β cell that activates the insulin containing vesicles causing them to fuse with the plasma membrane and release insulin.
What effect would a decrease in intracellular ATP concentration have on the ATP sensitive potassium channels (KATP channels) in pancreatic β cells?
ATP-sesnsitve potassium channels (KATP channels) are inhibited by ATP. A fall in ATP concentration would therefore result in more channels being open. This will cause more positively charged potassium ions leaving the cell through KATP channels resulting in the plasma membrane becoming hyperpolarised (i.e. the resting membrane potential becomes more negative). A more negative membrane potential will make the cell less excitable making it more difficult for voltage activated calcium channels to open. As it is influx of calcium ions into the β cell from the voltage activated calcium channels that drives the fusion of vesicles and subsequent release of insulin, a decrease in intracellular ATP (resulting from a lower concentration of glucose) will prevent insulin release.
what is the function of ghrelin?
It stimulates appetite, increases food intake and promotes fat storage.
briefly describe insulin synthesis in B cells
- pre-proinsulin translation, signal cleavage and proinsulin folding
- Proinsulin transported to the golgi apparatus in vesicles
- C-peptide cleaved in the golgi vesicles to produce insulin.
- Vesicles containing c-peptide and insulin waits under the cell membrane of the pancreatic beta cell.
how does the movement of potassium affect the resting membrane potential?
efflux of potassium leads to hyperpolarisation
influx of potassium leads to depolarisation
