Insulin Biology J Synthesis and Secretion

Insulin biology, synthesis
and secretion
INTRODUCTION
• The word “Insulin” is derived from latin word, insula meaning
island(islet).
• Insulin was discovered in Toronto in 1921 by Fredrick Banting and
Charles Best, and its purification was made possible by James Collip.
• It was the first protein in which amino acid sequencing was done.
• First protein to produced by recombinant DNA technology.
Structue of insulin
Insulin biosynthesis
• In humans, the gene encoding preproinsulin, the precursor of insulin,
is located on the short arm of chromosome 11.
• It is 1355 base pairs in length and its coding region consists of three
exons:
o the first encodes the signal peptide at the N terminus of
preproinsulin,
o The second : the B chain and part of the C (connecting) peptide,
o and the third : the rest of the C-peptide and the A chain
• The β cell responds to increases in the circulating concentrations of nutrients by
increasing insulin production in addition to increasing insulin secretion, thus
maintaining insulin stores.
• Acute (<2 h) increases in the extracellular concentration of glucose and other
nutrients result in a rapid and dramatic increase in the transcription of
preproinsulin mRNA and in the rate of proinsulin synthesis.
• There is a sigmoidal relationship between glucose concentrations and
biosynthetic activity, with a threshold glucose level of 2–4 mmol/L.
• This is slightly lower than the threshold for the stimulation of insulin secretion
(∼5 mmol/L), which ensures an adequate reserve of insulin within β cell.
Storage and release
• The major protein constituents of the Insulin secretory granules are insulin and C-
peptide, which account for ∼80% of granule protein.
• They also contain high concentrations of divalent cations, such as zinc (∼20
mmol/L), which is important in the crystallization and stabilization of insulin
within the granule.
• Zinc is transported into the insulin secretory granules by the islet specific zinc
transporter ZnT8, where it binds to insulin to form a crystalline lattice of insoluble
hexamers.
• The intragranular function of calcium (∼120 mmol/L) and magnesium (∼70
mmol/L) are uncertain, but they are co-released with insulin on exocytosis of the
secretory granule contents so they may have extracellular signaling roles via the
cell surface calcium-sensing receptor.
• Similarly, the adenine nucleotides found in insulin secretory granules (∼10
mmol/L) may have a signaling role when they are released into the extracellular
space.
Insulin granule pool and their intracellular
traffic
• Most insulin granules (perhaps 75–95% of an estimated 10,000) are stored within
the β-cell cytoplasm at some distance away from the cell membrane.
• The remainder move to the cell periphery along microtubule networks in an
AMPK- and kinesin1-dependent manner.
• To reach the plasma membrane, however, granules must cross a cortical actin
network that acts as a physical barrier to insulin secretion.
• The process is coordinated by the action of several small G-proteins and their
activating nucleotide exchange factors.
Release of insulin
• Insulin is released from secretory granules by exocytosis.
• The docking of the granules at the inner surface of the plasma membrane is via
the formation of a multimeric complex of proteins known as the SNARE(soluble
N-ethylmaleimide-sensitive factor attachment protein receptor) complex.
• The docked granules will fuse with the membrane and release their contents only
in the presence of elevated levels of intracellular calcium, which is sensed by
synaptotagmins, a class of calcium-binding granule proteins.
• The transport of granules from distant sites to the plasma membrane is regulated
independently from the final secretory process, with a reservoir of pre-docked
granules available at the inner surface of the plasma membrane.
• Fusion of this “readily releasable” pool of granules may account for the rapid first-
phase release of insulin in response to glucose stimulation.
Regulation of insulin secretion
• The major physiological determinant of insulin secretion in humans is the
circulating concentration of glucose and other nutrients, including amino acids
and fatty acids.
• so when nutrients are being absorbed from the GIT the βcell detects the changes
in circulating nutrients and releases insulin to enable the uptake and metabolism
or storage of the nutrients by the target tissues.
• The consequent decrease in circulating nutrients is detected by the βcells, which
switch off insulin secretion to prevent hypoglycemia.
Amino acids
• Several amino acids stimulate insulin secretion in vivo and in vitro. Leucine,
lysine, and arginine, can stimulate insulin secretion in the absence of glucose,
and therefore qualify as initiators of secretion.
• Leucine enters islets by a sodium-independent transport system and stimulates a
biphasic increase in insulin release.
• The charged amino acids lysine and arginine cross the β-cell plasma membrane
via a transport system specific for cationic amino acids
Beta-Cell Insulin Content
• Despite its small size, the endocrine pancreas has a large functional
reserve, as pancreatic insulin content has been estimated to be in the
range of 200 to 250 units (a 10-day supply for a healthy lean adult)
• The fraction of portal insulin that is removed by the liver in its first pass is about
65%, ranging between 50% and 70%.
• Once in the systemic circulation, insulin recirculates to, and is further cleared by,
the liver and, to a lesser extent, by skeletal muscle and the kidneys.
• Acute insulin response: is 10-15%
of what is secreted per hr during
2nd phase.
• Attenuate 1st phase insulin
secretion is a very sensitive marker
of early beta cell dysfunction.
Thank you

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