Diabetes Mellitus Biochemistry –
The pancreas has endocrine and exocrine functions.
• Endocrine include glucagon (alpha), insulin (beta), and somatostatin (delta) section.
• Exocrine include gastrin and amylase secretion.
Insulin is secreted in response to glucose to help put glucose into cells.
Glucagon is inhibited by insulin because the body wants to absorb glucose, not break it down,
when glucose is present. Glucagon increases glucose in the blood.
Uptake of glucose into cells is by GLUT2 transporter. When glucose is taken in by GLUT2
transporters, the cell depolarizes, causes calcium influx, allowing for release of insulin.
What causes increased insulin secretion? GIP, GRP 40, and GLP1. Somatostatin decreases
insulin secretion (because it is trying to put more glucose into the blood stream, not absorb it).
What does parasympathetic stimulation of beta (insulin) cells cause? Increased secretion of
insulin.
What does sympathetic stimulation of alpha (glucagon) cells cause? Decreased secretion of
insulin.
What is proinsulin? Insulin + c-peptide.
Does proinsulin act like insulin? Proinsulin has some properties of insulin but needs to be
cleaved to act like insulin.
Describe the way insulin is made and released. The insulin gene is on the short arm of
chromosome 11 and is transcribed to mRNA in the nucleus. The mRNA for insulin moves
outside the nucleus to the cytosol and comes into contact with cytosolic ribosomes, where the
mRNA codes for preproinsulin. The signal sequence of preproinsulin is cleaved, forming
proinsulin. Proinsulin is transported to the golgi where it is cleaved forming insulin and C-
peptide. Insulin and C-peptide are packaged in secretory vesicles and secreted when necessary.
What does insulin do at the receptor? Insulin binding activates RTKs leading to a cascade that
causes increased glucose uptake, increased glycogen synthesis, increased protein synthesis,
increased fat synthesis, decreased gluconeogenesis, decreased glycogenolysis, and decreased
lipolysis. Binding also recruits glucose transports from inside the cell. GLUT4 increases insulin
uptake of glucose into the cell GLUT4 moves back into the cell when insulin decreases and are
recycled.
When insulin binds to RTKs, this causes phosphorylation and activation or IRS. Activation of IRS
can have mitogenic or metabolic effects. Mitogenic effects would include IRS activating SOS
proteins, activating Ras (activates MAPK pathway cell growth and proliferation). Metabolic →
effects include IRS activating PI3K, activating PKB/AKT. AKT inactivates GSK3 and activates
mTOR (protein synthesis). This leads to GLUT4 delivery to the cell membrane from inside the
cell.
When the cell is in a low energy state or stressed, Foxo1 is active to promote catabolic
pathways. Activated AKT inhibits Foxo1. Insulin does the opposite of Foxo1 functions.
What does insulin do to the cells metabolism? Inhibits gluconeogenesis and FA oxidation.
What does insulin to do beta cells? Inhibits glucagon secretion by alpha cells.
What does insulin do in the liver? Induces glucokinase, glycogen synthase, and triglyceride
synthesis. Inhibits ketogenesis, glycogenolysis, and gluconeogenesis.
