Properties of Proinsulin and C-Peptide

Insulin and Proinsulin

• Insulin and proinsulin combine with zinc to form hexamers.
• Upon stimulation, mature granules fuse with the plasma membrane and release insulin and C-peptide into the extracellular fluid.
• Proinsulin has a longer plasma half-life than insulin, which can lead to an overestimation of insulin bioactivity in radioimmunoassays.
• C-peptide has no known biological role, but its immunoassay can distinguish between endogenous and exogenous insulin and quantify the former when anti-insulin antibodies are present.

Insulin Secretion and Regulation

• Insulin secretion is precisely regulated, with the human pancreas secreting 40-50 units of insulin daily, representing 15-20% of the hormone stored in the secretory gland.
• Glucose is the most important physiologic regulator of insulin secretion, with two proposed mechanisms:
• Glucose combining with a receptor on the B cell membrane to activate the release mechanism.
• Intracellular metabolites or metabolite flux through pathways (e.g., PPP, TCA cycle, glycolytic pathway) involved in insulin secretion.
• Hormonal factors, such as growth hormone, cortisol, placental lactogen, estrigens, and progestins, as well as gastrointestinal hormones, can increase insulin secretion.

Insulin Metabolism

• Insulin has no plasma carrier protein and has a half-life of 3-5 minutes in plasma under normal conditions.
• The major organs involved in insulin metabolism are the liver, kidney, and placenta.
• Insulin metabolism involves two enzyme systems:
• Insulin-specific proteases found in many tissues, which are sulfhydryl-dependent and active at physiological pH.
• Hepatic glutathione-insulin transhydrogenase, which reduces disulfide bonds and leads to rapid degradation of individual A and B chains.

Glucagon

• Glucagon is an insulin antagonist, synthesized mainly in A cells of pancreatic islets.
• Glucagon is a single-chain polypeptide (3,485 kDa) consisting of 29 amino acids, synthesized as a proglucagon precursor.
• Glucagon circulates in plasma in its free form, without association with transport proteins.
• Glucagon is inactivated by the liver, which removes the first two amino acids from the N-terminal end.

Diabetes Mellitus

• Type 1 diabetes typically results from an autoimmune attack on pancreatic β-cells, with genetic susceptibility and possible environmental cofactors.
• The onset of type 1 diabetes is usually during childhood or puberty, with symptoms developing suddenly.
• Type 2 diabetes has a more gradual onset, often present many years before diagnosis.

Dopamine and Catecholamines

• Dopamine is synthesized from the amino acid L-tyrosine, with a separate distribution in the brain, indicating its independent function as a neurotransmitter.
• Tyrosine hydroxylase is the most important enzyme in catecholamine synthesis, being the initial and rate-limiting step in the synthesis of dopamine, norepinephrine, and pinephrine.
• Dopamine is involved in motor control, reward mechanisms, and the production of other neurotransmitters.

Norepinephrine

• Norepinephrine is synthesized from dopamine, with the addition of a β-hydroxyl group.
• Norepinephrine is metabolized primarily to the alcohol metabolite, 3,4-dihydroxyphenylglycol (DHPG), and then further metabolized to 3-methoxy-4-hydroxyphenylglycol (MHPG).
• Patterns of norepinephrine metabolites differ among animal species, with MHPG being the predominant metabolite in human CSF.